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Purpose: Dexamethasone (DEX)-sparing strategies (one-day DEX) with palonosetron as doublet antiemetic prophylaxis have previously been studied. However, DEX-sparing regimens with 5-hydroxytryptamine-3 receptor antagonist (5-HT 3 RA) and aprepitant (APR), as triplet antiemetic prophylaxis, have not been evaluated. This study aimed to evaluate the efficacy of a combination of 5-HT 3 RA, APR, and DEX on day 1 of carboplatin (CBDCA)-based chemotherapy in patients with lung cancer., Methods: Data were pooled from a nationwide, multicenter, prospective observational study using propensity score-matched analysis to compare the incidence of chemotherapy-induced nausea and vomiting (CINV) between one- and multiple-day DEX regimens in combination with 5-HT 3 RA plus APR., Results: Incidence of delayed nausea was significantly higher in the one-day than in the multiple-day DEX group. Incidence of nausea was also significantly higher in the one-day than in the multiple-day DEX group on days 3-5. Kaplan-Meier curves for nausea showed a significant difference between the two groups; however, there was no significant difference in the occurrence of vomiting or the Kaplan-Meier curves of time to vomiting., Conclusion: To the best of our knowledge, this study is the first to evaluate the efficacy of a DEX-sparing regimen by comparing one- and multiple-day DEX combined with 5-HT 3 RA and APR concerning CINV incidence in lung cancer patients receiving CBDCA-based chemotherapy. Antiemetic regimens of one-day DEX result in poor control of delayed nausea; therefore, we recommend the application of the DEX-sparing strategy only after careful patient selection while considering the development of nausea., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Background: No effective molecular targeted therapy has been established for SCC. We conducted a comprehensive study of SCC patients using RNA-sequencing and TCGA dataset to clarify the driver oncogene of SCC., Method: Forty-six samples of 23 patients were totally analyzed with RNA-sequencing. We then searched for candidate-oncogenes of SCC using the TCGA database. To identify candidate oncogenes, we used the following 2 criteria: (1) the genes of interest were overexpressed in tumor tissues of SCC patients in comparison to normal tissues; and (2) using an integrated mRNA expression and DNA copy number profiling analysis using the TCGA dataset, the DNA copy number of the genes was positively correlated with the mRNA expression., Result: We identified 188 candidate-oncogenes. Among those, the high expression of SLC38A7 was a strong prognostic marker that was significantly associated with a poor prognosis in terms of both overall survival (OS) and recurrence-free survival in the TCGA dataset (P < 0.05). Additionally, 202 resected SCC specimens were also subjected to an immunohistochemical analysis. Patients with the high expression of SLC38A7 (alternative name is sodium-coupled amino acid transporters 7) protein showed significantly shorter OS in comparison to those with the low expression of SLC38A7 protein [median OS 3.9 years (95% confidence interval, 2.4-6.4 years) vs 2.2 years (95% confidence interval, 1.9-4.1 years); log rank test: P = 0.0021]., Conclusion: SLC38A7, which is the primary lysosomal glutamine transporter required for the extracellular protein-dependent growth of cancer cells, was identified as a candidate therapeutic target of SCC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Comprehensive analysis of clinical samples has recently identified molecular and immunological classification of hepatocellular carcinoma (HCC), and the CTNNB1 (β-catenin)-mutated subtype exhibits distinctive characteristics of immunosuppressive tumor microenvironment. For clarifying the molecular mechanisms, we first established human and mouse HCC cells with exon 3 skipping of β-catenin, which promoted nuclear translocation and activated the Wnt/β-catenin signaling pathway, by using newly developed multiplex CRISPR/Cas9-based genome engineering system. Gene set enrichment analysis indicated downregulation of immune-associated gene sets in the HCC cells with activated β-catenin signaling. Comparative analysis of gene expression profiles between HCC cells harboring wild-type and exon 3 skipping β-catenin elucidated that the expression levels of four cytokines were commonly decreased in human and mouse β-catenin-mutated HCC cells. Public exome and transcriptome data of 373 human HCC samples showed significant downregulation of two candidate cytokine genes, CCL20 and CXCL2, in HCC tumors with β-catenin hotspot mutations. T cell killing assays and immunohistochemical analysis of grafted tumor tissues demonstrated that the mouse Ctnnb1 Δex3 HCC cells evaded immunosurveillance. Taken together, this study discovered that cytokine controlled by β-catenin signaling activation could contribute to immune evasion, and provided novel insights into cancer immunotherapy for the β-catenin-mutated HCC subtype., (© 2021. The Author(s).)

Background: Although the risk factors for coronavirus disease 2019 (COVID-19) mortality have been identified, there is limited information about the risk factors for disease progression after hospitalization among Japanese patients with COVID-19 exhibiting no or mild symptoms., Methods: All 302 consecutive patients who were admitted to our institutions and diagnosed with COVID-19 between March and December 2020 were retrospectively assessed. Ultimately, 210 adult patients exhibiting no or mild symptoms on admission were included in the analysis. They were categorized into the stable (no oxygen needed) and worsened (oxygen needed) groups, and their characteristics and laboratory data were compared., Results: Among 210 patients, 49 progressed to a severe disease stage, whereas 161 did not. The mean patient age was 52.14 years, and 126 (60.0%) patients were male. The mean body mass index (BMI) was 23.0 kg/m 2 , and 71 patients were overweight (BMI ≥ 25 kg/m 2 ). Multivariate logistic analysis showed that old age, overweight, diabetes mellitus (DM), and high serum ferritin levels were independent risk factors for disease progression., Conclusions: Clinicians should closely observe patients with COVID-19, especially those with risk factors such as old age, overweight, DM, and high serum ferritin levels, regardless of whether they have no or mild symptoms., (© 2021. The Author(s).)

Aims: Histological categorisation of the desmoplastic reaction (DR) is an independent prognostic factor in colorectal cancer. However, it is unknown whether DR categorisation is predictive of oesophageal squamous cell carcinoma (OSCC) outcomes. This study aimed to evaluate the prognostic value of DR categorisation in OSCC patients., Methods and Results: Data were collected from 118 patients with OSCC who underwent a curative oesophagectomy with T2 or deeper wall invasion. The DR in each tumour was classified as mature, intermediate or immature based on the presence or absence of keloid-like collagen and myxoid stroma. We identified 49 mature DR tumours, 41 intermediate DR tumours and 28 immature DR tumours. The 5-year overall survival (OS) rate was highest in the mature DR group (42.8%), followed by the intermediate DR group (25.0%) and the immature DR group (19.9%) (P = 0.022, log-rank test; P = 0.006, log-rank trend test). The 5-year disease-specific survival (DSS) rate was also highest in the mature DR group (48.5%), followed by the intermediate DR group (30.8%) and the immature DR group (26.8%) (P = 0.031, log-rank test; P = 0.010, log-rank trend test, respectively). Multivariate analysis revealed that an immature DR was an independent poor prognostic factor of OS and DSS (P = 0.002 and P = 0.004)., Conclusions: DR categorisation of OSCC stroma following oesophagectomy is a useful diagnostic tool and an independent prognostic marker., (© 2021 John Wiley & Sons Ltd.)

Objectives: FOLFIRINOX (FFX, a combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin) and gemcitabine plus nab-paclitaxel (GnP) have been used as standard, first-line treatments for advanced pancreatic cancer. However, no study has compared the efficacy of the 2 regimens. This study retrospectively compared the efficacy and safety of the 2 regimens in patients with locally advanced pancreatic cancer., Methods: We reviewed the records of patients with locally advanced pancreatic cancer who started FFX or GnP as first-line chemotherapy as part of a multicenter retrospective study in patients with unresectable pancreatic cancer treated with FFX or GnP (NAPOLEON study)., Results: Sixteen of the 63 patients were treated with FFX, and the other 47 patients were treated with GnP between December 2013 and March 2017. There were no significant differences in median overall survival rate between the GnP (15.5 months) and FFX (14.3 months, P = 0.60) groups or median progression-free survival rate between the GnP (8.8 months) and FFX (8.1 months, P = 0.51) groups. Both treatments were generally well tolerated, although anorexia was more severe in the FFX group than in the GnP group., Conclusions: The effects of FFX and GnP were similar but resulted in different toxicities, which could guide agent choice., Competing Interests: M.S. received personal fees from Sysmex Corporation. A.M. received personal fees from Eli Lilly, Chugai, and Takeda. Ts.S. received personal fees from Taiho Pharmaceutical, Chugai, and Takeda. T.O. received personal fees from Chugai. The authors other declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The prognostic nutritional index (PNI) is an indicator of systemic immune-nutritional condition and is a well-known prognostic biomarker in lung cancer patients. Tumour-infiltrating lymphocytes (TILs) is a specific histological feature of cancers, influencing an individual's immunological tumour responses. However, whether PNI can reflect lung cancer patients' prognosis through local immunity such as TIL is unclear., Methods: We selected 64 lung squamous cell carcinoma patients who underwent curative operations. We investigated the significance of preoperative PNI level and evaluated the relationship between PNI and immune cells surrounding the lung cancer tissue using immunohistochemical analysis of a cluster of differentiation (CD)3, CD4, CD8 and CD68., Results: A low-PNI level was significantly associated with a worse postoperative prognosis (P = 0.042). The PNI (hazard ratio 2.768, 95% confidence interval 1.320-5.957; P = 0.007) was an independent prognostic factor. The low-PNI group had a significantly shorter recurrence-free survival and overall survival (P = 0.013 and P = 0.002, log-rank test) compared with the high-PNI group. A significant positive correlation between PNI components including preoperative peripheral blood lymphocyte count and serum albumin concentration, and TILs, was observed. Absolute numbers of TILs in the preoperative high-PNI group were significantly increased compared with those in the preoperative low-PNI group (CD3+ cells; P = 0.002, CD4+ cells; P = 0.049 and CD8+ cells; P = 0.024)., Conclusions: The preoperative PNI level was strongly associated with the postoperative outcome in lung cancer patients. Considering the positive relationship between preoperative PNI level and TIL status, preoperative immune-nutritional condition may influence lung cancer patients' postoperative prognosis through local immunity as well as systemic immune response., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

The gastrointestinal microbiota was reported as an important factor for the response to cancer immunotherapy. Probiotics associated with gastrointestinal dysbiosis and bacterial richness may affect the efficacy of cancer immunotherapy drugs. However, the clinical impact of probiotics on the efficacy of cancer immunotherapy in patients with nonsmall cell lung cancer (NSCLC) is poorly understood. The outcomes of 294 patients with advanced or recurrent NSCLC who received antiprogrammed cell death-1 (PD-1) therapy (nivolumab or pembrolizumab monotherapy) at three medical centers in Japan were analyzed in our study. We used inverse probability of treatment weighting (IPTW) to minimize the bias arising from the patients' backgrounds. The IPTW-adjusted Kaplan-Meier curves showed that progression-free survival (nonuse vs use: hazard ratio [HR] [95% confidence interval {CI}] = 1.73 [1.42-2.11], log-rank test P = .0229), but not overall survival (nonuse vs use: HR [95%CI] = 1.40 [1.13-1.74], log-rank test P = .1835), was significantly longer in patients who received probiotics. Moreover, the IPTW-adjusted univariate analyses showed that nonuse or use of probiotics was significantly associated with disease control (nonuse vs use: odds ratio [OR] [95%CI] = 0.51 [0.35-0.74], P = .0004) and overall response (nonuse vs use: OR [95%CI] = 0.43 [0.29-0.63], P < .0001). In this multicenter and retrospective study, probiotics use was associated with favorable clinical outcomes in patients with advanced or recurrent NSCLC who received anti-PD-1 monotherapy. The findings should be validated in a future prospective study., (© 2021 UICC.)

Background/aim: The aim of the study was to evaluate gemcitabine plus nanoparticle albumin-bound paclitaxel (GnP) and FOLFIRINOX for recurrent pancreatic cancer (rPC) after resection., Patients and Methods: Forty-four patients with rPC and 211 with de novo metastatic pancreatic cancer (mPC) who received GnP or FOLFIRINOX as first-line chemotherapy were retrospectively analyzed., Results: On crude analysis, the median overall survival (OS) was significantly longer in the rPC group than in the mPC group (14.0 vs. 10.6 months, respectively; p=0.02). However, the difference was not significant on adjusted analysis using the Cox proportional hazards model (adjusted p=0.90). Patients receiving FOLFIRINOX (n=10) and GnP (n=34) in the rPC group had comparable OS (medians, 12.2 vs. 14.4 months, respectively; p=0.82) even after adjusting for covariates using the Cox model (adjusted p=0.18)., Conclusion: The outcomes of patients in the rPC and mPC groups were comparable following chemotherapy. Both FOLFIRINOX and GnP may be reasonable options for treating rPC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The incidence and background factors of sarcopenia and obesity in long-term survivors of childhood leukemia/lymphoma were not clear in Japan., Methods: Between August 2018 and September 2019, we recruited adults aged ≥18 years who had childhood leukemia/lymphoma. Blood sampling, body composition measurement by bioelectrical impedance analysis and grip strength test were performed., Results: Among 81 adult survivors (34 men and 47 women) with a median age of 25.0 years, 9 (11%) had sarcopenia and 10 (12%) had obesity, of whom, 3 had metabolic syndrome. Sarcopenia was observed in 7 (21%) of 33 survivors with hematopoietic stem cell transplantation (HSCT) and 2 (4%) of 48 survivors without hematopoietic stem cell transplantation (P = 0.012). The incidence of obesity was significantly higher in the cranial radiotherapy (P = 0.021) and non-transplanted cases (P = 0.042). Univariate logistic regression analysis revealed that hematopoietic stem cell transplantation for sarcopenia (odds ratio, 6.19; 95% confidence interval, 1.2-32.0; P = 0.03) and cranial radiotherapy for obesity (odds ratio, 5.6; 95% confidence interval, 1.4-22.4; P = 0.015) were significantly associated. Hypertension was more prevalent among the obese survivors, and higher transaminase levels were found more in both the sarcopenia and obese survivors than in others., Conclusions: Young adult survivors of childhood leukemia/lymphoma could be at risk of developing sarcopenia after hematopoietic stem cell transplantation and obesity after cranial radiotherapy. Further studies are required to assess the body composition of long-term survivors to find detailed risk factors of sarcopenia and metabolic syndrome., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Despite being commonplace, polymerase chain reactions (PCRs) still contain many unknown aspects. One example is microsatellite PCR, which is now widely used for various purposes from ecology to cancer medicine. Since this category of repetitive DNA sequences induces polymerase slippage not only in vivo but also in vitro, microsatellite PCR products comprise a complex combination of DNA fragments with various lengths and have, therefore, been empirically interpreted. The primary obstacle for understanding microsatellite PCR was the intrinsic inaccuracy in sizing of DNA fragments in capillary electrophoresis (CE), which, however, has been overcome by elucidating intrinsic sizing errors in each fragment length range. Secondly, the slippage properties of the thermostable polymerases were first clarified in detail using primer extension assays. Furthermore, using the obtained slippage parameters and our original program, we have first reconstructed microsatellite PCR in silico. The entire processes of complex microsatellite PCR have, thus, been more clearly understood., (© 2021 Wiley-VCH GmbH.)

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has recently been established as a standard treatment option for chemotherapy-naive patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC). However, only about one-half of patients who have received prior treatment with a first- or second-generation EGFR-TKI are eligible for osimertinib therapy because its indication in the second-line setting is limited to metastatic NSCLC positive for the T790M resistance mutation of EGFR. The dose-escalation part of a study in which patients received osimertinib at doses of 20 to 240 mg once daily after the development of resistance to first- or second-generation EGFR-TKIs revealed a response rate of 21% and a median progression-free survival of 2.8 months for individuals whose tumors were negative for EGFR T790M. We have now designed a phase II study of osimertinib for patients with EGFR mutation-positive NSCLC who develop isolated central nervous system progression (T790M-negative or unknown) after first- or second-generation EGFR-TKI therapy (cohort 1) or who develop systemic disease progression (T790M-negative) after first- or second-generation EGFR-TKI therapy and platinum-based chemotherapy (cohort 2). A total of 70 patients (cohort 1, n = 17; cohort 2, n = 53) will be enrolled in this study, which originated from a suggestion of a dedicated network for patients with lung cancer in Japan., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Trifluridine/tipiracil (FTD/TPI) is an orally administrated anticancer drug with efficacy validated for patients with metastatic colorectal cancer (mCRC) or gastric cancer. FTD, a key component of FTD/TPI, exerts antitumor effects via its incorporation into DNA. Using specific antibodies against bromodeoxyuridine, FTD incorporation into DNA is detected in tumors and peripheral blood mononuclear cells (PBMC) of patients with mCRC who are administered FTD/TPI. The proportion of FTD-positive PBMC fluctuates according to the schedule of treatment, although the association between the proportion of FTD-positive PBMC and the clinical outcomes of patients is unknown. To answer this question, here we monitored the FTD-positive PBMC of 39 elderly patients with mCRC enrolled in KSCC1602, a single-arm phase 2 trial of FTD/TPI plus bevacizumab as a first-line treatment, for 1 month, during the first cycle of treatment. The median values and interquartile ranges of the percentage of FTD-positive PBMC on days 8, 15, and 29 were 39.3% (30.7%-52.2%), 66.9% (40.0%-75.3%), and 13.5% (5.7%-26.0%), respectively. Receiver operating characteristic analysis revealed that the percentage of FTD-positive PBMC on day 8 (the end of the first week of treatment) had moderate ability to accurately diagnose the occurrence of severe neutropenia and leukopenia within 1 month (area under the curve = 0.778 [95% confidence interval, 0.554-0.993]). This result suggests that excess FTD incorporation into PBMC at the initial phase of FTD/TPI plus bevacizumab treatment is a risk factor for early onset of severe hematological adverse events., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Immune checkpoint inhibitors (ICIs) have become a standard therapy in non-small cell lung cancer (NSCLC). Although lung cancer adjoining emphysematous bullae (Ca-ADJ) were reported to express higher programmed cell death-ligand 1 (PD-L1), the predictive impact of Ca-ADJ on the response to ICIs is unknown., Methods: Two hundred and fifty-seven advanced or recurrent NSCLC patients treated with ICI monotherapy at Kyushu University Hospital and National Hospital Organization Kyushu Cancer Center were analyzed. To minimize the bias arising from the patients' background, adjusted Kaplan-Meier survival curves and Cox proportional hazards regression analyses using inverse probability of treatment weights (IPTW) were performed., Results: Of the 257 patients, 55 had Ca-ADJ. Patients with Ca-ADJ were significantly associated with younger age (P = 0.0343), male sex (P = 0.0070), and smoking (P = 0.0080). The objective response rate of cases with Ca-ADJ was significantly higher than that of those without Ca-ADJ (36.4% vs. 20.8%, respectively; P = 0.0167). The disease control rate of cases with Ca-ADJ was also significantly higher than tumors without Ca-ADJ (63.6% vs. 47.5%, respectively; P = 0.0341). The IPTW-adjusted Kaplan-Meier curves showed that patients with Ca-ADJ had significantly longer progression-free survival (PFS) and overall survival (OS) than those without Ca-ADJ (P = 0.0407 and P = 0.0126, respectively). On IPTW-adjusted Cox analysis, Ca-ADJ was an independent predictor of PFS and OS (P < 0.0001 and P < 0.0001, respectively)., Conclusions: Patients with Ca-ADJ may be good candidates for ICIs. These findings should be validated prospectively.

Background: Pneumonitis can be triggered by anti-cancer therapies: cytotoxic chemotherapy, tyrosine kinase inhibitors, and immune checkpoint inhibitors. There are few treatment options for patients who develop such pneumonitis and their treatment including chemotherapy is generally difficult thus would limit patient's prognosis. In this study, we investigated the clinical course of patients with lung cancer who developed anti-cancer therapy-related pneumonitis., Patients and Methods: We retrospectively examined data of patients who had developed pneumonitis triggered by anti-cancer agents and required hospitalization from January 2014 to March 2019 and analyzed their subsequent clinical course and prognosis., Results: The median age of the 58 study patients was 68 years and 82.8% were men. The median interval between first receiving the responsible agent and drug-induced pneumonitis was 7.4 weeks. Approximately 38% of patients were subsequently able to receive some anti-cancer therapy. The median post-pneumonitis overall survival (OS) from commencement of anti-cancer treatment was 13.2 months. No significant differences were found in survival time between treatment agents. However, patients who received some anticancer therapy after pneumonitis had significantly longer survival times than those did not (HR = 4.11, p = 0.0003) and patients who took longer to develop pneumonitis had a longer survival (HR = 2.28, p = 0.0148). Multivariate analysis revealed that short interval to onset and no post-pneumonitis anticancer therapy were independent predictors of short survival., Conclusion: Although patients who developed pneumonitis had relatively short survival times, the interval between initial therapy and pneumonitis had survival impact. Survival can be prolonged by administering further cancer treatment after resolution of pneumonitis.

Background: Three immune-nutritional parameters exist for malignant tumors using serum C-reactive protein (CRP) and albumin: the Glasgow prognostic score (GPS), the modified GPS (mGPS), and the CRP-albumin ratio (CAR). However, it remains unclear which of the three parameters is the most predictive of prognosis. Therefore, this study compared the clinical and prognostic significance of these parameters for non-small cell carcinoma (NSCLC)., Methods: The study retrospectively enrolled 596 NSCLC patients who underwent surgical resection at the authors' institution from January 2010 to December 2015 and investigated the clinicopathologic significance of GPS, mGPS, and CAR. The optimal cutoff value for CAR was determined by a receiver operating curve (ROC)., Results: The median age of the patients was 69 years. Lymph node metastases were identified in 99 patients, and 455 patients had a diagnosis of stage 1 disease. The positivity for GPS was 7.6%, and that of mGPS (score, 1 or 2) was 12.2%. Of the 596 patients, 480 patients (80.5%) were classified in the high CAR group. In univariate survival analyses, all three parameters were associated significantly with postoperative survival. The multivariate analyses showed CAR to be an independent prognostic factor. Additionally, survival analyses of the stage 1 subgroup were performed because CAR was higher for patients with an advanced stage of disease or lymph node metastases. In these subgroup analyses, CAR also was an independent prognostic factor., Conclusion: As the most prognostic index, CAR may be useful among the immunonutritional parameters using CRP and albumin for resected NSCLC.

Background: Olanzapine is an inexpensive and durable agent for the treatment of chemotherapy-induced nausea and vomiting and is also superior to neurokinin-1 receptor antagonists in the control of nausea. This study aimed to investigate the efficacy and safety of a low dose of 5 mg olanzapine plus granisetron and dexamethasone for treatment of carboplatin (CBDCA)-induced nausea and vomiting in patients with thoracic malignancies., Materials and Methods: We conducted a prospective, open-label, single-arm, multicenter, phase II trial in four centers in Japan. Registered patients were scheduled to receive area under the curve (AUC) ≥5 mg/mL per minute of CBDCA and had never received moderately to highly emetogenic chemotherapy. Patients received olanzapine 5 mg/day orally after supper for 4 days, in combination with granisetron and dexamethasone. Primary endpoint was complete response (CR; no emesis and no use of rescue medication) rate during the overall phase (0-120 hours)., Results: Between February 2018 and June 2020, 51 patients were enrolled, and 50 patients were evaluated. The CR rates in the overall (0-120 hours), acute (0-24 hours), and delayed phases (24-120 hours) were 94.0%, 100%, and 94.0%, respectively. No grade 3 or higher adverse effects of olanzapine were observed., Conclusion: Prophylactic antiemetic therapy with a low dose of 5 mg olanzapine plus granisetron and dexamethasone showed durable efficacy with an acceptable safety profile. This three-drug combination appears to be a reasonable treatment approach in patients with thoracic malignancies receiving an AUC ≥5 mg/mL per minute of CBDCA-based regimen. Clinical trial identification number: UMIN000031267., Implications for Practice: The results of this phase II trial indicated that the prophylactic administration of low-dose of 5 mg olanzapine combined with granisetron and dexamethasone has promising activity with acceptable safety profile in patients with thoracic malignancy receiving high-dose carboplatin chemotherapy., (© 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Background: RAS/BRAF V600E mutations are the most remarkable oncogenic driver mutations in colorectal cancer (CRC) and play an important role in treatment selection. No data are available regarding the clinical and prognostic features of patients with detailed RAS/BRAF V600E -mutant metastatic CRC (mCRC) in Japan., Methods: A total of 152 chemotherapy-naïve patients with mCRC were included in this study between August 2018 and July 2019. Tumor samples were collected, and RAS/BRAF V600E status was investigated. RAS/BRAF V600E status was examined using a MEBGEN RASKET-B kit and polymerase chain reaction reverse sequence-specific oligonucleotide method., Results: RAS/BRAF V600E mutations were detected in 54% of cases (KRAS codon 12, 26%; KRAS codon 13, 17%; KRAS non-Exon2, 5%; NRAS, 5%; and BRAF V600E , 7%). BRAF V600E -mutant CRC mainly existed in the right colon, whereas KRAS non-Exon2 and NRAS-mutant CRC was predominantly present in the left colon. KRAS non-Exon2 and NRAS-mutant CRC were associated with shorter survival time than RAS wild-type CRC (hazard ratio [HR], 2.26; 95% confidence interval [CI], 0.64-8.03; p = 0.19; HR, 2.42; 95% CI, 0.68-8.61; p = 0.16) and significantly shorter overall survival than KRAS Exon2-mutant CRC (HR, 3.88; 95% CI, 0.92-16.3; p = 0.04; HR, 4.80; 95% CI, 1.14-20.2; p = 0.02)., Conclusions: In our multicenter study, the findings elucidated the clinical and prognostic features of patients with detailed RAS/BRAF V600E -mutant mCRC in Japan.

Purpose: Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX, FFX) and gemcitabine plus nab-paclitaxel (GnP) are considered standard treatments for patients with metastatic pancreatic cancer. Direct comparisons are not available that establish which is optimal., Methods: We conducted a propensity score-adjusted analysis of patients with metastatic pancreatic cancer to identify the therapeutic advantages of these standard therapies. We used clinical data as part of a multicenter retrospective study of patients with unresectable or recurrent pancreatic cancer treated with FFX or GnP (NAPOLEON study)., Results: FFX and GnP were initially administered to 102 and 153 patients, respectively. The GnP group comprised more patients of advanced age, worse performance status, lower body mass index, recurrence, and lower albumin concentrations. Median overall survival (OS) and progression-free survival (PFS) were 11.5 months and 5.8 months in the FFX group and 11.1 months and 5.9 months in the GnP group, respectively. Propensity score-adjusted analysis indicated that the administration of FFX or GnP was not independently associated with OS (adjusted hazard ratio [HR] 1.06; 95% confidence interval [CI] 0.76-1.47; P = 0.73). Similarly, the difference in PFS was not significant between groups (adjusted HR 0.93; 95% CI 0.68-1.26; P = 0.62). Gastrointestinal disorders were more common in the FFX group, whereas the frequencies of hematological, nervous system, and skin disorders were higher in the GnP group., Conclusion: The efficacies of FFX and GnP were comparable, although safety profiles differed and should be considered in selecting treatment.

Background: Trastuzumab emtansine (T-DM1) treatment for human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer after taxane with trastuzumab and pertuzumab is standard therapy. However, treatment strategies beyond T-DM1 are still in development with insufficient evidence of their effectiveness. Here, we aimed to evaluate real-world treatment choice and efficacy of treatments after T-DM1 for HER2-positive metastatic breast cancer., Methods: In this multi-centre retrospective cohort study involving 17 hospitals, 325 female HER2-positive metastatic breast cancer patients whose post-T-DM1 treatment began between April 15, 2014 and December 31, 2018 were enrolled. The primary end point was the objective response rate (ORR) of post-T-DM1 treatments. Secondary end points included disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), and overall survival (OS)., Results: The median number of prior treatments of post-T-DM1 treatment was four. The types of post-T-DM1 treatments included (1) chemotherapy in combination with trastuzumab and pertuzumab (n = 102; 31.4%), (2) chemotherapy concomitant with trastuzumab (n = 78; 24.0%), (3), lapatinib with capecitabine (n = 63; 19.4%), and (4) others (n = 82; 25.2%). ORR was 22.8% [95% confidence interval (CI): 18.1-28.0], DCR = 66.6% (95% CI 60.8-72.0), median PFS = 6.1 months (95% CI 5.3-6.7), median TTF = 5.1 months (95% CI 4.4-5.6), and median OS = 23.7 months (95% CI 20.7-27.4)., Conclusion: The benefits of treatments after T-DM1 are limited. Further investigation of new treatment strategies beyond T-DM1 is awaited for HER2-positive metastatic breast cancer patients.

Purpose: Systemic inflammation score (SIS) is a novel prognostic score (0, 1, or 2) for various cancers, based on preoperative serum albumin level and lymphocyte-to-monocyte ratio (LMR); modified SIS (mSIS) uses a different LMR cutoff value and was thought to be a more accurate predictor for cancer prognosis. Here, we assessed the prognostic value of SIS and mSIS in patients who receive hepatic resection for hepatocellular carcinoma (HCC)., Methods: We retrospectively evaluated SIS and mSIS of 314 patients after hepatic resection for HCC, against their clinicopathological factors and outcomes, using receiver operating characteristics (ROC) analysis over time., Results: Among patients with preoperative SIS 2, significantly more HCC specimens were poorly differentiated (P = 0.0281), larger (P = 0.0006), and had more microscopic vascular invasion (P = 0.0136) than the SIS 0-1 group; the mSIS 2 group also had significantly larger tumors (P = 0.0039) than the mSIS 0-1 group. In ROC analysis, SIS was a better predictor of overall survival (OS) and recurrence-free survival (RFS) than mSIS. The SIS 2 group had shorter OS (P = 0.0015) and RFS (P = 0.0065) than other patients. In multivariate analysis, SIS 2 was an independent risk factor for shorter OS (hazard ratio (HR) 1.53, P = 0.0497) and RFS (HR 1.58, P = 0.0053)., Conclusion: SIS is superior to mSIS in predicting prognosis of patients with HCC. mSIS is not a great predictor of prognosis in resected HCC.

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: Studies on the appropriate use of urinary catheters for cancer patients at the end of life are limited., Aim: To clarify the differences among institutions in the prevalence of and indications for urinary catheterization of advanced cancer patients at palliative care units., Design: Pre-planned secondary analysis of a multicenter, prospective cohort study; East-Asian collaborative cross-cultural Study to Elucidate the Dying process (EASED)., Setting/participants: This study enrolled consecutive advanced cancer patients admitted to palliative care units between January and December 2017. The final study group comprised 1212 patients from 21 institutions throughout Japan., Results: Out of the 1212 patients, 380 (31.4%; 95% confidence interval, 28.7%-34.0%) underwent urinary catheterization during their palliative care unit stay, and the prevalence of urinary catheterization in patients who died at palliative care units by institution ranged from 0.0% to 55.4%. When the 21 participating institutions were equally divided into three groups according to the institutional prevalence of catheterization, patients with difficulty in moving safely, exhaustion on movement, and restlessness or agitation were more likely to be catheterized in institutions with a high prevalence of catheterization than in those with a low or moderate prevalence ( p  < 0.008, p  = 0.008, and p  < 0.008, respectively)., Conclusion: This study revealed that the institutional prevalence of urinary catheterization in advanced cancer patients at palliative care units widely varied. Further studies are needed to establish the appropriate use of urinary catheters, especially in patients with difficulty in moving safely, exhaustion on movement, and restlessness or agitation.

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: Cervical intraepithelial neoplasia (CIN) is a precancerous lesion that may progress to invasive cervical cancer without intervention. We aim to examine the prognostic outcomes and risk factors for recurrence after laser vaporization for CIN 3, CIN 2 with high-risk human papillomavirus (HPV) infection, and CIN 1 persisting for more than 2 years., Methods: Between 2008 and 2016, a total of 1070 patients underwent cervical laser vaporization using a carbon dioxide laser. We performed a retrospective review of their medical records to assess their clinical characteristics, pathologic factors, and prognostic outcomes., Results: The mean patient age was 34 years (range 18-64 years). The preoperative diagnosis was CIN 1 in 27 patients, CIN 2 in 485 patients, and CIN 3 in 558 patients. Over a median follow-up period of 15 months, the 2-year recurrence rate was 18.9%, and the 5-year recurrence rate was 46.5%. The 2-year retreatment rate was 12.6%, and the 5-year retreatment rate was 30.5%. We diagnosed 9 patients with invasive cancer after treatment; all patients underwent combined multidisciplinary treatment, and there were no deaths during follow-up. The recurrence-free interval was correlated with patient age (hazard ratio [HR], 1.028; 95% CI 1.005-1.051; P = 0.0167), body mass index (HR, 1.052; 95% CI 1.008-1.098; P = 0.0191), and glandular involvement (HR, 1.962; 95% CI 1.353-2.846; P = 0.0004)., Conclusions: Cervical laser vaporization is effective and useful for patients with CIN who wish to preserve fertility. However, patients with glandular involvement, older age, and higher body weight require close follow-up for recurrence.

Background/aim: Albumin-bilirubin (ALBI) grade is an indicator of liver dysfunction and is useful for predicting postoperative prognosis of hepatocellular carcinomas. However, the significance of ALBI grade in non-small cell lung carcinoma (NSCLC) has not been elucidated., Patients and Methods: We analyzed 947 patients with pStage IA-IIIA NSCLC. We divided patients into ALBI grade 1 and grade 2/3 groups. We then analyzed the association of ABLI grade with clinicopathological characteristics and prognosis in NSCLC by using propensity-score matching., Results: ALBI grade 2/3 was significantly associated with older age, male sex, advanced pT status, and histological type. Even after propensity-score matching, ALBI grade 2/3 patients had significantly worse cancer-specific survival (CSS) than ALBI grade 1 patients (5-year CSS: 87.3% versus 92.8%; p=0.0247). In multivariate analysis, ALBI grade 2/3 was an independent predictor of CSS (HR=1.9; 95%CI=1.11-3.11; p=0.0177)., Conclusion: ALBI grade was an independent prognostic factor in surgically resected NSCLC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: Patients with triple-negative breast cancer (TNBC) who have not achieved pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) were considered for adjuvant capecitabine. This study was to explore the utility of the Neo-Bioscore in guiding post-surgical therapy in TNBC., Patients and Methods: The Neo-Bioscore was calculated for patients with non-metastatic primary breast cancer who received NAC at National Cancer Center Hospital East, Japan., Results: A total of 329 patients were evaluated. The Neo-Bioscore stratified prognosis after NAC better than clinical or pathological stage. The Neo-Bioscore performed well in the selection of patients with TNBC with excellent prognoses despite non-pCR; no death was observed in patients who had a Neo-Bioscore of 2, the lowest score in those with TNBC., Conclusion: The Neo-Bioscore can improve the prognostic stratification of patients after NAC for breast cancer over clinical and pathological staging and may enable the identification of patients with non-pCR TNBC who can avoid additional adjuvant chemotherapy., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

This study aimed to evaluate the optimal method for planning computed tomography (CT) for prostate cancer radiotherapy to avoid a dose difference of ≥3% between the actual and planned treatments using multiple acquisition planning CT (MPCT). We calculated the 3-dimensional (3D) displacement error between the pelvic bone and matching fiducial marker on MPCT and cone-beam CT scans of 25 patients who underwent prostate volumetric-modulated arc therapy for prostate cancer. The correlation of the 3D displacement error and the dose difference between planned and actual treatments was calculated using least squares second-order polynomial model. The 3D displacement error showed a moderate correlation with differences between planned and accumulated treatment doses (r = 0.587, p < 0.0001). Moreover, the improvement rate of the minimum 3D displacement error showed a strong correlation with the relative error between each MPCT image (r = 0.793, p < 0.0001). Significant differences were observed between planned and actual treatment doses (p < 0.0001) in the relative 3D displacement errors of <1 mm, 1 to 3 mm, and >3 mm. The 3D displacement error on MPCT (as the selection estimation index for optimal planning CT) is useful for monitoring patient-specific intensity-modulated radiation therapy quality assurance. This new method allows to estimate dose differences from the planned dose before commencing treatment, thereby ensuring high-quality therapy. As radiotherapy quality is critical for patient outcome, these findings may contribute to better management of prostate cancer., (Copyright © 2020 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

A key goal of regulatory agencies for medical products is to make innovative products available to patients and the medical community in a timely manner in order to improve the quality of public health and health care. Thus, regulators must respond quickly to emerging technologies. It is a horizon scanning method, based on which the Japanese regulatory agency will have the expertise prior to review of forthcoming products of evolving technologies., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

Background: The aims of this study are to evaluate the efficacy and safety of first-line treatment with chemotherapy plus cetuximab in real-world patients with recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) and to identify prognostic factors for overall survival (OS)., Methods: This is a prospective observation study involving 20 oncology institutions in Japan. Patients with RM-SCCHN treated with a first-line therapy consisting of cetuximab plus any chemotherapy regimen between December 2013 and February 2017 were enrolled. The primary objective of the study was 1-year OS. Secondary objectives included response rate and adverse events., Results: Of 120 patients recruited, 114 patients were analyzed. Median age was 64 years. Cetuximab in combination with platinum plus 5-FU (EXTREME regimen) was chosen in 86 patients (75.4%). The median OS was 12.4 months. A point estimate of the 1-year survival rate was 51.1%. Overall response rate was 26.3%. Grade 3 or worse adverse events included neutropenia (22.8%), hypokalemia (9.6%), acneiform rash (7.0%), pneumonitis (1.8%), and infusion-related reaction (0.9%). On multivariate analysis, regional lymph node metastasis, absence of intervention by dermatologists, lack of response to therapy, skin metastasis, and non-EXTREME regimen were identified as independent unfavorable prognostic factors for OS., Conclusion: The combination of cetuximab plus chemotherapy was tolerable and efficacious in patients with RM-SCCHN in a real-world setting. Clinical outcomes and prognostic factors extracted from this study provide a reference of the current clinical practice as well as for the future development of novel therapy in RM-SCCHN.

Background: In a randomized pivotal global phase III study, S-1 and oxaliplatin 100 mg/m 2 (SOX100) combination chemotherapy was as effective as S-1 and cisplatin for advanced gastric cancer (AGC) and showed a favorable safety profile. In this phase II study, we analyzed survival outcomes to assess the efficacy and safety of the SOX regimen with oxaliplatin 130 mg/m 2 (SOX130) in AGC., Methods: Patients with HER2-negative AGC received 80 mg/m 2 /day S-1 orally on days 1-14 and 130 mg/m 2 oxaliplatin intravenously on day 1 of each 21-day cycle until the criteria for treatment withdrawal were fulfilled. The primary endpoint was the response rate (RR), and the null hypothesis of RR in the current trial was 45%. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were recorded according to CTCAE version 4.0., Results: Seventy-one patients were enrolled from June 2015 to November 2016, but eight were excluded for ineligibility. Therefore, all final analyses were conducted with 63 patients. The confirmed RR was 46.0% (90% confidence interval [CI]: 36.1-56.3), and the disease control rate was 77.8% (90% CI: 68.1-85.1). The median PFS and OS were 4.9 (95% CI: 4.2-7.1) and 14.8 (95% CI: 11.1-18.9) months, respectively. Incidences of grade 3-4 AEs > 10% were anorexia (19.0%), peripheral neuropathy (12.7%), nausea (11.1%), and thrombocytopenia (11.1%)., Conclusions: This study represents the first evaluation of SOX130 in patients with HER2-negative AGC. SOX130 showed an acceptable safety profile, but the prespecified statistical efficacy targets were not achieved.

Background: The pack-year index, which is calculated by multiplying a smoking period by the number of cigarette packs smoked per day, is frequently used to investigate the risk of developing lung cancer. Notably, however, whether the smoking period or the number of packs per day is more predictive of postoperative prognosis remains unclear in non-small cell lung cancer (NSCLC) patients who receive curative lung resection., Patients and Methods: Initial screening included 2055 consecutive lung cancer patients who had underwent curative lung resection between 2000 and 2016 at a single center in Japan. Data from 1134 NSCLC patients with smoking history were ultimately analyzed. Time-dependent areas under the curve (AUCs) were used to compare diagnostic accuracy., Results: On univariate analysis, the number of packs smoked per day was not a significant predictor of disease-free survival (DFS; p = 0.2387) or overall survival (OS; p = 0.1357). On multivariable analysis, smoking period was an independent predictor of DFS and OS (both p < 0.0001). Time-dependent smoking period AUCs were superior to those of number of packs smoked per day. On subgroup analyses, patients with a smoking period ≥ 40 years had significantly shorter DFS and OS than those with a smoking period of < 40 years, independent of sex, clinical stage, and histological type., Conclusions: Smoking period was a significant prognostic indicator in NSCLC patients who underwent curative lung resection, which should be validated in further prospective and/or multicenter studies with large sample sizes.

Background & Aims: Small-for-size graft (SFSG) syndrome is a major cause of graft loss after living donor liver transplantation (LDLT). Splenectomy (Spx) is an option to prevent this catastrophic complication, but its effect remains controversial. Herein, we aimed to elucidate the effect of simultaneous Spx on graft function and long-term outcomes after LDLT., Methods: Three hundred and twenty patients were divided into 2 groups: those undergoing (n = 258) and those not undergoing (n = 62) simultaneous Spx. To overcome selection bias, propensity score matching (PSM) was performed (n = 50 in each group)., Results: Before PSM, recipients undergoing simultaneous Spx showed better graft function on post-operative day (POD) 7 and 14, as well as lower sepsis frequency within 6 months after LDLT and better graft survival rates compared to those not undergoing Spx. After PSM, compared to patients not undergoing Spx, those undergoing Spx had a lower frequency of early graft dysfunction on POD 7 (p = 0.04); a lower frequency of SFSG syndrome (p = 0.01), lower serum total bilirubin levels (p = 0.001), and lower international normalized ratio (p = 0.004) on POD 14; lower sepsis frequency within 6 months after LDLT (p = 0.02), and better graft survival rates (p = 0.04). Univariate analysis revealed that not undergoing Spx (hazard ratio 3.06; 95% CI 1.07-11.0; p = 0.037) was the only risk factor for graft loss after LDLT., Conclusions: Simultaneous Spx may prevent SFSG syndrome and is a predictive factor for graft survival after LDLT. Simultaneous Spx is recommended when a small graft (≤35% of standard liver weight) is predicted preoperatively, or for patients with portal hypertension or high portal pressure (above 20 mmHg) after reperfusion in LDLT., Lay Summary: Living donor liver transplantation (LDLT) for patients with acute or chronic liver failure is an alternative to overcome the deceased donor shortage. The potential mismatch between graft and body size is a problem that needs to be solved for LDLT recipients. Herein, we evaluated the impact of simultaneous splenectomy and showed that it was associated with favorable outcomes in patients undergoing LDLT., Competing Interests: Conflicts of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Delayed chemotherapy-induced nausea and vomiting (CINV) is not well controlled in colorectal cancer (CRC) patients undergoing oxaliplatin (L-OHP)-based chemotherapy. Whether neurokinin-1 receptor antagonist addition to a first-generation 5HT 3 antagonist (1st 5-HT 3 RA) and dexamethasone (DEX) is beneficial to these patients remains controversial. Furthermore, whether palonosetron (PALO) or aprepitant (APR) is more effective in controlling delayed CINV is unclear. We, therefore, investigated whether PALO+DEX or 1st 5-HT 3 RA+DEX+APR was more effective in controlling delayed CINV, and the risk factors for delayed CINV, in CRC patients undergoing L-OHP-based chemotherapy. Data were pooled from two prospective observational Japanese studies and a phase III trial to compare CINV incidence between the PALO + DEX (PALO) and 5-HT 3 RA+DEX+APR (APR) groups by propensity score-matched analysis. CINV risk factors were identified using logistic regression models. The CINV incidence was higher in the PALO group than in the APR group. Logistic regression analysis revealed alcohol consumption, motion sickness, and the PALO+DEX regimen as independent risk factors for delayed nausea, and female sex and the PALO+DEX regimen as those for delayed vomiting. Compared with prophylactic PALO + DEX, 1st 5-HT 3 RA+DEX+APR was more effective in controlling delayed CINV. Thus, CRC patients receiving L-OHP-based chemotherapy should be treated with three antiemetics, including APR., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objectives: Immune checkpoint inhibitors (ICIs) have become one of the standard therapies in non-small-cell lung cancer (NSCLC). Although inflammatory indices, including Glasgow prognostic score (GPS), modified Glasgow prognostic score (mGPS), and C-reactive protein/albumin ratio (CAR) were reported to be reliable predictors for survival in cancer patients, their clinical utility in NSCLC patients treated with ICIs is unknown., Materials and Methods: Advanced or recurrent NSCLC patients (n = 304) treated with ICI monotherapy at the National Hospital Organization Kyushu Cancer Center and Kyushu University Hospital between January 2016 and December 2019 were analyzed. Information on patient demographics, GPS, mGPS, and CAR at diagnosis were collected. The time-dependent area under curves (AUCs) of receiver operating characteristic curves for the prediction of overall survival (OS) for each factor were compared., Results: Of the three indices, GPS was the most significantly correlated with the degree of disease control rate (DCR) (DCR of GPS of 0, 1, and 2: 63.6 %, 49.4 %, and 41.4 %, respectively). The time-dependent AUC values of GPS for the prediction of OS were superior to those of mGPS and CAR (time-dependent AUC values of GPS, mGPS, and CAR for the prediction of 1-year OS: 0.7005, 0.6736, and 0.6565, respectively). GPS was significantly correlated with performance status (PS) (P <  0.0001) and clinical stage (P =  0.0139). GPS in combination with PS effectively predicted survival at 1 year ranging from 83.5 % (GPS = 0, PS = 0) to 25.0 % (GPS = 2, PS = 2, 3). A multivariable analysis revealed that GPS was an independent predictor of PFS and OS (P =  0.0009 and P =  0.0100, respectively)., Conclusions: We report for the first time that GPS represents a simple and useful prognostic factor in NSCLC patients treated with ICIs and should be validated prospectively., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: This study investigated whether preoperative serum transferrin, a rapid-turnover protein, was associated with prognosis after colorectal cancer (CRC) resection., Methods: We evaluated preoperative transferrin, which was calculated as iron and unsaturated iron-binding capacity, in 501 patients who underwent surgery for Stage I-III CRC. Transferrin level was directly proportional to total iron-binding capacity (TIBC), and TIBC < 250 μg/dl was defined as low transferrin. The associations between transferrin and prognosis were evaluated in univariate and multivariate Cox proportional hazards analyses., Results: Fifty-eight of 501 patients (11.5%) had low transferrin. In these patients, low transferrin was significantly associated with high age, female gender, low body mass index (<18.5), high white blood cell count, low total protein, low albumin, high C-reactive protein, low hemoglobin, and low neutrophil/lymphocyte ratio. In the univariate analysis, low transferrin was associated with shorter relapse-free survival (RFS) (hazard ratio [HR] 2.180, 95% confidence interval [CI] 1.417-3.354, P  < .001), overall survival (OS) (HR 2.930, 95% CI 1.784-4.811, P  < .001), and cancer-specific survival (CSS) (HR 2.122, 95% CI 1.053-4.275, P  = .035). In multivariate analysis, high age ( P  < .001), Glasgow Prognostic Score ( P  = .009), and low transferrin (HR 2.336, 95% CI 1.173-4.654, P  = .011) were independently associated with shorter OS, and depth of invasion pT4 ( P  = .015), presence of lymph node metastasis ( P  = .001), low hemoglobin ( P  = .034), and low transferrin (HR 2.638, 95% CI 1.113-5.043, P  = .025) were independently associated with shorter CSS., Conclusions: Preoperative serum transferrin in Stage I-III CRC patients was identified as a novel prognostic marker by univariate and multivariate analyses., Competing Interests: The authors declare no conflict of interests for this article., (© 2021 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)

Background: Patients with lung cancer who are treated with carboplatin-based chemotherapy regimens often experience chemotherapy-induced nausea and vomiting (CINV). However, knowledge on the effect of regimen and cofactors on the risk of CINV is limited. This study aimed to analyze and compare the incidence of CINV between lung cancer patients undergoing carboplatin plus pemetrexed (CBDCA+PEM) and those undergoing carboplatin plus paclitaxel (CBDCA+PTX) chemotherapy., Methods: Pooled data of 240 patients from two prospective observational studies were compared using propensity score matching. Separate multivariate logistic regression analyses were used to identify risk factors for nausea and vomiting following chemotherapy., Results: Delayed nausea was significantly more common in patients treated with CBDCA+PEM than in those treated with CBDCA+PTX (51.1% vs. 36.2%, P = 0.04), but the incidence of vomiting did not significantly differ between the two groups (23.4% vs. 14.9%, P = 0.14). The occurrence of CINV peaked on day 4 in the CBDCA+PTX group and on day 5 in the CBDCA+PEM group. Multivariate analysis showed that female sex, younger age, and CBDCA+PEM regimen were independent risk factors for delayed nausea, while female sex was an independent risk factor for delayed vomiting., Conclusions: The CBDCA + PEM regimen has a higher risk of causing delayed nausea than the CBDCA + PTX regimen, and aggressive antiemetic prophylaxis should be offered to patients treated with CBDCA + PEM.

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.

The development of hepatocellular carcinoma (HCC) is a multistep process with a complex interaction of various genetic backgrounds and the tumor microenvironment. In addition to the development of rational approaches to epidemiologic research, early detection, and diagnosis, considerable progress has been made in systemic treatment with molecular-targeted agents for patients with advanced HCC. Moreover, encouraging reports of recent clinical trials of combination therapy with immune-checkpoint inhibitors (ICIs) has raised high hopes. Each HCC is the result of a unique combination of somatic alterations, including genetic, epigenetic, transcriptomic, and metabolic events, leading to conclusive tumoral heterogeneity. Recent advances in comprehensive genetic analysis have accelerated molecular classification and defined subtypes with specific characteristics, including immune-associated molecular profiles reflecting the immune reactivity in the tumor. In considering the development of therapeutic strategies in combination with immunotherapy, proper interpretation of molecular pathological characterization could lead to effective therapeutic deployment and enable individualization of the management of HCC. Here, we review distinctive molecular alterations in the subtype classification of HCC, current therapies, and representative clinical trials with alternative immune-combination approaches from a molecular pathological point., (© 2020 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: A previous Phase I/II study demonstrated that TAS-102 (trifluridine/tipiracil [FTD/TPI]) plus bevacizumab (Bev) has encouraging efficacy and controllable safety for patients with previously treated metastatic colorectal cancer. Therefore, we designed for assessing the efficacy and safety of FTD/TPI plus Bev in elderly patients with previously untreated metastatic colorectal cancer., Methods: This is a multicenter, single-arm Phase II study included patients ≥70 years old with previously untreated, unresectable metastatic colorectal cancer. Treatment consisted of FTD/TPI plus Bev given every 4 weeks. The primary endpoint was progression-free survival (PFS), assuming a null hypothesis of a PFS of 5 months. The secondary endpoints were the overall survival (OS), overall response rate (ORR), and adverse events (AEs)., Results: Between 5 January 2017 and 13 March 2018, 39 patients were enrolled from 18 institutions. The median patient age was 76.0 years (range, 70-88); the ECOG-PS was 0 in 24 patients and 1 in 15 patients. The median PFS was 9.4 months as a primary endpoint, and the median OS was 22.4 months. The ORR was 40.5% and the disease control rate was 86.5%. Grade 3-4 AEs included neutropenia (71.8%), leukopenia (51.3%), anorexia (15.4%), febrile neutropenia (10.3%), and fatigue (10.3%)., Conclusions: FTD/TPI plus Bev is an effective and well-tolerated regimen for elderly patients with previously untreated metastatic colorectal cancer. Capecitabine/bevacizumab can be selected as a subsequent maintenance therapy without irinotecan and oxaliplatin because FTD/TPI has no cross-resistance with 5-fluorouracil., Clinical Trial Registration: UMIN clinical trials registry (UMIN000025241)., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Interleukin (IL)-38 was discovered in 2001 and is a member of the IL-1 family of cytokines. IL-38 shows anti-inflammatory activity in several inflammatory diseases. In lung adenocarcinoma, we previously demonstrated that high IL-38 expression in tumor cells was associated with poor prognosis. However, the role of IL-38 in the tumor microenvironment has not been clarified., Methods: IL-38-plasmid-transfected Lewis lung carcinoma cells (LLC-IL38) and empty vector-transfected LLC cells (LLC-vector) were established. Cell proliferation in vitro and tumor growth in vivo were examined, and immunohistochemical staining was used to assess tumor-infiltrating lymphocytes (TILs). A CD8 + lymphocyte depletion model was established to show the association between IL-38 and CD8 + lymphocytes. Moreover, we examined the association between IL-38 expression and CD8 + TILs in human samples, analyzing immunohistochemical staining in 226 patients with radically resected lung adenocarcinoma., Results: Tumor growth of LLC-IL38 in vivo was significantly increased compared with that of LLC-vector, although cell proliferation of LLC-IL38 in vitro was lower than that of LLC-vector. CD8 + TILs were significantly decreased in LLC-IL38 tumor compared with LLC-vector tumor. The difference in tumor growth between LLC-IL38 and LLC-vector became insignificant after depletion of CD8 + lymphocytes. In immunohistochemical staining in tissues from patients with lung adenocarcinoma, multivariate analysis showed high IL-38 expression was an independent negative predicter of high density of CD8 + TILs., Conclusion: We demonstrated that high IL-38 expression in tumor cells was significantly associated with reduction of CD8 + TILs and tumor progression. These results suggest that IL-38 could be a therapeutic target for lung cancer.

The WJOG8815L phase II clinical study involves patients with non-small cell lung cancer (NSCLC) that harbored the EGFR T790M mutation, which confers resistance to EGFR tyrosine kinase inhibitors (TKIs). The purpose of this study was to assess the predictive value of monitoring EGFR genomic alterations in circulating tumor DNA (ctDNA) from patients with NSCLC that undergo treatment with the third-generation EGFR-TKI osimertinib. Plasma samples of 52 patients harboring the EGFR T790M mutation were obtained pretreatment (Pre), on day 1 of treatment cycle 4 (C4) or cycle 9 (C9), and at diagnosis of disease progression or treatment discontinuation (PD/stop). CtDNA was screened for EGFR-TKI-sensitizing mutations, the EGFR T790M mutation, and other genomic alterations using the cobas EGFR Mutation Test v2 (cobas), droplet digital PCR (ddPCR), and targeted deep sequencing. Analysis of the sensitizing-and T790M-EGFR mutant fractions (MFs) was used to determine tumor mutational burden. Both MFs were found to decrease during treatment, whereas rebound of the sensitizing EGFR MF was observed at PD/stop, suggesting that osimertinib targeted both T790M mutation-positive tumors and tumors with sensitizing EGFR mutations. Significant differences in the response rates and progression-free survival were observed between the sensitizing EGFR MF-high and sensitizing EGFR MF-low groups (cutoff: median) at C4. In conclusion, ctDNA monitoring for sensitizing EGFR mutations at C4 is suitable for predicting the treatment outcomes in NSCLC patients receiving osimertinib (Clinical Trial Registration No.: UMIN000022076)., (© 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Pembrolizumab is effective in a limited number of patients with advanced urothelial carcinoma (UC). Therefore, we evaluated the prognostic value of clinical biomarkers following pembrolizumab treatment in patients with advanced UC., Methods: We retrospectively reviewed the medical records of 121 patients with platinum-refractory advanced UC who received pembrolizumab. Inflammation-based prognostic scores before and 6 weeks after the treatment were recorded. The categorical variables influencing overall survival (OS) and objective response rate (ORR) were analyzed., Results: Multivariate analyses showed that pretreatment Eastern Cooperative Oncology Group (ECOG) performance score (PS), presence of only lymph node metastasis (only LN mets), C-reactive protein (CRP), and neutrophil/lymphocyte ratio (NLR) were independent prognostic factors for OS (P = 0.0077; RR = 2.42, P = 0.0049; RR = 0.36, P = 0.0047; RR = 2.53, and P = 0.0079; RR = 2.33, respectively). The pretreatment risk stratification using ECOG PS, only LN mets, CRP, and NLR was used for estimating the OS (P < 0.0001) and ORR (P < 0.0001). Furthermore, changes in NLR in response to pembrolizumab were significantly associated with the OS (P = 0.0002) and ORR (P = 0.0023). This change was also significantly correlated with OS even in the high-risk group stratified by this pretreatment risk stratification (P = 0.0069)., Conclusions: This pretreatment risk stratification may be used for estimating the OS and ORR of patients with advanced UC treated with pembrolizumab. If changes in NLR in response to pembrolizumab treatment improve, pembrolizumab should be continued.

Background: Reactivation of hepatitis B virus (HBV) during anticancer treatment is a critical issue. When treating patients with solid tumors, it is unclear whether specific cancer types or treatments affect HBV reactivation in hepatitis B surface antigen (HBsAg)-negative and hepatitis B core antibody (HBcAb)-positive patients, so-called de novo hepatitis B patients. The risk of de novo hepatitis B may vary based on different background factors., Aim: To determine the frequency and risk factors for de novo hepatitis B during solid tumor treatment., Methods: This retrospective cohort study comprised 1040 patients without HBsAgs and with HBcAbs and/or hepatitis B surface antibodies (HBsAbs). The patients were treated for solid cancer from 2008 to 2018 at the National Kyushu Cancer Center and underwent HBV DNA measurements. Patient characteristics and disease and treatment information were investigated. HBV DNA measurements were performed using TaqMan polymerase chain reaction (PCR). To identify the risk factors associated with HBV DNA expression, the age, sex, original disease, pathology, treatment method, presence or absence of hepatitis C virus (HCV), and HBsAb and/or HBcAb titers of all subjects were investigated. In patients with HBV DNA, the time of appearance, presence of HBsAgs and HBsAbs at the time of appearance, and course of the subsequent fluctuations in virus levels were also investigated., Results: Among the 1040 patients, 938 were HBcAb positive, and 102 were HBcAb negative and HBsAb positive. HBV DNA expression was observed before the onset of treatment in nine patients (0.9%) and after treatment in 35 patients (3.7%), all of whom were HBcAb positive. The HBV reactivation group showed significantly higher median HBcAb values [9.00 (8.12-9.89) vs 7.22 (7.02-7.43), P = 0.0001] and significantly lower HBsAb values (14 vs 46, P = 0.0342) than the group without reactivation. Notably, the reactivated group showed a significantly higher proportion of cancers in organs related to digestion and absorption (79.0% vs 58.7%, P = 0.0051). A high HBcAb titer and cancers in organs involved in digestion and absorption were identified as independent factors for HBV reactivation (multivariate analysis, P = 0.0002 and P = 0.0095). The group without HBsAbs tended to have a shorter time to reactivation (day 43 vs day 193), and the frequency of reactivation within 6 mo was significantly higher in this group ( P = 0.0459) than in the other group., Conclusion: A high HBcAb titer and cancers in organs involved in digestion and absorption are independent factors that contribute to HBV reactivation during solid tumor treatment., Competing Interests: Conflict-of-interest statement: This work was partly supported by funding from Eisai (Grant No. HHCS20181030011) (Tokyo, Japan); however, that did not result in potential conflicts for this study because it was designed and performed independently of this funding agency., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Bifidobacterium longum is a symbiotic human gut bacterium that has a degradation system for β-arabinooligosaccharides, which are present in the hydroxyproline-rich glycoproteins of edible plants. Whereas microbial degradation systems for α-linked arabinofuranosyl carbohydrates have been extensively studied, little is understood about the degradation systems targeting β-linked arabinofuranosyl carbohydrates. We functionally and structurally analyzed a substrate-binding protein (SBP) of a putative ABC transporter (BLLJ&#95;0208) in the β-arabinooligosaccharide degradation system. Thermal shift assays and isothermal titration calorimetry revealed that the SBP specifically bound Araf-β1,2-Araf (β-Ara 2 ) with a K d of 0.150 μm, but did not bind L-arabinose or methyl-β-Ara 2 . Therefore, the SBP was termed β-arabinobiose-binding protein (BABP). Crystal structures of BABP complexed with β-Ara 2 were determined at resolutions of up to 1.78 Å. The findings showed that β-Ara 2 was bound to BABP within a short tunnel between two lobes as an α-anomeric form at its reducing end. BABP forms extensive interactions with β-Ara 2 , and its binding mode was unique among SBPs. A molecular dynamics simulation revealed that the closed conformation of substrate-bound BABP is stable, whereas substrate-free form can adopt a fully open and two distinct semi-open states. The importer system specific for β-Ara 2 may contribute to microbial survival in biological niches with limited amounts of digestible carbohydrates. DATABASE: Atomic coordinates and structure factors (codes 6LCE and 6LCF) have been deposited in the Protein Data Bank (http://wwpdb.org/)., (© 2020 Federation of European Biochemical Societies.)

Gastroenteropancreatic (GEP) neuroendocrine neoplasm (NEN) that consists of neuroendocrine tumor and neuroendocrine carcinoma (NEC) is a lethal but under-investigated disease owing to its rarity. To fill the scarcity of clinically relevant models of GEP-NEN, we here established 25 lines of NEN organoids and performed their comprehensive molecular characterization. GEP-NEN organoids recapitulated pathohistological and functional phenotypes of the original tumors. Whole-genome sequencing revealed frequent genetic alterations in TP53 and RB1 in GEP-NECs, and characteristic chromosome-wide loss of heterozygosity in GEP-NENs. Transcriptome analysis identified molecular subtypes that are distinguished by the expression of distinct transcription factors. GEP-NEN organoids gained independence from the stem cell niche irrespective of genetic mutations. Compound knockout of TP53 and RB1, together with overexpression of key transcription factors, conferred on the normal colonic epithelium phenotypes that are compatible with GEP-NEN biology. Altogether, our study not only provides genetic understanding of GEP-NEN, but also connects its genetics and biological phenotypes., Competing Interests: Declaration Of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: FOLFOXIRI plus bevacizumab is used as a first-line therapy for patients with unresectable or metastatic colorectal cancer. However, there are no clear recommendations for second-line therapy after FOLFOXIRI plus bevacizumab combination. Here, we describe our planning for the EFFORT study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC., Methods: EFFORT is an open-label, multicenter, single arm phase II study to evaluate whether a FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Patients with unresectable or metastatic colorectal cancer who received FOLFOXIRI plus bevacizumab as a first-line therapy will receive aflibercept and FOLFIRI (aflibercept 4 mg/kg, irinotecan 150 mg/m 2 IV over 90 min, with levofolinate 200 mg/m 2 IV over 2 h, followed by fluorouracil 400 mg/m 2 bolus and fluorouracil 2400 mg/m 2 continuous infusion over 46 h) every 2 weeks on day 1 of each cycle. The primary endpoint is progression-free survival (PFS). To achieve 80% power to show a significant response benefit with a one-sided alpha level of 0.10, assuming a threshold progression-free survival of 3 months and an expected value of at least 5.4 months, we estimated that 32 patients are necessary. Secondary endpoints include overall survival, overall response rate, safety, and exploratory biomarker analysis for differentiating anti-VEGF drug in 2nd-line chemotherapy for unresectable or metastatic colorectal cancer., Discussion: This is the first study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for unresectable or metastatic colorectal cancer. Switching to a different type of anti-VEGF drug in second-line therapy after FOLFOXIRI plus bevacizumab appears to be an attractive treatment strategy when considering survival benefit. It is expected that this phase II study will prove the efficacy of this strategy and that a biomarker for drug selection will be discovered., Trial Registration: Japan Registry of Clinical Trials jRCTs071190003 . Registered April 18, 2019.

Inflammatory biomarkers have been associated with clinical outcomes in non-small cell lung cancer (NSCLC). However, the best prognostic marker(s) has not been identified, and the association between inflammatory markers and clinical characteristics is poorly understood. We selected 1,237 patients with resected NSCLC from Kyushu University (2003-2015) and Kyushu Cancer Center (2009-2015) in Japan. Pearson product-moment correlation coefficient among inflammatory markers and area under curve (AUC) of receiver operating characteristic (ROC) curve analyses for overall survival (OS) were calculated. We analyzed the associations between inflammatory markers and clinical factors using Student's t-test. Univariate and multivariate analyses with Cox proportional hazards regression analyses were performed to evaluate the relationship between survival and clinical factors. The cut-off values for neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio, and derived NLR (dNLR) were determined by ROC curve analyses for OS. We found a strong positive correlation between NLR and dNLR (r = 0.9629). The AUC of LMR was the highest amongst the measured metrics, and the AUC of NLR was higher than dNLR. Levels of some inflammatory markers were associated with sex, smoking, squamous cell carcinoma, and pathological stage. LMR ≥ 5.11 and lactate dehydrogenase (LDH) concentration ≥ 222 (U/L) were independent predictors of both disease-free survival (DFS) and OS (LMR; P = 0.0009 and 0.0008, LDH; P = 0.0195 and 0.0187, respectively). Certain inflammatory markers, potentially linked to smoking, were associated with an advanced pathological stage in NSCLC. LMR and LDH were independent predictors of both DFS and OS., Competing Interests: The authors have declared that no competing interests exist.

Immunotherapy targeting programmed cell death-1 (PD-1) has become a standard pharmacological therapy. Although tumor mutation burden level was reported to depend on the tumor location in nonsmall cell lung cancer (NSCLC), predictive impact of the tumor location on the response to anti-PD-1 therapy is unknown. Two hundred and seventeen advanced or recurrent NSCLC patients treated with anti-PD-1 therapy at Kyushu University Hospital and National Hospital Organization Kyushu Cancer Center were analyzed. To minimize the bias arising from the patients' background, adjusted Kaplan-Meier survival curves and Cox proportional hazards regression analyses using inverse probability of treatment weights (IPTW) were performed. Of the 217 patients, 132, 27, and 58 had primary NSCLC in upper, middle, and lower lobes, respectively. Patients with NSCLC in upper lobe were significantly associated with younger age (P = .0070) and smoker (P = .0003). The epidermal growth factor receptor-wild type and tumor location in upper lobe were independent predictors of disease control (P = .0175 and P = .0425, respectively). The IPTW-adjusted Kaplan-Meier curves showed that patients with NSCLC in the upper lobes had significantly longer progression-free survival (PFS) and overall survival (OS) than those in middle/lower lobes (P = .0026 and P = .0015, respectively). On IPTW adjusted Cox analysis, NSCLC in the upper lobe was an independent predictor of PFS and OS (P = .0078 and P = .0034, respectively). Patients with primary NSCLC in the upper lobes may be good candidates for anti-PD-1 therapy. These findings should be validated prospectively., (© 2020 UICC.)