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Lymph node metastasis (LNM) is one of the most adverse prognostic factors in extrahepatic cholangiocarcinoma (EHCC) cases. As next-generation sequencing technology has become more widely available, the genomic profile of biliary tract carcinoma has been clarified. However, whether LNMs have additional genomic alterations in patients with EHCC has not been investigated. Here, we aimed to compare the genomic alterations between primary tumors and matched LNMs in patients with EHCC.Sixteen patients with node-positive EHCCs were included. Genomic DNA was extracted from tissue samples of primary tumors and matched LNMs. Targeted amplicon sequencing of 160 cancer-related genes was performed.Among the 32 tumor samples from 16 patients, 91 genomic mutations were identified. Genomic mutations were noted in 31 genes, including TP53, MAP3K1, SMAD4, APC, and ARID1A. TP53 mutations were most frequently observed (12/32; 37.5%). Genomic mutation profiles were highly concordant between primary tumors and matched LNMs (13/16; 81.3%), and an additional genomic mutation of CDK12 was observed in only one patient.Genomic mutations were highly concordant between primary tumors and matched LNMs, suggesting that genotyping of archived primary tumor samples may help predict genomic mutations of metastatic tumors in patients with EHCC.

Purpose: Palliative care should be provided for terminal cancer patients, but the remaining question is how oncologists are providing palliative care. Herein, we evaluated the effectiveness of palliative care provided via video telemedicine. Methods: Terminal cancer patients receiving the best supportive care were enrolled and divided into two groups: telemedicine and no telemedicine. The primary endpoint was quality of life (QOL), which was evaluated using the difference in the Functional Assessment of Cancer Therapy–General (FACT-G) scores between baseline and at the 1-month follow-up. Secondary endpoints included depression measured using the Center for Epidemiologic Studies depression (CES-D) scale, overall survival (OS), and patient satisfaction. Results: Overall, 50 patients were included in this study,with 25 patients in each group. FACT-G decreased by 0.30 vs 5.90 points in the telemedicine and no telemedicine groups, respectively. Although there was no significant difference (P = 0.088), the telemedicine group tended to maintain better QOL. CES-D increased by 0.96 vs 3.52 points in the telemedicine and no telemedicine groups, respectively. Depressive tendency was lower in the telemedicine group; however, there was no significant difference (P = 0.27). Median survival time (MST) was 7.82 (3.30 – 14.59) vs 6.37 (2.33 – 11.04) months in the telemedicine and no telemedicine groups, respectively, and the HR was 0.67 (95%CI 0.33 – 1.34, P = 0.25). Conclusion: There was a trend toward improved QOL in patients receiving video telemedicine. It is desirable to further evaluate the effectiveness of palliative care with telemedicine and link it to clinical applications.

Introduction: Over 40,000 cancer patients have taken comprehensive genomic profiling (CGP) tests under health insurance coverage in Japan since June 2019. However, the indication is limited only to cancer patients who have finished (or are expected to finish) standard treatments. The aim of this study is to evaluate patients’ outcomes, levels of understanding, and satisfaction of the patients who received CGP tests. Methods: We performed a nationwide surveillance of 933 cancer patients who examined CGP tests at 80 institutions in Japan under the approval of the institutional ethics committee. The responses to the questionnaire (either web-based or paper-based) were from patients (81.6%) or their families (18.4%). Results: The range of patients’ age was 70s at 29.6%, followed by 60s at 26.8%, and 50s at 20.8%. The level of understanding during informed consent for the CGP tests {11 scales from 0 (lowest) to 10 (highest)} were 7 or higher in 70.8%, and those about their test results were 7 or higher in 75.2 %. The information was predominantly provided by attending physicians (78.0%) or physicians specialized in genomic medicine (19.6%), and limitedly from cancer genome medical coordinators (11.4%) and nurses (10.4%). The patients underwent FoundationOne CDx® (56.3%), FoundationOne Liquid CDx® (11.6%), or a domestic tumor/normal paired panel (OncoGuideTM NCC Oncopanel System, 14.4%). 16.2% of the patients could not recall which CGP test they received. New treatments based on the CGP testing were suggested in 46.8%, and 20.8% of them were treated with a suggested treatment by an expert panel (i.e., molecular tumor board). The treatment type was (i) approved drugs, 70.3%, (ii) clinical trials, 16.5%, (iii) patient-proposed national basket trial, 3.2%, and (iv) off-label use, 1.1%. 77.4% of the patients requested disclosure of germline findings, 10.5% declined, and 11.4% did not remember their decision. Overall satisfaction scores (11 scales) were found to be 7 or higher at 64.6%. The reasons for satisfaction included having the opportunity to learn about cancer risks of relatives (21.0%), having received detailed explanation (19.7%), having received information on new therapies (18.4%), and having the opportunity to learn about their cancer in detail (15.9%). The reason for lower scores (6 or lower) was mainly due to not receiving recommendations to a genome-matched therapy (58.3%). Conclusion: Our surveillance highlighted the significance of drug accessibility, information from interdisciplinary collaboration team, and appropriate information about the test results. The opportunity to learn about their cancer in detail was valuable for the patients as well, even when the results of CGP testing did not lead to a novel therapy. Citation Format: Katsutoshi Oda, Hidenori Kage, Manabu Muto, Katsuya Tsuchihara, Natsuko Okita, Yusuke Okuma, Junko Kikuchi, Hidekazu Shirota, Hideyuki Hayashi, Toshio Kokuryo, Daisuke Sakai, Akira Hirasawa, Makoto Kubo, Hirotsugu Kenmotsu, Nana Akiyama, Hyangri Chang, Aya Shinozaki-Ushiku, Masahiko Tanabe, Tetsuo Ushiku, Kaori Muto, Kiyoshi Miyagawa, Yasuyuki Seto. Real-world surveillance from cancer patients about their experience of comprehensive genomic profiling tests in Japan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3225.

Purpose Immune checkpoint inhibitors (ICIs) have been approved for various types of cancer; however, they cause a broad spectrum of immune-related adverse events (irAEs). The association between the development of irAEs and the clinical benefit remains uncertain. We aimed to evaluate the association of irAEs and the treatment efficacy in real-world practice. Patients and Methods We conducted a retrospective study on patients with recurrent or metastatic non-small-cell lung cancer, malignant melanoma, renal cell carcinoma, or gastric cancer who received anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab, or atezolizumab) at the Keio University Hospital between September 2014 and January 2019. We recorded treatment-related AEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 4. We performed an overall survival (OS) analysis using a Cox proportional hazards model and the shared frailty model. Results Of 212 patients eligible for this study, 108 experienced irAEs and 42 developed multiple irAEs. The median OS was significantly longer in the irAEs than in the no-irAE group (28.1 months vs 12.7 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.33-0.73; P = 0.0004). Moreover, the OS of patients with multiple irAEs was significantly longer than that of patients with a single irAE (42.3 months vs 18.8 months; HR, 0.473; 95% CI, 0.346-0.647; P < 0.0001). Conclusion Our single-center retrospective study revealed a significant tendency associating the development of multiple irAEs with favorable prognoses.

Recent advances in neutron crystallographic studies have provided structural bases for quantum behaviors of protons observed in enzymatic reactions. Thus, we resolved the neutron crystal structure of a bacterial copper (Cu) amine oxidase (CAO), which contains a prosthetic Cu ion and a protein-derived redox cofactor, topa quinone (TPQ). We solved hitherto unknown structures of the active site, including a keto/enolate equilibrium of the cofactor with a nonplanar quinone ring, unusual proton sharing between the cofactor and the catalytic base, and metal-induced deprotonation of a histidine residue that coordinates to the Cu. Our findings show a refined active-site structure that gives detailed information on the protonation state of dissociable groups, such as the quinone cofactor, which are critical for catalytic reactions.

BACKGROUND Mechanical stress caused by blood flow, such as wall shear stress (WSS) and its related parameters, is key moderator of endothelial degeneration. However, an in vivo method to measure WSS on heart valves has not been developed. METHODS We developed a novel approach, based on vector flow mapping using intraoperative epi-aortic echocardiogram, to measure WSS and oscillatory shear index (OSI) on the aortic valve. We prospectively enrolled 15 patients with normal valves, who underwent coronary artery bypass graft. RESULTS Systolic WSS on the ventricularis (2.40 ± 0.44 Pa [1.45-3.00 Pa]) was higher than systolic WSS on the fibrosa (0.33 ± 0.08 Pa [0.14-0.47 Pa], P

Background Gemcitabine plus nab-paclitaxel (GnP) has been a standard treatment for unresectable pancreatic cancer (uPC); however, the current treatment status and usefulness in older adults with uPC remain unclear. Therefore, we aimed to investigate the patient background and compare the efficacy and safety of GnP versus other treatments in older adults with uPC. Patients and Methods In this prospective observational study, we enrolled 233 eligible patients aged ≥76 years with pathologically proven, clinically uPC, and no history of chemotherapy from 55 Japanese centers during September 2018-September 2019. The main endpoints were overall survival (OS), progression-free survival (PFS), and safety. Geriatric assessments were performed upon registration and after 3 months. To adjust for confounders, we conducted propensity score-matched analyses. Results GnP, gemcitabine alone (Gem), best supportive care, and other therapies were administered to 116, 72, 16, and 29 patients, respectively. In the propensity score-matched analysis, 42 patients each were selected from the GnP and Gem groups. The median OS was longer in the GnP group than in the Gem group (12.2 vs. 9.4 months; hazard ratio [HR], 0.65; 95% CI, 0.37-1.13). The median PFS was significantly longer in the GnP group than in the Gem group (9.2 vs. 3.7 months; HR, 0.38; 95% CI, 0.23-0.64). The incidence of severe adverse events was higher with GnP than with Gem; however, the difference was not significant. Conclusion GnP is more efficacious than Gem in patients aged ≥76 years with uPC despite demonstrating a higher incidence of severe adverse events.

Right heart remodeling and tricuspid regurgitation (TR) are common in patients with chronic thromboembolic pulmonary hypertension. This study aimed to investigate the significance of right heart remodeling and TR after pulmonary endarterectomy (PEA) in patients with chronic thromboembolic pulmonary hypertension.Patients who underwent PEA with preoperative and postoperative transthoracic echocardiograms at our center between June 2010 and July 2019 were retrospectively reviewed. The composite end point was defined as death or hospitalization due to worsening heart failure, bleeding, or recurrent pulmonary embolism.In total, 158 patients were included for analysis. Right ventricular basal (48 [45-52] vs 43 [39-47] mm, P .001), midcavitary (46 [42-50] vs 38 [34-42] mm, P .001), and longitudinal dimensions (87 [83-93] vs 80 [75-84] mm, P .001), along with the right atrial volume index (37 [25-51] vs 24 [18-34] mL/mSignificant improvements in right heart remodeling were seen following PEA. However, residual TR was a poor prognostic marker.

The aim of this study was to evaluate the fluid dynamics in the aortic valve and proximal aorta during continuous-flow left ventricular assist device (LVAD) support using epiaortic echocardiography and vector flow mapping technology. A total of 12 patients who underwent HeartMate 3 implantation between December 2018 and February 2020 were prospectively examined. The wall shear stress (WSS) on the ascending aorta, aortic root, and aortic valve was evaluated before and after LVAD implantation. The median age of the cohort was 62 years and 17% were women. The peak WSS on the ascending aorta (Pre 1.48 [0.86-1.69] [Pascal {Pa}] vs. Post 0.33 [0.21-0.58] [Pa]; p = 0.002), aortic root (Pre 0.46 [0.31-0.58] (Pa) vs. Post 0.18 [0.12-0.25] (Pa); p = 0.001), and ventricularis of the aortic valve (Pre 1.76 [1.59-2.30] (Pa) vs. Post 0.30 [0.10-0.61] (Pa); p = 0.001) was significantly lower after LVAD implantation. No difference in WSS was observed on the fibrosa of the aortic valve (Pre 0.36 [0.22-0.53] (Pa) vs. Post 0.38 [0.38-0.52] (Pa); p = 0.850) before and after implantation. The WSS on the ascending aorta, aortic root, and ventricularis of the aortic valve leaflets was significantly altered by LVAD implantation, providing preliminary data on the potential contribution of fluid dynamics to LVAD-induced aortic insufficiency and root thrombus.

Recent advances in serial femtosecond X-ray crystallography (SFX) using X-ray free-electron lasers have paved the way for determining radiation-damage-free protein structures under nonfreezing conditions. However, the large-scale preparation of high-quality microcrystals of uniform size is a prerequisite for SFX, and this has been a barrier to its widespread application. Here, a convenient method for preparing high-quality microcrystals of a bacterial quinoprotein enzyme, copper amine oxidase from Arthrobacter globiformis, is reported. The method consists of the mechanical crushing of large crystals (5–15 mm3), seeding the crushed crystals into the enzyme solution and standing for 1 h at an ambient temperature of ∼26°C, leading to the rapid formation of microcrystals with a uniform size of 3–5 µm. The microcrystals diffracted X-rays to a resolution beyond 2.0 Å in SFX measurements at the SPring-8 Angstrom Compact Free Electron Laser facility. The damage-free structure determined at 2.2 Å resolution was essentially identical to that determined previously by cryogenic crystallography using synchrotron X-ray radiation.

Threonine synthase catalyses the conversion of O-phospho-l-homoserine and a water molecule to l-threonine and has the most complex catalytic mechanism among the pyridoxal 5′-phosphate-dependent enzymes. In order to study the less-characterized earlier stage of the catalytic reaction, we studied the reaction of threonine synthase with 2-amino-5-phosphonopentanoate, which stops the catalytic reaction at the enamine intermediate. The global kinetic analysis of the triphasic spectral changes showed that, in addition to the theoretically expected pathway, the carbanion is rapidly reprotonated at Cα to form an aldimine distinct from the external aldimine directly formed from the Michaelis complex. The Kd for the binding of inhibitor to the enzyme decreased with increasing pH, showing that the 2-amino-group-unprotonated form of the ligand binds to the enzyme. On the other hand, the rate constants for the proton migration steps within the active site are independent of the solvent pH, indicating that protons are shared by the active dissociative groups and are not exchanged with the solvent during the course of catalysis. This gives an insight into the role of the phosphate group of the substrate, which may increase the basicity of the ε-amino group of the catalytic lysine residue in the active site.

Background Atrial fibrillation (AF) is the most common arrhythmia in patients undergoing percutaneous coronary intervention (PCI). Hypothesis Large administrative data may provide further insight into temporal trends in the prevalence and burden of AF in patients who underwent PCI. Methods Using the National Inpatient Sample database in the U.S., AF patients ≥18 years who underwent PCI between 2005 and 2014 and were identified by the International Classification of Diseases, ninth revision, Clinical Modification, were examined. In‐hospital mortality, morbidity, resource use, and medical costs were evaluated in crude and propensity‐matched analyses. Results Among an estimated 6 272 232 hospitalizations, of patients undergoing PCI, AF prevalence was 9.9% and steadily increased from 8.6% to 12.0% between 2005 and 2014 (P

O-acetylhomoserine sulfhydrylase (OAHS) is a pyridoxal 5'-phosphate-dependent enzyme involved in microbial methionine biosynthesis. In this study, we report gene cloning, protein purification, and some biochemical characteristics of OAHS from Clostridioides difficile. The enzyme is a tetramer with molecular weight of 185 kDa. It possesses a high activity in the reaction of L-homocysteine synthesis, comparable to reported activities of OAHSes from other sources. OAHS activity is inhibited by metabolic end product L-methionine. L-Propargylglycine was found to be a suicide inhibitor of the enzyme. Substrate analogue Nγ -acetyl-L-2,4-diaminobutyric acid is a competitive inhibitor of OAHS with Ki = 0.04 mM. Analysis of C. difficile genome allows to suggest that the bacterium uses the way of direct sulfhydrylation for the synthesis of L-methionine. The data obtained may provide the basis for further study of the role of OAHS in the pathogenic bacterium and the development of potential inhibitors.

Background Atrial fibrillation (AF) can lead to a decrease in stroke volume (SV) despite a preserved left ventricular ejection fraction (LVEF). However, no previous studies have evaluated the prognostic importance of the decreased SV in patients with AF and concomitant heart failure with preserved ejection fraction (HFpEF). Methods We retrospectively studied the cases of 1520 consecutive patients who had undergone right heart catheterization. HFpEF (New York Heart Association functional class ≥II and LVEF ≥50%) was observed in 574 patients. We selected 47 patients with persistent AF with a heart rate of 40–110 bpm and HFpEF without other underlying heart diseases. Results Among a total of 47 patients, 16 (34%) had normal SV [SV index (SVI) >35 ml/m2 and 31 (66%) patients had low SV (SVI ≤ 35 ml/m2)]. During the follow-up period of 1115 ± 305 days, 14 patients (30%) met the composite endpoint defined as cardiac death and admission due to worsening heart failure. Cox proportional hazard ratio analysis showed that SVI was a predictor of the endpoint, independently of the cardiac index and other parameters. Kaplan–Meyer analysis showed that low SVI was significantly associated with a poor prognosis, with an event-free rate of 58% at the mean follow-up period of 991 days (log-rank p = 0.02). In the multiple regression analysis, a high systemic vascular resistance index and a high heart rate were independent determinants of low SVI. Conclusions Our findings suggest that low SV had a significant impact on prognosis in patients with AF despite the preserved LVEF. The SVI depended on the heart rate and SVRI.

Background: Using the normal values for the East Asian population, we evaluated age- and body size-adjusted left ventricular end-diastolic dimension (LVEDD) and its prognostic impact in a hospital-based population in Japan. Methods and Results: We retrospectively analyzed data obtained from 4, 444 consecutive patients who had undergone both transthoracic echocardiography and electrocardiography at Kitano Hospital in 2013. Those who presented with a history of previous episodes of myocardial infarction and severe or moderate valvular disease or with low ejection fraction (

Background Readmissions after in-hospital cardiopulmonary resuscitation (ICPR) are common and contribute to increased health care utilization and costs. This study aimed to estimate the burden and patterns of 30-day readmission after ICPR from the US Nationwide Readmission Database (NRD). Methods Using International Classification of Diseases-Ninth Revision-Clinical Modification codes, patients who underwent ICPR in the 2014 NRD were included. The incidence, predictors, causes, and costs of 30-day readmission were analyzed with discharge weights to obtain national estimates. Results Among the 27,278 index admissions that survived to hospital discharge after ICPR, 5439 (20.0%) were readmitted within 30 days. Length of stay (LOS) ≥11 days during index hospitalization, chronic pulmonary disease, congestive heart failure, renal failure, discharge from the teaching metropolitan hospital, Medicare insurance, depression, and diabetes were independent predictors of 30-day readmission. The most common causes of readmission among the 5439 cases were sepsis (13.7%), heart failure (10.9%), and respiratory failure (6.4%). The estimated median costs of readmission were $10,498 (interquartile range, $5797–21,364), which accounted for 25.7% of the total episodes of care (index + readmission). The median LOS of readmission was 5 (3–9) days. Conclusions Thirty-day readmissions after ICPR were associated with patient comorbidities and significant cost burden. Recognition of these predictors and individualization of care would allow for the provision of appropriate interventions, and reduce readmissions and healthcare costs.

A 66-year-old woman with diabetes who was treated with prednisolone (15 mg/day) for autoimmune hepatitis developed multiple erythematous nodules with retention of purulent fluid on her lower right limb. Candida albicans was cultured from the nodules. She was started on oral fluconazole, and the lesions subsided. However, multiple dark-red abscesses and indurations newly appeared on the left crus. Histopathological examination showed numerous branched hyphae, and tissue culture yielded a Rhizopus microsporus-related fungus. She was treated with liposomal amphotericin B combined with drainage and debridement. However, she died because of poor control of the infection and hepatic disorder.

Background Chest radiography (CR) is employed as the evaluation of pneumoconiosis; however, we sometimes encounter cases in which computed tomography (CT) is more effective in detecting subtle pathological changes or cases in which CR yields false-positive results. Purpose To compare CR to CT in the diagnosis of early-stage pneumoconiosis. Material and Methods CR and CT were performed for 132 workers with an occupational history of mining. We excluded 23 cases of arc-welder’s lung. Five readers who were experienced chest radiologists or pulmonologists independently graded the pulmonary small opacities on CR of the remaining 109 cases. We then excluded 37 cases in which the CT data were not sufficient for grading. CT images of the remaining 72 cases were graded by the five readers. We also assessed the degree of pulmonary emphysema in those cases. Results The grade of profusion on CR (CR score) of all five readers was identical in only 5 of 109 cases (4.6%). The CR score coincided with that on CT in 40 of 72 cases (56%). The CT score was higher than that on CR in 13 cases (18%). On the other hand, the CT score was lower than that on CR in 19 cases (26%). The incidence of pulmonary emphysema was significantly higher in patients whose CR score was higher than their CT score. Conclusion CT is more sensitive than CR in the evaluation of early-stage pneumoconiosis. In cases with emphysema, the CR score tends to be higher in comparison to that on CT.

Background: Various malignancies exhibit high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). The MSI-IVD kit, which can detect MSI status using a polymerase chain reaction (PCR)-based method, was approved as the first tumor-agnostic companion diagnostic for pembrolizumab in patients with MSI-H solid tumors in Japan. Recently, next-generation sequencing (NGS), which can also detect MSI-H/dMMR, has been made clinically available. However, the real-world concordance in MSI-H/dMMR between the PCR-based testing and NGS is yet to be thoroughly investigated.Methods: A retrospective study was conducted to evaluate the utility of MSI testing using PCR-based testing and NGS assay in patients eligible for both MSI testing and any NGS platform. Co-primary endpoints included positive and negative predictive values of MSI-H/dMMR.Results: Between December 2018 and June 2020, 40 patients underwent both PCR-based MSI testing and NGS assay for MSI. Two patients with gastric neuroendocrine carcinoma and ovarian cancer were confirmed to have MSI-H/dMMR in both examinations. Among the 38 patients diagnosed as microsatellite stable by PCR-based testing, 2 (5.2%) with pancreatic cancer were diagnosed as MSI-H after NGS analyses. NGS had positive and negative predictive values of 100% (2/2) and 94.7% (36/38), respectively, for MSI-H, while the concordance between NGS and PCR-based testing was 94.9% (38/40).Conclusion: Similar to PCR-based MSI testing, NGS can be useful for evaluating MSI/MMR status in clinical practice and could be an important alternative method for detecting MSI-H/dMMR in the future.

The aim of this study was to determine the risk factors for immune-related adverse events (irAEs) induced by immune checkpoint inhibitors. The authors conducted a retrospective study in which patients with malignant melanoma, non-small-cell lung cancer, gastric cancer or renal cell carcinoma who received anti-PD-1/PD-L1 antibodies were included. Of 247 patients, 118 developed a total of 182 irAEs. In the multivariate Fine–Gray regression analysis, serum albumin level ≥3.6 g/dl (hazard ratio: 1.62; 95% CI: 1.10–2.39; p = 0.015) and history of Type I hypersensitivity reactions (hazard ratio: 1.48; 95% CI: 1.02–2.14; p = 0.037) were significantly associated with the development of irAEs. High serum albumin levels and history of Type I hypersensitivity reactions are risk factors for irAEs.

Assessing Erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification status in breast and gastric cancer is necessary for deciding the best therapeutic strategy. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are currently used for assessing protein levels and gene copy number (CN), respectively. The use of next-generation sequencing (NGS) to measure ERBB2 CN in breast cancer is approved by the United States Federal Drug Administration as a companion diagnostic. However, a CN of less than 8 is evaluated as “equivocal”, which means that some ERBB2 amplification cases diagnosed as “HER2 negative” might be false-negative cases. We reviewed the results of gene profiling targeting 160 cancer-related genes in breast (N = 90) and non-breast (N = 19) cancer tissue, and compared the ERBB2 CN results with the IHC/FISH scores. We obtained an estimated CN from the measured CN by factoring in the histological proportion of tumor cells and found that an ERBB2-estimated CN of 3.2 or higher was concordant with the combined IHC/FISH outcome in 98.4% (88/90) of breast cancer cases, while this was not always evident among non-breast cancer cases. Therefore, NGS-estimated ERBB2 CN could be considered a diagnostic test for anti-HER2 therapy after the completion of adequate prospective clinical trials.

Lessons Learned Background OX-IRIS is a new combination therapy of oxaliplatin, irinotecan, and S-1 for unresectable pancreatic ductal adenocarcinoma (PDAC), which may be beneficial because S-1 is administered orally and continuous infusion of 5-fluorouracil (5-FU) is not needed. Methods Patients who had not received prior therapy for unresectable PDAC were enrolled. Adenocarcinoma or adenosquamous histology was required. Oxaliplatin and irinotecan were administered on days 1 and 15; S-1 was administered orally twice a day on days 1–14, followed by 14 days of rest (one cycle). Primary endpoints were dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). Secondary endpoints were safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results In level 0 (oxaliplatin, 85 mg/m2; irinotecan, 100 mg/m2; S-1, 80 mg/m2), two of five patients experienced DLT. In level −1 (oxaliplatin, 65 mg/m2; irinotecan, 100 mg/m2; S-1, 80 mg/m2), DLT could not be evaluated in two of eight patients because one cycle was not completed; one of the remaining six patients experienced DLT. Anemia, thrombocytopenia, fatigue, nausea, anorexia, diarrhea, and peripheral sensory neuropathy were seen frequently in levels 0 and −1. ORR was 30% in levels 0 and −1. Median progression-free survival and median overall survival were 4.1 months (95% confidence interval [CI], 0.0–8.9 months) and 13.7 months (95% CI, 4.8–22.6 months), respectively. Conclusion MTD of OX-IRIS therapy was estimated to be level 0, and the recommended dose (RD) for future trial was level −1.

Introduction The mechanism underlying carcinogenesis and the genomic features of superficial non-ampullary duodenal epithelial tumors (SNADETs) have not been elucidated in detail. In this study, we examined the genomic features of incipient SNADETs, such as small lesions resected via endoscopic treatment, using next-generation sequencing (NGS). Methods Twenty consecutive patients who underwent endoscopic treatment for SNADETs of less than 20 mm between January 2017 and December 2017 were enrolled. Targeted genomic sequencing was performed through NGS using a 160 cancer-related gene panel. We examined the alteration/mutation frequencies in SNADETs. Results The maximum size of the SNADETs examined in this study was 12 mm in diameter. Five SNADETs were classified as low grade dysplasia (LGD) tumors, while 14 SNADETs were classified as high grade dysplasia tumors. Only one carcinoma-in-situ tumor was detected. We obtained NGS data for 16 samples. APC alterations were detected in 81% of samples (13/16). KRAS, BRAF, and TP53 alterations were detected in 25% (4/16), 18.8% (3/16), and 6.3% (1/16) of cases, respectively. Conclusions We detected APC alterations in most small SNADETs resected via endoscopic treatment, from LGD to carcinoma samples. Even in SNADETs classified as small LGD, KRAS and BRAF alterations were present in a few samples.

3131 Background: Human epidermal growth factor receptor 2 (HER2) gene amplification or mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. Despite its considerable therapeutic potential, the evidence has not been established. To address this unmet need, we conducted an organ-agnostic basket trial targeting HER2-amplified solid tumors. Methods: JUPITER is a multicenter, single-arm, phase 2 basket trial for solid tumor patients (pts) with HER2 amplification determined by next-generation sequencing (NGS). Both tissue and liquid NGS results were allowed. HER2 amplification by ISH or HER2 overexpression by IHC were not used for inclusion. Pts had treatment-refractory metastatic tumors, or rare cancers without established standard of care. Breast, gastric, and colorectal cancers were excluded. Pts were treated with intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and pertuzumab (840 mg loading dose followed by 420 mg) every 3 weeks until disease progression or any other reason for discontinuation. Tumor response was assessed using RECIST v1.1. Primary endpoint was ORR by blinded independent central review (BICR), and secondary endpoints were ORR assessed by the investigators, progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. We set the ORR threshold 5% and expected ORR was 20%. Estimated sample size was 38 patients with one-sided alpha 2.5% and power 80%. Results: Between April 2019 and June 2020, 42 pts were consented, and 40 pts were treated. Median age was 62 (range, 21-86) and 60% were females. The most common diagnosis was biliary tract cancer (20%), followed by salivary ductal carcinoma (12.5%) and endometrial cancer (12.5%). At data cutoff (1 Sep 2021), ORR by BICR was 22.5% (95%CI: 10.8%-38.5%). ORR assessed by the investigator was 25% (95%CI: 12.7%-41.2%). PFS, OS and DOR were not reached at data cutoff; 3 responders remained on treatment. Of 40 pts, 32.5% had grade ≥ 3 adverse events; 10% were treatment-related, including neutropenia, hypertension, peripheral sensory neuropathy and lymphoedema (all grade 3). No treatment-related death was observed. Exploratory biomarker analysis of response and resistance is in progress. Conclusions: Combination therapy with trastuzumab and pertuzumab was well tolerated and showed promising efficacy for the patients with HER2-amplified solid tumors determined by NGS. Clinical trial information: jRCT2031180150.

The coronavirus disease 2019 (COVID-19) pandemic is a worldwide peril. The PCR tests are widely used to detect infections. However, multiple regression analysis revealed no correlation between the examination rate among population (ER) and the success of containment, which is achieved by social distancing. ER and fatality rate were even positively correlated. Japan has been criticized for its very low ER, but it achieved better containment than other major countries with much higher ER on 29 May. The estimation of the true infection rate (TIR) among population revealed that the low fatality rate in Japan and other Asian countries is partly due to low TIR. Fatality of COVID-19 is highly accentuated in aged persons. Despite having the highest aging rate in the world, the fatality rate in Japan is relatively low. The corrected fatality rate of Japan is the second-lowest among the G20 countries. Mimicking the attenuation of viral virulence due to natural selection would be a promising strategy to overcome pandemic. The prevention of in-hospital transmission, especially from severe cases, would be the key to achieve this. Attenuation of the viral virulence in the second wave is evident in many European countries, and also in Tokyo.

We report the status of CO2-Sn-LPP (Laser-produced-plasma) EUV light source that is being developed at Gigaphoton. Our unique and original technologies are; the combination of a pulsed CO2 laser with Sn droplets, dual wavelength laser application and Sn mitigation with a magnetic field. With these technologies, we achieved >250W (clean burst power at I/F) during more than 10 Billion pulses of operation. At the conference, we will present the development progress of system key components of our EUV light source and the evaluation results of the rate of decrease in reflectivity of actual collector mirrors at >250W.

Aims While mechanical stress caused by blood flow, e.g. wall shear stress (WSS), and related parameters, e.g. oscillatory shear index (OSI), are increasingly being recognized as key moderators of various cardiovascular diseases, studies on valves have been limited because of a lack of appropriate imaging modalities. We investigated the influence of aortic root geometry on WSS and OSI on the aortic valve (AV) leaflet. Methods and results We applied our novel approach of intraoperative epi-aortic echocardiogram to measure the haemodynamic parameters of WSS and OSI on the AV leaflet. Thirty-six patients were included, which included those who underwent valve-sparing aortic root replacement (VSARR) with no significant aortic regurgitation (n = 17) and coronary artery bypass graft (CABG) with normal AV (n = 19). At baseline, those who underwent VSARR had a higher systolic WSS (0.52 ± 0.12 vs. 0.32 ± 0.08 Pa, respectively, P < 0.001) and a higher OSI (0.37 ± 0.06 vs. 0.29 ± 0.04, respectively, P < 0.001) on the aortic side of the AV leaflet than those who underwent CABG. Multivariate regression analysis revealed that the size of the sinus of Valsalva had a significant association with WSS and OSI. Following VSARR, WSS and OSI values decreased significantly compared with the baseline values (WSS: 0.29 ± 0.12 Pa, P < 0.001; OSI: 0.26 ± 0.09, P < 0.001), and became comparable to the values in those who underwent CABG (WSS, P = 0.42; OSI, P = 0.15). Conclusions Mechanical stress on the AV gets altered in correlation with the size of the aortic root. An aneurysmal aortic root may expose the leaflet to abnormal fluid dynamics. The VSARR procedure appeared to reduce these abnormalities.

Background Bartholin gland carcinomas (BGCs) are rare tumor types, for which no molecular analyses including genomic sequencing have been reported to date. Adenoid cystic carcinomas (ACCs) of the Bartholin’s glands are an atypical histological type of BGC, and currently nothing is known regarding their genetic profiles or similarity to ACC carcinogenesis in other organs including the salivary glands, thereby limiting possible therapeutic options using precision medicine. Case presentation We used targeted gene sequencing to analyze the occurrence of 160 cancer-related genes in two patients with BG-ACC. KRAS and KDM6A mutations were detected in tumor samples collected from each patient. No KRAS mutations have been previously reported in salivary gland ACCs, indicating that the carcinogenesis of BG-ACC differs from that of the salivary gland ACCs. KDM6A mutations are often reported in salivary gland ACCs and facilitate novel gene-targeted therapy, including the use of BET and HDAC inhibitors. Conclusions A better understanding of the underlying genetic mechanisms will help to clarify the carcinogenesis of BG-ACC. In turn, this will enable treatment with novel targeting agents, as well as the initial exploration of gene-based precision oncological therapies, which aim to improve treatment outcomes for patients with this disease.

Precision medicine is a promising strategy for cancer treatment. In this study, we developed an in‐house clinical sequencing system to perform a comprehensive cancer genomic profiling test as a clinical examination and analyzed the utility of this system. Genomic DNA was extracted from tumor tissues and peripheral blood cells collected from 161 patients with different stages and types of cancer. A comprehensive targeted amplicon exome sequencing for 160 cancer‐related genes was performed using next‐generation sequencing (NGS). The sequencing data were analyzed using an original bioinformatics pipeline, and multiple cancer‐specific gene alterations were identified. The success rate of our test was 99% (160/161), while re‐biopsy was required for 24% (39/161) of the cases. Potentially actionable and actionable gene alterations were detected in 91% (145/160) and 46% (73/160) of the patients, respectively. The actionable gene alterations were frequently detected in PIK3CA (9%), ERBB2 (8%), and EGFR (4%). High tumor mutation burden (TMB) (≥10 mut/Mb) was observed in 12% (19/160) of the patients. The secondary findings in germline variants considered to be associated with hereditary tumors were detected in 9% (15/160) of the patients. Seventeen patients (11%, 17/160) were treated with genotype‐matched therapeutic agents, and the response rate was 47% (8/17). The median turnaround time for physicians was 20 days, and the median survival time after the initial visit was 8.7 months. The results of the present study prove the feasibility of implementing in‐house clinical sequencing as a promising laboratory examination technique for precision cancer medicine., In‐house clinical sequencing system is a promising laboratory examination for precision cancer medicine.

We investigated the relation between PCR examination rate among population and the success of containment of COVID-19 for each country. Although there was moderate correlation, multiple regression revealed that the success of containment was solely explained by Gross Domestic Product per capita (GDP), which may well be related to the strict compliance to social distancing. Close inspection of individual countries supported this hypothesis. The social distancing must be the largest factor to achieve containment, and the contribution of broad PCR tests is small.

We established an outpatient service in November 2017 to provide cancer gene profiling test services to cancer patients. To date, we have seen approximately 100 patients. Our staff includes genetic counselors and nurses specialized in genetic medicine. Our experience highlights the importance of healthcare professionals having in-depth knowledge of cancer therapeutic drugs and/or investigational drugs based on cancer genome medicine. Recently, poly(ADP-ribose) polymerase (PARP) inhibitors have been approved for treating breast cancer patients with germline BRCA mutation; thus, in-depth knowledge of genetics and skills for genetic counseling are often considered indispensable in working with cancer patients. However, because the prompt treatment of clear and present cancer is the top priority in clinical settings, providing genetic information at that time, including that of unaffected family members, is of low priority for most patients who are dealing with the severe side effects of anti-cancer therapies. Pharmacists have an essential role to play in cancer therapeutics, talking with patients in order to assess their condition and to clarify the status of their treatment with anticancer agents. Genetic pharmacists should therefore work closely with genetics nurses and genetic counselors in the clinical practice of cancer genomic medicine. In this symposium, I would like to describe our experience caring for patients through our outpatient service, and to discuss the ideal framework for multidisciplinary cooperation to promote cancer genomic medicine.

Background Data on FOLFIRINOX as a second-line chemotherapy for advanced pancreatic cancer are limited. In the JASPAC06 study—a nationwide, multicenter, observational study—FOLFIRINOX for patients with unresectable or recurrent pancreatic cancer as any line of treatment showed favorable efficacy and safety in Japanese clinical practice. Methods We performed exploratory analyses of patients with unresectable or recurrent pancreatic cancer who received FOLFIRINOX as the second-line chemotherapy in Japanese clinical settings. Results Of the 399 evaluable patients, 44 were eligible for inclusion in the analysis. The patients’ characteristics were as follows: median age, 62 years; men, 26 (59%); Eastern Cooperative Oncology Group-Performance status 0/1, 30 (68%)/14 (32%); disease status, recurrent/local/metastatic: 4 (9%)/8 (18%)/32 (73%). The initial dose was reduced in 28 (64%) patients. The median time to treatment failure and number of cycles were 4.5 (range, 0.2–19.1) months and 6 cycles (range, 1–13 or more), respectively. The major grade 3/4 adverse events were neutropenia in 29 (66%), leucopenia in 17 (39%), anorexia in 7 (16%), febrile neutropenia in 5 (11%), and anemia in 5 (11%) patients. The median overall survival, progression-free survival, and 1-year survival rates were 10.3 (95% confidence interval [CI], 7.2–13.3), 4.1 (95% CI, 2.6–5.5) months, and 30%, respectively. Conclusion Our findings suggest that FOLFIRINOX as a second-line chemotherapy for advanced pancreatic cancer was effective in patients with a good performance status. It displayed toxicity similar to that observed with its use as a first-line treatment.

A 74-year-old woman, with a history of aortic valve replacement and open mitral commissurotomy due to rheumatic aortic and mitral stenosis, presented with dyspnea. She developed severe tricuspid regurgitation (TR), requiring tricuspid valve replacement (TVR). Despite an uneventful postoperative course, she was readmitted for dyspnea 2 months later. Trans-thoracic echocardiogram revealed severe mitral regurgitation (MR), despite mild MR at the time of TVR, which has not been previously reported. The main MR mechanism was increased left ventricular preload due to improved TR. Increased diuresis has controlled her congestive heart failure, but her MR remained moderate.

Functional mitral regurgitation (MR) (FMR) and atrial fibrillation (AF) are common in patients undergoing left ventricular assist device (LVAD) implantation. However, the impact of FMR and AF on clinical outcomes is uncertain. This study aimed to investigate the characteristics and prognostic significance of FMR and AF in patients with LVADs.We retrospectively reviewed all patients who underwent LVAD implantation at our center between January 2010 and December 2017. We defined significant FMR as the ratio of MR color jet area to left atrial area of20% and persistent or permanent AF (PeAF) as persistent or permanent AF at LVAD implantation.A total of 380 patients were included in this analysis. Patients were divided into 6 groups: patients with no PeAF and no significant FMR (Group 1), patients with no PeAF but with significant FMR (Group 2), patients with PeAF but no significant FMR (Group 3), patients with PeAF and significant FMR (Group 4), patients with concomitant mitral valve surgery (MVS) at LVAD implantation and without PeAF (Group 5), and patients with concomitant MVS and with PeAF (Group 6). A total of 56 patients (15%) died within 2 years. Kaplan-Meier curve analysis demonstrated a 2-year survival of 81% in Group 1, 89% in Group 2, 87% in Group 3, 47% in Group 4, 87% in Group 5, and 79 % in Group 6 (log-rank test, p0.001). The multivariable Cox proportional-hazards model showed that classification in Group 4 was an independent predictor of mortality (hazard ratio, 4.31; 95% CI: 2.19-8.46; p0.001).The coexistence of significant FMR and PeAF may represent a poor prognostic marker in patients undergoing LVAD implantation.