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Aims: To evaluate the perceptions of parents on general health, oral health, and dental care for children with Down syndrome (DS), and to investigate factors related to parents' perceptions of oral health., Methods and Results: An online questionnaire survey was conducted of parents of children with DS. Forty-three percent and 81% of the parents rated their child's oral health and general health as good, respectively. Parent-rated oral health was strongly associated with general health, followed by the parents' satisfaction with their child's dentist, halitosis, difficulty in dental examination, and the number of times they helped their child with toothbrushing. Seventy-seven percent of the parents were satisfied or rather satisfied with their child's dentist. The parents expected the dentist to reassure their child and to be specialized in the treatment of persons with disabilities. Seventy-three percent of the parents brushed their child's teeth at least once a day, and 92% brushed their own teeth at least twice a day. The number of times the parents brushed their own teeth was strongly associated with the frequency of brushing their child's teeth., Conclusion: General health, a trusting relationship with the dentist, and parental perceptions of oral hygiene affect parent-rated oral health of children with DS., (© 2024 Special Care Dentistry Association and Wiley Periodicals LLC.)

Porphyromonas gingivalis is the most pathogenic periodontal bacterium in the world. Recently, P. gingivalis has been considered responsible for dysbiosis during the development of periodontitis. This study aimed to evaluate a novel immunochromatographic device using monoclonal antibodies against P. gingivalis in subgingival plaques. A total of 72 patients with chronic periodontitis and 53 periodontally healthy volunteers underwent clinical and microbiological examinations. Subgingival plaque samples were analyzed for the presence of P. gingivalis and compared using real-time polymerase chain reaction (PCR). In the periodontitis group, a significant positive correlation was observed between the test device scores and the real-time PCR results. The specificity, positive predictive value, negative predictive value, and accuracy of the test device for P. gingivalis , as determined by real-time PCR, were 98%, 94%, 89%, and 90%, respectively. There were significant differences in bacterial counts by real-time PCR among the groups with different ranges of device scores. Additionally, there was a significant positive correlation between the device scores for P. gingivalis and periodontal parameters. These results suggest that this novel immunochromatographic device can be effectively used for rapid detection and semi-quantification of P. gingivalis in subgingival plaques.

Background: This study examined temporal shifts in adjuvant therapy patterns in Japanese patients with resectable gastric cancer (GC) and treatment patterns of first-line and subsequent therapy among those with recurrent disease., Methods: This retrospective analysis of hospital-based administrative claims data (April 1, 2008 to March 31, 2022) included adults (aged ≥ 20 years) with GC who started adjuvant therapy on or after October 1, 2008 (adjuvant cohort) and patients in the adjuvant cohort with disease recurrence (recurrent cohort), further defined by the time to recurrence (≤ 180 or > 180 days after adjuvant therapy)., Results: In the adjuvant cohort (n = 17,062), the most common regimen during October 2008-May 2016 was tegafur/gimeracil/oteracil potassium (S-1; 95.7%). As new standard adjuvant regimen options were established, adjuvant S-1 use decreased to 65.0% and fluoropyrimidine plus oxaliplatin or docetaxel plus S-1 use increased to 15.0% and 20.0%, respectively, in September 2019-March 2022. In the recurrent cohort with no history of trastuzumab/trastuzumab deruxtecan treatment (n = 1257), the most common first-line regimens were paclitaxel plus ramucirumab (34.0%), capecitabine plus oxaliplatin (CapeOX; 17.0%), and nab-paclitaxel plus ramucirumab (10.1%) in patients with early recurrence, and S-1 plus oxaliplatin (26.3%), S-1 plus cisplatin (15.3%), CapeOX (14.0%), S-1 (13.2%), and paclitaxel plus ramucirumab (10.8%) in those with late recurrence., Conclusions: This study demonstrated temporal shifts in adjuvant treatment patterns that followed the establishment of novel regimens, and confirmed that post-recurrent treatment patterns were consistent with the Japanese Gastric Cancer Association guideline recommendations., (© 2024. The Author(s).)

Older adults often experience poor oral functions, hindering rehabilitation post-acute disease treatment. However, characteristics of hospitalized patients who would benefit from professional oral-health management (POHM) have not been clarified. Therefore, we aimed to elucidate systemic and oral characteristics of patients requiring POHM during hospitalization in a convalescent hospital. This study included 312 participants admitted to the rehabilitation department of a convalescent hospital for a year. The patients were categorized according to POHM requirements (no-POHM group: 137 patients; POHM group: 175 patients) by discharge. Age, sex, primary disease at admission, Glasgow coma scale (GCS), Functional Independence Measurement (FIM), Mini nutritional assessment-short form (MNA-SF), Functional oral intake scale (FOIS), number of present and functional teeth, Oral Health Assessment Tool (OHAT) scores, and POHM details provided during patient hospitalization were compared. Binomial logistic-regression analysis identified patients requiring POHM as those who had suffered a stroke and had a low number of present teeth, poor overall oral health, low food form, and low motor skills at admission. A high percentage of POHM interventions comprised oral-hygiene care and denture treatment. In summary, patients whose oral health has deteriorated and those experiencing oral-intake difficulties upon admission to a convalescent hospital may require oral-health management.

Purpose Postoperative infections pose an important problem for patients with cardiac disease. Moreover, oral health status is associated with the risk of longer hospital stays. Therefore, the oral health status of patients was assessed before open-heart surgery. This study aimed to determine the relationship between oral health status and postoperative status. Methods The study included 25 patients who underwent open-heart surgery at our university hospital in 2020. Upon admission, dentists conducted an oral examination and assessed the oral health status of the patients, also using the Japanese version of the Oral Health Assessment Tool (OHAT-J), Revised Oral Assessment Guide (ROAG), oral moisture level, oral bacteria, and other relevant factors. The study investigated the association with postoperative status. Findings Significant postoperative infections were found in patients aged ≥70 years, with an OHAT-J score of ≥5, OHAT-J lip score of ≥1, Streptococcus γ count of 1.0 × 10^6 or higher (CFU/mL), and increased Streptococcus γ before and after surgery. The duration of hospitalization correlated with the OHAT-J, OHAT-J gum and tissue, and ROAG scores. The duration of intensive care unit (ICU) stays correlated with the OHAT-J score. Conclusions The study demonstrates that OHAT-J scores are linked with predicting not just postoperative infection but also the length of hospitalization and ICU stay. As OHAT-J scores do not necessitate specialized dental instruments, they are straightforward and beneficial for healthcare professionals outside of dentistry., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The Ethics Review Committee for Research in Human Subjects, Showa University Graduate School of Medicine issued approval 3033. The study protocol was performed in accordance with the Declaration of Helsinki. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: This study was funded by the Grants-in-Aid for Scientific Research (KAKENHI) - Scientific Research 18K17294. The authors declare no conflicts of interest associated with this manuscript. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Ono et al.)

Background: The aim of this study was to explore the clinical utility of serum HER2 extracellular domain (sHER2 ECD) using data from a clinical trial evaluating trastuzumab combined S-1 plus oxaliplatin (SOX) in HER2 positive gastric cancer., Methods: sHER2 ECD were prospectively measured at baseline and subsequent treatment courses. Based on each quantile point of baseline sHER2 ECD levels and its early changes, patients were divided into two groups and compared clinical outcomes., Results: 43 patients were enrolled, and 17 patients (39.5%) were positive for baseline sHER2 ECD. Higher baseline sHER2 ECD levels tended to have lower hazard ratios (HRs). When divided into two groups by baseline sHER2 ECD of 19.1 ng/ml, median progression-free survival (PFS) and overall survival (OS) was longer in the higher group (mPFS: 16.8 vs 8.7 months, p = 0.359. mOS: 35.5 vs 20.6 months, p = 0.270), respectively. After initiation of treatment, sHER2 ECD significantly decreased up until the third cycle. Higher reduction rates of sHER2 ECD within 3 cycles also tended to have lower HRs. When divided into two groups by reduction rate of 42.5%, mPFS and mOS was longer in the higher reduced group (mPFS: 17.2 vs 8.7 months, p = 0.095. mOS: 65.0 vs 17.8 months, p = 0.047), respectively. Furthermore, higher reduction rates could surrogate higher objective response rates (ORR) (ORR: 90% vs 63.2% for 29.5%, p = 0.065. 100% vs 70% for 42.5%, p = 0.085), respectively., Conclusions: Baseline sHER2 ECD levels and its early decline may be useful biomarkers for SOX plus trastuzumab efficacy in HER2 positive gastric cancer., (© 2024. The Author(s).)

Porphyromonas gingivalis, a Gram-negative anaerobic bacillus, is the primary pathogen in periodontitis. Herein, we cultivated strains of oral bacteria, including P. gingivalis and the oral commensal bacteria Actinomyces viscosus and Streptococcus mutans, and recorded the infrared absorption spectra of the gases released by the cultured bacteria at a resolution of 0.5 cm -1 within the wavenumber range of 500-7500 cm -1 . From these spectra, we identified the infrared wavenumbers associated with characteristic absorptions in the gases released by P. gingivalis using a decision tree-based machine learning algorithm. Finally, we compared the obtained absorbance spectra of ammonia (NH 3 ) and carbon monoxide (CO) using the HITRAN database. We observed peaks at similar positions in the P. gingivalis gases, NH 3 , and CO spectra. Our results suggest that P. gingivalis releases higher amounts of NH 3 and CO than A. viscosus and S. mutans. Thus, combining Fourier transform infrared spectroscopy with machine learning enabled us to extract the specific wavenumber range that differentiates P. gingivalis from a vast dataset of peak intensity ratios. Our method distinguishes the gases from P. gingivalis from those of other oral bacteria and provides an effective strategy for identifying P. gingivalis in oral bacteria. Our proposed methodology could be valuable in clinical settings as a simple, noninvasive pathogen diagnosis technique., (© 2024. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)

Background: Trifluridine/tipiracil (FTD/TPI) plus bevacizumab has shown clinical benefit for metastatic colorectal cancer (mCRC) refractory to standard therapy. However, few data have been available for patients with pretreated mCRC who are intolerant of intensive therapy (vulnerable)., Methods: We performed a multicenter retrospective study (WJOG14520G; TWILIGHT) of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC. Eligibility criteria included previous chemotherapy (although patients treated with all key cytotoxic agents, a fluoropyrimidine, oxaliplatin, and irinotecan, were excluded) and intolerance of full-dose combination therapy with oxaliplatin or irinotecan at the start of FTD/TPI plus bevacizumab., Results: The median age of 93 evaluable patients was 79 years (range, 21-90). Intolerance of intensive therapy was attributable to an older age in 60 (65%) patients, serious concomitant disease in 24 (26%) patients, and a poor performance status in 19 (20%) patients. FTD/TPI plus bevacizumab was administered as second-line treatment in 74 (80%) patients and as third- or fourth-line treatment in 19 (20%) patients. The objective response rate was 4.9% (95% confidence interval [CI], 1.4%-12.2%), and the disease control rate was 67.9% (95% CI, 56.6%-77.8%). With a median follow-up time of 21.6 months, median overall survival and progression-free survival were 18.6 months (95% CI, 12.1-23.2) and 6.3 months (95% CI, 5.0-8.3), respectively. Neutropenia of grade ≥3 developed in 50 (54%) patients, whereas 2 (2%) patients experienced febrile neutropenia, and no treatment-related death was observed., Conclusion: Our data show the potential efficacy and acceptable safety profile of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Non-inferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) to irinotecan/fluoropyrimidine plus BEV in metastatic colorectal cancer was investigated in the phase III TRUSTY study, and we conducted a phase II study of FOLFIRI (5-FU+leucovorin+irinotecan) plus zib-aflibercept (AFL) after FTD/TPI plus BEV. However, the TRUSTY study failed during the recruitment of our patients., Objective: We present the findings of a phase II study on the efficacy of FOLFIRI plus zib-aflibercept (AFL) after FTD/TPI plus BEV, including clinical results with plasma biomarker analyses., Methods: This was a multicenter, single-arm, phase II study in patients with metastatic colorectal cancer refractory or intolerant to oxaliplatin, fluoropyrimidine, BEV, and FTD/TPI. The primary endpoint was progression-free survival. Fifteen plasma angiogenesis-associated biomarkers were analyzed using a Luminex ® multiplex assay U-kit., Results: Between January 2020 and May 2022, 26 patients (median age, 68 years) from 15 sites were enrolled. The median progression-free survival was 4.9 months (85% confidence interval, 3.4 month-not estimated). The overall response and disease control rates were 8% and 62%, respectively. The median levels of vascular endothelial growth factor-A and placental growth factor, both targets of AFL, were below the measurable limit of 30 pg/mL and 16 pg/mL, respectively. Patients were divided into two groups at the median levels of baseline biomarkers. The progression-free survival did not differ between high and low expressers of placental growth factor (p = 0.7), while it tended to be shorter in those with high levels of osteopontin (p = 0.05), angiopoietin-2 (p = 0.07), and tissue inhibitor of matrix metalloproteinases-1 (p = 0.1)., Conclusions: This study did not meet the primary endpoint. Hence, FOLFIRI plus AFL should not be used after FTD/TPI plus BEV for metastatic colorectal cancer. Further studies are needed to determine factors not targeted by AFL that may affect the efficacy of the treatment., Clinical Trial Registration: jRCTs041190100., (© 2024. The Author(s).)

Background: Oral health management has become increasingly important for acute inpatients. Older patients often require extended periods of medical care, and oral health management is necessary in the convalescent period following the acute period. During the convalescent period, oral health management remains unclear as convalescent hospitals have limited dental resources, and effective dental care must be provided if the objective of hospitalization is to improve life functions. This study aimed to clarify the relationship between daily functioning and oral health status at the time of admission to a convalescent hospital to aid in improving daily functioning in the convalescent period., Methods: We included patients admitted to the rehabilitation department of a specific convalescent hospital from January to December 2021. A total of 375 patients were included in the study, with complete data records. At admission, we gathered information from the medical records, including the patient's age, sex, primary disease, Charlson Comorbidity Index, Mini Nutritional Assessment Short-Form (MNA-SF), Functional Oral Intake Scale (FOIS), Functional Independence Measure (FIM), number of teeth, and Oral Health Assessment Tool (OHAT). Statistical analysis was conducted using SPSS Ver. 27, with a significance level of 5%., Results: The mean age of the 375 participants (189 men and 186 women) was 75.0 ± 12.1 years (range, 42-97 years), and over 80% were > 65 years. About 30% of major diseases could be attributed to strokes and fractures, followed by spinal cord and spine diseases. In non-stroke patients, multiple regression analysis using FIM motor, FIM cognitive, and FIM and OHAT total scores as objective variables showed that higher total scores of MNA-SF, FOIS, and lower modified Rankin Scale and OHAT were significantly associated with better FIMs. Lower OHAT scores were significantly associated with lower FOIS and MNA-SF scores, male sex, having fewer teeth, and poor dietary patterns., Conclusions: The convalescent period is an opportune time to provide intensive dental care due to the generally stable condition and extended hospital stay. Our results suggest that oral health management, such as dysphagia rehabilitation and denture treatment, is important for maintaining and improving independence, a key objective of convalescent rehabilitation, and malnutrition improvement., (© 2023. The Author(s).)

Importance: Substantial heterogeneity exists in treatment recommendations across molecular tumor boards (MTBs), especially for biomarkers with low evidence levels; therefore, the learning program is essential., Objective: To determine whether a learning program sharing treatment recommendations for biomarkers with low evidence levels contributes to the standardization of MTBs and to investigate the efficacy of an artificial intelligence (AI)-based annotation system., Design, Setting, and Participants: This prospective quality improvement study used 50 simulated cases to assess concordance of treatment recommendations between a central committee and participants. Forty-seven participants applied from April 7 to May 13, 2021. Fifty simulated cases were randomly divided into prelearning and postlearning evaluation groups to assess similar concordance based on previous investigations. Participants included MTBs at hub hospitals, treating physicians at core hospitals, and AI systems. Each participant made treatment recommendations for each prelearning case from registration to June 30, 2021; participated in the learning program on July 18, 2021; and made treatment recommendations for each postlearning case from August 3 to September 30, 2021. Data were analyzed from September 2 to December 10, 2021., Exposures: The learning program shared the methodology of making appropriate treatment recommendations, especially for biomarkers with low evidence levels., Main Outcomes and Measures: The primary end point was the proportion of MTBs that met prespecified accreditation criteria for postlearning evaluations (approximately 90% concordance with high evidence levels and approximately 40% with low evidence levels). Key secondary end points were chronological enhancements in the concordance of treatment recommendations on postlearning evaluations from prelearning evaluations. Concordance of treatment recommendations by an AI system was an exploratory end point., Results: Of the 47 participants who applied, 42 were eligible. The accreditation rate of the MTBs was 55.6% (95% CI, 35.3%-74.5%; P < .001). Concordance in MTBs increased from 58.7% (95% CI, 52.8%-64.4%) to 67.9% (95% CI, 61.0%-74.1%) (odds ratio, 1.40 [95% CI, 1.06-1.86]; P = .02). In postlearning evaluations, the concordance of treatment recommendations by the AI system was significantly higher than that of MTBs (88.0% [95% CI, 68.7%-96.1%]; P = .03)., Conclusions and Relevance: The findings of this quality improvement study suggest that use of a learning program improved the concordance of treatment recommendations provided by MTBs to central ones. Treatment recommendations made by an AI system showed higher concordance than that for MTBs, indicating the potential clinical utility of the AI system.

Many older patients admitted to convalescent hospitals present with impaired oral function, which is an important function of daily life. This study aimed to investigate the actual status of the oral healthcare needs of inpatients in a convalescent hospital and to clarify the relationship between the level of independence at admission and the oral function. The participants were 147 patients (94 males, 53 females, mean age: 74.6 ± 13.1 years) who received dental visits during their stay at a convalescent hospital. Information regarding general and oral health was extracted from medical records. Most patients were found to have low Functional Independence Measure motor scores, and approximately 70% had some form of oral intake, but approximately 80% had nutritional problems. The mean number of present and functional teeth were 16.6 and 20.8, respectively, and 65% of patients lost molar occlusal support. Multiple regression analysis showed significant positive correlations of high functional independence measure with age, eating status, nutritional status, and the number of functional teeth. This implied that oral health management is important for patients in a convalescent hospital and that enhancing oral health may be related to improved eating textures and better nutritional status.

Colorectal cancer is the third most common disease and the second most common cause of death around the world. The drug for second-line treatment depends on the drugs used in first-line treatment and the biomarker status. As biomarkers, the RAS gene, BRAF gene, and dMMR/MSI-H, TMB-H, and HER2 statuses have been established in clinical practice, and the corresponding molecularly targeted therapeutic agents are selected based on the biomarker status. Given the frequency of biomarkers, it is assumed that when patients move on to second-line treatment, an angiogenesis inhibitor is selected in many cases. For second-line treatment, three angiogenesis inhibitors, bevacizumab (BEV), ramucirumab (RAM), and aflibercept (AFL), are available, and one of them is combined with cytotoxic agents. These three angiogenesis inhibitors are known to inhibit angiogenesis through different mechanisms of action. Although no useful biomarkers have been established for the selection of angiogenesis inhibitors, previous biomarker studies have suggested that angiogenesis-related factors such as VEGF-A and VEGF-D might be predictors of the therapeutic efficacy of angiogenesis inhibitors. These biomarkers are measured as protein levels in plasma and are considered to be promising biomarkers. We consider that the rationale for selecting among these three angiogenesis inhibitors should be clarified to benefit patients., Competing Interests: Satoshi Otsu has a financial interest in Eli Lilly, ONO PHARMACEUTICAL CO., LTD., DAIICHI SANKYO COMPANY, LIMITED. Shuichi Hironaka has a financial interest in Eli Lilly, CHUGAI PHARMACEUTICAL CO., LTD., ONO PHARMACEUTICAL CO, Sanofi K.K., Bristol Myers Squibb, MSD KK, Yakult Honsha Co., Ltd., DAIICHI SANKYO COMPANY, LIMITED, Kyowa Kirin Co., Ltd.

Purpose: Pembrolizumab demonstrated antitumor activity in programmed death ligand 1 positive (combined positive score (CPS) ≥ 1) gastric/gastroesophageal junction cancer in KEYNOTE-059 (third line or beyond), KEYNOTE-061 (second line), and KEYNOTE-062 (first line). We characterized efficacy and safety of pembrolizumab monotherapy in Japanese patients across several lines of therapy in these studies., Methods: This analysis was conducted in 34 patients from KEYNOTE-059 cohort 1 (all pembrolizumab), including 13 patients with CPS ≥ 1, 65 patients with CPS ≥ 1 from KEYNOTE-061 (pembrolizumab, n = 27; chemotherapy, n = 38), and 70 patients with CPS ≥ 1 from KEYNOTE-062 (pembrolizumab, n = 38; chemotherapy, n = 32). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were evaluated., Results: In KEYNOTE-059, ORR with pembrolizumab was 9%, median PFS was 2 months, and median OS was 10 months. In KEYNOTE-061, median OS was 12 months with pembrolizumab versus 10 months with chemotherapy (hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.39-1.15). Median PFS (pembrolizumab vs. chemotherapy) was 2 months versus 4 months (HR, 1.21; 95% CI, 0.69-2.13); ORR was 7% versus 18%. In KEYNOTE-062, median OS was 20 months with pembrolizumab versus 18 months with chemotherapy (HR, 0.76; 95% CI, 0.43-1.33). Median PFS (pembrolizumab vs. chemotherapy) was 6 months versus 7 months (HR, 1.03; 95% CI, 0.61-1.74); ORR was 29% versus 34%., Conclusions: The current analysis provides valuable information that anti-PD-1 therapies are worthy of further assessment for gastric cancer., Trial Registration: ClinicalTrials.gov: NCT02335411 (KEYNOTE-059), NCT02370498 (KEYNOTE-061), and NCT02494583 (KEYNOTE-062)., (© 2023. Merck&Co., Inc., Rahway NJ, USA and its affiliates and the Author(s).)

Background: Trifluridine/tipiracil (FTD/TPI) prolongs survival in the third- or later-line treatment for advanced gastric cancer (GC), esophagogastric junction (EGJ) adenocarcinoma, and colorectal cancer. While single-arm phase II trials showed promising outcomes of FTD/TPI plus ramucirumab (RAM) as third- or later-line treatments for advanced GC or EGJ cancer, there have been no clinical trials to directly compare FTD/TPI plus RAM with FTD/TPI monotherapy. Therefore, we have started a randomised phase II trial to evaluate the efficacy and safety of FTD/TPI plus RAM compared with FTD/TPI monotherapy as third- or later-line treatments in patients with advanced GC and EGJ adenocarcinoma., Methods: This RETREVE trial (WJOG15822G) is a prospective, open-label, randomised, multicentre phase II trial comparing FTD/TPI plus RAM versus FTD/TPI monotherapy in a third- or later-line setting. Eligibility criteria include age of > 20 years; performance status of 0 or 1; unresectable or recurrent gastric or EGJ adenocarcinoma; confirmed HER2 status; refractory or intolerant to fluoropyrimidine, taxane or irinotecan; refractory to RAM (not intolerant); and at least a measurable lesion per RECIST 1.1. FTD/TPI (35 mg/m 2 twice daily, evening of day 1 to morning of day 6 and evening of day 8 to morning of day 13) was administered orally every 4 weeks, and RAM (8 mg/kg) was administered intravenously every 2 weeks. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival, objective response rate, disease control rate, and safety. The expected hazard ratio of PFS is set as 0.7, assuming 4-month PFS rate of 27% in FTD/TPI monotherapy and 40% in FTD/TPI plus RAM. The number of subjects was 110, with a one-sided alpha error of 0.10 and power of 0.70., Discussion: This study will clarify the additional effect of RAM continuation beyond disease progression on FTD/TPI in the third- or later-line setting for patients with advanced GC or EGJ cancer., Trial Registration: jRCTs041220120., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Chemotherapy plus antiangiogenic agents, including bevacizumab, ramucirumab and aflibercept, is a standard second-line treatment for patients with metastatic colorectal cancer, but which specific agents should be selected is ambiguous due to a lack of clear evidence from prospective studies. Previous reports have suggested ramucirumab and aflibercept could be more effective than bevacizumab in patients with high VEGF-D and high VEGF-A, respectively. JCOG2004 is a three-arm, randomized, phase II study to identify predictive biomarkers for these agents in patients who have failed first-line treatment. The study will enroll 345 patients from 52 institutions for 2 years, with progression-free survival in high VEGF-D (bevacizumab vs ramucirumab) and high VEGF-A (bevacizumab vs aflibercept) serving as the primary end point. Clinical Trial Registration: jRCTs031220058 (www.jrct.niph.go.jp).

Background: We herein investigated the association between early tumor shrinkage (ETS) and depth of response (DpR) and clinical outcomes in patients with metastatic esophageal cancer treated with 2-weekly docetaxel combined with cisplatin plus fluorouracil (bDCF) using data from the JCOG0807, a phase I/II trial of bDCF as first-line chemotherapy for metastatic esophageal cancer., Methods: ETS was defined as a percent decrease in the sum of the target lesions' longest diameter after 8 weeks, whereas DpR was defined as a percentage of the maximal tumor shrinkage during the treatment course. Multivariable analyses were conducted to identify significant prognostic variables in progression-free survival (PFS) and overall survival (OS): one for ETS and covariates, and another for DpR and covariates., Results: Among 53 patients, 35 patients with ETS ≥ 20% (66.0%) had longer PFS (7.5 vs. 3.4 months, hazard ratio [HR]: 0.26, 95% confidence interval [95% CI] 0.14-0.49), OS (13.8 vs. 6.1 months, HR 0.20, 95% CI 0.11-0.39), and PPS (6.4 vs. 2.8 months, HR 0.38, 95% CI 0.20-0.72) than those with ETS < 20%. In addition, 37 patients with DpR ≥ 30% (69.8%) had longer PFS (7.5 vs. 2.9 months, HR 0.17, 95% CI 0.08-0.34), OS (13.8 vs. 6.0 months, HR 0.14, 95% CI 0.07-0.27), and PPS (6.8 vs. 2.8 months, HR 0.30, 95% CI 0.15-0.58) than those with DpR < 30%. Multivariable analyses revealed that each ETS and DpR was an independent factor of longer PFS and OS., Conclusions: ETS and DpR might be associated with clinical outcomes in patients with metastatic esophageal cancer treated with bDCF., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Competing Interests: Conflict of Interest: The authors declare that there are no conflicts of interest.

Background: Patients with cancer of unknown primary site are divided into two distinct groups, favourable and unfavourable subsets. For the unfavourable subset, empiric treatment or site-specific treatment is recommended, but limited knowledge exists about the efficacy of site-specific treatment compared with empiric treatment in clinical practice., Methods: In this multicentre retrospective study, we reviewed the medical records of patients with cancer of unknown primary site treated with chemotherapy (or chemoradiotherapy) as first-line treatment from eight institutions during 2006-18. We investigated the workup modality and categorized the patients into favourable and unfavourable subsets, which were further divided into site-specific and empiric treatment groups. Site-specific treatment is defined as a standard chemotherapy for an estimated primary site. We examined the efficacy in the favourable and unfavourable subsets and performed multivariable analysis for estimating the overall survival in the unfavourable subset., Results: Of 177 patients with cancer of unknown primary site, 33 and 144 were categorized into favourable and unfavourable subsets, respectively. In the unfavourable subset, 84 patients (58.3%) received empiric therapy, and 60 patients (41.7%) received site-specific treatment. Median overall survival was 10.0 and 10.1 months in site-specific and empiric treatment groups, respectively, with no significant difference (hazard ratio 1.01, 95% confidence interval 0.70-1.45, P = 0.95). Multivariable analysis revealed performance status, number of metastatic sites and hypoalbuminaemia as independent prognostic factors for overall survival in the unfavourable subset., Conclusions: Overall survival in site-specific and empiric treatment groups was similar in the unfavourable cancer of unknown primary site subset in this study. Further research is needed to prolong overall survival in patients in the unfavourable cancer of unknown primary site subset., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The real-world survival benefit of FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus anti-VEGF therapy (Triplet) over doublet chemotherapy (Doublet) remains controversial in patients with BRAF V600E mutant metastatic colorectal cancer (mCRC)., Patients and Methods: WJOG13219G was a multicenter, retrospective, registry-based study of patients with BRAF V600E mutant mCRC who received first-line triplet or doublet chemotherapy from January 2014 to December 2019 in Japan. Inverse probability of treatment weighting (IPTW) was used to adjust for patient background., Results: The analysis included 79 and 91 patients in the Triplet and Doublet groups, respectively. The Triplet group was significantly younger and had better performance status. No statistical difference was noted in progression-free survival (PFS; HR, 0.82; 95% CI, 0.60-1.13; P = .22) and overall survival (OS; HR, 0.88; 95% CI, 0.62-1.25; P = .48) between both groups. IPTW analysis also showed no difference between the 2 groups in PFS (HR, 0.86; 95% CI, 0.69-1.08; P = .20) and OS (HR, 0.93; 95% CI, 0.73-1.20; P = .59). The Triplet and Doublet groups had an objective response rate of 53% and 41%, respectively (P = .10). At least one grade 3 or 4 adverse event was seen in 51 (65%) and 43 (47%) patients in the Triplet and Doublet groups, respectively, with the incidence of neutropenia being significantly higher in the former., Conclusion: Triplet therapy had no survival benefit versus doublet therapy in the overall and IPTW cohorts or specific subgroups for real-world patients with BRAF V600E mutant mCRC., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this prospective study was to assess the ability of plasma vascular endothelial growth factor-A short isoforms (pVEGF-Asi) to predict bevacizumab (BV) efficacy and to explore other circulating biomarkers in metastatic colorectal cancer (mCRC) patients treated with modified FOLFOX6/XELOX plus BV (mFOLFOX6/XELOX + BV)., Patients and Methods: Pre-treatment plasma samples were collected from 100 mCRC patients receiving first-line chemotherapy with mFOLFOX6/XELOX + BV. The plasma levels of 11 angiogenesis-associated molecules, including pVEGF-Asi and 22 cancer-associated gene mutations in circulating tumor DNA, were analyzed. For the primary endpoint, we assumed that the hazard ratio (HR) for progression-free survival (PFS) calculated using a Cox proportional hazards model was <1.15, comparing patients with a high versus those with a low pVEGF-Asi level divided according to the median pVEGF-Asi value., Results: The median value of pVEGF-Asi was 37 (range 6.5-262) pg/ml. The HR for PFS between the high and low pVEGF-Asi patient groups was 1.3 [95% confidence interval (CI) 0.8-2.1; log rank, P = 0.25], which was larger than the predefined threshold of 1.15. The multivariate analysis demonstrated that PFS was significantly associated with plasma intercellular adhesion molecule-1 (pICAM-1) (≥190.0 versus <190.0 ng/ml; HR 2.1; 95% CI 1.3-3.5), RAS (mutant versus wild; HR 2.5; 95% CI 1.5-4.3), and FBXW7 (mutant versus wild; HR 2.8; 95% CI 1.2-6.8), whereas overall survival was significantly associated with pICAM-1 (HR 2.0; 95% CI 1.1-3.7) and RAS (HR 2.6; 95% CI 1.5-4.6)., Conclusions: The addition of BV was unable to compensate for the poor PFS associated with a high pVEGF-Asi level, suggesting that pVEGF-Asi is unlikely to be a good predictive biomarker of the efficacy of mFOLFOX6/XELOX + BV therapy. The clinical significance of circulating ICAM-1, mutant RAS, and mutant FBXW7 levels should be studied further., (Copyright © 2022. Published by Elsevier Ltd.)

Despite recent advances in sequencing technology and large-scale drug screenings employing hundreds of cell lines, the predictive accuracy of mutation-based biomarkers is still insufficient as a guide for cancer therapy. Therefore, novel types of diagnostic methods using alternative biomarkers would be highly desirable. We have hypothesized that sensitivity-specific changes in the phosphorylation of signaling molecules could be useful in this respect. Here, with the aim of developing a method for predicting the response of cancers to cisplatin using a combination of specific biomarker(s) and patient-derived tumor organoids (PDOs), we found that cisplatin-sensitive cell lines or PDOs showed enhanced phosphorylation of c-Jun (p-c-Jun) within 24 h after cisplatin treatment. We also compared the responses of 6 PDOs to cisplatin with the therapeutic effect of neoadjuvant chemotherapy (docetaxel/cisplatin/5-fluorouracil) in 6 matched patients. Mechanistically, the c-Jun induction was partly related to TNF signaling induced by cisplatin. Our data suggest that enhanced phosphorylation of c-Jun in response to cisplatin treatment could be a predictive biomarker for the efficacy of cisplatin in selected cancer patients., (© 2022. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.)

Purpose: Definitive chemoradiotherapy (CRT) is the standard treatment for patients with locally advanced esophageal cancer (EC) who refuse surgery as the initial therapy. However, poor survival, a high incidence of late toxicities, and severe complications after salvage surgery remain issues to be resolved. This single-arm multicenter trial (JCOG0909) aimed to confirm the efficacy of CRT modifications, including salvage treatment for reducing CRT-related toxicities and facilitating salvage treatment for improved survival., Methods and Materials: Patients with clinical stage II/III EC (International Union Against Cancer sixth edition, non-T4) were eligible. Chemotherapy comprised cisplatin (75 mg/m 2 on days 1 and 29) and 5-fluorouracil (1000 mg/m 2 /d on days 1-4 and 29-32). Radiation therapy was administered at a total dose of 50.4 Gy. Good responders received 1 to 2 additional cycles of chemotherapy. For residual or recurrent disease, salvage endoscopic resection or salvage surgery was performed based on specific criteria. The primary endpoint was 3-year overall survival (OS). The calculated sample size was 95 patients, with a 1-sided alpha of 5% and a power of 80%. The expected and threshold 3-year OS were 55% and 42%, respectively., Results: Overall, 96 patients were enrolled, and 94 were included in the efficacy analysis. A complete response was achieved in 55 patients (59%). Salvage endoscopic resection and salvage surgery were performed in 5 (5%) and 25 patients (27%), respectively. R0 resection by salvage surgery was achieved in 19 patients (76%). Five patients (20%) showed grade 3 or 4 early operative complications, and 9 patients (9.6%) showed grade 3 late toxicities during the long-term follow-up. The 3-year OS was 74.2% (90% confidence interval, 65.9%-80.8%)., Conclusion: The combination of definitive CRT and salvage treatment has lower CRT-related toxicities and yields good OS, thus making it a promising novel treatment option for patients with locally advanced EC., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The standard treatment for unresectable advanced/recurrent esophageal cancer in Japan is 5-fluorouracil plus platinum-containing drugs as first-line chemotherapy and taxanes as second-line chemotherapy. However, the standard regimen after patients become refractory to these treatments remains to be established. Therefore, we investigated the efficacy of trifluridine/tipiracil (FTD/TPI) in patients with esophageal cancer who are refractory or intolerant to 5-fluorouracil, platinum-containing drugs, and taxanes., Methods: This single-arm phase II trial was conducted in seven hospitals in Japan. Eligible patients were those with unresectable advanced/recurrent esophageal cancer that was refractory or intolerant to 5-fluorouracil, platinum-containing drugs, and taxanes. The primary endpoint was the 3-month progression-free survival rate, and the secondary endpoints were the 6-month progression-free survival rate, progression-free survival, overall survival, response rate, disease control rate, and toxicity., Results: Forty-two patients were enrolled between October 2015 and June 2016. All tumors were squamous cell carcinomas. The progression-free survival rates at 3 and 6 months were 15.4% (90% confidence interval 7.4-26.0%) and 7.7% (90% confidence interval 2.6-16.6%), respectively. The median progression-free survival and median overall survival were 1.3 (95% confidence interval 1.0-1.8) months and 4.5 (95% confidence interval 3.6-5.7) months, respectively. The response rate was 0%, and the disease control rate was 23.8% (95% confidence interval 13.5-38.5%). The major grade 3/4 toxicities were neutropenia (47.6%), leukocytopenia (35.7%), and anemia (21.4%). No treatment-related deaths occurred. Exploratory subgroup analyses showed better progression-free survival in the subgroup without distant metastasis at diagnosis., Conclusions: Trifluridine/tipiracil monotherapy is feasible and shows modest activity in patients with refractory esophageal squamous cell carcinoma., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

We undertook genomic analyses of Japanese patients with stage I esophageal squamous cell carcinoma (ESCC) to investigate the frequency of genomic alterations and the association with survival outcomes. Biomarker analysis was carried out for patients with clinical stage T1bN0M0 ESCC enrolled in JCOG0502 (UMIN000000551). Whole-exome sequencing (WES) was performed using DNA extracted from formalin-fixed, paraffin-embedded tissue of ESCC and normal tissue or blood sample. Single nucleotide variants (SNVs), insertions/deletions (indels), and copy number alterations (CNAs) were identified. We then evaluated the associations between each gene alteration with a frequency of 10% or more and progression-free survival (PFS) using a Cox regression model. We controlled for family-wise errors at 0.05 using the Bonferroni method. Among the 379 patients who were enrolled in JCOG0502, 127 patients were successfully analyzed using WES. The median patient age was 63 years (interquartile range, 57-67 years), and 78.0% of the patients ultimately underwent surgery. The 3-year PFS probability was 76.3%. We detected 20 genes with SNVs, indels, or amplifications with a frequency of 10% or more. Genomic alterations in FGF19 showed the strongest association with PFS with a borderline level of statistical significance of P = .00252 (Bonferroni-adjusted significance level is .0025). Genomic alterations in FGF4, MYEOV, CTTN, and ORAOV1 showed a marginal association with PFS (P < .05). These genomic alterations were all CNAs at chromosome 11q13.3. We have identified new genomic alterations associated with the poor efficacy of ESCC (T1bN0M0). These findings open avenues for the development of new potential treatments for patients with ESCC., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Although cisplatin and 5-chloro-2,4-dihydropyrimidine (dihydropyrimidine dehydrogenase inhibitor contained in S-1) are excreted into the urine, it remains unknown how creatinine clearance (CrCl) affects the safety and efficacy of cisplatin plus S-1 and docetaxel plus cisplatin plus S-1 in patients with advanced gastric cancer., Methods: Among the 741 participants in JCOG1013 comparing cisplatin plus S-1 with docetaxel plus cisplatin plus S-1, 723 with serum creatinine levels ≤1.2 mg/dL were categorized into A1 (CrCl ≥ 80 mL/min), A2 (60 ≤ CrCl <80) and A3 (CrCl < 60) in the cisplatin plus S-1 arm and similarly B1, B2 and B3 in the docetaxel plus cisplatin plus S-1 arm. The initial dose modification by CrCl was pre-specified in the docetaxel plus cisplatin plus S-1 arm but not in the cisplatin plus S-1 arm., Results: The numbers of patients categorized as A1/A2/A3 and B1/B2/B3 were 169/136/57 and 170/138/53, respectively. In the cisplatin plus S-1 arm, a lower CrCl was associated with higher incidences of grade 4 leukopenia (P = 0.006), neutropenia (P = 0.002), and grade 3/4 anorexia (P = 0.004) and febrile neutropenia (P = 0.049), whereas there was no association in the docetaxel plus cisplatin plus S-1 arm. No significant differences were observed according to CrCl in the overall survival [median: 15.4/15.5/15.4 months in A1/A2/A3 (P = 0.886) and 15.3/13.7/13.7 months in B1/B2/B3 (P = 0.719)], progression-free survival [median: 7.1/6.8/6.2 months in A1/A2/A3 (P = 0.884) and 7.5/7.2/7.8 months in B1/B2/B3 (P = 0.851)] and response rates [58.9/57.8/46.9% in A1/A2/A3 (P = 0.311) and 62.0/61.5/51.5% in B1/B2/B3 (P = 0.362)]., Conclusions: Renal impairment was associated with severe adverse events in cisplatin plus S-1 therapy but not with the efficacy in cisplatin plus S-1 and docetaxel plus cisplatin plus S-1 therapy., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Clinical trials have proven the efficacy and safety of new therapies for advanced gastric cancer (AGC), but how those therapies are used in the real world is poorly described. Real-world treatment patterns of antitumor therapies and factors associated with overall therapy duration in patients with AGC in Japan were investigated., Methods: This retrospective cohort study used a Japanese administrative claims database (June 2014 to September 2019). Patients with AGC who started the guideline-recommended first-line combination regimens with platinum and fluoropyrimidine agents between June 2015 and July 2019 were included. Cox regression analysis was performed to identify factors associated with overall therapy duration (first line to last administration of guideline-listed agent)., Results: Of the 10,581 patients included, the most common first-line combination regimen without trastuzumab was S-1 plus oxaliplatin (4327/9069 patients; 47.7%) and with trastuzumab was capecitabine plus cisplatin (608/1512 patients; 40.2%). Most common second- and third-line regimens were ramucirumab plus taxane (3650/5358 patients; 68.1%) and nivolumab (1229/2390 patients; 51.4%), respectively. Factors positively associated with longer overall therapy duration were: oral fluoropyrimidine in first line (hazard ratio [95% confidence interval]: 0.63 [0.57-0.69]); trastuzumab in any line (0.73 [0.68-0.78]); treatment at a designated cancer hospital (0.89 [0.84-0.94]); dietary consultation within 1 month before/after start of first line (0.92 [0.86-0.98]); and treatment at a surgical department (0.94 [0.89-0.99]). Negatively associated factors were: edema (1.21 [1.07-1.37]); physical therapy (1.21 [1.12-1.31]); nutritional intervention (1.21 [1.14-1.28]) within 1 month before/after start of first line; thrombosis (1.13 [1.04-1.23]); renal disease (1.11 [1.02-1.21]); age (1.07 [1.02-1.13]); and peritoneal metastasis/ascites (1.06 [1.01-1.13])., Conclusions: In real-world treatment practice for AGC in Japan, therapy choice after the recommended first-line chemotherapy was consistent with guidelines. Factors associated with overall therapy duration were identified, which may assist in optimizing treatment sequence., (© 2021. The Author(s).)

Background: In the phase II ATTRACTION-1 study, nivolumab demonstrated a promising antitumor activity among Japanese patients with treatment-refractory advanced esophageal cancer. Here, we report the follow-up results of ATTRACTION-1 of > 5 years., Methods: We enrolled patients with esophageal cancer that was refractory or intolerant to a standard chemotherapy. Then, nivolumab (3 mg/kg) was administered every 2 weeks. The primary endpoint was a centrally assessed objective response rate., Results: Nivolumab was administered to 65 patients with esophageal squamous-cell carcinoma (ESCC). The centrally assessed objective response rate was 17.2%. The overall survival rates at 3 and 5 years were 10.9% and 6.3%, respectively. Three-year survivors tended to have more reduced target lesions. A total of 63.1% of the patients exhibited treatment-related adverse events, and no new safety signal was observed. Patients with select adverse events tended to have better overall survival than those without. No apparent chronological order was observed between the first response and the onset of select adverse events., Conclusion: Our follow-up analysis of more than 5 years is currently the longest and is the first to demonstrate that nivolumab has long-term efficacy and safety for advanced ESCC., (© 2021. The Author(s).)

Purpose: Cumulative sensory neurotoxicity induced by oxaliplatin impairs patients' quality of life and treatment continuation. This study investigated the relationship between physician-assessed and patient-reported oxaliplatin-induced peripheral neuropathy (OIPN) during treatment of metastatic colorectal cancer (mCRC) over time., Methods: A post hoc analysis was conducted for 191 patients with mCRC who received mFOLFOX6 plus bevacizumab in the WJOG4407G trial. Physician-assessed OIPN was graded by CTCAE every 2 weeks. Patient-reported OIPN was assessed with the FACT/GOG-Ntx (11 items, best score 44) at baseline and at 3, 6, and 9 months. Physician underestimation was defined as when the highest scores of the NTX1-4 sensory subscale/CTCAE grade were 2/0, 3/0-1, or 4/0-1, and overestimation as 0/2-3, 1/2-3, or 2/3., Results: The median total dose (range) of oxaliplatin was 762 (85-5950) mg/m 2 . Overall, the least squares mean of FACT/GOG-Ntx scores (standard error), estimated by a linear mixed model, were 36 (0.8), 34 (0.9), 29 (1.0), and 27 (1.1) for CTCAE grades 0, 1, 2, and 3, respectively. FACT/GOG-Ntx scores were weakly-to-moderately correlated with CTCAE grade (Spearman's r = - 0.24 [p = 0.0026], - 0.46 [p < 0.0001], and - 0.56 [p < 0.0001] at 3, 6, and 9 months, respectively). OIPN was underestimated in 85/159 (54%), 43/109 (39%), and 18/69 (26%) patients at 3, 6, and 9 months, respectively. In contrast, OIPN was overestimated in less than 5% of the patients at any time., Conclusion: During early treatment, physician underestimation of OIPN in patients with mCRC is likely.

Objective: We evaluated the efficacy and safety of first-line S-1 plus cisplatin in combination with cetuximab for Japanese patients with advanced gastric cancer, including gastroesophageal junction adenocarcinoma., Methods: This open-label, single arm, multicenter, phase 2 trial was conducted to assess first-line cetuximab plus S-1 plus cisplatin for advanced gastric cancer. A total of 40 patients from 10 centers were enrolled. Cetuximab was administered weekly, with the initial infusion at 400 mg/m2 and then 250 mg/m2 each subsequent week. S-1 plus cisplatin chemotherapy was concomitantly conducted in a 5-week cycle: S-1 (40-60 mg, adjusted for body surface area) was given twice daily for 3 consecutive weeks, followed by a 2-week rest period, and cisplatin (60 mg/m2) was given on day 8 of each cycle for a maximum of 8 cycles. Treatment continued until the occurrence of radiographically confirmed progressive disease, unacceptable toxicity or withdrawal of consent. The primary endpoint was the best overall response. Secondary endpoints included progression-free survival and safety., Results: A total of 40 patients were evaluable. One patient (2.5%) had a complete response; 15 patients (37.5%) had a partial response. The observed overall response rate according to the independent review committee was 40.0% (95% confidence interval, 24.9-56.7; P = 0.7043 [one-sided null hypothesis: overall response rate ≤ 43%]); median PFS was 5.6 months (95% confidence intervals, 4.2-8.3). No adverse events leading to death were reported during the study, and no specific safety concerns were observed., Conclusions: Overall, the addition of cetuximab to S-1 plus cisplatin was well tolerated in patients with advanced gastric cancer but provided no additional clinical benefit in this study. ClinicalTrials.gov identifier: NCT01388790., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: This study evaluated the association between early tumor response at 8 weeks, previously reported as a positive outcome prognosticator, and health-related quality of life (HRQOL) in advanced gastric cancer (AGC) patients enrolled in the ABSOLUTE trial., Methods: HRQOL was assessed using the EuroQol-5 Dimension (EQ-5D) utility index score in patients with complete response (CR) + partial response (PR) and progressive disease (PD) at 8 weeks, and time-to-deterioration (TtD) of the EQ-5D score, with the preset minimally important difference (MID) of 0.05, was compared between these populations. Among the enrolled patients, 143 and 160 patients were assessable in weekly solvent-based paclitaxel (Sb-PTX) arm and weekly nanoparticle albumin-bound paclitaxel (nab-PTX) arm, respectively., Results: Changes of the EQ-5D score from baseline to 8 weeks in the nab-PTX arm were 0.0009 and - 0.1229 in CR + PR and PD patients, respectively; the corresponding values for the Sb-PTX arm were - 0.0019 and - 0.1549. For both treatments, changes of the EQ-5D score from baseline at 8 weeks were significantly larger in patients with PD than in those with CR + PR. The median TtD was 3.9 and 2.2 months in patients with CR + PR and PD, respectively, for nab-PTX [hazard ratio (HR) = 0.595, 95% confidence interval (CI) 0.358-0.989]. For Sb-PTX, the corresponding values were 4.7 and 2.0 months (HR = 0.494, 95% CI 0.291-0.841)., Conclusions: Early tumor shrinkage was associated with maintained HRQOL in AGC patients on the second-line chemotherapy with taxanes.

Purpose: We conducted a phase I/II study to investigate the safety and efficacy of nivolumab with paclitaxel plus ramucirumab., Patients and Methods: Patients with advanced gastric cancer (AGC) refractory to first-line chemotherapy were included. Patients received nivolumab (3 mg/kg on days 1 and 15) combined with paclitaxel (80 mg/m 2 on days 1, 8, and 15) and ramucirumab (8 mg/kg on days 1 and 15) every 4 weeks. After feasibility evaluation in six patients (phase I), 37 additional patients were enrolled in the phase II part with the primary endpoint of 6-month progression-free survival (PFS) rate with two-sided 80% confidence interval (CI). The combined positive score (CPS) was defined as the number of programmed death-ligand 1-positive cells divided by the total number of viable tumor cells multiplied by 100., Results: Forty-three patients were enrolled. Of these, 60.5% had CPS ≥ 1. Dose-limiting toxicities were observed in two patients, and the recommended dose was determined as level 1. Thirty-nine (90.7%) patients experienced treatment-related adverse events (AEs) grade ≥3 and 14 (32.6%) patients experienced immune-related AEs grade ≥3. The overall response rate was 37.2% (95% CI, 23.0%-53.5%) and the 6-month PFS rate was 46.5% (80% CI, 36.4%-55.8%; P = 0.067). Median survival time was 13.1 months (95% CI, 8.0-16.6 months): 13.8 months (95% CI, 8.0-19.5 months) in patients with CPS ≥ 1 and 8.0 months (95% CI, 4.8-24.1 months) in patients with CPS < 1., Conclusions: Nivolumab with paclitaxel plus ramucirumab demonstrated promising antitumor activity with manageable toxicities as second-line treatment for AGC., (©2020 American Association for Cancer Research.)

Nivolumab (NIVO) plus low-dose ipilimumab (IPI) has shown a promising survival benefit in first-line treatment of microsatellite instability-high (MSI-H) colorectal cancer. We hypothesized that this regimen might also be beneficial for MSI-H gastric cancer (GC), which accounts for ~5% of all GC cases. NO LIMIT (WJOG13320G/CA209-7W7) is an investigator-initiated, single-arm, open-label, 14-center phase 2 trial of NIVO plus low-dose IPI for MSI-H GC in the first-line setting. Eligibility criteria include unresectable advanced, recurrent, or metastatic gastric or esophagogastric junction cancer with a histologically confirmed diagnosis of adenocarcinoma; confirmed MSI-H status with the MSI-IVD Kit (FALCO); no prior systemic anticancer therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and a measurable lesion per RECIST 1.1. The primary objective of the study is to determine the overall response rate (ORR) for the NIVO+IPI regimen as assessed by blinded independent central review. Secondary end points include progression-free survival, overall survival, duration of response, safety, tolerability, and biomarkers. The number of patients was set at 28 on the basis of the threshold and expected ORR values of 35 and 65%, respectively, with a one-sided alpha error of 0.025 and power of 0.80. Subjects will receive treatment with nivolumab (240 mg) biweekly in combination with ipilimumab (1 mg/kg) every 6 weeks. The results of this study should clarify the therapeutic potential of NIVO+IPI for MSI-H GC in the first-line setting. Trial registration: JapicCTI-205400.

Background: The relationship between chemotherapy-induced leukopenia (CIL) and survival has not been investigated in patients undergoing preoperative chemotherapy for esophageal squamous cell carcinoma (ESCC). We analyzed the association of CIL with survival outcomes using data from JCOG9907 on the efficacy of preoperative chemotherapy for stage II/III ESCC., Methods: Preoperative chemotherapy consisted of two courses of 5-FU (800 mg/m 2 days 1-5) and cisplatin (80 mg/m 2 day 1) repeated every 3 weeks. Patients in the preoperative chemotherapy arm receiving at least one course of chemotherapy and undergoing subsequent surgery in JCOG9907 were divided into two subgroups: CIL ( +), those with grade 2-4 leukopenia at least once during preoperative chemotherapy; and CIL (-), those with grades 0-1. The association of CIL with overall survival (OS) and progression-free survival (PFS) was analyzed., Results: Among 164 patients enrolled in JCOG9907, 152 patients were included in this analysis, 52 in CIL ( +) and 100 patients in CIL (-) subgroups. The 3-year OS for CIL ( +) was inferior to that for CIL (-) (48.1% vs. 73.9%); hazard ratio (HR) = 1.94 (95% CI 1.18-3.16, P < .01). For 3-year PFS, a similar tendency was observed (44.2% vs. 55.8%; HR = 1.38 (95% CI 0.88-2.17, P = .16). Multivariable analysis revealed that CIL was not an independent factor for OS (HR = 1.14, 95% CI 0.63-2.07, P = .67)., Conclusion: We showed that CIL during preoperative chemotherapy might not be a prognostic factor in patients with ESCC.

Background and Objective: Gastric cancer has been associated with notable geographic heterogeneity in previous multi-regional studies. In particular, patients from Japan have better outcomes compared with patients from other regions. Here, we assess patient-focused outcomes for the subgroup of Japanese patients in the global RAINBOW study., Methods: Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) at baseline and 6-week intervals. Investigators assessed performance status before each 4-week cycle. Time-to-deterioration in each QLQ-C30 scale was defined as randomization to first worsening of ≥ 10 points (on a 100-point scale). Time-to-deterioration in performance status was defined as first worsening to ≥ 2. Hazard ratios were estimated using Cox proportional hazards models., Results: The Japan subgroup contained 140 patients (ramucirumab plus paclitaxel, n = 68; placebo plus paclitaxel, n = 72); baseline QoL data were available for all patients. At baseline, QLQ-C30 scores were similar between study arms. Of the 15 QLQ-C30 scales, nine had a hazard ratio < 1, indicating similar or numerically longer time-to-deterioration in QoL for ramucirumab plus paclitaxel; all 95% confidence intervals included 1. Best mean change from baseline numerically favored ramucirumab plus paclitaxel in most QoL scales. The hazard ratios for time-to-deterioration of performance status to ≥ 2 were 0.64 in the Japan subgroup and 0.88 in the non-Asian subgroup. The Japan subgroup had better QoL at baseline compared with the non-Asian subgroup., Conclusions: Treatment with ramucirumab plus paclitaxel maintained QoL and performance status over time compared with placebo plus paclitaxel in the Japan subgroup of the RAINBOW trial. These data suggest that the heterogeneity in gastric cancer between geographic regions includes multiple measures of QoL., Trial Registration Number: NCT01170663 (first submitted 21 July, 2010).

Background: JCOG0909 is a phase II trial of definitive chemoradiotherapy including salvage treatment for cStage II-III thoracic esophageal cancer; the radiation field for elective regional lymph node irradiation, which can affect patient outcome and adverse event, varied based on the primary tumor site, i.e., upper (Ut), middle (Mt), and lower thoracic (Lt) esophagus. The impact of different primary sites on the safety and efficacy of definitive chemoradiotherapy in JCOG0909 is not well characterized., Methods: Patients were categorized into three groups (Ut, Mt, and Lt) according to the primary tumor location. We compared acute adverse events during definitive chemoradiotherapy, complete response (CR) rate, 3-year progression-free survival (PFS), and overall survival (OS) among the 3 groups., Results: Out of the 96 patients enrolled in JCOG0909 between April 2010 and August 2014, 94 patients (16, 59, and 19 patients in the Ut, Mt, and Lt groups, respectively) were included in this exploratory analysis. The proportion of patients with cStage III was 25% in the Ut, 37% in the Mt, and 47% in the Lt group. Grade 3-4 leukopenia, neutropenia, and thrombocytopenia were more frequently observed in the Mt (66%, 54%, and 15%) and Lt groups (84%, 68%, and 16%) than in the Ut group (38%, 44%, and 0%). There was no significant between-group difference with respect to 3-year OS (73.3%, 77.9%, and 57.9%), 3-year PFS (60.0%, 59.3%, and 47.4%), or CR rate (62.5%, 62.7%, and 42.1%)., Conclusions: In JCOG0909, the incidence of severe hematological toxicity had a trend toward higher in the Mt and Lt than the Ut esophageal cancer; however, no remarkable difference by primary sites was observed with respect to efficacy endpoints.

The phase III West Japan Oncology Group (WJOG) 4407G study showed noninferiority of folinic acid, bolus/continuous fluorouracil, and irinotecan plus bevacizumab to modified folinic acid, bolus/continuous fluorouracil, and oxaliplatin 6 plus bevacizumab in progression-free survival (PFS) as first-line chemotherapy for patients with metastatic colorectal cancer. The aim of this study was to evaluate the predictive and prognostic value of morphologic response in patients with colorectal liver metastases (CLM) as a post hoc analysis of the WJOG4407G study.Morphologic response was assessed by comparing contrast-enhanced computed tomography (CT) images at baseline and week 8. Three blinded radiologists evaluated CT images and classified their response as optimal, incomplete, or no response according to the morphologic criteria. Response evaluation criteria in solid tumors (RECIST) response, early tumor shrinkage (ETS), and depth of response (DpR) were also evaluated.Among 395 patients who were eligible for efficacy analysis in the WJOG4407G study, 70 patients had liver-limited disease. We finally evaluated 55 of these patients. Optimal morphologic response was identified in 19 of 55 patients (34.5%). The median PFS was 10.7 months for patients with optimal response and 10.1 months in those with incomplete/no response (log-rank, P = .96). The median overall survival (OS) was 26.2 and 35.5 months, respectively (log-rank, P = .062). According to univariate analysis, morphologic response was not associated with PFS or OS, whereas RECIST response was significantly associated with both PFS and OS, with ETS and DpR being associated with significantly longer PFS.Morphologic response might be neither a predictive nor a prognostic factor in patients with CLM undergoing chemotherapy containing bevacizumab, whereas RECIST response was significantly associated with both PFS and OS.

Background: Cetuximab has been shown to be clinically active when given in combination with irinotecan in patients with irinotecan-refractory metastatic colorectal cancer (mCRC). However, it has remained unclear whether panitumumab is effective when combined with irinotecan. We compared efficacies of both regimens in this randomised phase II study., Patients and Methods: Patients with wild-type KRAS exon 2 mCRC previously treated with fluorouracil-, oxaliplatin- and irinotecan-based chemotherapies were randomised (1:1) to either panitumumab plus irinotecan (panitumumab arm) or cetuximab plus irinotecan (cetuximab arm). The primary end-point was progression-free survival (PFS). The planned sample size was 120, expecting a hazard ratio (HR) of 1.0 with non-inferiority margin of 1.3 (one-sided alpha error 0.2 and power 0.7). Major secondary end-points were overall survival (OS), response rate and safety., Results: From December 2011 to September 2014, 121 patients were enrolled, and 61 and 59 patients were randomised to the panitumumab and cetuximab arms, respectively (1 patient excluded). Most patients (97%) had received prior chemotherapies containing bevacizumab. The median PFS was 5.42 months in the panitumumab arm and 4.27 months in the cetuximab arm (HR = 0.64, 95% confidence interval [CI] = 0.44-0.94, P < 0.001 for non-inferiority, P = 0.058 for superiority), and median OS was 14.85 and 11.53 months (HR = 0.66, 95% CI = 0.44-1.00, P = 0.050 for superiority), respectively. The incidence of grade 3 or 4 hypomagnesaemia was higher in the panitumumab arm than that in the cetuximab arm (17% vs. 7%)., Conclusion: Panitumumab may be non-inferior to cetuximab in combination with irinotecan in survival of patients with irinotecan-refractory mCRC., Competing Interests: Conflict of interest statement DS reports grants from Yakult Honsha, Chugai, Ono, Eli Lilly, Daiichi Sankyo, Incyte and Taiho, and personal fee from Chugai, outside the submitted work. T.T. reports receiving personal fees from Merck Serono Co., Ltd, and Takeda Pharmaceutical Co., Ltd., during the conduct of the study, and receiving grants from Ono Pharmaceutical, Bristol-Myers Squibb and Japan AMED, outside the submitted work. N.S. reports receiving personal fees from Merck-Biopharm and Takeda Pharmaceutical Co.Ltd. , and ONO Pharmaceutical Co.,Ltd., MSD, Sanofi, Daiichi Sankyo, Parexel International, Sumitomo Dainippon Pharma, Bristol-Myers Squibb, Solasia Pharma, Chugai Parmaceutical, Taiho Pharmaceutical and Eli Lilly, outside the submitted work. T.N. reports grants and personal fees from Taiho pharma, grants and personal fees from Chugai pharma, grants from Daiichi sankyo pharma, grants from MSD, grants and personal fees from Ono pharma, grants and personal fees from Bristol myers squibb, grants and personal fees from Lilly pharma, grants from Dainippon sumitomo pharma, outside the submitted work. H.H. reports paid consulting or advisory roles for MSD and Ono; honoraria from Bayer, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Kyowa Hakko Kirin, Lilly, Merck Biopharma, MSD, Ono, Sanofi, Taiho, Takeda and Yakult; and research funding from Astellas, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Incyte, LSK BioPharma, Merck Biopharma, MSD, Ono, Pfizer, and Taiho, outside the submitted work. T.E. reports research funding from Taiho, MSD, Eli Lilly, Daiichi Sankyo, Ono, Bayer, Novartis, Astellas, Astellas Amgen Biopharma, BeiGene, Pierre Fabre Medicament, Ignyta, Array BioPharma, Dainippon Sumitomo, and honoraria from Taiho, MSD, Eli Lilly, Daiichi Sankyo, Ono, Bayer, Chugai, Nihon Kayaku, Sanofi, Takeda, Merck Serono, Bristol, Eisai. T.D. reports personal fees from SAWAI Pharmaceutical Co, personal fees from Sysmex, grants from MSD, grants from ONO Pharmaceutical, outside the submitted work. T.S. reports receiving personal fees from Merck-BioPharm and Takeda Pharmaceutical and grants and personal fees from Yakult Honsha and Daiichi-Sankyo, outside the submitted work. A.M. reports receiving personal fees from Lily, Chugai and Takeda, outside the submitted work. A.H. reports receiving personal fees from Taiho Pharmaceutical, Takeda Pharmaceutical, Ono Pharmaceutical, Novartis, Eisai, Chugai Pharmaceutical, Eli Lilly, Daiichi Sankyo, Teijin Pharma, Sanofi and Merck Biopharma and grants from Chugai Pharmaceutical, Taiho Pharmaceutical, Ono Pharmaceutical, Eisai and Yakult Honsha, outside the submitted work.T.M. reports receiving grants and personal fees from Taiho Pharmaceutical, Yakult Honsha and Takeda Pharmaceutical; receiving personal fees from Chugai Pharmaceutical, Novelpharma, Merck Serono and Sanofi and receiving grants from Boehringer Ingelheim and Eisai, outside the submitted work. H.Y. reports research funding from MSD, Daiichi Sankyo, and Ono Pharmaceutical, personal fees from Taiho Pharmaceutical, honoraria from Chugai Pharma, Bristol-Myers Squibb Japan, Daiichi Sankyo, TERUMO, Eli Lilly Japan, Merk Biopharma, and Yakult Honsha, outside the submitted work. A.T. reports receiving personal fees from Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Merck Serono Co., Ltd. E.B. reports receiving grants and personal fees from Ono, Merck-Serono, Taiho, Chugai and Daiichi-Sankyo and personal fees from BMS, Takeda, Eli lilly, Tsumura, Kyowa-Kirin and Yakult, outside the submitted work. K.S. reports personal fees from SHIONOGI & CO., LTD., personal fees from Takeda Pharmaceutical Company Limited, personal fees from Taiho Pharmaceutical Co Ltd, personal fees from ONO PHARMACEUTICAL CO., LTD., personal fees from Merck Biopharma Co., Ltd, personal fees from NIPPON KAYAKU Co., Ltd., personal fees from Asahi Kasei Pharma, from Eisai Co., Ltd., personal fees from Bayer Yakuhin, Ltd., personal fees from Kyowa Hakko Kirin Co., Ltd., personal fees from CHUGAI PHARMACEUTICAL CO., LTD., personal fees from MOCHIDA PHARMACEUTICAL CO.,LTD., personal fees from Eli Lilly Japan K.K., personal fees from DAIICHI SANKYO COMPANY, LIMITED, outside the submitted work. M.G. reports receiving grants, personal fees and non-financial support from Taiho Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Ono Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., and Chugai Pharmaceutical Co., Ltd., during the conduct of the study and personal fees and non-financial support from Takeda Pharmaceutical Co., Ltd., Novartis Pharmaceuticals and Bayer Yakuhin, Ltd., outside the submitted work. S.K. reports receiving grants and personal fees from Eli Lilly, Taiho Pharmaceutical, Ono Pharmaceutical and Bristol-Myers Squibb and personal fees from Chugai Pharma, Merck Serono, Bayer, Eisai and Yakult Honsha, outside the submitted work. Y.K. reports receiving research grants and personal fees from AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim Japan, Ono Pharmaceutical, Bristol-Myers Squibb, and Tosoh Corp., research grants from MSD, Toppan Printing, Terumo and On-chip Biotechnologies, and personal fees from Thermo Fisher, and Lilly outside the submitted work. K.Y. reports receiving personal fees and other fees from Chugai, Bayer and MSD; personal fees from Takeda, Taiho, Yakult, Daiichi Sankyo, Merck Serono, Sanofi, Lily and other fees from Boehringer Ingelheim, outside the submitted work. S.H. reports receiving personal fees from Ono Pharm, Bristol-Myers Squibb, Taiho Pharm, Yakult Honsha, Daiichi Sankyo, Lilly, Chugai Pharm, Nihonkayaku and Tsumura & Co., outside the submitted work. N.B. reports receiving research grant from Ono, Bristol-Myers Squibb and Taiho and honorarium from Ono, Bristol-Myers Squibb, Taiho, Eli-Lilly and Chugai. I.H. reports receiving grants and personal fees from Chugai, Taiho, Takeda, Ono, Daiichi-Sankyo and Yakult-Honsha and personal fees from Merck-Serono, outside the submitted work. K.M. reports receiving grants and personal fees from ONO Pharmaceutical CO.,LTD. and Sanofi, and grants from Daiichi Sankyo, Parexel International, Shionogi Pharmaceutical, Sumitomo Dainippon Pharma, MSD, Pfizer, Mediscience Planning, Solasia Pharma, and Merck Serono. He also reports receiving personal fees from Eli Lilly, Chugai Pharmaceutical, Takeda Pharmaceutical, Taiho Pharmaceutical, Bristol-Myers Squibb, and Bayer; outside the submitted work. The other authors declare no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: S-1 plus leucovorin and oxaliplatin showed promising efficacy for treatment of advanced gastric cancer in a randomised phase 2 study. We aimed to evaluate the efficacy and safety of oral TAS-118 (S-1 plus leucovorin) and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer., Methods: We did a randomised, open-label, phase 3 trial in 62 centres across Japan and South Korea. Patients aged 20 years or older, with a histologically confirmed advanced gastric cancer with negative or unknown HER2 status, with Eastern Cooperative Oncology Group performance status of 0 or 1, measurable or evaluable metastatic lesions, and no previous treatment were randomly assigned (1:1) via an interactive web response system using the minimisation method, stratified by performance status, presence of a measurable lesion, and country, to receive TAS-118 (S-1 40-60 mg and leucovorin 25 mg orally twice daily for 7 days) plus oxaliplatin (85 mg/m 2 intravenously on day 1) every 2 weeks, or S-1 (40-60 mg orally twice daily) for 21 days plus cisplatin (60 mg/m 2 intravenously on day 1 or 8) every 5 weeks. The primary endpoint was overall survival in patients who had advanced gastric cancer with measurable or evaluable metastatic lesions and who received the study drug. Safety was assessed in all patients who received the study drug. This study was registered at ClinicalTrials.gov, NCT02322593., Findings: Between Jan 28, 2015, and Dec 5, 2016, 711 patients were randomised to TAS-118 plus oxaliplatin (n=356) or S-1 plus cisplatin (n=355). 11 untreated patients and 19 ineligible patients were excluded from the primary analysis (TAS-118 plus oxaliplatin group n=347, S-1 plus cisplatin group n=334) following recommendation from the independent data monitoring committee. After median follow-up of 26·0 months (IQR 22·0-32·8), median overall survival was 16·0 months (95% CI 13·8-18·3) in the TAS-118 plus oxaliplatin group and 15·1 months (95% CI 13·6-16·4) in the S-1 plus cisplatin group (hazard ratio 0·83, 95% CI 0·69-0·99; p=0·039). The most common grade 3 or higher adverse events in the 352 patients in the TAS-118 plus oxaliplatin group and the 348 patients in the S-1 plus cisplatin group were anaemia (56 [16%] vs 64 [18%]), neutropenia (54 [15%] vs 88 [25%]), decreased appetite (53 [15%] vs 46 [13%]), diarrhoea (33 [9%] vs 15 [4%]), and peripheral sensory neuropathy (30 [9%] vs one [<1%]). Serious adverse events were observed in 155 (44%) of 352 patients in the TAS-118 plus oxaliplatin group and 159 (46%) of 348 patients in the S-1 plus cisplatin group. Two treatment-related deaths occurred in the TAS-118 plus oxaliplatin group (pulmonary tuberculosis and viral pneumonia)., Interpretation: TAS-118 plus oxaliplatin showed a clinically meaningful improvement in efficacy compared with S-1 plus cisplatin, and could be considered a new first-line treatment option for advanced gastric cancer in Asian patients., Funding: Taiho Pharmaceutical and Yakult Honsha., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: Oral frailty (OF) has been shown to be a predictor of disability. Therefore, it is important to be able to identify factors associated with OF in order to prevent long-term dependence. The purpose of this study was to clarify the relationships between OF, social frailty (SF), and physical frailty (PF) in community-dwelling older adults, with the overarching aim of informing the future development of effective measures to prevent frailty., Methods: Oral, physical, and social function, nutritional and psychological status, and medical history were examined in 682 community-dwelling individuals (267 men, 415 women) aged ≥ 65 years. Ordinal logistic regression analysis with SF and PF as independent variables was performed with pass analysis to determine the relationship between the different types of frailty., Results: Logistic regression analysis revealed significant associations between OF and decline in social function, physical function, and nutritional status, and an increase in the number of medications used. Path analysis showed that SF was directly related to OF and that OF and SF were directly related to PF., Conclusions: These findings suggest that a decline in social function may directly influence a decline in oral and physical function. The results of this study provide initial evidence, that may guide the future development of measures that aim to prevent and manage OF., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Gastric cancer patients with severe peritoneal metastases, defined as massive ascites and/or inadequate oral intake, have been excluded from clinical trials of new treatments due to poor prognosis and tumor-related complications, such as ileus. Based on the results of the JCOG1108/WJOG7312G study, their prognosis when treated with 5-fluorouracil/ l -leucovorin or 5-fluorouracil/ l -leucovorin plus paclitaxel remained extremely poor in this setting. Retrospective studies have shown the promising efficacy of the modified FOLFOX6 (mFOLFOX6) regimen, with improved ascites and oral intake. Therefore, we planned a Phase II study of mFOLFOX6 in gastric cancer patients with severe peritoneal metastases (jRCTs041180007). The primary end point is overall survival, with an exploratory analysis comparing the findings with those of the JCOG1108/WJOG7312G study using Bayes' theorem. Trial registration Identifier: jRCTs041180007 (jRCTs: the Japan Registry of Clinical Trials).

Background: Ramucirumab (RAM) with weekly paclitaxel (wPTX) is a standard second-line therapy for advanced or recurrent gastric cancer. Nanoparticle albumin-bound paclitaxel (nab-PTX), an albumin-bound form of PTX, was developed to improve the therapeutic index of taxane treatment. However, the ABSOLUTE trial showed the non-inferiority of weekly nab-PTX (w-nab-PTX) to wPTX with respect to overall survival (OS) as second-line therapy for advanced or recurrent gastric cancer, and subgroup analysis of patients with peritoneal dissemination showed favourable OS and progression-free survival (PFS) in the w-nab-PTX arm compared to those in the wPTX arm. This study evaluated whether w-nab-PTX plus RAM is more effective than wPTX plus RAM for patients with peritoneal dissemination., Methods: The P-SELECT trial (WJOG10617G) is a prospective, open-label, multicentre, randomised phase II study evaluating wPTX plus RAM (arm A) versus w-nab-PTX plus RAM (arm B). Key eligibility criteria include the following: 1) histologically proven adenocarcinoma, 2) unresectable or recurrent gastric cancer, 3) peritoneal dissemination, 4) intolerance or refractory to first-line therapy including fluoropyrimidines, and 5) ECOG Performance Status (PS) 0-2. Patients are randomised to either arm at a 1:1 ratio stratified by institution, PS, and severity of ascites. PTX (80 mg/m 2 ; days 1, 8, and 15) and RAM (8 mg/kg; days 1 and 15) are administered every 4 weeks in arm A, while nab-PTX (100 mg/m 2 ; days 1, 8, and 15) instead of PTX is administered in arm B. The primary endpoint is OS, and the main secondary endpoints are PFS, objective response rate, safety, neuropathy-specific quality of life, and biomarkers. To maintain a probability of ≥70% to ensure the hazard ratio for OS in arm B is lower than 0.90, 105 subjects are required. The study was initiated in October 2018 and is being conducted in 58 centres of the West Japan Oncology Group., Discussion: The results of this study will determine whether w-nab-PTX plus RAM has the potential to be a preferred therapeutic option for advanced and recurrent gastric cancer with peritoneal dissemination, compared to wPTX plus RAM., Trial Registration: This study was prospectively registered in the Japan Registry of Clinical Trials (jRCTs031180022, October 1, 2018).

Purpose: This study evaluated the continuous use of trastuzumab beyond progression (TBP) in human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastroesophageal junction (G/GEJ) cancer., Patients and Methods: Patients with HER2-positive advanced G/GEJ cancer refractory to first-line chemotherapy with trastuzumab in combination with fluoropyrimidine and platinum were eligible. Patients were randomly assigned to the paclitaxel (80 mg/m 2 , days 1, 8, and 15, every 4 weeks) or paclitaxel with trastuzumab (PT; initially 8 mg/kg followed by 6 mg/kg, every 3 weeks) arms. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), response rate, and safety. Biomarkers such as HER2 expression status in tumor tissue after first-line treatment, HER2 amplification evaluated in serum cell-free DNA, and soluble HER2 levels were analyzed., Results: Overall, 91 patients were allocated to the paclitaxel (n = 46) and PT (n = 45) arms. The median PFS in the paclitaxel and PT arms was 3.2 and 3.7 months, respectively (hazard ratio [HR], 0.91; 80% CI, 0.67 to 1.22; P = .33), and the median OS in both arms was 10 months (HR, 1.2; 95% CI, 0.75 to 2.0; P = .20). The overall response rates in the paclitaxel and PT arms were 32% and 33%, respectively ( P = 1.00), and safety was comparable between the 2 arms. On exploratory analyses, HER2 positivity of tumor tissues was lost after first-line chemotherapy in 11 (69%) of 16 patients whose tumor tissues were available, and circulating HER2 DNA amplification was detected in 41 (60%) of 68 patients. However, no biomarkers associated with efficacy of TBP were found., Conclusion: The TBP strategy failed to improve PFS in patients with HER2-positive advanced G/GEJ cancer, and no beneficial biomarkers were found.

The long-term efficacy of nivolumab in esophageal squamous cell carcinoma and its association with disease biomarkers are currently not well known. Therefore, we investigated the association in Japanese patients with treatment-refractory advanced esophageal cancer who participated in an open-label, single-arm, multicenter phase II study. Patients received nivolumab 3 mg/kg i.v. every 2 weeks until disease progression or unacceptable toxicity, and were followed up for 2 years after the initial dosing of the last patient. Archival tissue samples were collected before treatment and analyzed for programmed death ligand-1 (PD-L1) and CD8 + status of tumors and tumor-infiltrating lymphocytes (TILs) and human leukocyte antigen class 1. Efficacy end-points included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to response, and duration of response. Of 65 enrolled patients (83% male), 64 were evaluable for efficacy and 41 (63%) for biomarkers. The ORR, median OS, and survival rate were 17.2%, 10.78 months, and 17.2%, respectively. Time to response was 1.45 months and duration of response was 11.17 months. The PD-L1 positivity of tumor cells was possibly associated with better PFS (2.04 vs 1.41 months, cut-off 1%) and OS (11.33 vs 6.24 months, cut-off 1%). Median OS was prolonged in patients with a median number of TILs greater than 63.75% vs 63.75% or less (11.33 vs 7.85 months). Nivolumab showed continued long-term efficacy, as seen by the stability of PFS and OS, in Japanese patients with esophageal squamous cell carcinoma. Further investigation of PD-L1 tumor expression and TILs as potential biomarkers for predicting patients likely to benefit from nivolumab therapy is warranted., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: A simple and predictable method of evaluating eating and swallowing has not been yet established; thus, it is difficult to implement advance care planning according to deterioration in this function. This study aimed to clarify the association between a simple evaluation of eating and swallowing function and 1-year mortality in advanced dementia patients in nursing homes in Japan., Methods: The study included 325 residents with advanced dementia. In a baseline survey, we examined medical history, physical function, and eating and swallowing function. We recorded mortality for 1 year from baseline. Kaplan-Meier survival analysis and Cox proportional regression were performed to investigate the association between the simple evaluation of eating and swallowing function and mortality., Results: Statistical analysis included data from 312 of the 325 residents who had completed the baseline survey (7 individuals with non-oral ingestion and 6 who were alive but did not reside in the nursing home 1 year later were excluded). The participants' mean age was 85.2 years, and 79.5 % of participants were female. At the 1-year follow-up, 70 patients had died. According to Cox proportional regression analysis, age, male gender, history of cerebrovascular disorder, poor results of palpation of masseter muscle tension, and modified water swallowing test were significantly associated with 1-year mortality., Conclusion: The results of palpation of masseter muscle tension and modified water swallowing test were associated with 1-year mortality. These routine observations can predict mortality, and may thus provide evidence of the opportunity to implement advance care planning., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: The phase II/III GATSBY study (NCT01641939) showed that trastuzumab emtansine did not have an efficacy benefit over taxane in patients with previously treated, human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic gastric or gastroesophageal junction cancer. We evaluated patients from Japanese centers within GATSBY., Methods: In stage one, patients (randomized 2:2:1) received trastuzumab emtansine 3.6 mg/kg every 3 weeks, trastuzumab emtansine 2.4 mg/kg weekly, or physician's choice of taxane (docetaxel 75 mg/m² every 3 weeks or paclitaxel 80 mg/m² weekly). In stage two, patients (randomized 2:1) received trastuzumab emtansine 2.4 mg/kg weekly or taxane. Eligible patients had centrally assessed HER2-positive disease and progression during or after first-line therapy. Primary endpoint was overall survival. We present the 2.4 mg/kg weekly data., Results: Eighty-two patients were randomized (intention-to-treat: 48 to trastuzumab emtansine 2.4 mg/kg weekly, 23 to taxane; September 2012-August 2014) at 19 sites. Median overall survival was 11.8 months (95% confidence interval [CI], 9.3-16.3) with trastuzumab emtansine 2.4 mg/kg weekly and 10.0 months (95% CI, 7.1-18.2) with taxane (unstratified hazard ratio = 0.94, 95% CI, 0.52-1.72). Trastuzumab emtansine 2.4 mg/kg weekly, versus taxane, was associated with fewer grade ≥3 adverse events (AEs; 52.1% vs 68.2%) and serious AEs (14.6% vs 18.2%). There were no fatal AEs., Conclusions: Efficacy in Japanese patients within GATSBY was consistent with the overall population; overall survival was not prolonged with trastuzumab emtansine 2.4 mg/kg weekly versus taxane. The safety profile of trastuzumab emtansine was similar to the overall population., (© 2019 John Wiley & Sons Australia, Ltd.)

Background: A multicenter phase 2 trial analysed chemoselection with docetaxel plus 5-fluorouracil and cisplatin (DCF) induction chemotherapy (ICT) and subsequent conversion surgery (CS) for locally advanced unresectable esophageal cancer. This study presents updated 3-year analyses to further characterize the impact of DCF-ICT followed by CS., Methods: Esophageal cancer patients with clinical T4 disease, unresectable supraclavicular lymph node metastasis, or both were eligible for this study. The treatment starts with DCF-ICT, followed by CS if the cancer is resectable, or by concurrent chemoradiation if it is not resectable. This updated analysis presents 3-year overall survival (OS), 3-year progression-free survival (PFS), and pattern of relapse., Results: The median follow-up period for the patients surviving without death was 39.3 months. The estimated 1-year OS was 66.7%, and the lower limit of the 80% confidence interval (CI) was 54.6%. The estimated 3-year OS was 46.6% (95% CI 34.2-63.5%). The OS for the patients who underwent R0 resection (n = 19) was significantly longer than for those who did not (3-year OS: 71.4% vs. 30.1%). The estimated 1-year PFS was 50.6%, and the 3-year PFS was 39.6%. The PFS for R0 was significantly longer than for non-R0 (3-year PFS: 61.3% vs 25.0%). Recurrence or progression at the primary site was observed in 31% of the non-R0 group. The rate of distant metastasis did not differ significantly between the non-R0 and R0 groups (21% vs 16%)., Conclusions: Long-term follow-up evaluation confirmed that DCF chemoselection aimed at CS is feasible and promising in terms of survival for patients with locally advanced esophageal cancer.