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Importance: Biomarker testing for driver mutations is essential for selecting appropriate non-small cell lung cancer (NSCLC) treatment but is insufficient., Objective: To investigate the status of biomarker testing and drug therapy for NSCLC in Japan for identifying problems in treatment., Design, Setting, and Participants: The REVEAL cohort study included retrospective data collection and prospective follow-up from 29 institutions across Japan. Of 1500 patients diagnosed with advanced or recurrent NSCLC between January 1 and March 18, 2021, 1479 were eligible. Cases recognized at the wrong clinical stage (n = 12), diagnosed outside the study period (n = 6), not treated according to eligibility criteria before recurrence (n = 2), and with deficient consent acquisition procedure (n = 1) were excluded., Main Outcomes and Measures: The primary end point was the biomarker testing status. Treatment-related factors were examined., Results: Among the 1479 patients included in the analysis, the median age was 72 (range, 30-95) years; 1013 (68.5%) were men; 1161 (78.5%) had an Eastern Cooperative Oncology Group performance status 0 or 1; 1097 (74.2%) were current or past smokers; and 947 (64.0%) had adenocarcinoma. Biomarker status was confirmed in 1273 patients (86.1%). Multigene testing was performed in 705 cases (47.7%); single-gene testing, in 847 (57.3%); and both, in 279 (18.9%). Biomarker testing was performed for EGFR in 1245 cases (84.2%); ALK, in 1165 (78.8%); ROS1, in 1077 (72.8%); BRAF, in 803 (54.3%); and MET, in 805 (54.4%). Positivity rates among 898 adenocarcinoma cases included 305 (34.0%) for EGFR, 29 (3.2%) for ALK, 19 (2.1%) for ROS1, 11 (1.2%) for BRAF, and 14 (1.6%) for MET. Positivity rates among 375 nonadenocarcinoma cases were 14 (3.7%) for EGFR, 6 (1.6%) for ALK, 1 (0.3%) for ROS1, 3 (0.8%) for BRAF, and 8 (2.1%) for MET. Poor physical status, squamous cell carcinoma, and other comorbidities were associated with hampered multigene testing. Targeted therapy was received as first-line treatment by 263 of 278 cases (94.6%) positive for EGFR, 25 of 32 (78.1%) positive for ALK, 15 of 24 (62.5%) positive for ROS1, 9 of 12 (75.0%) positive for BRAF, and 12 of 19 (63.2%) positive for MET. Median overall survival of patients with positive findings for driver gene alteration and who received targeted therapy was 24.3 (95% CI, not reported) months; with positive findings for driver gene alteration and who did not receive targeted therapy, 15.2 (95% CI, 7.7 to not reported) months; and with negative findings for driver gene alteration, 11.0 (95% CI, 10.0-12.5) months. Multigene testing for nonadenocarcinomas and adenocarcinomas accounted for 705 (47.7%) of all NSCLC cases., Conclusions and Relevance: These findings suggest that multigene testing has not been sufficiently implemented in Japan and should be considered prospectively, even in nonadenocarcinomas, to avoid missing rare driver gene alterations.

Objectives: In non-small cell lung cancer (NSCLC), T factor plays an important role in determining staging. The present study aimed to determine the validity of preoperative evaluation of clinical T (cT) factor by comparing radiological and pathological tumor sizes., Methods: Data for 1,799 patients with primary NSCLC who underwent curative surgery were investigated. The concordance between cT and pathological T (pT) factors was analyzed. Furthermore, we compared groups with an increase or decrease of ≥ 20% and groups with an increase or decrease of < 20% in the size change between preoperative radiological and pathological diameters., Results: The mean sizes of the radiological solid components and the pathological invasive tumors were 1.90 cm and 1.99 cm, respectively, correlation degree = 0.782. The group with increased pathological invasive tumor size (≥ 20%) compared with the radiologic solid component was significantly more likely female, consolidation tumor ratio (CTR) ≤ 0.5, and within cT1. Multivariate logistic analysis identified CTR < 1, cT ≤ T1, and adenocarcinoma as independent risk factors for increased pT factor., Conclusion: The radiological invasive area of tumors with cT1, CTR < 1, or adenocarcinoma on preoperative CT may be underestimated compared with pathological invasive diameter., (© 2023. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Purpose: Modified reduced FOV diffusion-weighted imaging (DWI) using spatially-tailored 2D RF pulses with tilted excitation plane (tilted r-DWI) has been developed. The purpose of this study was to evaluate the impact on image quality and quantitative apparent diffusion coefficient (ADC) values of tilted r-DWI for pancreatic ductal adenocarcinomas (PDAC) in comparison to conventional full-FOV DWI (f-DWI)., Methods: This retrospective study included 21 patients (mean 70.7, range 50-85 years old) with pathologically confirmed PDAC. All MR images were obtained using 3 T systems. Two radiologists evaluated presence of blurring or ghost artifacts, susceptibility artifacts, and aliasing artifacts; anatomic visualization of the pancreas; interslice signal homogeneity; overall image quality; and conspicuity of the PDAC. For quantitative analysis, contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR), signal-intensity ratio (SIR) and ADC values were measured using regions of interest., Results: All image quality scores except aliasing artifacts in tilted r-DWI were significantly higher than those in f-DWI (p < 0.01). The CNR and SIR of PDAC were significantly higher in tilted r-DWI than in f-DWI (6.7 ± 4.4 vs. 4.7 ± 3.9, 2.02 ± 0.72 vs. 1.72 ± 0.60, p < 0.01). Conversely, the SNR of PDAC in tilted r-DWI was significantly lower than that in f-DWI (56.0 ± 33.1 vs. 113.6 ± 67.3, p < 0.01). No significant difference was observed between mean ADC values of the PDAC calculated from tilted r-DWI (tilted r-ADC) and those from f-DWI (f-ADC) (1225 ± 250 vs. 1294 ± 302, p = 0.11)., Conclusion: The r-DWI using 2D RF techniques with a tilted excitation plane was shown to significantly improve the image quality and CNR and reduce image artifacts compared to f-DWI techniques in MRI evaluations of PDAC without significantly affecting ADC values., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Two authors (T.B., H.I.) were employees of Siemens Healthcare, but the other authors, who are not Siemens Healthcare employees, had control of inclusion of any data and information. The other authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Main Problems: In non-small-cell lung cancer, ground-glass opacity on computed tomography imaging reflects pathological noninvasiveness and is a favorable prognostic factor. However, the significance of pathological noninvasive areas (NIAs) has not been fully revealed. In this study, we aimed to elucidate the prognostic impact of NIAs on lung adenocarcinoma., Methods: We analyzed 402 patients with pathological stage (p-Stage) IA lung adenocarcinoma who underwent surgery in 2013-2016 at two institutions and examined the association of the presence of NIAs with clinicopathological factors and prognosis. Furthermore, after using propensity-score matching to adjust for clinicopathological factors, such as age, sex, smoking history, pathological invasive area size, pathological T factor (p-T), p-Stage, and histological subtype (lepidic predominant adenocarcinoma [LPA] or non-LPA), the prognostic impact of NIAs was evaluated., Results: Patients were divided into NIA-present (N = 231) and NIA-absent (N = 171) groups. Multivariable analysis showed that NIA-present was strongly associated with earlier p-T, earlier p-Stage, LPA, and epidermal growth factor receptor mutation. Kaplan-Meier survival analysis showed that the NIA-present group displayed a better prognosis than the NIA-absent group in disease-free survival (DFS) and overall survival (OS) (5-year DFS 94.6% vs. 87.2%, 5-year OS 97.2% vs. 91.1%). However, after adjusting for clinicopathological factors by propensity score matching, no significant differences in prognosis were identified between the NIA-present and NIA-absent groups (5-year DFS 92.4% vs 89.6%, 5-year OS 95.6% vs 94.3%)., Conclusions: Our current study suggests that the prognostic impact of the presence of NIAs on lung adenocarcinoma is due to differences in clinicopathological factors., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Objectives: Programmed death ligand 1 and 2 (PD-L1 and PD-L2) bind programmed death 1 (PD-1). PD-L1 is an established predictive biomarker of response to immunotherapies targeting PD-1 and PD-L1 in lung adenocarcinoma (LUAD). However, the clinical relevance of PD-L2 expression in patients with LUAD remains unclear; we aimed to examine this aspect using LUAD specimens., Materials and Methods: PD-L2 expression status was immunohistochemically evaluated in 980 surgically resected LUAD specimens. PD-L2 expression status was classified based on the tumor proportion score (TPS) as negative (<1%), weakly positive (1-49%), or strongly positive (≥50%). Correlations between PD-L2 and PD-L1 expression status, clinicopathological features, driver oncogene alterations (EGFR, KRAS, ALK, ROS1, and RET), and prognosis were also analyzed., Results: PD-L2 expression was negative in 720 (73%) of 980 LUADs, weakly positive in 190 (19%), and strongly positive in 70 (7%). The concordance rate between PD-L1 and PD-L2 expression was 60%. Male sex, smokers, tumors > 3 cm in size, high-grade tumors, tumors without EGFR mutation or ALK fusion, and tumors with KRAS mutation were more common in patients with PD-L2-positive tumors (TPS ≥ 1%) than in patients with PD-L2-negative tumors (TPS < 1%). PD-L2 expression was not associated with overall survival (OS) or relapse-free survival (RFS). However, positive PD-L2 expression tended to be associated with better OS/RFS in PD-L1-positive patients and worse OS/RFS in PD-L1-negative patients., Conclusions: PD-L2-positive LUADs showed biologically aggressive characteristics. PD-L2 expression status was not associated with survival outcomes, but tended to show contrasting prognostic impacts based on PD-L1 expression status., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The microbial population of the intestinal tract and its relationship to specific diseases has been extensively studied during the past decade. However, reports characterizing the bile microbiota are rare. This study aims to investigate the microbiota composition in patients with pancreaticobiliary cancers and benign diseases by 16S rRNA gene amplicon sequencing and to evaluate its potential value as a biomarker for the cancer of the bile duct, pancreas, and gallbladder., Results: We enrolled patients who were diagnosed with cancer, cystic lesions, and inflammation of the pancreaticobiliary tract. The study cohort comprised 244 patients. We extracted microbiome-derived DNA from the bile juice in surgically resected gallbladders. The microbiome composition was not significantly different according to lesion position and cancer type in terms of alpha and beta diversity. We found a significant difference in the relative abundance of Campylobacter, Citrobacter, Leptotrichia, Enterobacter, Hungatella, Mycolicibacterium, Phyllobacterium and Sphingomonas between patients without and with lymph node metastasis., Conclusions: There was a significant association between the relative abundance of certain microbes and overall survival prognosis. These microbes showed association with good prognosis in cholangiocarcinoma, but with poor prognosis in pancreatic adenocarcinoma, and vice versa. Our findings suggest that pancreaticobiliary tract cancer patients have an altered microbiome composition, which might be a biomarker for distinguishing malignancy., (© 2022. The Author(s).)

Background: The mainstream first-line chemotherapy for advanced/recurrent gastric cancer (ARGC) is combination therapy including platinum-based agents. With the progressive aging of the society, the incidence of gastric cancer in elderly patients is increasing. However, elderly patients cannot tolerate these agents because of renal dysfunction or low quality of life. The KSCC1701 study explored the efficacy and safety of S-1 + ramucirumab in elderly patients with ARGC., Patients and Methods: Chemotherapy-naive patients aged ≥70 years with ARGC were eligible. Patients received S-1 (40-60 mg twice daily for 4 weeks in 6-week cycles) and ramucirumab (8 mg/kg every 2 weeks) until disease progression. The primary end-point was the 1-year overall survival (OS) rate. The anticipated lower threshold of 1-year survival was set at 40% in light of previous S-1-based regimens. The secondary end-points included progression-free survival (PFS), OS, the overall response rate (ORR) and safety., Results: Between September 2017 and November 2019, 48 patients (34 men and 14 women) were enrolled in this study. The median patient age was 77.5 years, and all patients had a performance status of 0 (n = 20) or 1 (n = 28). The 1-year OS rate was 65.2%, which met the primary end-point. The median survival time and median PFS were 16.4 and 5.8 months, respectively. The ORR was 41.9%. The most frequent grade 3/4 (≥15%) adverse events were neutropenia, anorexia and anaemia., Conclusion: Considering these findings, S-1 + ramucirumab appears to be an excellent treatment option for elderly patients with ARGC. (250 words). This trial has been registered with the Japan Registry of Clinical Trials Registry under the number jRCTs071180066., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Perioperative chemotherapy is the standard of care for locally advanced gastric cancer (LAGC). This phase II study investigated the efficacy and safety of S-1 and oxaliplatin (SOX) as neoadjuvant chemotherapy (NAC) for LAGC and esophagogastric junction cancer (EGJC)., Methods: Patients completed up to three cycles of SOX 130 (oxaliplatin 130 mg/m 2 on day 1, oral S-1 40-60 mg twice daily for 2 weeks every 3 weeks), followed by gastrectomy and D2 lymphadenectomy. The primary endpoint was the pathological response rate (pRR). The anastomosis leakage rate was the secondary endpoint in patients with EGJC, and other secondary endpoints were the R0 resection, overall survival (OS), and relapse-free survival (RFS) rates., Results: Between April 2016 and July 2017, 47 patients (24 EGJC, 23 LAGC) were enrolled in this study. Forty-two patients (89.4%, 95% confidence interval [CI] = 76.9-96.5) underwent surgery, and R0 resection was achieved in 41 patients. The pRR was 59.5% (90% CI = 45.7-72.3). The major grade 3 or 4 toxicities were appetite loss in six patients (12.8%), thrombocytopenia in five patients (10.6%), and neutropenia and diarrhea in three patients (6.4%) each. The rate of severe anastomotic leakage (Clavien-Dindo classification grade III or higher) in 20 EGJC was 25.0% (90% CI = 10.4-45.6). The 3-year OS and RFS rate were 62.9% (95% CI = 47.2-75.1) and 53.2% (95% CI = 38.1-66.2), respectively., Conclusion: SOX 130 demonstrated substantial benefit for LAGC and EGJC. However, special attention should be paid to anastomotic leakage during surgery for EGJC., (© 2021. The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Objective: To investigate whether radical hysterectomy (RAH) can effectively treat true Stage IIB (pTIIB) cervical adenocarcinoma (AC) because FIGO (clinical) Stage IIB cervical cancer is rarely treated with RAH and radiotherapy has unfavorable effects on AC., Methods: We retrospectively analyzed data for 82 patients with Stage pTIIB cervical cancer who underwent RAH at our institution between January 1997 and December 2017. The end points were disease-free survival (DFS) and overall survival (OS) among squamous cell carcinoma (SCC) (n = 60) and AC (n = 22) patients. Kaplan-Meier survival analysis with and without propensity score matching was conducted to identify the impact of RAH., Results: Para-aortic lymph node metastasis and tumor diameter were significant factors for recurrence, and adjuvant chemotherapy prevented recurrence on multivariate analysis. After propensity score matching, there was no significant difference in DFS and OS between the groups. Five-year DFS and OS of the SCC group were 0.505 (95% confidence interval [CI] 0.268-0.702) and 0.619 (95% CI 0.351-0.803), respectively, and those of the AC group were 0.444 (95% CI 0.232-0.638) and 0.602 (95% CI 0.351-0.782), respectively., Conclusion: Bulky Stage pTIIB cervical cancer is hard to cure, but RAH plus adjuvant therapy might be an option for radio-resistant pTIIB cervical AC., (© 2020 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Background: Several inflammation-based prognostic scores have a prognostic value in patients with various cancers. This study investigated the prognostic value of various inflammation-based prognostic scores in patients who underwent a surgery for adenocarcinoma of the esophagogastric junction (AEG) and upper gastric cancer (UGC)., Methods: We reviewed data of 206 patients who underwent surgery for AEG and UGC. We calculated neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), Glasgow Prognostic Score (GPS), modified GPS (mGPS), C-reactive protein (CRP)/albumin (Alb) ratio, prognostic index (PI), and prognostic nutritional index (PNI) and analyzed the relationship between these biomarkers and postoperative prognosis., Results: In multivariate analyses for overall survival, mGPS (P = 0.0337, hazard ratio [HR] = 5.211), PI (P = 0.0002, HR = 21.20), and PNI (P < 0.0001, HR = 6.907) were identified as independent predictive factors. A multivariate analysis for recurrence-free survival showed that only PI (P = 0.0006, HR = 11.89) and PNI (P = 0.0002, HR = 4.972) were independent predictive factors among the above-mentioned inflammation-based prognostic scores., Conclusions: In various inflammation-based prognostic scores, PI and PNI were more strongly associated with poor prognosis in patients who underwent surgery for AEG and UGC.

Background: Preoperative chemoradiotherapy (CRT), the current standard of care for locally advanced rectal cancer (LARC), is associated with many radiotherapy (RT)-related side effects. We aimed to evaluate whether S-1 and oxaliplatin (SOX) or folinic acid, 5-FU, and oxaliplatin (mFOLFOX6) can be as effective as neoadjuvant chemotherapy (NAC) regimens for LARC without RT., Methods: Patients with untreated resectable LARC were randomly assigned to receive SOX or mFOLFOX6. The NAC protocol period was 3 months. The primary endpoint was 3-year disease-free survival (DFS), and the secondary endpoints included pathological effects, surgical completion rate, 3-year survival, and safety., Results: From September 2013 to October 2015, 56 and 54 patients were enrolled in the SOX and mFOLFOX6 arms, respectively. The 3-year DFS rates were 69.4% (95% confidence interval [CI] 54.9-83.6) and 73.4% (95% CI 58.7-83.6) in the SOX and mFOLFOX6 arms, respectively; no significant differences were found between the arms (log-rank test; P = 0.5315, hazard ratio: 0.808, 95% CI 0.414-1.578). The 3-year survival rates were 92.3 and 91.8% in the SOX and mFOLFOX6 arms, respectively. The surgical completion rate was 98.1% overall, 100% in the SOX arm, and 96.0% in the mFOLFOX6 arm. The incidences of pathological response rates ≥grade 1b were 41.5 and 43.8% in the SOX and mFOLFOX6 arms, respectively. Both treatments were manageable and tolerable., Conclusion: We demonstrated the effectiveness and safety of SOX and mFOLFOX6, both of which may be new neoadjuvant treatment candidates in previously untreated LARC cases., Trial Registration: Date of enrolment of the first participant to the trial: 3rd Oct 2013; This study was registered in the UMIN clinical trials registry on 14th Aug, 2013. (Prospectively registered, UMIN-CTR number UMIN000011486). https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&recptno=R000013441&language=J.

Background: Triweekly capecitabine plus irinotecan (CAPIRI) was not a replacement for fluorouracil, leucovorin, and irinotecan (FOLFIRI) in the treatment of metastatic colorectal cancer (mCRC) because of the potential for greater toxicity. Recently, it has reported that mCAPIRI is well tolerated and non-inferior to FOLFIRI. In this study, we conducted a multicenter phase II trial to assess the efficacy and safety of biweekly CAPIRI plus bevacizumab as second-line chemotherapy for mCRC with reduced toxicity and preserved efficacy., Methods: Patients with mCRC who had received prior chemotherapy, including oxaliplatin-based regimens, were eligible for this study. The treatment protocol administered capecitabine at 1000 mg/m 2 twice daily from the evening of day 1 to the morning of day 8, intravenous irinotecan at 150 mg/m 2 on day 1, and bevacizumab at 10 mg/kg on day 1 every 2 weeks. Primary endpoints for this study were progression-free survival (PFS) and safety. Secondary endpoints were overall survival (OS), time to treatment failure, response rate (RR), and disease control rate (DCR)., Results: Fifty-one patients were enrolled in this study. Median PFS was 5.5 months [95% confidence interval (CI) 4.23-7.40 months], and median OS was 13.5 months (95% CI 11.57-20.23 months). The RR was 14.6% (95% CI 6.5-28.4%), and the DCR was 66.7% (95% CI 51.5-79.2%). Hypertension was the most common Grade 3 adverse event (27.5%), followed by neutropenia (17.6%). Only two patients suffered from grade 3 hand-foot syndrome., Conclusions: In mCRC patients, biweekly CAPIRI + bevacizumab appears effective and feasible as a second-line chemotherapy with relatively low toxicities, and has potential as a useful substitute for FOLFIRI + bevacizumab.

Background: Programmed death-ligand 1 (PD-L1) expression on lung cancer cells is a prognostic marker and a predictive biomarker for response to immunotherapy. However, previous clinical trials have suggested that other programmed cell death 1 ligands, including programmed death-ligand 2 (PD-L2), might have clinical impacts. This study aimed to analyze the prognostic significance of PD-L2 expression in lung adenocarcinoma patients., Methods: The study included 433 patients who underwent surgical resection for lung adenocarcinoma between 2003 and 2012 at Kyushu University Hospital. Both PD-L1 and PD-L2 expression were evaluated by immunohistochemistry. The cutoff value for PD-L2 positivity was set at 1% according to a time-dependent receiver operating characteristic curve for 5-year survival., Results: Of the 433 patients, 306 (70.7%) were positive for PD-L2. No significant association between PD-L1 and PD-L2 expression was observed (P = 0.094). The multivariate analysis showed that the independent predictors of PD-L2 positivity were never-smoker status (P = 0.002), poor differentiation grade (P = 0.008), and advanced stage (P = 0.048). The PD-L2-positive patients had significantly shorter disease-free survival (DFS) (P = 0.018) and overall survival (OS) (P = 0.016). Both PD-L1 and PD-L2 positivity were independent predictors of OS (P < 0.001 and P = 0.027, respectively). In the subgroup analysis of the PD-L1-negative patients, PD-L2 positivity was significantly associated with shorter DFS (P = 0.018)., Conclusions: The study demonstrated that the clinical characteristics of patients with PD-L1 expression may differ from those of patients with PD-L2 expression, and that both might contribute to poor prognoses. The potential role of PD-L2 expression as a predictive biomarker for response to immunotherapy should be investigated in future studies.

Background: Anti-HER2 therapy has not demonstrated a survival advantage in the second-line setting of patients with HER2-positive gastric cancer. We conducted this study to assess changes in HER2 status and to identify possible biomarkers for acquired resistance after the use of trastuzumab as the first-line therapy., Patients and Methods: Patients with advanced or recurrent HER2-positive gastric adenocarcinoma who were diagnosed with progressive disease after the first-line trastuzumab-based therapy and developed pathologically confirmed adenocarcinoma within 3 months after completion of trastuzumab-based therapy were enrolled in this study. We collected re-biopsied samples from the HER2-positive patients who had developed resistance to trastuzumab and re-evaluated their HER2 status. Amplification of EGFR and c-met, as well as PIK3CA mutation, were comparatively analysed when samples were available., Results: Among 33 eligible patients, loss of HER2 was identified in 20 patients (60.6%) with refractory disease. Immunohistochemistry showed that the rate of HER2 overexpression was greatly reduced after therapy (pre-HER2 3+: 24 [72.7%] vs. post-HER2 3+: 13 [39.4%]). We found that the use of fixatives other than 10% neutral buffered formalin significantly reduced the HER2-positive rate. EGFR amplification, c-met amplification and PIK3CA mutation before and after trastuzumab-based therapy were observed in 10.3% and 3.8%, 17.9% and 4.2% and 4.0% and 4.2% of cases, respectively., Conclusion: Re-evaluation of HER2 status is needed to determine the appropriate use of anti-HER2-targeted therapy after disease progression. Our results also highlight the importance of formalin fixation conditions for HER2 testing., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim: A combination of immune-checkpoint inhibitors that target the programmed cell death 1 (PD1)/programmed cell-death ligand 1 (PDL1) pathway and indoleamine 2,3-dioxygenase 1 (IDO1) is a promising treatment for non-small-cell lung cancer. Herein, we investigated clinical features of IDO1 + /PDL1 + primary lung adenocarcinoma., Materials and Methods: IDO1 and PDL1 expression in 388 resected primary lung adenocarcinoma samples was evaluated using immunohistochemistry, and the radiological features of patients with IDO1 + /PDL1 + lung adenocarcinoma were analyzed., Results: Of 388 specimens, 229 (59.0%) were IDO1 + , 131 (33.8%) were PDL1 + , and 109 (28.1%) were IDO1 + /PDL1 + In multivariate analysis, vascular convergence and the absence of surrounding ground glass opacity were significantly associated with IDO1 + /PDL1 + tumors. Fisher's exact test showed high consolidation/tumor ratio was also significantly associated with IDO1 + /PDL1 + tumors. Moreover, maximum standardized uptake in 18 F-fluorodeoxyglucose positron-emission tomography/computed tomography was significantly higher in patients with IDO1 + /PDL1 + tumors than in those with IDO1 - or PDL1 - tumors., Conclusion: IDO1/PDL1 co-expression was significantly related to radiological invasiveness and malignancy in lung adenocarcinoma. This study may help select patients likely to benefit from combination therapy using immune-checkpoint inhibitors., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive effector, and its expression is associated with prognosis in several cancer types. Here, we investigated the relationship between IDO1 expression in lung adenocarcinoma and patient prognosis and clinicopathological features, including programmed cell death-ligand 1 (PD-L1) expression., Materials and Methods: In this study, surgically resected primary lung adenocarcinoma specimens from 427 patients were evaluated for IDO1 and PD-L1 expression by immunohistochemistry, and lung adenocarcinoma cell lines were evaluated for IDO1 and PD-L1 protein expression by enzyme-linked immunosorbent assay and flow cytometry and for messenger RNA levels by real-time reverse-transcriptase polymerase chain reaction analysis., Results: IDO1 was expressed in 260 patients (60.9%) at 1% cut-off and 63 patients (14.8%) at 50% cut-off. Tissues from 145 patients (34.0%) were positive for PD-L1 using the cut-off of 1%. Multivariate analysis showed that ≥1% IDO1 positivity was significantly associated with higher tumour grade, vascular invasion and PD-L1 expression. IDO1 and PD-L1 proteins were co-expressed in 123 patients (28.8%), and co-expressing tumours exhibited significantly more malignant traits than those positive for one or neither protein. In multivariate analysis, co-expression of IDO1 and PD-L1 was significantly associated with shorter disease-free survival and overall survival. Both proteins were upregulated in lung adenocarcinoma cell lines by treatment with interferon-γ and transforming growth factor-β., Conclusion: These results suggest that IDO1 and PD-L1 co-expression may define an aggressive form of lung adenocarcinoma., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Recent sequencing analyses have shed light on heterogeneous patterns of genomic aberrations in human gastric cancers (GCs). To explore how individual genetic events translate into cancer phenotypes, we established a biological library consisting of genetically engineered gastric organoids carrying various GC mutations and 37 patient-derived organoid lines, including rare genomically stable GCs. Phenotype analyses of GC organoids revealed divergent genetic and epigenetic routes to gain Wnt and R-spondin niche independency. An unbiased phenotype-based genetic screening identified a significant association between CDH1/TP53 compound mutations and the R-spondin independency that was functionally validated by CRISPR-based knockout. Xenografting of GC organoids further established the feasibility of Wnt-targeting therapy for Wnt-dependent GCs. Our results collectively demonstrate that multifaceted genetic abnormalities render human GCs independent of the stem cell niche and highlight the validity of the genotype-phenotype screening strategy in gaining deeper understanding of human cancers., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have been approved as a standard therapy for metastatic non-small cell lung cancer (NSCLC). Although PD-L1 expression serves as a predictive biomarker for the efficacy of immunotherapy, there are no established biomarkers to predict the expression of PD-L1. The inflammatory markers C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) were recently shown to predict the efficacy of nivolumab for NSCLC patients. Therefore, here we investigated the potential association of PD-L1 expression with systemic inflammatory markers, including CRP, NLR, lymphocyte-monocyte ratio and platelet-lymphocyte ratio., Methods: We retrospectively examined tumor PD-L1 expression in 508 surgically resected primary NSCLC cases by immunohistochemical analysis (cut-off value: 1%). The association of PD-L1 expression with preoperative systemic inflammatory markers was assessed by univariate and multivariate analyses. We generated a PD-L1 association score (A-score) from serum CRP level (cut-off value: 0.3 mg/dl) and smoking status to predict PD-L1 expression., Results: Among the total 508 patients, 188 (37.0%) patients were positive for PD-L1 expression at the 1% cut-off value and 90 (17.5%) had elevated serum CRP level. Multivariate logistic regression revealed that PD-L1 positivity was significantly associated with advanced stage, the presence of vascular invasion and high serum CRP level (P = .0336, .0106 and 0.0018, respectively). Though not significant, smoking history tended to be associated with PD-L1 protein expression (P = .0717). There was no correlation with other inflammatory markers. Smoking history with elevated CRP level (A-score: 2) was strongly associated with PD-L1 protein expression (odds ratio: 5.18, P < .0001), while it was inversely associated with EGFR mutation (odds ratio: 0.11, P < .0001)., Conclusions: Our results indicate that among all systemic inflammatory markers examined, serum CRP seems to predict PD-L1 expression in patients with NSCLC however the clinical applicability is limited given the obtained area under the receiver operating characteristic curve values., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: The development of immune checkpoint inhibitors against programmed death 1 has paved the way for a new era of treatment of lung cancer. Programmed death-ligand 1 (PD-L1) is expected to predict the response of immune checkpoint inhibitors in lung cancer. Predicting PD-L1 expression using a noninvasive method before immunotherapy would, therefore, help identify patients for whom immunotherapy can be successful., Patients and Methods: A total of 394 patients with resected lung adenocarcinoma who had undergone preoperative thin-section computed tomography (CT) were analyzed for PD-L1 expression by immunohistochemistry and evaluated to determine the association between PD-L1 expression and CT characteristics, including convergence, surrounding ground glass opacity (GGO), air bronchogram, notching, pleural indentation, spiculation, and cavitation., Results: Of the 394 patients, 78 (19.8%) were positive and 316 (80.2%) were negative for PD-L1 expression. Univariate analysis demonstrated that PD-L1 + adenocarcinoma was significantly associated with the presence of convergence (P < .01), notching (P < .01), spiculation (P < .01), and cavitation (P < .01) and the absence of surrounding GGO (P < .01) compared with PD-L1 - cases. On multivariate analysis, the presence of convergence (P < .01) and cavitation (P < .01) and the absence of surrounding GGO (P = .02) and air bronchogram (P = .03) were significantly associated with PD-L1 expression., Conclusion: PD-L1 + adenocarcinoma cases showed convergence and cavitation more frequently than did PD-L1 - cases. In contrast, surrounding GGO and air bronchogram were observed less frequently in PD-L1 + cases than in PD-L1 - cases. These results will prove helpful in identifying PD-L1-expressing adenocarcinoma by CT before immunotherapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: The clinicopathological features of carcinomas expressing programmed death ligand 1 (PD-L1) and their associations with common driver mutations, such as mutations in the EGFR gene, in lung adenocarcinoma are not clearly understood. Here, we examined PD-L1 protein expression in surgically resected primary lung adenocarcinoma and the association of PD-L1 protein expression with clinicopathological features, EGFR mutation status, and patient outcomes., Methods: The expression of PD-L1 protein in 417 surgically resected primary lung adenocarcinomas was evaluated by immunohistochemical analysis. The cutoff value for defining PD-L1 positivity was determined according to the histogram of proportions of PD-L1-positive cancer cells., Results: Samples from 85 patients (20.4%) and 144 patients (34.5%) were positive for PD-L1 protein expression according to 5% and 1% PD-L1 cutoff values, respectively. Fisher's exact tests showed that PD-L1 positivity was significantly associated with male sex, smoking, higher tumor grade, advanced T status, advanced N status, advanced stage, the presence of pleural and vessel invasions, micropapillary or solid predominant histological subtypes, and wild-type EGFR. Univariate and multivariate survival analyses revealed that patients with PD-L1 positivity had poorer prognoses than those without PD-L1 protein expression at the 1% cutoff value (disease-free survival p < 0.0001, overall survival p < 0.0001)., Conclusions: PD-L1 protein expression was significantly higher in smoking-associated adenocarcinoma and in EGFR mutation-negative adenocarcinoma. PD-L1 protein expression was associated with poor survival in patients with lung adenocarcinoma. The PD-L1/programmed cell death 1 pathway may contribute to the progression of smoking-associated tumors in lung adenocarcinoma., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Jumonji domain-containing 2B, JMJD2B, has been shown to play an important role in the pathogenesis of lung cancer cells. However, the significance of JMJD2B in patients with lung cancer remains to be elucidated., Patients and Methods: Seventy-eight patients with resected adenocarcinoma, whose data regarding oncogenic drivers in lung cancer were available, were included in the study. Immunohistochemical analysis was performed with a specific antibody for JMJD2B to investigate JMJD2B expression and the significance of JMJD2B expression in survival after surgery was evaluated., Results: Among the 78 patients, 50 (64%) exhibited JMJD2B immunopositivity. The overall survival (OS) of the 50 JMJD2B-positive patients after surgery was significantly inferior to that of the JMJD2B-negative patients (five-year survival=56.7% vs. 92.6%; log-rank: p=0.01). Multivariate analysis showed that JMJD2B positivity was an independent prognostic factor., Conclusion: JMJD2B may be a novel prognostic factor for resected lung adenocarcinoma., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Introduction: Results from several randomised trials suggest that the sequential use of cytotoxic agents in patients with metastatic colorectal cancer (mCRC) has the potential to improve overall survival compared with combination chemotherapy. This study is designed to investigate whether sequential treatment with bevacizumab-based first-line treatment with oxaliplatin is superior to combination treatment of mCRC., Methods and Analysis: The C-cubed (C(3)) study is a two-arm, multicentre, open-label, randomised phase III trial in Japan comparing the efficacy and safety of sequential capecitabine or 5-fluorouracil plus bevacizumab (Cape/5-FU-Bmab) with escalation to capecitabine or 5-fluorouracil plus oxaliplatin plus bevacizumab (CapeOX/mFOLFOX6-Bmab) versus combination CapeOX/mFOLFOX6-Bmab as the first-line treatment of mCRC. In the sequential arm (Arm A: oxaliplatin 'wait-and-go'), treatment escalation from Cape/5-FU-Bmab to CapeOX/mFOLFOX6-Bmab is recommended in the case of progressive disease. In the combination arm (Arm B: oxaliplatin 'stop-and-go'), de-escalation from CapeOX/mFOLFOX6-Bmab to Cape/5-FU-Bmab is possible after 12 weeks of treatment. Re-escalation to CapeOX/mFOLFOX6-Bmab after progressive disease is considered only for patients who received de-escalation of oxaliplatin after 12 weeks of treatment not caused by oxaliplatin-associated toxicity. A target sample size of 304 evaluable patients is considered sufficient to validate an expected HR for time to failure of strategy of the sequential approach 'wait-and-go' compared to the combination approach 'stop-and go' with 80% power and 2-sided 5% α in case of a true HR<0.69., Ethics and Dissemination: This study is conducted according to the standards of Good Clinical Practice and in compliance with the Declaration of Helsinki 2013 and local regulations, and has been submitted and approved by the Ethical Committee of the Non-Profit Organization MINS Institutional Review Board. The protocol and the trial results, even inconclusive, will be presented at international oncology congresses and published in peer-reviewed journals., Trial Registration Number: UMIN000015405, Pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Adjuvant chemotherapy (AC) is recommended as a standard treatment after curative resection in patients with pancreatic adenocarcinoma (PA). Although patients who failed to complete AC had significantly worse survival compared with those who completed AC for cancers in various organs, the effects of complete AC on survival in patients with PA have not been investigated. The purpose of this study was to clarify the impact of complete AC on PA patient survival and to identify independent risk factors for incomplete AC., Methods: Medical records of 236 consecutive PA patients who planned to undergo surgical resection with curative intent between January 2000 and September 2012 at Kobe University Hospital were retrospectively reviewed. Of these, the complete AC (n = 75) and the incomplete AC (n = 30) groups due to adverse events were compared., Results: Patient survival was significantly better in the complete AC group than in the incomplete AC group (median survival time 48.9 vs. 17.9 months; 5-year survival rate 42.7 vs. 17.1 %; p < 0.0001). Preoperative white blood cell count and postoperative serum albumin level were identified as independent risk factors for incomplete AC. By receiver operating characteristic curve analysis, the cutoff value of postoperative serum albumin level was 3.1 mg/dL., Conclusions: PA patients who completed AC had significantly better survival than those who failed to complete AC. Postoperative serum albumin level is a marker for failure to complete AC. Further prospective studies are needed to determine whether perioperative nutritional intervention could increase AC completion rate and improve prognosis in PA patients.

Cetuximab-containing treatments for metastatic colorectal cancer have been shown to have higher overall response rates and longer progression-free and overall survival than other systemic therapies. Cetuximab-related manifestations, including severe skin toxicity and early tumor shrinkage, have been shown to be predictors of response to cetuximab. We hypothesized that early skin toxicity is a predictor of response and better outcomes in patients with advanced colorectal carcinoma. We retrospectively evaluated 62 patients with colorectal adenocarcinoma who had unresectable tumors and were treated with cetuximab in our institution. Skin toxicity grade was evaluated on each treatment day. Tumor size was evaluated using computed tomography prior to treatment and 4-8 weeks after the start of treatment with cetuximab.Patients with early tumor shrinkage after starting treatment with cetuximab had a significantly higher overall response rate (P = 0.0001). Patients with early skin toxicity showed significantly longer overall survival (P = 0.0305), and patients with higher skin toxicity grades had longer progression-free survival (P = 0.0168).We have shown that early tumor shrinkage, early onset of skin toxicity, and high skin toxicity grade are predictors of treatment efficacy and/or outcome in patients with advanced colorectal carcinoma treated with cetuximab.

Human colorectal tumors bear recurrent mutations in genes encoding proteins operative in the WNT, MAPK, TGF-β, TP53 and PI3K pathways. Although these pathways influence intestinal stem cell niche signaling, the extent to which mutations in these pathways contribute to human colorectal carcinogenesis remains unclear. Here we use the CRISPR-Cas9 genome-editing system to introduce multiple such mutations into organoids derived from normal human intestinal epithelium. By modulating the culture conditions to mimic that of the intestinal niche, we selected isogenic organoids harboring mutations in the tumor suppressor genes APC, SMAD4 and TP53, and in the oncogenes KRAS and/or PIK3CA. Organoids engineered to express all five mutations grew independently of niche factors in vitro, and they formed tumors after implantation under the kidney subcapsule in mice. Although they formed micrometastases containing dormant tumor-initiating cells after injection into the spleen of mice, they failed to colonize in the liver. In contrast, engineered organoids derived from chromosome-instable human adenomas formed macrometastatic colonies. These results suggest that 'driver' pathway mutations enable stem cell maintenance in the hostile tumor microenvironment, but that additional molecular lesions are required for invasive behavior.

Purpose: Lung adenocarcinomas among never-smokers are more common in females than in males. This implies that gender-dependent hormones promote smoking unrelated lung adenocarcinoma. We therefore investigated mRNA expression of aromatase, an intrinsic estrogen synthetase, in lung adenocarcinoma and assessed its correlation to clinicopathologic factors, including EGFR mutations and postsurgical prognosis., Experimental Design: Aromatase mRNA expression in primary tumor samples from 110 patients with lung adenocarcinoma was evaluated with qRT-PCR. Inhibitory effects of the aromatase inhibitor exemestane were assessed in lung adenocarcinoma cell lines (11-18 and HCC4006), which have EGFR mutations, separately and combined with EGFR tyrosine kinase inhibitor erlotinib., Results: Aromatase gene expression was not correlated with patients' clinicopathologic factors, including EGFR mutation status. High aromatase expression was associated with poor prognosis for both recurrence-free survival (P = 0.004) and overall survival (P = 0.003). In addition, the prognostic significance of aromatase expression was limited to females, never-smokers, and patients with EGFR mutations, but not in their counterparts. HCC4006, which has a low aromatase mRNA expression level, was not sensitive to exemestane, either alone or combined with erlotinib. In contrast, growth of 11-18 cells, which have high aromatase expression, was significantly inhibited by exemestane, both alone and combined with erlotinib., Conclusions: Aromatase is a candidate prognostic factor in patients with lung adenocarcinoma, especially in those with EGFR mutations, and may also be a beneficial therapeutic target in those patients., (©2014 American Association for Cancer Research.)

Objective: To identify prognostic factors of recurrent endometrial cancer, and clarify whether the treatment-free interval (TFI) predicts outcome in a wide spectrum of patients., Study Design: The clinical data of 60 patients treated for recurrent stage I-IV endometrial cancer between 1997 and 2012 were reviewed retrospectively. The Kaplan-Meier method and Cox regression analysis were used to estimate overall survival (OS) following recurrence and determine the factors influencing outcomes., Results: The median age at initial treatment was 59 (range 38-80) years and the median post-recurrence overall survival time was 40.0 (range 1.8-156.7) months. Multivariate analysis showed lymph node metastasis (hazard ratio (HR) 2.80; 95% confidence interval (95%CI) 1.29-6.09; p=0.009), TFI (HR 0.33; 95% CI 0.15-0.76; p=0.008), and symptomatic recurrence (HR 2.31, 95% CI 1.11-4.83, p=0.0025) were independent prognostic factors. Patients whose tumors recurred after a TFI≥12 months had better response rates than did those with a TFI<12 months (p<0.001)., Conclusion: TFI is a significant prognostic factor in recurrent endometrial cancer. Furthermore, the effect of chemotherapy on recurrent endometrial cancer is probably influenced by the duration of TFI., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)