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Background: Preoperative chemoradiotherapy (CRT) followed by surgery is the standard treatment for locally advanced rectal cancer (LARC). We reported the short-term outcomes of the VOLTAGE trial that investigated the safety and efficacy of preoperative CRT followed by nivolumab and surgery. Here, we present the 3-year outcomes of this trial. Methods: Thirty-nine patients with microsatellite stable (MSS) LARC and five patients with microsatellite instability-high (MSI-H) LARC underwent CRT (50.4 Gy) followed by five doses of nivolumab (240 mg) and surgery. The 3-year relapse-free survival (RFS), overall survival (OS), and associations with biomarkers were evaluated. Results: The 3-year RFS rates in patients with MSS and MSI-H were 79.5% and 100%, respectively, and the 3-year OS rates were 97.4% and 100%, respectively. Of the MSS patients, those with pre-CRT PD-L1 positivity, pre-CRT high CD8 + T cell/effector regulatory T cell (eTreg) ratio, pre-CRT high expression of Ki-67, CTLA-4, and PD-1 had a trend toward better 3-year RFS than those without. Conclusions: Three-year outcomes of patients with MSI-H were better than those of patients with MSS. PD-L1 positivity, elevated CD8/eTreg ratio, and high expression of Ki-67, CTLA-4, and PD-1 could be positive predictors of prognosis in patients with MSS. Clinical trial registration: ClinicalTrials.gov Identifier: NCT02948348. [ABSTRACT FROM AUTHOR]

Background: Identifying biomarkers to predict immune checkpoint inhibitor (ICI) efficacy is warranted. Considering that somatic mutation-derived neoantigens induce strong immune responses, patients with a high tumour mutational burden reportedly tend to respond to ICIs. However, there are several conflicting data. Therefore, we focused on the original function of neoantigenic mutations and their impact on the tumour microenvironment (TME). Methods: We evaluated 88 high-frequency microsatellite instability (MSI-H) colorectal cancers and analysed the function of the identified neoantigenic mutations and their influence on programmed cell death 1 (PD-1) blockade efficacy. The results were validated using The Cancer Genome Atlas (TCGA) datasets. Results: We identified frameshift mutations in RNF43 as a common neoantigenic gene mutation in MSI-H tumours. However, loss-of-function RNF43 mutations induced noninflamed TME by activating the WNT/β-catenin signalling pathway. In addition, loss of RNF43 function induced resistance to PD-1 blockade even in neoantigen-rich tumours. TCGA dataset analyses demonstrated that passenger rather than driver gene mutations were related to the inflamed TME in diverse cancer types. Conclusions: We propose a novel concept of "paradoxical neoantigenic mutations" that can induce noninflamed TME through their original gene functions, despite deriving neoantigens, suggesting the significance of qualities as well as quantities in neoantigenic mutations. [ABSTRACT FROM AUTHOR]

Aging leads to numerous changes that affect many components of the immune system, called "immunosenescence". Indeed, elderly individuals exhibit dysregulated immune responses against pathogens, poor responses to vaccination, and increased susceptibility to many diseases including cancer, autoimmune disorders, and other chronic inflammatory diseases. Despite progressed understanding of immunosenescence, its detailed mechanisms are still not fully understood. With advances in medicine, the population of older cancer patients is expected to rapidly increase in the coming years. Cancer immunotherapies, including immune checkpoint inhibitors (ICIs), have been shown to be effective for multiple cancer types, whereas to date, few specific data for elderly individuals have been published. Some systemic reviews have demonstrated that ICIs exhibit similar efficacy in older cancer patients, but they seem to be less effective in very old patients. In addition, toxicities might be more frequently observed in such patients. Here, we provide a summary to better understand immunosenescence and an overview of its relationship with cancer and antitumor immunity, including the efficacy and toxicity of ICIs. [ABSTRACT FROM AUTHOR]

Although transcriptome alteration is an essential driver of carcinogenesis, the effects of chromosomal structural alterations on the cancer transcriptome are not yet fully understood. Short-read transcript sequencing has prevented researchers from directly exploring full-length transcripts, forcing them to focus on individual splice sites. Here, we develop a pipeline for Multi-Sample long-read Transcriptome Assembly (MuSTA), which enables construction of a transcriptome from long-read sequence data. Using the constructed transcriptome as a reference, we analyze RNA extracted from 22 clinical breast cancer specimens. We identify a comprehensive set of subtype-specific and differentially used isoforms, which extended our knowledge of isoform regulation to unannotated isoforms including a short form TNS3. We also find that the exon–intron structure of fusion transcripts depends on their genomic context, and we identify double-hop fusion transcripts that are transcribed from complex structural rearrangements. For example, a double-hop fusion results in aberrant expression of an endogenous retroviral gene, ERVFRD-1, which is normally expressed exclusively in placenta and is thought to protect fetus from maternal rejection; expression is elevated in several TCGA samples with ERVFRD-1 fusions. Our analyses provide direct evidence that full-length transcript sequencing of clinical samples can add to our understanding of cancer biology and genomics in general. Namba et al develop a new pipeline called MuSTA to enable the efficient assembly of transcriptome from long-read sequencing data of breast cancer samples. This method enables the authors to discover subtype-specific isoforms, find that fusion transcript structures depend on their genomic context and identify a double-hop fusion that results in aberrant expression of an endogenous retroviral gene. [ABSTRACT FROM AUTHOR]

Single-cell level analysis is powerful tool to assess the heterogeneity of cellular components in tumor microenvironments (TME). In this study, we investigated immune-profiles using the single-cell analyses of endoscopically- or surgically-resected tumors, and peripheral blood mononuclear cells from gastric cancer patients. Furthermore, we technically characterized two distinct platforms of the single-cell analysis; RNA-seq-based analysis (scRNA-seq), and mass cytometry-based analysis (CyTOF), both of which are broadly embraced technologies. Our study revealed that the scRNA-seq analysis could cover a broader range of immune cells of TME in the biopsy-resected small samples of tumors, detecting even small subgroups of B cells or Treg cells in the tumors, although CyTOF could distinguish the specific populations in more depth. These findings demonstrate that scRNA-seq analysis is a highly-feasible platform for elucidating the complexity of TME in small biopsy tumors, which would provide a novel strategies to overcome a therapeutic difficulties against cancer heterogeneity in TME. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors may enhance the efficacy of radiotherapy (RT) in cancer treatment but the effect remains unknown in metastatic gastric cancer (mGC). This study aimed to compare the tumor shrinkage by palliative RT for mGC patients with or without previous exposure to anti-PD-1 therapy. Methods: Data of 36 mGC patients who had received palliative RT from April 2013 to May 2019 were analyzed. Primary tumor responses were evaluated through a volumetric measurement-based method using computed tomography (CT) and endoscopic responses were evaluated in patients who underwent endoscopy before and after RT. Tumor microenvironment (TME) immune status was investigated by analyzing tumor-infiltrating lymphocytes by flow cytometry. Results: Among 36 patients, 18 had previous exposure to anti-PD-1 before RT showing no significant differences in baseline characteristics with the other 18 patients without exposure to anti-PD-1 treatment. Tumor responses were observed in 28% (5/18) and none (0/18) in the anti-PD-1-exposed vs. naïve group, respectively (P = 0.045). Five out of eight patients in the anti-PD-1-exposed group, who underwent endoscopy after RT showed partial response, but none in the anti-PD-1-naïve patients showed response (P = 0.026). Increase in the CD8+ T cell/effector regulatory T cell ratio in TILs after anti-PD-1 therapy was noted in three responders to RT, but not in the other three non-responders. Conclusions: Prior exposure to anti-PD-1 therapy increases tumor response to RT. Immune profiling suggests that anti-PD-1 therapy may enhance the efficacy of RT by immunoactivation in the TME. [ABSTRACT FROM AUTHOR]

Background: Recently, the U.S. Food and Drug Administration approved pembrolizumab for patients (pts) with PD-L1-positive metastatic gastric cancer (MGC) based on 22C3 immunohistochemistry (IHC) assay. However, little is known about detailed clinicopathological features of 22C3 PD-L1 expression in MGC.Patients and methods: Pts with histologically confirmed MGC were eligible for this prospective observational study. PD-L1 expression (22C3) on tumor cell (TC) or immune cell (IC) and mismatch repair (MMR) were analyzed by IHC. Epstein-Barr virus (EBV) was detected by in situ hybridization. The expressions of tyrosine kinase receptors (RTKs) and cancer genome alterations were evaluated by IHC or next-generation sequencing.Results: A total of 225 pts were analyzed in this study. PD-L1 expression on TC, PD-L1 on IC, MMR-deficient (D-MMR), and EBV positivity were identified in 8.4, 65.3, 6.2, and 6.2% cases, respectively. PD-L1 expression in TC was more frequently observed in pts with D-MMR (P < 0.001), PIK3CA mutation (P = 0.020), and KRAS mutation (P = 0.002), and PD-L1 on IC was associated with EBV positivity (P = 0.034), and lymph-node metastasis (P < 0.001). PD-L1 expression on either IC or TC was less frequently observed in pts with peritoneal metastasis and Borrmann Type 4. A significant association was not observed between PD-L1 expression and RTKs expression or presence of other gene alterations. PD-L1 expression on either TC or IC was not prognostic factor.Conclusions: 22C3 PD-L1 expression in MGC was associated with distinct clinicopathological features, but was not a prognostic factor. [ABSTRACT FROM AUTHOR]

Background: Erlotinib shows large inter-patient pharmacokinetic variability, but the impact of early drug exposure and genetic variations on the clinical outcomes of erlotinib remains fully investigated. The primary objective of this study was to clarify the population pharmacokinetics/pharmacodynamics of erlotinib in Japanese patients with non-small cell lung cancer (NSCLC). The secondary objective was to identify genetic determinant(s) for the cerebrospinal fluid (CSF) permeability of erlotinib and its active metabolite OSI-420. Methods: A total of 88 patients treated with erlotinib (150 mg/day) were enrolled, and CSF samples were available from 23 of these patients with leptomeningeal metastases. Plasma and CSF concentrations of erlotinib and OSI-420 were measured by high-performance liquid chromatography with UV detection. Population pharmacokinetic analysis was performed with the nonlinear mixed-effects modelling program NONMEM. Germline mutations including ABCB1 (1236C>T, 2677G>T/A, 3435C>T), ABCG2 (421C>A), and CYP3A5 (6986A>G) polymorphisms, as well as somatic EGFR activating mutations if available, were examined. Early exposure to erlotinib and its safety/efficacy relationship were evaluated. Results: The apparent clearance of erlotinib and OSI-420 were significantly decreased by 24 and 35 % in patients with the ABCG2 421A allele, respectively ( p < 0.001), while ABCB1 and CYP3A5 polymorphisms did not affect their apparent clearance. The ABCG2 421A allele was significantly associated with increased CSF penetration for both erlotinib and OSI-420 ( p < 0.05). Furthermore, the incidence of grade ≥2 diarrhea was significantly higher in patients harboring this mutant allele ( p = 0.035). A multivariate logistic regression model showed that erlotinib trough (C) levels on day 8 were an independent risk factor for the development of grade ≥2 diarrhea ( p = 0.037) and skin rash ( p = 0.031). Interstitial lung disease (ILD)-like events occurred in 3 patients (3.4 %), and the median value of erlotinib C levels adjacent to these events was approximately 3 times higher than that in patients who did not develop ILD (3253 versus 1107 ng/mL; p = 0.014). The objective response rate in the EGFR wild-type group was marginally higher in patients achieving higher erlotinib C levels (≥1711 ng/mL) than that in patients having lower erlotinib C levels (38 versus 5 %; p = 0.058), whereas no greater response was observed in the higher group (67 %) versus the lower group (77 %) within EGFR mutation-positive patients ( p = 0.62). Conclusions: ABCG2 can influence the apparent clearance of erlotinib and OSI-420, and their CSF permeabilities in patients with NSCLC. Our preliminary findings indicate that early exposure to erlotinib may be associated with the development of adverse events and that increased erlotinib exposure may be relevant to the antitumor effects in EGFR wild-type patients while having less of an impact on the tumor response in EGFR mutation-positive patients. [ABSTRACT FROM AUTHOR]

Mutation of the epidermal growth factor receptor gene ( EGFR mutation) is a very important marker in the treatment for non-small cell lung cancer. Since signaling from this receptor induces tumor-associated angiogenesis, we hypothesized that lung cancers with EGFR mutations tend to develop locally with increased angiogenesis. Thus, the association between vascular-poor area of primary tumors and EGFR status was retrospectively investigated in advanced lung adenocarcinomas. To assess vascular-poor area, contrast-enhanced computed tomography scans taken before initial treatment for lung cancer were analyzed, together with primary tumor location (peripheral or central) and size. We analyzed 178 patients with advanced lung adenocarcinoma. EGFR mutations were detected in 95 of the 178 patients (53.4 %). EGFR mutation was found to be significantly related to women ( P = 0.0070), never-smokers ( P < 0.0001), and tumors without vascular-poor area ( P < 0.0001). Based on a multivariate analysis, presence of EGFR mutations was independently associated with never-smokers ( P = 0.0046), lack of vascular-poor area ( P = 0.0001), and tumor size >30 mm ( P = 0.0080). EGFR mutations were found in 41 of 51 never-smokers without vascular-poor area (80.4 %), 19 of 36 never-smokers with vascular-poor area (52.8 %), 19 of 37 current or former-smokers without vascular-poor area (51.4 %), and 16 of 54 current or former-smokers with vascular-poor area (29.6 %). This study showed an association between vascular-poor area of primary tumors and EGFR status. As a consequence, evaluation using a combination of smoking status and vascular-poor area allows us to predict presence of EGFR mutations at a high frequency. [ABSTRACT FROM AUTHOR]

Purpose: Several cases have been reported in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) resistant to gefitinib were improved by erlotinib. However, there has been no study in which cerebrospinal fluid (CSF) concentrations of gefitinib and erlotinib are directly compared. Thus, we aimed to compare them. Methods: We examined 15 Japanese patients with NSCLC and CNS metastases with epidermal growth factor receptor gene mutations who received CSF examinations during epidermal growth factor receptor-tyrosine kinase inhibitors treatment (250 mg daily gefitinib or 150 mg daily erlotinib). Plasma and CSF concentrations were determined using high-performance liquid chromatography with tandem mass spectrometry. Results: The concentration and penetration rate of gefitinib (mean ± standard deviation) in the CSF were 3.7 ± 1.9 ng/mL (8.2 ± 4.3 nM) and 1.13 ± 0.36 %, respectively. The concentration and penetration rate of erlotinib in the CSF were 28.7 ± 16.8 ng/mL (66.9 ± 39.0 nM) and 2.77 ± 0.45 %, respectively. The CSF concentration and penetration rate of erlotinib were significantly higher than those of gefitinib ( P = 0.0008 and <0.0001, respectively). The CNS response rates of patients with erlotinib treatment were preferentially (but not significantly) higher than those with gefitinib treatment. (1/3 vs. 4/7, respectively). Leptomeningeal metastases in one patient, which were refractory to gefitinib, dramatically responded to erlotinib. Conclusions: This study suggested that higher CSF concentration could be achieved with erlotinib and that erlotinib could be more effective for the treatment for CNS metastases, especially leptomeningeal metastases, than gefitinib. [ABSTRACT FROM AUTHOR]

A study of patients with advanced non-squamous non-small cell lung cancer (NSCLC) evaluated epidermal growth factor receptor (EGFR) mutation status and serum hepatocyte growth factor (HGF) for their associations with response to gefitinib therapy and prognostic impact. An enzyme-linked immunosorbent assay was used to determine levels of HGF in serum from 96 Japanese patients with advanced non-squamous NSCLC. The peptic nucleic acid-locked nucleic acid clamp method was used to determine their EGFR somatic mutation status. We evaluated the relationship between each independent clinicopathological variable and the response to gefitinib therapy and risk factors associated with prognosis. HGF-positive serum status (hazard ratio, 1.536; 95% confidence interval, 1.042-2.400; P = 0.0295) had a significant and independent negative effect on progression-free survival among patients with wild-type EGFR. We demonstrate that having HGF-positive serum is predictive of a negative response to gefitinib therapy in patients with advanced NSCLC who harbor wild-type EGFR. [ABSTRACT FROM AUTHOR]

Background: Subgroup analyses of randomized studies have consistently shown that pemetrexed is exclusively effective in non-small-cell lung cancer (NSCLC) other than squamous cell carcinoma and the combination of pemetrexed and platinum agents is recommended for first-line chemotherapy in advanced non-squamous NSCLC; however, there have been few prospective studies of a selected population. Patients and methods: This was a single-arm phase II study of carboplatin and pemetrexed in Japanese patients with chemo-naive advanced non-squamous NSCLC. Patients received six cycles of pemetrexed (500 mg/m) combined with carboplatin (area under the curve: AUC 6) every 3 weeks. Maintenance chemotherapy with pemetrexed was permitted in patients whose disease did not progress after combination chemotherapy. The primary endpoint was the response rate, and secondary endpoints were safety and survival. Results: Fifty-one patients were enrolled between November 2009 and March 2011, and 49 patients were evaluable for both safety and efficacy. All but one patient had adenocarcinoma histology. Forty-four (90 %) patients completed four cycles, and 33 (67 %) completed six cycles of chemotherapy. Partial response was achieved in 25 patients (response rate: 51 %) and stable disease in 18 patients (37 %). Median progression-free survival (PFS) and overall survival (OS) were 6.3 months and 24.3 months, respectively. The median PFS and OS were 7.9 months and 24.3 months in patients with epidermal growth factor receptor (EGFR) mutation, and 6.3 months and 21.0 months in patients with EGFR wild type or unknown. There were no statistical differences between EGFR mutants and non-mutants for both PFS ( p = 0.09) and OS ( p = 0.23). Grade 3/4 neutropenia and thrombocytopenia were observed in 16 (33 %) and 9 (18 %) patients, respectively. Non-hematologic toxicities were generally mild, and there were no treatment-related deaths. Conclusions: The combination of carboplatin and pemetrexed was safe and effective in advanced non-squamous NSCLC. Although the sample size was small, our results indicate that pemetrexed is a key drug for advanced non-squamous NSCLC, irrespective of the EGFR mutation status (UMIN-CTR number 000002451). [ABSTRACT FROM AUTHOR]

A standard, valid assay of comorbidities for elderly patients with advanced non-small-cell lung cancer (NSCLC) who have received antitumor therapy is needed to provide useful prognostic information. The aim of this study was to analyze prognostic factors and validate classic Charlson comorbidity index (CCI) and comorbidity scores in elderly patients with advanced NSCLC treated with chemotherapy or epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). A retrospective analysis was conducted on 162 patients with advanced NSCLC over 70 years old at diagnosis, who were treated with cytotoxic chemotherapy or with EGFR-TKIs between April 2003 and April 2009 at Kyoto University Hospital. Collected data included clinical assessments, treatments, toxicities, and outcomes. Survival was estimated using the Kaplan-Meier method. Prognostic factors were evaluated with log-rank and Cox regression tests. Based on multivariate analysis, unspecified NSCLC histology [Hazard ratio (HR), 1.631; 95% Confidence interval (CI), 1.184-2.263; P = 0.0016], more than 3 comorbidities (HR, 1.317; 95% CI, 1.020-2.675; P = 0.0350), and a CCI of more than 3 (HR, 1.321; 95% CI, 1.031-1.664; P = 0.0285) were significant independent negative prognostic factors for survival. Our results indicate that CCI and the number of comorbidities are independent predictors of survival in elderly patients undergoing systemic chemotherapy including EGFR-TKIs for advanced NSCLC. These factors should be taken into consideration in the pretreatment assessment as important factors predicting survival outcome. [ABSTRACT FROM AUTHOR]

Purpose: Recent reports indicate that refractory central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) are improved by high-dose gefitinib or erlotinib administration. We describe a Japanese woman with NSCLC and CNS metastases who was resistant to 75 mg daily erlotinib, but the metastases were improved by 150 mg daily erlotinib. We investigated the plasma and CSF concentrations of erlotinib at each dose as well as the correlation between the plasma and CSF concentrations of erlotinib. Methods: Including this patient, we administered 150 mg erlotinib daily to nine NSCLC patients with CNS metastases and measured the plasma and CSF concentrations just before administration on day 8. The concentrations were determined using high-performance liquid chromatography with ultraviolet detection. Results: The plasma and CSF concentrations of erlotinib at a dose of 75 mg were 433 and 14 nM, respectively. The plasma and CSF concentrations of erlotinib at a dose of 150 mg were increased to 1,117 and 44 nM, respectively. The mean ± standard deviation of CSF concentrations and penetration rates were 106 ± 59 nM and 4.5 ± 1.5%, respectively. There was a good correlation ( R = 0.84) between plasma and CSF concentrations ( P = 0.0005). Conclusions: This study indicates that CSF concentrations of erlotinib depend on its plasma concentration. As seen in this patient, high CSF concentrations of erlotinib can be achieved by high-dose administration, and this finding suggests the efficacy of high-dose administration, especially to refractory CNS metastases of NSCLC patients. [ABSTRACT FROM AUTHOR]

The aims of this study are to: (a) confirm the prognostic significance of the procoagulant molecules D dimer, thrombin-antithrombin complex (TAT), and plasmin-α2-plasmin inhibitor complex (PIC); (b) to evaluate hemostatic activation in patients with advanced non-small cell lung cancer (NSCLC); and (c) to delineate the relationships between markers of hemostasis and other clinical characteristics. In this study, a low PIC/TAT ratio and poor PS were significant independent negative prognostic factors for survival in patients with advanced NSCLC. The PIC/TAT ratio may become a surrogate marker for treatment with anticoagulants in the future. [ABSTRACT FROM AUTHOR]

Purpose: The objectives of this phase I trial were to evaluate the toxicity of the nedaplatin/gemcitabine regimen, determine the maximum tolerated doses (MTDs) of these agents, and observe the anti-tumor effects of this regimen on advanced squamous cell lung cancer. Methods: Patients with previously untreated advanced squamous cell lung cancer were eligible if they had a performance status of 0 or 1 with adequate organ function. The doses of gemcitabine (days 1 and 8) and nedaplatin (day 8) studied were 800/70, 1,000/80, 1,000/90, and 1,000/100 (mg/m), repeated every 3 weeks. Results: Toxicity and response could be assessed in all 13 patients enrolled. The patients included 12 men and one woman with a median age of 69 years (range 57-81 years). Three patients had stage IIIB disease and 10 patients had stage IV disease. The MTDs were reached at 1,000 mg/m gemcitabine and 80 mg/m nedaplatin. The most frequent toxic effects were thrombocytopenia and neutropenia; grade 3 or 4 thrombocytopenia was observed in 23% of patients, and grade 3 or 4 neutropenia was seen in 46% of patients. Non-hematologic toxicities were mild. Grade 3 fatigue, nausea/vomiting, and appetite loss occurred in two patients. The overall response rate was 62%. Conclusions: We recommend doses of 800 mg/m gemcitabine and 70 mg/m nedaplatin for phase II study. This combination chemotherapeutic regimen is active and well tolerated. [ABSTRACT FROM AUTHOR]

Internal jugular vein thrombosis is much less common than deep venous thrombosis of lower limbs and is generally caused by an indwelling venous catheter or otological infection. Several cases of internal jugular vein thrombosis associated with malignancy have been also reported. Bevacizumab, a monoclonal neutralizing antibody against vascular endothelial growth factor, has shown benefits in the treatment of many types of malignancy and its use is increasing. Serious adverse effects, however, are associated with the use of bevacizumab, including venous thromboembolism. In this article, we present a rare case of non-small cell lung cancer complicated by pulmonary embolism due to internal jugular vein thrombosis associated with bevacizumab. [ABSTRACT FROM AUTHOR]