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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 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.

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.

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.

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.

A 76-year-old woman with hereditary hemorrhagic telangiectasia (HHT) showed elevated serum hepatobiliary enzyme levels, and abdominal imaging studies revealed a hepatic tumor. Her serum alpha-fetoprotein level was 759.5 ng/mL. A pathological examination after hepatectomy confirmed a diagnosis of hepatocellular carcinoma (HCC). An examination of the surrounding liver revealed dilated vessels and thickened endothelial cells without inflammations. HHT patients without other risk factors (like this patient) reportedly have a lower incidence of common cancers, including HCC, in comparison to the unaffected population. One intriguing hypothesis that might explain the hepatocarcinogenesis in this situation is the ischemic liver cirrhosis theory, which suggests that chronic ischemia may cause parenchymal strain and promote inappropriate hepatocyte proliferation.

A 73-year-old woman was admitted for closer investigation into an abdominal tumor. Abdominal ultra-sonography, CT, and magnetic resonance imaging showed a discrete abdominal tumor. Especially on MRI, the tumor appeared as a relatively ill-defined whorled soft-tissue thickening within the mesenteric fat, causing angulation or speculation of adjacent bowel mesentery. Surgery was performed under a presumptive diagnosis of a mesojejunum desmoid. The tumor was invading the transverse mesocolon and mesojejunum as well as the third portion of the duodenum and the middle colic artery, and it was close to but apart from the superior mesenteric artery. The tumor was resected, including removal of part of the duodenum and transverse colon. The specimen contained a white solid tumor measuring 14×12×8cm. Pathologic examination showed differentiated fibroblasts and copious collagen fibers. The tumor was negative for CD34, c-kit, S-100, and α-SMA, but positive for β-catenin. On the basis of these findings, we established a diagnosis of mesenteric desmoid tumor of the small intestine. The patient has been followed postoperatively for 2 years, no sign of recurrence, to date.

Objective The aim of this study was to investigate the impact of adverse events (AEs) on health utility and health-related quality of life (HRQOL) in patients with metastatic breast cancer undergoing first-line chemotherapy. Methods We analyzed the data from the SELECT BC study, a multicenter, open-label, randomized, phase III study conducted in Japan, which compared first-line S-1 with taxane therapies. Heath utility and HRQOL were assessed using the EQ-5D-3L and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at baseline and 3, 6, and 12 months after treatment initiation. Health utility was calculated based on societal preferences, and AEs were reported at each cycle of the study treatment. Linear marginal mean models were used to quantify the impact of the last AEs (with 10 or more incidences) observed before HRQOL assessment on health utility and HRQOL. Results Analysis included 380 patients and 12 (of 15) AEs. Grade 1 nausea and oral mucositis, grade 1 and 2 edema, and grade 2 fatigue, motor and sensory neuropathy, and myalgia were significantly associated with disutility, measured using the EQ-5D-3L. Grade 1 oral mucositis, grade 1 and 2 fatigue, and grade 2 sensory neuropathy were significantly associated with impaired global health status in the EORTC QLQ-C30. AEs associated with decrements in the five functioning scales included fatigue, oral mucositis, nausea, edema, motor and sensory neuropathy, and myalgia. Conclusions We reported disutilities caused by AEs in patients with metastatic breast cancer under chemotherapy. These findings can be applied to future model-based cost-effectiveness analyses. Trial Registration Number C000000416. Electronic supplementary material The online version of this article (doi:10.1007/s40273-017-0580-7) contains supplementary material, which is available to authorized users.

The decrease in carcinoembryonic antigen (CEA) level is faster and greater during cetuximab treatment than bevacizumab treatment and correlates with prolonged survival in patients with metastatic colorectal cancer (mCRC) who receive cetuximab. We investigated if the degree of change in the CEA value can serve as a diagnostic tool for predicting survival, as well as tumor regression in mCRC patients treated with cetuximab combined regimen as first-line treatment. Associations among the CEA decrease, depth of response (DpR), and clinical outcomes were evaluated in 113 patients with mCRC from two phase II trials of first-line therapy: the JACCRO CC-05 trial of cetuximab plus FOLFOX and the CC-06 trial of cetuximab plus SOX. Analysis was performed using Spearman’s rank correlation coefficient. A 75% decrease in the CEA was used as the cut-off value to define the CEA response and discriminate CEA responders on the basis of the results of a previous study. Ninety-two patients were eligible for analyses of both CEA and DpR. The median CEA decrease was 67.4%, and the median time to CEA nadir was 2.8 months, which was similar to the median time to DpR of 3.0 months. The DpR was associated with PFS and OS (rs = 0.56, P

Primary tumor location is a critical prognostic factor in metastatic colorectal cancer (mCRC); however, it remains unclear whether tumor location is a predictor of the response to cetuximab treatment. It is also uncertain if BRAF mutation contributes to the impact of tumor location on survival. We assessed the prognostic impact of tumor location on clinical outcomes in mCRC patients treated with first-line cetuximab chemotherapy.The associations of tumor location with overall survival and progression-free survival were evaluated in mCRC patients with KRAS exon 2 wild-type tumors who were enrolled onto 2 clinical trials: JACCRO CC-05 of cetuximab plus FOLFOX (n = 57, UMIN000004197) and CC-06 of cetuximab plus SOX (n = 61, UMIN000007022). Tumors proximal or from splenic flexure to rectum were defined as right-sided or left-sided, respectively. In addition, exploratory RAS and BRAF mutation analyses were performed.A total of 110 patients were assessable for tumor location; 90 had left-sided tumors. Left-sided tumors were significantly associated with longer overall survival (36.2 vs. 12.6 months, hazard ratio = 0.28, P .0001) and progression-free survival (11.1 vs. 5.6 months, hazard ratio = 0.47, P = .0041) than right-sided tumors; similar results were obtained in multivariate analysis. A subanalysis showed that the association was evident in the FOLFOX group and that tumor location was an independent prognostic factor irrespective of BRAF status in RAS wild-type patients.Primary tumor location might be a predictor of survival independent of BRAF status in mCRC patients who receive first-line cetuximab combined with oxaliplatin-based chemotherapy.

The Japan Association of Breast and Thyroid Sonology (JABTS) proposed, in 2003, a conceptual classification system for non-mass abnormalities to be applied in addition to the conventional concept of masses, to facilitate detecting ductal carcinoma in situ (DCIS) lesions. The aim of this study was to confirm the utility of this system and to clarify the distribution of these findings in DCIS lesions. Data on 705 surgically treated DCIS lesions from 16 institutions in Japan were retrospectively reviewed. All 705 DCIS lesions could be classified according to the JABTS classification system. The most frequent findings were hypo-echoic areas in the mammary gland (48.6%), followed by solid masses (28.0%) and duct abnormalities (10.2%) or mixed masses (8.1%). Distortion (1.3%), clustered microcysts (1.4%) and echogenic foci without a hypo-echoic area (2.5%) were uncommon. These results suggest that the concept of non-mass abnormalities is useful in detecting DCIS lesions.

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.

A solid pseudo-papillary tumor of the pancreas is a rare neoplasm which mainly occurs in young women. Here, we report two cases of solid-pseudopapillary neoplasm of the pancreas (SPN) with contrasting imaging findings. One was a 59-year-old woman having no symptomatic complaint with a pancreatic cystic tumor in the tail. The tumor was 60 mm in diameter with a cyst composed of a calcified wall and low-density content which was poorly perfused on contrast-enhanced computed tomography (CT). We diagnosed SPN based on imaging findings and performed distal pancreatectomy. Histology revealed SPN, and the patient had two years of recurrence -free survival (RFS). The other case was a 34-year-old man with an asymptomatic solid tumor in the pancreatic tail. Contrast-enhanced CT showed low peripheral attenuation of a 25-mm solid tumor, with the main duct dilated distal from tumor. We diagnosed him with pancreatic cancer with atypical image findings. Pathological findings revealed SPN, and the patient had five years of RFS. Small-sized SPN is being increasingly recognized because of the recent advances in CT and MRI. We should consider SPN even if it occurs in a male, and endoscopic ultrasound -guided fine-needle aspiration has recently been reported to be useful in diagnosing SPN.

Coronary subclavian vertebral steal syndrome (CSVSS) is a rare but important complication of coronary artery bypass graft surgery (CABG) when an internal mammary artery (IMA) is used. This syndrome is defined as a retrograde flow from coronary artery via the IMA and the vertebral artery to the subclavian artery due to a proximal subclavian artery stenosis. We describe a case of a 64-year-old female who underwent CABG, complaining of dyspnea and chest pain by exercise of left arm, and dizziness when she turned her face to the left. Her blood pressure was 113/69 mmHg in the left arm and 137/84 mmHg in the right arm. Coronary angiography revealed retrograde flow from the left anterior descending (LAD) artery to the left IMA. Aortography showed that the ostium of the left subclavian artery had a severe stenosis and that the left vertebral artery was visualized retrogradely. Thereby, the diagnosis of CSVSS was made. The stenosis of the left subclavian artery was successfully treated with a percutaneous transluminal angioplasty and stent implantation, resulting in the restoration of antegrade flow from the left IMA to the LAD artery and from the left subclavian artery to the left vertebral artery. She was discharged with no chest pain and dizziness.

86 Background: Triplet regimens, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab have been shown to be superior in terms of early tumor shrinkage (ETS) and depth of response (DpR) compared to doublet regimen plus bev or triplet regimen in patients with RAS wild-type metastatic colorectal cancer (mCRC), in the TRIBE trial ( N Engl J Med 2014) or VOLFI trial ( J Clin Oncol 2019), respectively. There have been few studies which directly compared cetuximab (cet) with bev when combined with triplet regimen. Therefore, we investigated the efficacy and safety of bev vs. cet in combination with FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. 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 first-line treatment in terms of the DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC (ClinicalTrials.gov Identifier: NCT02515734). The experimental arm with cet was considered to be active if the difference of median DpR was over 12.5% compared with the bev arm, under the conditions of significance level of 0.05 and power of 0.85. Secondary endpoints included the ETS at week 8, progression-free survival, overall survival, secondary resection rate, and toxicity. Results: A total of 359 patients were enrolled between July 2015 and June 2019. For the safety analysis set (median age 65y, 64% male, PS0/1:91%/9%, left/right primary:83%/17%), 173 and 175 patients were randomly assigned to the cet and bev arms, respectively, some patients were excluded for the safety analysis due to the violation of inclusion criteria (6 for cet arm and 5 for bev). On the cutoff date of September 2020, median number of cycles administered was 10 (range, 1-51) for the cet arm and 12 (range, 1-51) for the bev arm. The incidence of severe adverse events (AEs) was 25.4% (44/173) for the cet arm and 25.7% (45/175) for the bev arm, respectively. The following AEs of grade 3-4 were observed more frequently in the cet arm compared to the bev arm: oral mucositis (9.2% vs. 2.3%), diarrhea (12.1% vs. 8.0%), dermatitis acneiform (12.1% vs. 0%), and hypomagnesemia (4.0% vs. 0%). The treatment-related death occurred in 2 patients of the cet arm, while no patients in the bev arm. The rate of treatment discontinuation due to AEs of any cause was comparable between the cet and bev arms (7% vs. 9%). Conclusions: This safety analysis indicated that both regimens of m-FOLFOXIRI plus cet or bev were tolerable in RAS wt mCRC patients although some frequent severe AEs were observed. Clinical trial information: UMIN000018217.

The use of color Doppler ultrasound (CD) for distinguishing between benign and malignant breast lesions remains controversial. This study (JABTS BC-04 study) was aimed at confirming the usefulness of our CD diagnostic criteria. We evaluated ultrasound images of 1408 solid breast masses from 16 institutions in Japan (malignant: 839, benign: 569). Multivariate analysis indicated that vascularity (amount of blood flow), vascular flow pattern ("surrounding marginal flow" or "penetrating flow") and the incident angle of penetrating flow were significant findings for distinguishing between benign and malignant lesions. However, the sensitivity and specificity of B-mode alone did not improve significantly with CD addition (97.6% → 97.9%, 38.3% → 41.5%, respectively). We explored the causes of these negative results and found that age should have been considered when evaluating vascularity. Simulation experiments suggested that specificity is significantly improved when age is taken into consideration (38.3% → 46.0%, p0.001) and we thereby improved our diagnostic criteria.

Objective Nivolumab has changed the treatment of advanced gastric cancer (AGC). Nivolumab shows better outcome compared to best supportive care in AGC patients who received at least two prior regimen. Although there is not reliable date of poor performance status(PS) AGC patients who received nivolumab.We investigated efficacy and safety of nivolumab for AGC patients with poor PS. Methods We retrospectively collected clinicopathologic data from patients with AGC who received nivolumab monotherapy in our institution from October 2017 to January 2019. Results 37 AGC patients received nivolumab in Himeji Red Cross hospital from October 2017 to January 2019.We analyzed 17 patients who were PS over 1. 15 patients was male, median age was 64 (42-80), 10 patients was PS 2 and 7 patients PS 3, 11 patients were diffuse type, median number of metastatic organ was 2(range 1-5), 3 patients had liver metastasis, 13 patients had peritoneum dissemination and ascites.12 patients received 2 prior regimen, 5 patients received over 2 regimen. Median progression free survival was 29 days(95% CI: 21-65 days) and overall survival was 85 days(95% CI: 35-111 days), response rate was 6%, disease control rate was 19%, and 6 months survival rate was 12%. Immune-related adverse events(iRAEs) were observed 4 patients(24%), colitis was observed 2patients(12%), hypothyroidism was observed 2patients(12%), and liver dysfunction was observed 1 patient(6%). Severe iRAEs was only one patients(colitis). Conclusion This study suggested that nivolumab has a modest effect and is feasible as third line or later line for AGC patients.

Kounis syndrome, which is known as allergic angina and allergic myocardial infarction today, was described as the coexistence of acute coronary syndrome with allergic reactions in 1991 by Kounis and Zavras. We report a case of a 79-year-old man with hypertension, hepatocellular carcinoma (HCC), and no allergic history. He had received transcatheter arterial chemoembolization (TACE) for treatment of HCC five times without allergic reactions. At the sixth time of TACE, he presented an anaphylactic reaction such as systemic erythema and severe arterial hypotension. Simultaneously, he complained of anterior chest pain and electrocardiogram showed significant ST segment elevation in inferior leads, indicating inferior myocardial infarction. Emergency coronary angiography, however, did not demonstrate any organic stenoses or occluded lesions of the coronary arteries. We made the diagnosis of Kounis syndrome associated with TACE. Although Kounis syndrome is a rare condition, physicians should be aware of possible co-occurrence of anaphylactic reactions and acute coronary syndrome.

Background: Many breast cancer patients suffer hair loss due to chemotherapy, and not only scalp hair loss, but also eyebrow loss, eyelash loss and nail changes induced by chemotherapy are traumatic for patients. These side effects diminish self-esteem and greatly reduce quality of life. However, there has been little research in this field until now. To clarify the actual situation concerning appearance issues in breast cancer patients who received adjuvant chemotherapy, and to consider a support system for these patients, we conducted a questionnaire survey. Methods: Disease-free breast cancer patients who have received adjuvant chemotherapy containing anthracycline and/or taxane within 5 years were recruited from 47 hospitals or clinics in Japan from April to October 2013. The patients participating in this survey completed a 65-question questionnaire concerning appearance issues (48) and their perception of physical and non-physical side effects (17). The drugs administered and treatment period were filled out by their doctors beforehand. The completed questionnaires were mailed directly to the data center by the patients. Results: A total of 1511 patients returned the questionnaire to the data center with a response rate of 82% (1511/1853). Since 33 patients did not meet the entry criteria, the questionnaires returned by 1478 patients were analyzed in this survey. The mean age was 54.7 years (+-10.4, range 17-79). The distribution of the patients by time from the end of chemotherapy to this survey was as follows: < 1 year: 28%; 1 to 2 years: 24%; 2 to 3 years: 19%; 3 to 4 years: 15%; 4 to 5 years: 13%. In this survey, the side effect that most patients (92%) considered traumatic was hair loss. The second most traumatic side effect was fatigue (83%), while the 7th place was taken by nail changes (72%) and nausea/vomiting was in the 10th place (56%). During chemotherapy, scalp hair loss occurred in 98% of patients. Eyebrows fell out in 90% and complete eyebrow loss occurred in 36%. Eyelashes fell out in 88% and complete eyelash loss occurred in 37%. Fingernail changes occurred in 77% and toenail changes in 62%. In 60-70%, scalp hair, eyebrow and eyelashes recovered to the original appearance by 1 to 1.5 years after chemotherapy, but in 3-7%, scalp and face hair loss did not recover at all by 1 to 1.5 years. This proportion remained almost the same for 1.5 to 5 years too. During or after chemotherapy, 84% of patients used wigs. This decreased to 47% by 1 year after chemotherapy and 15.2% by 1.5 years. However 10% of patients were still using a wig 4 to 5 years after chemotherapy. Approximately 30% of the patients had trouble using and selecting a wig. In 51% of the patients, sufficient information on scalp hair loss was obtained. However, sufficient information on eyebrow loss, eyelash loss and nail changes was only obtained from 28%, 25% and 31%, respectively. Conclusions: Our survey demonstrated the outline of hair loss and appearance issues in breast cancer patients who received chemotherapy. Hair loss is the most distressing and occasionally long-lasting side effect. Lack of information is a serious problem. These facts suggested a need for long-time and careful support of these patients. Citation Format: Takanori Watanabe, Hiroshi Yagata, Mitsue Saito, Hiroko Okada, Tomoko Takayama, Hirohisa Imai, Yuko Yoshida, Nao Tamai, Keiko Nozawa, Tamiko Yajima, Kojiro Shimozuma. National survey of chemotherapy-induced appearance issues in breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-09.

Background: Altered appearance due to chemotherapy is a very distressing adverse event and can remain unrecovered for a long time after chemotherapy. To clarify the current status of appearance change and its support systems, we conducted a national questionnaire survey of patients with breast cancer who had received chemotherapy in Japan. Here, we report on the long-term recovery of scalp hair loss during and after chemotherapy. Patients and methods: A questionnaire was distributed to patients in hospitals throughout Japan between April and October 2013. The questionnaire was regarding the current status of the patients’ appearance issues (scalp hair, eyebrows, eyelashes, nails, skin) related to chemotherapy and its support systems, including chemotherapy regimens received, endocrine therapy received, and duration after chemotherapy. Eligible patients were women with breast cancer without any recurrence who had received adjuvant or neoadjuvant chemotherapy containing anthracycline (A) and/or taxanes (paclitaxel, P; docetaxel, D) and who were within 5 years from the last chemotherapy treatment. The physicians of each hospital asked their patients to fill out the questionnaire and mail it directly to the data center. The scalp hair status was analyzed in a cross-sectional manner according to the duration from chemotherapy. Results: The questionnaires were returned from 1511 patients in 47 hospitals (response rate, 82%; 1511/1853). Thirty-three patients were excluded, mainly because >5 years had passed since chemotherapy. In total, 1478 questionnaires were ultimately analyzed. The median age was 50 (range, 17–79) years. The distribution of patients according to time from the last chemotherapy treatment was as follows: 80% hair loss. Hair growth began during chemotherapy in 13.1% of patients and after chemotherapy in 80.3% (6.6% left the question unanswered). Within 6 months from the start of hair growth, 65% of patients felt a change in hair thickness, while 82% felt it was becoming thin. Of the patients, 70% felt a change in quality, while 48% felt that it had become unruly; 44% felt a color change, while 80% felt that they were growing more gray hair. Of the patients who answered the questions, >80% hair volume recovery was seen in 52.7% of patients within 1 year; in 63.5%, in 1–3 years; and in 61.7%, even after 3 years. After 3 years, volume recovery was seen in 67.8% of patients after an A+P–containing regimen; in 43.4%, after A+D; in 63.5%, after D; and in 88.9%, after A. Patients who had received A+P, D, and A+D had significantly less volume recovery than patients who had received A (P Conclusions: Almost all patients with breast cancer experienced severe hair loss during standard chemotherapy, but a recovery trend was noted after chemotherapy. However, hair remained unrecovered to various degrees in a significant number of patients even 3–5 years after chemotherapy, especially in those who had received taxane-containing regimens. We should consider the support needs of patients who experience chemotherapy-induced hair loss. Citation Format: Hiroshi Yagata, Takanori Watanabe, Hiroko Okada, Mitsue Saito, Tomoko Takayama, Hirohisa Imai, Yuko Yoshida, Nao Tamai, Keiko Nozawa, Tamiko Yajima, Kojiro Shimozuma. National survey of long-term recovery from chemotherapy-induced hair loss in patients with breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-17.

Background: Treatment goals of metastatic breast cancer (MBC) are to prolong survival and improve health-related quality of life (HRQOL). Current standard first-line chemotherapy for MBC are the taxanes or anthracyclines; however treatment-related adverse events greatly reduce HRQOL. S-1 is an oral 5-fluorouracil derivative, and phase II trials showed good clinical efficacy and tolerability. We conducted a phase III randomized controlled trial to establish non-inferiority of S-1 in overall survival (OS) and superiority in HRQOL to taxanes, when given as first-line chemotherapy for MBC. Methods: Patients with HER2-negative non-life-threatening MBC, naïve to chemotherapy for metastatic disease, were randomly assigned to the taxane or S-1 groups. In the taxane group, patients received docetaxel 60-75mg/m2 q3w, paclitaxel 80-100mg/m2 q1w, or paclitaxel 175 mg/m2 q3w according to institutional policy. In the S-1 group, patients received S-1 40–60 mg twice daily based on body surface area using a 28 days on;14 days off regimen. Treatment was repeated until tumor progression or for at least 6 cycles (taxane) or 4 cycles (S-1). After failure of the first-line protocol therapy, another cytotoxic agent was administered, based on the investigator’s discretion. HRQOL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, the Patient Neurotoxicity Questionnaire (PNQ) and the EQ-5D at baseline and 3, 6, 12 months after the start of the treatment. The primary endpoint was OS. Secondary endpoints were time to treatment failure (TTF), adverse events, and HRQOL. Results: A total of 618 women were enrolled. After a median follow-up of 34.6 months, median OS was 37.2 months in the taxane group (n=309) and 35.0 months in the S-1 group (n=309) (hazard ratio [HR] 1.05, 95% confidence interval [CI] 0.86–1.27, non-inferiority test p=0.015). Median TTF was 8.9 months in the taxane group and 8.0 months in the S-1 group (HR 1.10, 95% CI 0.93–1.30, p=0.022). The incidence of the following grade 3-4 adverse events, allergic reaction, edema and sensory neuropathy, were statistically significantly more frequent in the taxane group (p=0.038, 0.0013 and 0.0077, respectively). Hematologic and non hematologic toxicities except above did not differ significantly between the two groups. The results of the EORTC QLQ-C30 under study treatment indicated that the S-1 was better than the taxanes in global health status/QOL (p=0.044), physical functioning (p=0.002), role functioning (p=0.002), emotional functioning (p=0.004), cognitive functioning (p=0.026), social functioning (p Conclusions: This study clearly demonstrated that S-1 was superior to taxanes in terms of HRQOL and toxicity, without compromising the prolonged OS. S-1 should be considered as a new standard for first-line chemotherapy for MBC. We are conducting another similar trial (UMIN000005449) that compares first-line anthracycline with S-1 in terms of OS and HRQOL. Citation Format: Takanori Watanabe, Kojiro Shimozuma, Kentaro Imi, Hiroyoshi Doihara, Hiromitsu Akabane, Hiroaki Ueo, Shinji Ohno, Masahiro Kashiwaba, Atsushi Fukuuchi, Kenichi Watanabe, Michiko Tsuneizumi, Hirotsugu Isaka, Yukari Uemura, Yasuo Ohashi, Hirofumi Mukai. Randomized phase III trial of taxanes versus S-1 as first-line chemotherapy for metastatic breast cancer (SELECT BC: CSPOR- MBC01) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-10-01.

Objective: To evaluate the effects of S-1, an orally administered 5-FU agent, versus taxane on patient-reported outcomes (PROs) in the SELECT BC trial. Methods: Patients with HER2-negative and endocrine treatment-resistant breast cancer with metastasis or recurrence after surgery were randomly assigned to receive first-line taxane or S-1. PROs (secondary endpoint) were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Patient Neurotoxicity Questionnaire (PNQ) at baseline and at 3, 6, and 12 months. We conducted a responder analysis for the QLQ-C30 and PNQ and created cumulative distribution function (CDF) plots as a sensitivity analysis. Results: The questionnaire response rates were over 80% from 386 patients, who completed at least one baseline questionnaire. S-1 was significantly superior to taxane with respect to 6 scales (physical functioning [p = 0.03], role functioning [p = 0.04], social functioning [p < 0.01], financial difficulties [p = 0.01], global health status [p = 0.02], and constipation [p < 0.01]) and sensory neuropathy (p = 0.01). The CDF plots partially supported the conclusions and their robustness. Conclusion: First-line S-1 therapy has clinical benefits with respect to many aspects of health-related quality of life for metastatic breast cancer patients.

121 Background: We have conducted the multicenter, phase Ib/II study to assess the activity and safety of biweekly Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) combination for pts with metastatic colorectal cancer (mCRC) who were refractory or intolerant to standard therapies, and the primary endpoint of investigator assessed progression-free survival rate at 16 weeks (16w-PFS) was met [Kotaka M, ASCO-GI 2018]. We show longer follow-up data from this prospective study. Methods: Patients with unresectable mCRC; refractory or intolerant to standard chemotherapies were enrolled. Phase Ib part is designed to determine the recommended phase II dose (RP2D), and the treatment was determined as biweekly FTD/TPI (70mg/m2/day on day 1-5, every 2 weeks) with BEV (5mg/kg, every 2 weeks). The primary endpoint in phase II part was a 16w-PFS with a hypothesis of 15% considered unacceptable and 38.7% deemed promising. Given a one-sided α of 0.025 and statistical power of 90%, a minimum of 40 pts were required for phase II part. This trial registered in University Hospital Medical Information Network, number UMIN000029198. Results: From October 2017 to January 2018, totally 46 pts were enrolled. Nine patients (20.5 %) received regorafenib before enrollment. Of the 44 eligible pts, 16w-PFS rate was 40.9 %. With a median follow up of 15.36 months (range, 2.79-16.93), median PFS was 4.29 months (95% CI: 2.54 to 5.83), median TTF was 4.16 months (95% CI: 2.39 to 5.82), and median OS was 10.86 months (95% CI:8.32 to 13.68), respectively. Disease control rate was 59.1 % (95%CI: 43.3 to 73.7 %). Patients received the study treatment for a median of 6.5 cycles (range, 1 to 24). The median relative dose intensity of FTD/TPI and BEV was 80.9% (range: 44.0 to 100%), 81.5% (range: 50.0 to 100%), respectively. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (11.4 %) and leucopenia (11.4 %). Conclusions: An update analysis confirmed that biweekly FTD/TPI plus BEV showed promising anti-tumor effect with acceptable less toxicities, and might be one of the treatment options for patients with heavily treated mCRC. Clinical trial information: UMIN000029198.

399 Background: Prognosis for locally advanced gastric cancer (LAGC), such as clinical T4 disease, bulky nodal metastases, type 4 and large type 3 gastric cancer, was not satisfactory even by D2 gastrectomy followed by adjuvant chemotherapy. Neoadjuvant chemotherapy is another promising approach, therefore, we have conducted a phase II study to evaluate the efficacy and safety of the neoadjuvant chemotherapy of S-1 and oxaliplatin (G-SOX) followed by gastrectomy with D2/3 lymph node dissection for LAGC, and the primary endpoint of curative resection rate was met [Miki A, ESMO 2019]. We show longer follow-up data from this study. Methods: Patients with adenocarcinoma of the stomach; clinical T4; clinically resectable gastric cancer of type 4 or large type 3; bulky nodal involvement around major branched arteries to the stomach were enrolled. Patients receive two cycles of neoadjuvant chemotherapy with S-1 (80 mg/m2, p.o., days 1-14 followed by 1 week rest) and oxaliplatin (130 mg/m2 at day 1), followed by D2 or higher surgery with no residual disease. Patients with pathological R0/1 resection received S-1 (80 mg/m2, p.o., days 1-28 followed by 2 week rest) for 1 year as adjuvant chemotherapy. Primary endpoint was curative resection rate. Results: Between August 2015 and March 2017, forty-one patients were in enrolled. Of the patients, 39 patients (95%) completed the two courses of neoadjuvant chemotherapy of G-SOX, 37 (90%) received gastrectomy, and 36 (87.8%) received curative resection (R0/1). Grade 3 or higher toxicities during neoadjuvant chemotherapy of G-SOX were neutropenia (7%), fatigue (7%), diarrhea (5%) and thrombocytopenia (2%). No treatment related deaths were observed. Surgical complications including postoperative complications were observed in 13 patients (35%). Pathological response rate after neoadjuvant G-SOX was 40%. With a median follow-up period of 33.8 months, 3year-relapse free survival and 3year-ovearll survival was 54.3% and 73.1%, respectively. Conclusions: An update analysis confirmed that neoadjuvant chemotherapy of G-SOX is a feasible and might be one of the promising strategies for patients with LAGC. Clinical trial information: UMIN000018661.

Aim The aim of this study was to evaluate the advantages of laparoscopic cornuotomy in treating interstitial pregnancy, and the effect of the procedure on reproductive outcomes. Methods Thirteen patients were treated for interstitial pregnancy by laparoscopic cornuotomy with or without local methotrexate injection, between March 2000 and January 2012 at NTT East Japan Tohoku Hospital and Sendai City Hospital. The patients were followed to assess the outcomes of subsequent pregnancies for at least 1 year after the operation. Results All 13 cases of interstitial pregnancy were successfully treated by laparoscopic cornuotomy, without performing cornual resection or laparotomy. The mean gestational age was 7.6 ± 1.3 weeks, and the average serum hCG level was 20 800 ± 18 100 IU/L. The mean cornual mass size was 34.6 ± 10.2 mm. Eight of the patients later obtained a spontaneous intrauterine pregnancy. Three patients that delivered by cesarean section showed no uterine dehiscence or thinning of the scar at the site of the earlier cornual incision and repair. None of the patients experienced uterine rupture. Conclusion Interstitial pregnancy can be selectively treated by laparoscopic cornuotomy with local methotrexate injection, if managed carefully.

Background We have determined the recommended dose of weekly cetuximab (cet) plus SOX (oxaliplatin 130mg/m2 on day 1 and S-1 40 mg/m2 twice daily on days 1-14, every 3 weeks) regimen and showed that it was an effective and tolerable 1st-line regimen in the JACCRO CC-06 trial for KRAS exon2 wild-type (wt) and EGFR-expressing mCRC [J Clin Oncol 2014 32:3_suppl, 571]. However, the follow-up time was short; therefore, the detailed data was missing. Methods The primary endpoint of phase II part was objective response rate (ORR). Progression-free survival (PFS), overall survival (OS), early tumor shrinkage (ETS) at 8 weeks after treatment, depth of response (DpR), and safety were secondary endpoints. The tumor shrinkage was evaluated every 8 weeks by the external review board. Non-preplanned updated analysis was performed in January 2019. Results 59 pts (median 64-y old, 51% male, 85% PS0, 19% right-side) were enrolled into the phase II part. The median cycle of SOX was 6 (range 1-20) with relative dose intensity (RDI) of 80% for oxaliplatin and 83% for S-1. Cet was administered at median times of 17 (range 1-57), the RDI was 95%. Fifty-two (88%) pts discontinued the protocol therapy due to progression (46%) or toxicity (38%). The ORR was 62.7% (95%CI 50.4-75.1), median PFS was 9.1 months (95%CI 6.2-11.6), and median OS was 32.0 months (95%CI 21.5-44.2). In sub-analyses, pts with ETS had significantly longer PFS and OS compared to those without ETS (9.4 vs 3.8 months and 37.0 vs 22.5 months, respectively). Moreover, ETS rate and DpR were comparable between primary tumor sides (left vs. right, 70% vs 80%, 48% vs 46%, respectively). Exploratory analysis by RAS status indicated that ORR was 76.3%, median PFS was 9.4 months, and median OS was 32.0 months in RAS wt population (n = 38). Conclusions SOX plus cet regimen is active with good tumor shrinkage for KRAS wt mCRC regardless of primary tumor sidedness. Pts who experience ETS may potentially have a favorable prognosis.

1083 Background: Anthracycline regimens and taxane have been first line chemotherapeutic options for HER2 negative metastatic breast cancer. In a previous phase III trial (SELECT BC), non-inferiority of S-1 was demonstrated in terms of overall survival (OS). The SELECT BC-CONFIRM study was designed to confirm the results of the SELECT BC study and to combine the two randomized studies. Methods: Patients (n = 618) in the first trial were randomly assigned (1:1) to the S-1 group or the taxane group. Patients (n = 230) in the second trial (SELECT BC-CONFIRM) were randomly assigned to the anthracycline group or the S-1 group. Treatment continued until tumor progression, unacceptable toxic effects, or completion of six courses in the standard regimen group and four courses in the S-1 group. The primary endpoint was OS and secondary endpoints were progression-free survival (PFS), time to treatment failure, adverse events, HRQOL and cost-effectiveness. A pooled analysis of the two studies was predefined to confirm the results of the SELECT BC study. Results: 1. The HR for the anthracycline group was 1.09 [95%CI 0.80-1.48] in SELECT BC-CONFIRM, and the estimated predictive posterior probability that the HR does not exceed the threshold 1.333 was 90.27%. 2. Median OS was 32.7 months (S-1 group) and 36.3 months (standard treatment group). S-1 was not inferior to standard treatment in terms of OS (p non-inferiority = 0.0062). Median PFS was 11.2 months (S-1 group) and 11.2 months (standard treatment group). 3. Treatment was discontinued due to adverse events (i.e., neutropenia, febrile neutropenia, fatigue and edema) in 5.7% in the S-1 group and 6.6% in the standard treatment group 4. The EORTC QLQ-C30 questionnaire (global health status) revealed that there was no difference between the S-1 and anthracycline groups (p = 0.257), but there was a significant difference between the S-1 and taxane groups (p = 0.0039). Conclusions: S-1 is not inferior to taxane or anthracycline with respect to OS as a first-line treatment for MBC. S-1 should be considered a new option as a first-line chemotherapy for HER2-negative metastatic breast cancer patients. Clinical trial information: UMIN000005449.

TPS3621 Background: A randomized phase II trial, DEEPER (JACCRO CC-13) [NCT02515734], is on-going to evaluate FOLFOXIRI plus cetuximab (cet) vs. FOLFOXIRI plus bevacizumab (bev) in terms of depth of response as primary endpoint in 360 mCRC patients (pts) with RAS wild-type tumors, PS0-1, and no previous chemotherapy. This is a head-to-head comparative trial of 2 key monoclonal antibodies in mCRC treatment; therefore, it would be of interest to perform the biomarker study for developing novel predictors of cet or bev. The clinical utility of circulating tumor DNA (ctDNA) analysis has been largely validated for monitoring during treatment and companion diagnostics after chemotherapy. However, there are few published results regarding ctRNA in cancer treatment. Use of ctRNA from liquid biopsies would enhance tumor profiling through the trending of actionable biomarkers not found in ctDNA, and allow for patient monitoring by measuring dynamic changes in levels of gene expressions. Methods: This study will enroll pts with willing to undergo biopsies of both tissue and blood among participants of the DEEPER trial. The estimated number is 250. The main purpose is to find novel predictors for efficacy of cet or bev in mCRC using liquid biopsies, which are performed to obtain ctDNA and ctRNA at 6 time points: pre-treatment, 8 weeks after treatment start, beginning of maintenance phase in FOLFOXIRI-regimen, progression, before and 8 weeks after 2nd-line treatment. The tissue samples collected before chemotherapy will be used for analyzing intra-tumoral genetic alterations. Associations between analytes in blood/tissue and the clinical outcomes of each treatment (with cet or bev) will be assessed using Fisher’s exact test, Kaplan-Meier curves, and log-rank tests in univariate analyses. We will evaluate on whether transcriptomic analysis in ctRNA could predict treatment efficacy more accurately compared to genomic analysis in ctDNA, and verify the clinical utility of ctRNA testing in mCRC treatment. Accrual will continue until the DEEPER trial is completed. Clinical trial information: UMIN000018412.

Background Pulmonary hypertension (PH) is a life-threatening complication in patients with chronic kidney disease on hemodialysis (CKD-HD). Objectives To determine whether subcutaneous infusion of treprostinil was effective and tolerable CKD-PH. Methods and results A 57-year-old man was admitted to our hospital due to presyncope and dyspnea during exercise with a history of CKD-HD. Cardiac catheterization revealed high pulmonary arterial pressure (PAP) of 53/24/32 mmHg and pulmonary vascular resistance (PVR) of 11.2 w.u. Upfront combination therapy with bosentan and sildenafil was started. However, 6-month therapy did not attenuate his symptoms, probably due to the high PAP and PVR (60/19/30 mmHg and 5.9 w.u.). We added subcutaneous treprostinil. Surprisingly, 9-month treprostinil (50 ng/kg/min) normalized hemodynamics (PAP: 25/4/13 mmHg and PVR: 1.9 w.u.). His symptoms during excise disappeared without any adverse effects. Conclusion This is the first report that subcutaneous treprostinil was very effective and tolerable in a PH patient with CKD-HD.

Sensory loss or paresthesia due to division of the intercostobrachial nerve (ICBN) is a complication of axillary lymph node dissection (ALND). Preservation of the ICBN may be of value, but few prospective studies have shown an impact of preservation on sensory changes or health-related quality of life (HRQOL) after breast cancer surgery. This prospective study was performed to evaluate the association between ICBN preservation and sensory change and HRQOL at 1 (baseline), 6, 12, and 24 months after breast cancer surgery in 140 patients. The sensory examination included dysesthesia, paresthesia, and abnormal touch and pain sensation in the upper arm. Division of the ICBN did not influence the frequency or severity of subjective dysesthesia and paresthesia. There was no marked difference in touch or pain sensation at baseline between patients with a preserved (group P) and divided (group D) ICBN. In group P, the percentage of patients aware of a sensory deficit or loss decreased with time, and that of patients aware of a hypersensitive sensation increased. These changes did not occur in group D, leading to a significant difference between the groups at 24 months. The main difference between the groups was the area with reduced touch or pain sensation. This area decreased with time in group P, but not in group D. ICBN preservation or division did not influence HRQOL. ICBN preservation in ALND has a benefit of a reduced area with long-term axillary hypoesthesia, but has no influence on improvement of pain and HRQOL.