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Siberia, which experienced disastrous heat waves in 2010 and 2012, is one of the regions in which extreme climate events have occurred recently. To compare the long-term trends of extreme climate events in the southern part of Siberia with those of surrounding regions, we calculated 11 extreme climate indexes from observational data for 1950–2019 and analyzed the trends in Siberia and other parts of Russia using statistical techniques, i.e., Welch’s t-test, the Mann–Kendall test, Sen’s slope estimator, and a cluster analysis. We clarified that high-temperature events in March are more frequent in Siberia than in the surrounding areas. However, the increasing trends of high temperatures in Siberia were lower than those in northwestern China and Central Asia. The intensity of heavy precipitation is increasing in Siberia, as it is in the surrounding areas. Compared to the surrounding areas analyzed in previous studies, the trend of heavy precipitation in Siberia has not increased much. In particular, Siberia shows a more remarkable decreasing trend in heavy precipitation during the summer than other regions. The dry trends in the summer, however, do not occur in Siberia as a whole, and the opposite trend of summer precipitation was observed in some areas of Siberia.

The usefulness of angiogenesis inhibitors as second-line treatment after the progression of anti-epidermal growth factor receptor antibody drug-containing regimens for RAS wild-type metastatic colorectal cancer (mCRC) has not been fully investigated. Therefore, we conducted a phase II study to verify the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab (SIRB regimen) as second-line treatment for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC.Patients with mCRC who had previously received oxaliplatin and cetuximab-containing regimen were eligible for this study. Patients were infused with bevacizumab 7.5 mg/kg and irinotecan 150 mg/mIn total, 17 patients were enrolled in this study. The 6-month PFS rate was 64.7% [95% confidence interval (CI)=41.99-87.43], median PFS was 10.1 months (95%CI=4.11-17.28), and median overall survival was 21.8 months (95%CI=9.79-37.91). The response rate was 23.5% (95%CI=6.81-49.90%). Grade ≥3 adverse events were observed in 10% of patients, and included leukopenia [3 (17.6%)], neutropenia [5 (29.4%)], anorexia [2 (11.8%)], diarrhea [2 (11.8%)], and hypertension [3 (17.6%)]. No treatment-related deaths or febrile neutropenia were observed.The SIRB regimen might be a promising second-line treatment option for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC in terms of efficacy and safety.

We evaluated the role of raw-material features for machine-learning prediction of the flux crystal growth of Al2O3 in MoO3 based on 185 types of growth trials.

Background: Regorafenib is a standard salvage line therapy used for advanced colorectal cancer (CRC). Recently, FTD/TPI plus bevacizumab also showed promising efficacy as a salvage line therapy for advanced CRC. However, the efficacy and safety of regorafenib for patients with advanced CRC who have previously received trifluridine/tipiracil (TFTD) plus bevacizumab is unclear.Results: We retrospectively collected clinicopathologic data from patients with advanced CRC who received regorafenib after TFTD plus bevacizumab in multiple institutions between April 2017 and June 2020.Thirty-four advanced CRC patients who received regorafenib were analyzed. The median age was 66.5 (range 43−81 years), 11 patients were male, and all had an ECOG performance status(PS) of 0 or 1. Twenty-two patients had left-sided tumors, 18 patients had RAS mutants, and 1 patient had a BRAF V600E mutation. The response rate was 0%, and the disease control rate was 31%. The median progression-free survival was 70 days (95% CI: 56−91), and the overall survival was 233 days (95% CI: 188−324). Treatment was discontinued in 32 patients, and 28 (82%) discontinued treatment due to progressive disease. The major grade 3 and4 toxicities were proteinurea (29%), hypertension (26%), hand-foot syndrome(15%), and platelet decrease (6%).Conclusion: Regorafenib after TFTD plus bevacizumab showed efficacy similar to that of the previous study, and no new adverse events were observed.

Regorafenib and trifluridine/tipiracil are standard third-line chemotherapies for colorectal cancer patients, but their efficacy is limited. Anti-epidermal growth factor receptor antibody rechallenge has been reported to be promising for patients who have obtained clinical benefit from first-line cetuximab-based chemotherapy. Moreover, panitumumab showed non-inferior efficacy to cetuximab. This study assessed the efficacy and safety of third-line panitumumab rechallenge in patients with metastatic KRAS exon 2 wild-type metastatic colorectal cancer who obtained clinical benefit from first-line panitumumab-based chemotherapy. This was a prospective, multicenter, phase II trial conducted from October 2013 to August 2017. Major eligibility criteria included KRAS exon 2 wild-type and achievement of complete response, partial response, or continued stable disease for at least 6 months in first-line panitumumab-based therapy. Irinotecan plus panitumumab treatment was continued until disease progression or unacceptable toxicity was observed. The primary endpoint was the 3-month progression-free survival (PFS) rate. Twenty-five patients were enrolled in this study. Their median age was 66.5 years, and the 3-month PFS rate was 50.0% (95% confidence interval 30.0–70.0). The median PFS and overall survival were 3.1 months and 8.9 months, respectively. The response rate and disease control rate were 8.3% and 50.0%, respectively. Common grade 3/4 adverse events were acneiform rash (17%), hypomagnesemia (13%), and dry skin (13%). No treatment-related deaths occurred. Irinotecan plus panitumumab rechallenge is a promising third-line treatment regimen in patients with metastatic wild-type KRAS colorectal cancer. UMIN000015916.

Lessons Learned Background The role of neoadjuvant and adjuvant chemotherapy in the management of initially resectable colorectal cancer liver metastases (CLM) is still unclear. We evaluated the feasibility of 3-month adjuvant treatment with capecitabine plus oxaliplatin in combination (CAPOX) for postcurative resection of CLM. Methods Patients received one cycle of capecitabine followed by four cycles of CAPOX as adjuvant chemotherapy after curative resection of CLM. Oral capecitabine was given as 1,000 mg/m2 twice daily for 2 weeks in a 3-week cycle, and CAPOX consisted of oral capecitabine plus oxaliplatin 130 mg/m2 on day 1 in a 3-week cycle. Primary endpoint was the completion rate of adjuvant chemotherapy. Secondary endpoints included recurrence-free survival (RFS), overall survival (OS), dose intensity, and safety. Results Twenty-eight patients were enrolled. Median age was 69.5 years, 54% of patients had synchronous metastases, and 29% were bilobar. Mean number of lesions resected was two, and mean size of the largest lesion was 31 mm. Among patients, 20 (71.4%; 95% confidence interval, 53.6%–89.3%) completed the protocol treatment and met its primary endpoint. The most common grade 3 or higher toxicity was neutropenia (29%). Five-year recurrence-free survival and overall survival were 65.2% and 87.2%, respectively. Conclusion Three-month adjuvant treatment with CAPOX is tolerable and might be a promising strategy for postcurative resection of CLM.

Purpose Breast ultrasound has been widely used as an essential examination for diagnosing breast cancer. However, standardized diagnostic criteria are as yet lacking. This study aimed to develop a simple diagnostic flowchart for beginners learning breast ultrasonography. The diagnostic flowchart was developed based on the recall criteria widely used in Japan. Methods We conducted a multicenter study to examine recall criteria usefulness in the diagnostic phase of breast disease. Women with ultrasound-visible breast masses who underwent B-mode breast ultrasound examination were recruited from 22 hospitals in Japan between September 2009 and January 2010. B-mode images were evaluated by members of the centralized image interpretation committee. We developed the new diagnostic flowchart based on the results. The usefulness of the diagnostic flowchart was assessed by employing datasets from the current study and another study which we conducted (BC-04 study). Results We evaluated 1045 solid masses (malignant: 495, benign: 550). Multivariate analysis showed that shape, margin, echogenic halo, interruption of the mammary gland interface, and depth width ratio were significant findings for distinguishing between benign and malignant masses. We modified the recall criteria and developed our novel diagnostic flowchart using these findings. The sensitivity and specificity of the new flowchart (current study: 0.97, 0.45; BC-04 study dataset: 0.95, 0.45) were similar to those of experts (current study: 0.96, 0.54; BC-04 study dataset: 0.98, 0.38). Conclusion We developed a simple diagnostic flowchart for breast ultrasound. This flowchart is anticipated to be applicable to educating beginners learning breast ultrasound.

Background Regorafenib or trifluridine/tipiracil as third-line treatment have limited efficacy in metastatic colorectal cancer (mCRC). Methods This Phase 2 trial evaluated the efficacy and safety of irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type mCRC patients who achieved clinical benefit with first-line cetuximab-containing therapy. The primary endpoint was 3-month progression-free survival (PFS) rate. A sample size was calculated; 30 patients with a 3-month PFS rate of 45% deemed promising and 15% unacceptable. Patients with greater and less than the cut-off value of cetuximab-free intervals (CFIs) were classified into the long and short CFI groups, respectively, in subgroup analyses. Results Among 34 eligible patients who received treatment at least once, 3-month PFS rate was 44.1% (95% confidence interval, 27.4–60.8%). The median PFS and overall survival (OS) were 2.4 and 8.2 months, respectively. The response and disease control rates were 2.9 and 55.9%, respectively. PFS and OS were significantly longer in the long- than in the short CFI group. Conclusions Irinotecan plus cetuximab rechallenge as third-line treatment for KRAS wild-type mCRC was safe and had promising activity, especially in those with a long CFI, warranting further investigation in a Phase 3 randomised trial. Clinical trial registration UMIN000010638

Aquaporins (AQPs) are a family of transmembrane water channel proteins distributed in various human tissues. Recent studies revealed that AQPs play important roles in cancer biology. Few studies have documented the relationship between the prognosis, stage, and histological grade of uterine endometrioid carcinoma, with AQP expression. Hence, the present study aimed to investigate this relationship between uterine endometrioid carcinoma and AQP expression. We retrospectively reviewed records of the patients who underwent surgery for uterine body cancer between 1990 and 2010 at the National Defense Medical College Hospital, Saitama, Japan. In 241 cases of endometrioid carcinoma, we immunohistochemically examined the expression of AQP 1, 2, 3, 4, and 5, and their relationship with clinicopathological parameters and the patients’ prognosis. We investigated the relationship between the clinicopathological parameters and AQP3 expression, and found that as the FIGO stage and histological grade progressed, the percentage of AQP3 expression tends to decrease. Furthermore, we analyzed progression-free survival/overall survival (PFS/OS) using the log-rank test, and found that the AQP3-positive group had a better prognosis than AQP3-negative group (PFS: P

Background: It is critical that a large proportion of eligible patients should participate in clinical trials. However, recruitment into clinical trials requires informed consent and involves some difficult and complex problems. Therefore, it is important to know what factors affect the participation of eligible patients in clinical trials. Patients and Methods: Patients with metastatic breast cancer (MBC) who were eligible to participate in the SELECT BC or SELECT BC-CONFIRM trials were recruited to a prospective study accompanying them named SELECT BCFEEL. The SELECT BC and SELECT BC-CONFIRM trials were randomised controlled trials (RCTs) that compared taxanes or anthracyclines, respectively, with the oral regimen of S-1 in the first line setting for Japanese patients with MBC. The SELECT BC FEEL was conducted to identify factors affecting the rates at which informed consent was obtained, using a self-administered questionnaire we developed. The questionnaire included the following items: Physician recommendation, family or friend recommendation, satisfaction with the explanation about the trial, both from the doctor or clinical research coordinator and from printed matter, regimens used, understanding of the concept of the trial, benefit to future patients, relationship with the doctor, attitude toward random assignment, concerns about privacy, burden on the patient, and potential adverse effects. We also asked the patients their age, whether they received prior chemotherapy, and about the time needed to decide whether or not to participate, communication with their doctor or other patients, potential adverse effects they were concerned about, and other people's opinions that affected their decision. The patients were asked to answer most of the questions in 5-point Likert scales. To investigate the associations between patients’ decision regarding whether or not to participate in the RCTs and their responses to each question, the Chi-square test, the Mann-Whitney U test, and the t-test were used. P values of < 0.05 were considered statistically significant. Results: Two hundred and thirty-two patients participated in the present study. Data were missing for 3 patients, and they were excluded from the analyses. One hundred and eighty five participated in the RCT, but 44 did not. The patients who chose to participate in these RCTs were more likely to answer that they decided to participate because "My doctor wanted me to participate in this trial" (69.2% vs. 25.6%; P Conclusions: To enhance the consent rate in randomised trials of Japanese breast cancer patients, the concepts of the trials must be considered important and acceptable by the doctors and families of the patients. Citation Format: Yasuo Hozumi, Shozo Ohsumi, Hirofumi Mukai, Masato Takahashi, Hiromitsu Akabane, Youngjin Park, Eriko Tokunaga, Tsutomu Takashima, Takanori Watanabe, Yoshiaki Sagara, Tetsuji Kaneko, Yasuo Ohashi. Factors affecting enrolment in randomised controlled trials of Japanese patients with metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-21-01.

120 Background: Triplet regimen, FOLFOXIRI, plus bevacizumab is considered as one of standard first-line treatments in metastatic colorectal cancer (mCRC). On the contrary, FOLFOXIRI plus anti-EGFR antibody has been shown to be a promising regimen with greater depth of response (DpR) in patients with RAS wild-type mCRC from the VOLFI and MACBETH trials (J Clin Oncol 2019, JAMA Oncol 2018). We therefore performed a randomized phase II study, DEEPER trial (JACCRO CC-13) [NCT02515734], to investigate the efficacy and safety of cetuximab (cet) vs. bevacizumab (bev) in combination with modified (m)-FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. We have reported a significantly better DpR of m-FOLFOXIRI plus cet compared to bev as the primary endpoint (Tsuji A, et al. ASCO 2021). Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) plus cet vs. bev as initial treatment in terms of DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC. The aim of the trial was to show that median DpR of cet arm was more than 12.5% higher than bev arm, with a power of 85% at a significance level of 0.05, in per protocol set (PPS) consisted of patients evaluable for the DpR. Secondary endpoints included progression-free survival, overall survival, overall response rate, early tumor shrinkage rate, secondary resection rate, and toxicity. A total of 359 patients were enrolled between July 2015 and June 2019. For the PPS (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 84%/16%), 159 and 162 patients were randomly assigned to the cet and bev arms, respectively. Clinical outcomes will be analyzed according to primary tumor sidedness which is included in the stratification factor. Additionally, we will collect data of BRAF status, and analyze the clinical outcomes in mCRC patients with RAS/ BRAF wild-type tumors and/or left-sided tumors. Pre-planned survival analysis will be performed to compare the two treatment arms at the time of 3 years after last patients’ enrollment using a log-rank test. All statistical tests are two-sided, and P values ≤ 0.05 are deemed significant. Statistical analyses will be performed using SAS version 9.4. Clinical trial information: NCT02515734 .

Background Recent studies have demonstrated that uric acid (UA) enhances arginase activity, resulting in decreased NO in endothelial cells. However, the role of lung UA in pulmonary arterial hypertension (PAH) remains uncertain. We hypothesized that increased lung UA level contributes to the progression of PAH. Methods and Results In cultured human pulmonary arterial endothelial cells, voltage‐driven urate transporter 1 (URATv1) gene expression was detected, and treatment with UA increased arginase activity. In perfused lung preparations of VEGF receptor blocker (SU5416)/hypoxia/normoxia‐induced PAH model rats, addition of UA induced a greater pressure response than that seen in the control and decreased lung cGMP level. UA‐induced pressor responses were abolished by benzbromarone, a UA transporter inhibitor, or L‐norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by administering 2% oxonic acid significantly increased lung UA level and induced greater elevation of right ventricular systolic pressure with exacerbation of occlusive neointimal lesions in small pulmonary arteries, compared with nonhyperuricemic PAH rats. Administration of benzbromarone to hyperuricemic PAH rats significantly reduced lung UA levels without changing XOR (xanthine oxidoreductase) activity, and attenuated right ventricular systolic pressure increase and occlusive lesion development. Topiroxostat, a XOR inhibitor, significantly reduced lung XOR activity in PAH rats, with no effects on increase in right ventricular systolic pressure, arterial elastance, and occlusive lesions. XOR‐knockout had no effects on right ventricular systolic pressure increase and arteriolar muscularization in hypoxia‐exposed mice. Conclusions Increased lung UA per se deteriorated PAH, whereas XOR had little impact. The mechanism of increased lung UA may be a novel therapeutic target for PAH complicated with hyperuricemia.

Background We have previously demonstrated S-1 is non-inferior to taxane with respect to overall survival as first-line chemotherapy for HER2-negative metastatic breast cancer. We aimed to confirm whether S-1 is also non-inferior to anthracycline-containing regimens in the same setting. Methods We conducted an open-label, non-inferiority, Phase 3 study. Individuals who had HER2-negative metastatic breast cancer, had received no chemotherapy for advanced disease and had endocrine therapy resistance, were randomly assigned to the anthracycline-containing regimens or S-1. The primary endpoint was overall survival. A pre-planned combined analysis of our two Phase 3 studies was also carried out. Results We enrolled 230 patients (anthracycline, n = 115; S-1, n = 115). Median overall survival was 30.1 months (95% CI 24.9-35.8) with the S-1 group and 33.7 months (95% CI 25.5-36.9) with the anthracycline group. The HR for the anthracycline group was 1.09 (95% CI 0.80-1.48). The combined analysis constituted 814 patients (395 assigned to standard treatment (anthracycline or taxane); 419 assigned to S-1). Median overall survival was 36.3 months in the standard treatment group and 32.7 months in the S-1 group. S-1 was non-inferior to standard treatment in terms of overall survival (HR 1.06 (95% CI 0.90-1.25); P non-inferiority = 0.0062). Conclusions S-1 could be considered a new treatment option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer. Clinical trial registration The University Hospital Medical Information Network, Japan: UMIN000005449. This trial was registered on 15 April, 2011.

Hormone receptor and human epidermal growth factor receptor 2 (HER2) protein tests in metastatic breast cancer tissue are recommended in the guidelines of the American Society of Clinical Oncology/American Pathology Association. As part of a multi-institutional study by the National Hospital Organization, we conducted an investigation to examine these molecular markers, using cytological specimens as a substitute for tissue specimens from breast cancer metastasis. To confirm the usefulness of receptors tested in metastatic lesions, the treatment course of registered metastatic breast cancer patients was analyzed. During the April 2015 to March 2016 registration period, there were 62 registrations. Types of metastatic lesions include pleural fluid (44 samples), ascites (14 samples), lymph nodes (2 samples), pericardial fluid (1 sample), and dorsal subcutaneous mass (1 sample). A stable test result was obtained by adopting the receptor examination method, using cell block for immunostaining cytological specimens. The discordance rates of estrogen receptor (ER), progesterone receptor (PR), and HER2 protein expression were 18.2% (95% confidence interval (CI): 7.9-28.8%), 36.4% (95% CI: 23.7-49.1%), and 8.2% (95% CI: 0.1-16.3%), respectively, between the primary tumor and metastatic lesion. Patients who changed from primary negative to metastatic positive ER status had taken a significantly longer time for metastatic foci to appear. Patients with positive ER status in metastatic lesions had significantly better prognosis than ER-negative cases (P = 0.030) by the Log-Rank test. The ER status of the metastatic lesion and the metastatic site were independent prognostic factors by Cox multivariate analysis. Receptor examination with cytological specimens in metastatic lesions has been useful as it provides guidance for the treatment of metastatic breast cancer.

PurposeAlthough the number of ductal carcinoma in situ (DCIS) cases has increased with the spread of breast cancer screening in Japan, there are very few reports that summarize ultrasound image features of DCIS. The Japan Association of Breast and Thyroid Sonology (JABTS) investigated the incidence of DCIS with masses and non-mass abnormalities and the characteristics of US images in a retrospective, multicenter, observational study (JABTS BC-02 study). The purpose of this report is to clarify the proportion of DCIS with abnormalities of the ducts with each ultrasound finding and the characteristics of US images.MethodsThe JABTS BC-02 study population was comprised of patients who were examined by ultrasonography, underwent surgery, and were histopathologically diagnosed with DCIS at each study site between January 2008 and December 2012. The US images of DCIS and pathology and clinical information were retrospectively collected from 16 institutions in Japan. The US images were evaluated by 22 experts on the Central Image Interpretation Committee of JABTS.ResultsAbnormalities of the ducts were noted in 78 (10.5%) of 705 US images of DCIS. Of the 78 cases, the distribution of abnormalities of the ducts was focal or segmental. The second characteristic was the presence of internal echoes in dilated ducts. All cases were accompanied by intraductal solid echoes, and 40 cases (51.3%) were accompanied by echogenic foci. In addition, intraductal solid echoes were continuous or multiple in 72 cases (92.4%), and the shape of the solid echoes was broad-based and/or irregular in 62 cases (79.5%).ConclusionDCIS cases with duct abnormalities on ultrasound were investigated in this study. The important characteristics were as follows: (1) the distribution of ductal dilatation was focal or segmental, (2) solid parts were present in the dilated ducts, (3) the distribution of internal echoes was continuous or multiple, (4) the shape of solid echoes was broad-based and/or irregular, and (5) internal echoes were sometimes accompanied by echogenic foci. Accurate evaluation of these findings may be useful for diagnosing DCIS. Although the duct abnormalities are included in “ASSOCIATED FEATURES” in ACR BI-RADS ATLAS (USA), we emphasize that this concept is very important for understanding US characteristics of DCIS.

Background Recent accumulating evidence suggests that toll‐like receptor 9 (TLR9) is involved in the pathogenesis of cardiovascular diseases. However, its role in pulmonary hypertension remains uncertain. We hypothesized that TLR9 is involved in the development of pulmonary hypertension. Methods and Results A rat model of monocrotaline‐induced pulmonary hypertension was used to investigate the effects of TLR9 on hemodynamic parameters, vascular remodeling, and survival. Monocrotaline‐exposed rats significantly showed increases in plasma levels of mitochondrial DNA markers, which are recognized by TLR9, TLR9 activation in the lung, and interleukin‐6 mRNA level in the lung on day 14 after monocrotaline injection. Meanwhile, monocrotaline‐exposed rats showed elevated right ventricular systolic pressure, total pulmonary vascular resistance index and vascular remodeling, together with macrophage accumulation on day 21. In the preventive protocol, administration (days −3 to 21 after monocrotaline injection) of selective (E6446) or nonselective TLR9 inhibitor (chloroquine) significantly ameliorated the elevations of right ventricular systolic pressure and total pulmonary vascular resistance index as well as vascular remodeling and macrophage accumulation on day 21. These inhibitors also significantly reduced NF‐κB activation and interleukin‐6 mRNA levels to a similar extent. In the short‐term reversal protocol, E646 treatment (days 14–17 after monocrotaline injection) almost normalized NF‐κB activation and interleukin‐6 mRNA level, and reduced macrophage accumulation. In the prolonged reversal protocol, E6446 treatment (days 14–24 after monocrotaline injection) reversed total pulmonary vascular resistance index and vascular remodeling, and improved survival in monocrotaline‐exposed rats. Conclusions TLR9 is involved in the development of pulmonary hypertension concomitant via activation of the NF‐κB‒IL‐6 pathway. Inhibition of TLR9 may be a novel therapeutic strategy for pulmonary hypertension.

Background Hyperuricemia occurs in approximately 80% in patients with pulmonary arterial hypertension (PAH) and is positively correlated with pulmonary arterial pressure (PAP). It has been reported that uric acid (UA) reduced endothelium derived nitric oxide (NO) production in porcine pulmonary arterial endothelial cells (PAEC). However, the effects of UA and xanthine oxidoreductase (XOR), catalytic enzyme of UA, on the development of PAH have not been fully elucidated. Purpose We examined the followings; (1) the effects of hyperuricemia on the endothelial function and the development of PAH in rats (2) the therapeutic effects of UA transporter inhibitor on PAH in rats, and (3) the role of XOR in PAH in mice. Methods We used normal and 5-wk Sugen5416/Hypoxia/Normoxia-exposed (SU/Hx/Nx) rats. Gene expression levels of URATv1, a UA transporter, were measured by RT-PCR. We determined the isometric tension of PA rings isolated from normal rats. The study with the isolated perfused lung preparation was performed in SU/HX/Nx rats. To investigate the chronic effect of UA on the development of PAH, hyperuricemia was induced by the administration of 2% oxonic acid (OA) in diet for 6-wk. Benzbromarone (BBR, 10mg/kg/day, diet, from weeks 0 to 5), a URATv1 transporter inhibitor, was administered in the SU/Hx/Nx-rats with or without 2%OA. To examine the role of XOR in PAH, XOR+/− and wild type (WT) mice were exposed to 3-wk Nx or Hx (10% O2). Results The mRNA of URATv1 was detected in the normal lungs. Isometric tension study showed that UA (8 mg/dl) inhibited acetylcholine-induced vasorelaxation. In perfused lung preparations, UA acutely increased estimated PVR in a dose-dependent manner (1.6–16.0mg/dl) with reducing cGMP levels in the lungs. BBR significantly attenuated the pressor response to UA. UA levels in the plasma and the lung tissues were significantly elevated in SU/Hx/Nx-rats with 2%OA (normal vs. vehicle vs. 2%OA, plasma: 0.24±0.01 vs. 0.80±0.14 and 1.44±0.17 mg/dl; lung tissues: 68±3 vs. 142±3 and 377±46 pmol/g tissue). They exhibited further elevation of right ventricle systolic pressure (RVSP) (31±2 vs. 72±6 vs. 101±3 mmHg) and Ea (a marker of RV afterload) (0.24±0.04 vs. 0.97±0.15 vs. 2.36±0.49 mmHg/μL) with the exacerbation of occlusive lesions of PAs. BBR had no changes in the UA levels in the plasma (1.93±0.30 mg/dL), but significantly reduced the UA levels in the lung tissues (101±10 pmol/g tissue) and attenuated the increase in RVSP (53±8mmHg) and Ea (0.21±0.05 mmHg/mL) in the SU/Hx/Nx-rats with 2%OA. On the other hand, BBR had no effects on RVSP (76±7 mmHg) and Ea (0.91±0.15 mmHg/mL) in the SU/Hx/Nx-rats without 2%OA. There were no significant differences in RVSP between XOR+/− mice with Hx and WT with Hx (26±2 vs. 26±2 mmHg). Conclusions Hyperuricemia itself impairs endothelial function and deteriorates PAH via URATv1 in a XOR-independent manner. UA can be a novel therapeutic target for PAH. Funding Acknowledgement Type of funding source: None

Introduction The previous randomized phase 3 trial (SELECT BC) showed that S-1 as a first-line chemotherapy for metastatic breast cancer (MBC) is non-inferior to taxane with respect to overall survival. This study aimed to identify the usefulness of metabolism-related genes as predictive biomarkers for the response to S-1 compared with taxane using tumor tissue samples from the previous trial. Patients and Methods In this SELECT BC-EURECA study, 147 patients with human epidermal growth factor 2 (HER2)-negative MBC who received either S-1 or taxane were evaluated. Formalin-fixed paraffin-embedded specimens were collected, and 14 genes involved in the pyrimidine metabolic pathway, estrogen receptor, progesterone receptor, HER2, Ki67, and beta-tubulin were measured using reverse transcription polymerase chain reaction in microdissected tumor specimens. The expression of each gene was categorized as low, intermediate, and high by tertile values. Results Interaction tests to identify biomarkers for the response to S-1 compared with taxane, revealed the following as the top 3 biomarkers: RRM1 (P value = 0.24), GGH (P value = 0.25), and MTHFR (P value = 0.28). In the S-1 group, lower GGH and higher MTHFR expression were significantly correlated with better time to treatment failure. In the taxane group, there was no gene that was identified as a significant indicator of treatment failure. Conclusion This biomarker analysis from SELECT BC did not identify any predictive biomarkers for the response to S-1 compared with taxane. Future studies with larger sample size and information on not only mRNA, but also protein and DNA for broad functional analyses are needed.

The usefulness of color Doppler ultrasound (CD) in distinguishing between benign and malignant breast lesions remains controversial. Our prior study, the Japan Association of Breast and Thyroid Sonology (JABTS) BC-04 study (malignant: 839, benign: 569), found CD was useful in breast cancer diagnosis, and we developed CD diagnostic criteria. The first aim of the current study (the CD-CONFIRM study) was to evaluate the usefulness of the CD diagnostic criteria. The second aim was to evaluate the relationship between CD and elastography. We evaluated ultrasound images of breast masses from 13 institutions (malignant: 639, benign: 712). While the sensitivity of B-mode alone was very high and was not significantly improved with CD, the specificity was significantly improved with CD (61.2%-69.2%, p < 0.0001). Furthermore, the specificity of the combination of B-mode and CD improved significantly with the addition of elastography (72.8%-79.0%, p < 0.0001). This study found that the CD criteria are useful, and CD and elastography are independent.

Lessons Learned A biweekly TAS-102 plus BEV schedule in patients with heavily pretreated mCRC showed equivalent efficacy with less toxicity compared with the current schedule of TAS-102 plus BEV combination. Biweekly TAS-102 plus BEV combination could reduce unnecessary dose reduction of TAS-102, maintain higher doses, and possibly be effective even in cases without chemotherapy-induced neutropenia (CIN). The prespecified subgroup analysis of this study showed an obvious association between CIN within the first two cycles and prognosis of biweekly TAS-102 plus BEV. Background TAS-102 (trifluridine/tipiracil) plus bevacizumab (BEV) combination therapy has shown promising activity in patients with metastatic colorectal cancer (mCRC). However, the previously reported dose and schedule for the TAS-102 (70 mg/m2/day on days 1–5 and 8–12, every 4 weeks) plus BEV (5 mg/kg on day 1, every 2 weeks) regimen is complicated by severe hematological toxicities and difficult administration schedules. Here, we evaluated the efficacy and safety of a more convenient biweekly TAS-102 plus BEV combination. Methods Patients with mCRC who were refractory or intolerant to standard chemotherapies were enrolled. Patients received biweekly TAS-102 (twice daily on days 1–5, every 2 weeks) with BEV (5mg/kg on day 1, every 2 weeks). The primary endpoint was progression-free survival rate at 16 weeks (16-w PFS rate). Results From October 2017 to January 2018, 46 patients were enrolled. The recommended phase II dose was determined to be TAS-102 (70 mg/m2/day). Of the 44 eligible patients, the 16-w PFS rate was 40.9% (95% confidence interval, 26.3%–56.8%), and the null hypothesis was rejected (p < .0001). Median progression-free survival (PFS) and overall survival were 4.29 months and 10.86 months, respectively. Disease control rate was 59.1%. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (15.9%), and leucopenia (15.9%). Conclusion Biweekly TAS-102 plus BEV showed promising antitumor activity with safety.

Background It is critical to obtain informed consent from eligible patients to complete clinical trials. We investigated the factors that affect the participation rates of eligible patients. Patients and methods Patients with metastatic breast cancer who were eligible for SELECT BC or SELECT BC-CONFIRM trials, randomized controlled trials conducted for patients with chemotherapy-naive metastatic breast cancer were recruited to prospective studies, SELECT BC-FEEL and SELECT BC-FEEL II, respectively. SELECT BC FEEL and SELECT BC-FEEL II were conducted to identify the factors affecting the rates at which informed consent was obtained, using a self-administered questionnaire we developed. Results In total, 232 patients participated in the studies. The patients who agreed to take part in the randomized trials were more likely than the refusers to answer that they decided to participate because: ‘My doctor wanted me to participate in this trial’ (P = 0.00000), ‘ My family or friends wanted me to participate in this trial’ (P = 0.00000), ‘Both treatment regimens used in the trial are suitable to me’ (P = 0.00383), ‘I know that the trial is conducted to determine which is a better treatment’ (P = 0.01196), and ‘ I think that my participation in the trial will contribute to the benefit to future patients with the same disease’ (P = 0.00756). Conclusions To enhance the consent rate in randomized trials of metastatic breast cancer patients, concepts of the trials must be considered important and acceptable not only by patients but also by doctors and their families.

112 Background: Ramucirumab (RAM) plus FOLFIRI has been considered as the standard care of second-line treatment in metastatic colorectal cancer (mCRC). However, there have been few data which prospectively evaluated the efficacy and safety of RAM or other anti-VEGF drugs plus FOLFIRI after anti-EGFR antibody therapy in RAS wild-type mCRC. We therefore investigated the efficacy and safety of RAM plus FOLFIRI as second-line treatment in patients with RAS wild-type mCRC previously treated with oxaliplatin-containing chemotherapy with anti-EGFR antibody. Methods: The JACCRO CC-16 was a multicenter, phase 2 trial to evaluate the efficacy and safety of RAM (8 mg/kg) plus FOLFIRI (irinotecan 150 mg/m2, bolus 5-FU 400 mg/m2, infusional 5-FU 2400 mg/m2) in mCRC patients with RAS wild-type tumors and ECOG PS 0 or 1, after first-line doublet or triplet plus anti-EGFR antibody therapy. The primary endpoint was 6-month progression-free survival (PFS) rate. The secondary endpoints included PFS, overall survival, objective response rate (ORR), early tumor shrinkage (ETS), and safety. We hypothesized a threshold 6-month PFS rate of 30% and an expected 6-month PFS rate of 45% for the protocol treatment. A sample size of 74 patients was required (one-sided α, 0.05; β, 0.2). Results: A total of 92 patients were enrolled between October 2018 and December 2020. Ninety-one patients, excluding one ineligible patient, were analyzed as the full analysis set: median age 66.0-y (range, 29–84), 46% female, 81% ECOG PS 0, 40% with primary tumor, 95% left-sided (rectum, sigmoid or descending colon) primary tumors, 70%/42% with liver/lung metastases. In prior first-line treatment, 19 (21%) patients were treated with triplet plus anti-EGFR antibody. The median number of treatment cycles was 10 (range, 1–56). Primary endpoint was met; at data cut-off, with 76 events, 6-month PFS rate was 58.2% (95% CI; 47.4-67.6). The median PFS was 7.0 months. The ORR, disease control rate, and ETS were 10.7%, 86.9%, and 16.9%, respectively. In the safety population of 92 patients, any grade adverse events (AEs) were neutropenia (75%), hypertension (59%), proteinuria (34%), and diarrhea (33%). Grade 3-4 AEs were neutropenia (48%), hypertension (27%), proteinuria (4%), diarrhea (3%), and febrile neutropenia (3%). No treatment-related death was observed. Conclusions: This is the first prospective study to demonstrate that RAM plus FOLFIRI as second-line treatment has favorable PFS rate and tolerability after anti-EGFR antibody containing chemotherapy in RAS wild-type mCRC patients. Clinical trial information: jRCTs061180002.

Tetrahymena can facilitate plasmid transfer among Escherichia coli or from E. coli to Salmonella Enteritidis via vesicle accumulation. In this study, whether ciliates promote the interactive transfer of plasmids encoding blaIMP-1 between fecal E. coli and environmental Aeromonas caviae was investigated. Both bacteria were mixed with or without ciliates and incubated overnight at 30°C. The frequency of plasmid-acquired bacteria was estimated by colony counts using an agar plate containing ceftazidim (CAZ) followed by determination of the minimum inhibitory concentration (MIC). Cultures containing ciliates interactively transferred the plasmid between E. coli and Aeromonas with a frequency of 10-4 to 10-5 . All plasmid-acquired bacteria showed a MIC against CAZ of >128 μg/mL and the plasmid transfer was confirmed by PCR amplification of the blaIMP-1 gene. Fluorescent observation showed that both bacteria accumulated in the same vesicle and that transwell sequestering significantly decreased the transfer frequency. Although ciliates preferentially ingested E. coli rather than A. caviae, both bacteria were co-localized into the same vesicles of ciliates, indicating that their meeting is associated with the gene transfer. Thus, ciliates interactively promote plasmid transfer between E. coli and A. caviae. The results of this study will facilitate control of the spread of multiple-antibiotic resistant bacteria.

We explored the bacteria present in the vaginal microbiota facilitating the prevalence of Chlamydia trachomatis in women visiting a community hospital in Sapporo, Japan, by amplicon sequencing. A total of 273 cervical swab samples were collected, and bacterial vaginosis was evaluated in all specimens by assessment of the Nugent score. In 16 of the samples, bacterial 16S rDNA could not be detected and they were therefore omitted from subsequent experiments (n = 257). A significant negative correlation was observed between the Nugent scores and the amount of Lactobacillus 16S rDNA. Among the 257 samples, chlamydial plasmid was detected in 20 samples and was used for amplicon sequencing. No significant association between the Nugent score and the prevalence of C. trachomatis was detected. Based on the results of chlamydial plasmid detection and the Nugent score, chlamydia-negative samples (n = 27) were randomly selected. Finally, the number of operational taxonomic units (OTUs) obtained from amplicon sequencing was compared between chlamydia-positive (n = 20) and -negative samples (n = 27), revealing that a significant difference was only detected for the OTU numbers of Enterobacteriaceae between the C. trachomatis-positive and -negative groups. However, almost all of the samples utilized for amplicon sequencing failed to grow on MacConkey agar plates and produce indole. Taken together, we concluded that traces of bacteria, not live bacteria, belonging to the Enterobacteriaceae indicated the flow of bacteria through the anogenital route along with gut indole, and the resulting impact on the prevalence of C. trachomatis in the cervicogenital tract of women in Japan.