Whole-transcriptome sequencing in advanced gastric or gastroesophageal cancer: A deep dive into its clinical potential.

Advanced gastric and gastroesophageal junction cancers (GC/GEJCs) harbor diverse molecular signatures, highlighting the need for intricate evaluations to identify potential therapeutic targets. Although whole-transcriptome sequencing (WTS) has emerged as a useful tool for understanding these molecular intricacies, its clinical implications have yet to be fully elucidated. This study evaluated the correlation between immunohistochemistry (IHC) and WTS, compared their clinical significance, and identified potential therapeutic targets undetectable through IHC alone. We enrolled 140 patients with advanced GC/GEJC and assessed them using IHC for six pivotal biomarkers: claudin-18 (CLDN18), human epidermal growth factor receptor 2 (HER2), multiple receptor tyrosine kinases (RTKs), and programmed death ligand 1 (PD-L1). Concurrently, WTS was employed as part of the analyses in MONSTAR-SCREEN-2, a multicenter multiomics study. IHC analysis revealed 16.4% HER2, 39.3% CLDN18 (2+/3 + ≥75%), and 15.8% PD-L1 (combined positive score ≥ 10) positivity, among other molecular markers. Significant correlations were observed between IHC and WTS for all six pivotal biomarkers. Among nineteen HER2 IHC-positive patients treated with anti-HER2 therapeutics, ERBB2 status in WTS was significantly associated with progression-free survival (ERBB2-high vs. -low: median 9.0 vs. 5.6 months, log-rank p = 0.046). IHC-based molecular profiling revealed significantly high expression of CLDN18 in RTK-negative patients, with 78.4% positive for either CLDN18 or PD-L1. Additionally, WTS revealed elevated expression of pivotal biomarkers in patients displaying negative targetable biomarkers via IHC. Our findings highlighted the significant correlation between IHC and WTS, reinforcing the clinical utility of WTS. A subset with IHC-negative but WTS-positive status may benefit from specific biomarker-targeted therapies.

Early gastric cancer with RhoGAP fusion is linked to frequent nodal metastasis and a part of microtubular-mucocellular histology.

INTRODUCTION: Gastric cancer with fusion genes involving the Rho GTPase-activating protein domain (RhoGAP-GC) is mainly included in the genomically stable type of The Cancer Genome Atlas classification. Clinical implications and histological characteristics of RhoGAP-GC in the early phase remain unclear. METHODS: We analyzed 878 consecutive pT1b GCs for RhoGAP and its partner genes using fluorescence in situ hybridization assay. RESULTS: RhoGAP fusion was detected in 57 (6.5%) GCs. Univariate analysis revealed that female sex, middle-lower third tumor location, advanced macroscopic type, tumor diameter > 2 cm, pT1b2, lymphatic invasion, venous invasion, negative EBER-ISH, and RhoGAP fusion were significantly associated with lymph node metastasis (LNM). Multivariate analysis presented RhoGAP fusion, lymphatic invasion, tumor diameter > 2 cm, advanced macroscopic type, venous invasion, and middle-lower third tumor location as independent risk factors for LNM. Notably, RhoGAP fusion had the highest odds ratio (3.92) for LNM among analyzed parameters (95% CI 2.12-7.27; p < 0.001). Compared to non-RhoGAP-GCs, RhoGAP-GCs were significantly frequent in younger females and showed the highest incidence of lymphatic invasion (56.2%) and LNM (49.1%) (p < 0.001). Histologically, microtubular architecture with pseudo-trabecular interconnection and small aggregations of tumor cells with a varied amount of cytoplasmic mucin, named "microtubular-mucocellular (MTMC) histology," was found in 93.0% (53 of 57) of RhoGAP-GCs in the intramucosal area. MTMC histology showed high sensitivity and negative predictive value (93.0% and 99.4%, respectively) for RhoGAP fusion, albeit positive predictive value is low (34.9%). CONCLUSION: RhoGAP-GC is linked to a characteristic MTMC histology and a high incidence of LNM.

Analysis of Adverse Events Associated with Trastuzumab Deruxtecan in Patients with Gastric and Breast Cancer: A Retrospective Study.

Trastuzumab deruxtecan (T-DXd) has displayed demonstrable efficacy and manageable toxicity in previously treated patients with advanced gastric and breast cancer, and it has been approved in Japan. However, there is a lack of data on the optimal management in clinical practice. Therefore, we assessed the adverse event (AE) profiles of T-DXd in patients with advanced gastric or breast cancer to provide guidance for appropriate management. This retrospective study was conducted at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. We reviewed the medical records of patients with advanced gastric or breast cancer who received T-DXd between May 2020 and December 2021. AEs occurring within the first three cycles of T-DXd were evaluated according to Common Terminology Criteria for Adverse Events version 5.0. Thirty-six patients were enrolled (gastric: n = 19, breast: n = 17). All 15 males had gastric cancer, whereas 4 and 17 females had gastric and breast cancer, respectively. Interstitial lung disease (ILD) occurred in five patients (14%), but no patients had severe ILD. Gastrointestinal (GI) toxicities, including nausea (61%), vomiting (22%), decreased appetite (33%), and diarrhea (39%), were the most common AEs. The incidence of GI toxicities did not differ by cancer type; however, nausea was significantly more common in females (81 vs. 33%; p < 0.01). T-DXd was safely administered in clinical practice in patients with previously treated advanced gastric or breast cancer. The management of GI toxicities is important in the clinical implementation of T-DXd.

Clinical outcomes and prognostic factors of concurrent chemoradiotherapy for anal squamous cell carcinoma in Japan.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locoregional anal squamous cell carcinoma (ASCC) in western countries. However, there have been few reports on the clinical outcomes of CCRT in Japan. This study aimed to evaluate the clinical outcomes of CCRT, prognostic factors, and the clinical impact of programmed cell death-ligand 1 (PD-L1) expression of ASCC in Japan. METHODS: Patients with locoregional ASCC were enrolled between 2007 and 2017. All patients received CCRT consisting of ≥ 45 Gy of radiation, 5-fluorouracil, and mitomycin C. Disease-free survival (DFS), overall survival (OS), and adverse events (AEs) were estimated. Expression of p16 and PD-L1 were assessed by immunohistochemical staining (IHC). RESULTS: This study included 36 patients, of whom 30 (83.3%) were female. Among the participants, 32 (88.9%) achieved complete clinical remission, while six (16.7%) experienced recurrence. The five-year DFS and five-year OS were 72.2% and 84.7%, respectively. Grades ≥ 3 serious AEs included neutropenia in 10 (27.7%) and perianal dermatitis in eight (22.2%). In a univariate analysis, male sex, lymph node metastasis, and large tumor size were significantly associated with worse outcome. In a multivariate analysis, tumor size was an independent factor associated with short DFS. Of the 30 patients whose biopsy specimens were available for IHC, 29 (96.7%) were positive for p16, and 13 (43.3%) were positive for PD-L1. However, PD-L1 expression did not show any clinical impact. CONCLUSIONS: The comparative etiology, clinical outcomes, and prognostic factors of CCRT observed in Japanese patients with locoregional ASCC were consistent with western data.

Exploratory analysis of serum HER2 extracellular domain for HER2 positive gastric cancer treated with SOX plus trastuzumab.

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

Single-organ pulmonary metastasis is a favorable prognostic factor in metastatic colorectal cancer patients treated with FOLFIRI and vascular endothelial growth factor inhibitors.

BACKGROUND: Few studies have focused on the impact of single-organ pulmonary metastases on progression-free survival and overall survival in patients with metastatic colorectal cancer. Recognizing differences in prognosis and chemotherapeutic efficacy based on metastasized organs may help in optimizing treatment strategies. The exploratory study was conducted to evaluate the comparative clinical outcomes and prognoses of patients with metastatic colorectal cancer presenting with single-organ pulmonary metastases and treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy. METHODS: This retrospective study included 289 patients with metastatic colorectal cancer treated with second-line folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors. The response rate, disease control rate, progression-free survival, and overall survival were assessed in the participants. RESULTS: Among the 289 patients enrolled, 26 (9.0%) had single-organ pulmonary metastasis with left-sided primary locations, lower levels of tumor markers at the initiation point of chemotherapy, a significantly higher disease control rate (96.2% vs. 76.7%, P = .02), and a longer progression-free survival (median 29.6 months vs. 6.1 months, P < .001) and overall survival (median 41.1 months vs. 18.7 months, P < .001) than patients with other forms of metastatic colorectal cancer. Multivariate analysis showed that single-organ pulmonary metastasis was an independent predictor of longer progression-free survival (hazard ratio 0.35, P = .00075) and overall survival (hazard ratio 0.2, P = .006). CONCLUSION: Single-organ pulmonary metastasis was a strong predictor of progression-free survival and overall survival in patients with metastatic colorectal cancer treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy; this provides preliminary evidence for medical guidelines and clinical decision-making on novel therapeutic strategies for these patients.

Perioperative TAS-118 plus oxaliplatin in patients with locally advanced gastric cancer: APOLLO-11 study.

BACKGROUND: We investigated the feasibility of perioperative chemotherapy with S-1 and leucovorin (TAS-118) plus oxaliplatin in patients with locally advanced gastric cancer. METHODS: Patients with clinical T3-4N1-3M0 gastric cancer received four courses of TAS-118 (40-60 mg/body, orally, twice daily for seven days) plus oxaliplatin (85 mg/m2, intravenously, day one) every two weeks preoperatively followed by gastrectomy with D2 lymphadenectomy, followed by postoperative chemotherapy with either 12 courses of TAS-118 monotherapy (Step 1) or eight courses of TAS-118 plus oxaliplatin (Step 2). The primary endpoints were completion rates of preoperative chemotherapy with TAS-118 plus oxaliplatin and postoperative chemotherapy with TAS-118 monotherapy (Step 1) or TAS-118 plus oxaliplatin (Step 2). RESULTS: Among 45 patients enrolled, the preoperative chemotherapy completion rate was 88.9% (90% CI 78.0-95.5). Major grade ≥ 3 adverse events (AEs) were diarrhoea (17.8%) and neutropenia (8.9%). The R0 resection rate was 95.6% (90% CI 86.7-99.2). Complete pathological response was achieved in 6 patients (13.3%). Dose-limiting toxicity was not observed in 31 patients receiving postoperative chemotherapy (Step 1, n = 11; Step 2, n = 20), and completion rates were 90.9% (95% CI 63.6-99.5) for Step 1 and 80.0% (95% CI 59.9-92.9) for Step 2. No more than 10% of grade ≥ 3 AEs were observed in patients receiving Step 1. Hypokalaemia and neutropenia occurred in 3 and 2 patients, respectively, receiving Step 2. The 3-year recurrence-free and overall survival rates were 66.7% (95% CI 50.9-78.4) and 84.4% (95% CI 70.1-92.3), respectively. CONCLUSIONS: Perioperative chemotherapy with TAS-118 plus oxaliplatin with D2 gastrectomy is feasible.

Genomic features of Helicobacter pylori-naïve diffuse-type gastric cancer.

Helicobacter pylori (HP) is a major etiologic driver of diffuse-type gastric cancer (DGC). However, improvements in hygiene have led to an increase in the prevalence of HP-naïve DGC; that is, DGC that occurs independent of HP. Although multiple genomic cohort studies for gastric cancer have been conducted, including studies for DGC, distinctive genomic differences between HP-exposed and HP-naïve DGC remain largely unknown. Here, we employed exome and RNA sequencing with immunohistochemical analyses to perform binary comparisons between 36 HP-exposed and 27 HP-naïve DGCs from sporadic, early-stage, and intramucosal or submucosal tumor samples. Among the samples, 33 HP-exposed and 17 HP-naïve samples had been preserved as fresh-frozen samples. HP infection status was determined using stringent criteria. HP-exposed DGCs exhibited an increased single nucleotide variant burden (HP-exposed DGCs; 1.97 [0.48-7.19] and HP-naïve DGCs; 1.09 [0.38-3.68] per megabase; p = 0.0003) and a higher prevalence of chromosome arm-level aneuploidies (p < 0.0001). CDH1 was mutated at similar frequencies in both groups, whereas the RHOA-ARHGAP pathway misregulation was exclusive to HP-exposed DGCs (p = 0.0167). HP-exposed DGCs showed gains in chromosome arms 8p/8q (p < 0.0001), 7p (p = 0.0035), and 7q (p = 0.0354), and losses in 16q (p = 0.0167). Immunohistochemical analyses revealed a higher expression of intestinal markers such as CD10 (p < 0.0001) and CDX2 (p = 0.0002) and a lower expression of the gastric marker, MUC5AC (p = 0.0305) among HP-exposed DGCs. HP-naïve DGCs, on the other hand, had a purely gastric marker phenotype. This work reveals that HP-naïve and HP-exposed DGCs develop along different molecular pathways, which provide a basis for early detection strategies in high incidence settings. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Randomized phase II study comparing neoadjuvant 5-fluorouracil/oxaliplatin/docetaxel versus docetaxel/oxaliplatin/S-1 for patients with type 4 or large type 3 gastric cancer.

Macroscopic type 4 and large type 3 gastric cancer, mostly overlapping with scirrhous or linitis plastica type, exhibit a highly invasive nature and show unfavorable prognosis after curative surgery, even with adjuvant chemotherapy. A randomized phase III trial (JCOG0501) failed to demonstrate a survival advantage of neoadjuvant chemotherapy with S-1 plus cisplatin for this population. The current authors initiated a randomized phase II study comparing neoadjuvant chemotherapy with 5-fluorouracil/oxaliplatin/docetaxel versus docetaxel/oxaliplatin/S-1 for type 4 and large type 3 gastric cancer. 76 patients are planned to be enrolled over two years. The primary end point is the proportion of patients with a pathological response (grade 1b or higher) and secondary end points include overall survival and adverse events. Clinical Trial Registration: jRCTs031230231 (rctportal.niph.go.jp).

Perioperative immune checkpoint inhibitor therapy for gastric and gastroesophageal junction cancers: a review of current approaches and future perspectives.

Metastatic gastric and gastroesophageal junction cancers have been treated with chemotherapy, but the landscape of cancer treatment is rapidly shifting towards immune-based therapies. As established by the CheckMate 649 and ATTRACTION-4 trials, combination therapy with fluorouracil, platinum, and nivolumab, an immune checkpoint inhibitor, is now recognized as the standard first-line chemotherapy for HER2-negative gastric and gastroesophageal junction cancer. The potential of immune checkpoint inhibitors extends beyond metastatic disease. For locally advanced gastric and gastroesophageal junction cancer, perioperative chemotherapy with gastrectomy has been regarded as the standard of care, especially in Western nations. Besides, the introduction of immune checkpoint inhibitors as neoadjuvant and adjuvant treatments is currently underway, indicating a significant paradigm shift in the treatment strategies. This review summarizes the clinical developments and future perspectives of immune checkpoint inhibitor therapy with or without chemotherapy as perioperative treatment for gastric, esophageal, and gastroesophageal junction cancer.

Treatment efficacy of ramucirumab-containing chemotherapy in patients with alpha-fetoprotein producing gastric cancer.

BACKGROUND: Alpha-Fetoprotein Producing Gastric Cancer (AFPGC) is an aggressive subgroup of gastric cancer. Recently ramucirumab has shown survival benefits in hepatocellular carcinoma, but only in those with higher Alpha-Fetoprotein (AFP) levels. However, the efficacy of ramucirumab-containing chemotherapy in AFPGC remains unclear. METHODS: We retrospectively assessed 352 patients who received ramucirumab-containing chemotherapy between June 2015 and December 2019. AFPGC was defined when serum AFP levels were elevated at diagnosis and correlated with the disease state during treatment. Non-AFPGC was defined when serum AFP levels were normal at diagnosis. RESULTS: Among the 352 patients, 28 patients were defined as AFPGC and 246 patients were defined as non-AFPGC. AFPGC was characterized by high frequency of liver metastasis and low frequency of peritoneal metastasis compared to non-AFPGC. Ramucirumab containing chemotherapy showed higher response rates in AFPGC (39.1% vs 24.8%, p = 0.198) and disease control rates (86.9% vs 61.5%, p = 0.028) than those of non-AFPGC, respectively. Median progression-free survival (PFS) was 5.5 months (95%CI 3.9-7.1) in AFPGC and 4.0 months (95%CI 3.6-4.6) in non-AFPGC (HR: 0.91, 95% CI 0.61-1.36, p = 0.66), and median overall survival (OS) was 10.7 months (95% CI 7.4-20.8) in AFPGC and 9.2 months (95% CI 8.1-10.4) in non-AFPGC (HR: 0.72, 95% CI 0.48-1.08, p = 0.11), respectively. In multivariate analysis, AFPGC was not a negative prognostic factor both for PFS and OS. CONCLUSION: Ramucirumab containing chemotherapy showed higher response and comparable survival in AFPGC compared to those of non-AFPGC. Considering the generally poor prognosis of AFPGC, ramucirumab-containing chemotherapy might be a promising treatment option in AFPGC.

Morphological response and tumor shrinkage as predictive factors in metastatic colorectal cancer treated with first-line capecitabine, oxaliplatin, and bevacizumab.

BACKGROUND: Morphologic response (MR) is a novel chemotherapeutic efficacy predictor of solid tumors, especially those treated with anti-vascular endothelial growth factor antibodies. Nevertheless, the importance of systemic chemotherapy MR for colorectal liver metastases (CLM) remains unclear. We aimed to evaluate the usefulness of MR as a factor associated with the therapeutic effects of chemotherapy plus bevacizumab for initially unresectable CLM cases. METHODS: We retrospectively evaluated the associations between MR and/or Response Evaluation Criteria in Solid Tumors (RECIST), progression-free survival (PFS), and overall survival (OS) in patients who received first-line capecitabine, oxaliplatin, and bevacizumab treatment for initially unresectable CLM using multivariate analysis. Patients who showed a complete or partial response based on the RECIST, or an optimal response based on MR, were defined as "responders." RESULTS: Ninety-two patients were examined, including 31 (33%) patients who responded optimally. PFS and OS estimates were comparable in MR responders and non-responders (13.6 vs. 11.6 months, p = 0.47; 26.6 vs. 24.6 months, p = 0.21, respectively). RECIST responders showed better PFS and OS than non-responders (14.8 vs. 8.6 months, p < 0.01; 30.7 vs. 17.8 months, p < 0.01, respectively). The median PFS and OS estimates of MR and RECIST responders were better than those of single responders or non-responders (p < 0.01). Histological type and RECIST response were independently associated with PFS and OS. CONCLUSION: MR predicts neither PFS nor OS; nevertheless, it may be useful when combined with the RECIST. The Ethics Committee of The Cancer Institute Hospital of JFCR approved this study in 2017 (No. 2017-GA-1123): retrospectively registered.

Profiling chromosomal-level variations in gastric malignancies.

Aneuploidy arises from persistent chromosome segregation errors, or chromosomal instability. Although it has long been known as a hallmark of cancer cells, reduced cellular fitness upon induced ploidy alterations hinders the understanding of how aneuploidy relates to cancer development in the body. In this study, we used FISH analysis targeting centromeres to indicate ploidy changes, and quantitatively evaluated the ploidy statuses of gastric tumors derived from a total of 214 patients, ranging from early to advanced disease. We found that cancer cells reveal a marked elevation of aneuploid population, increasingly in cases diagnosed in advanced stages. The expansion of the aneuploid population is well associated with p53 deficiency, consistent with its essential role in genome maintenance. Comparisons among multiple locations within the tumor, or between the primary and metastatic tumors, indicated that cancer cells mostly retain their ploidy alterations throughout primary tumors, but metastatic tumors may consist of cells with either increased or decreased levels of aneuploidy. We also found that a notable proportion of polyploid cells are often already present in chronic gastritis epithelia. These observations underscore that chromosome-level variations are widespread in gastric cancers, shaping their genetic heterogeneity and malignant properties.

Clinical Progress in Inoperable or Recurrent Advanced Gastric Cancer Treatment from 1004 Single Institute Experiences Between 2007 and 2018.

BACKGROUND: In the past decade, several successful clinical trials provided new therapeutic agents approved for advanced gastric cancer (AGC). This study evaluated whether these practice-changing results actually altered the clinical practice. PATIENTS AND METHODS: We retrospectively reviewed medical records of treatment-naive AGC patients who received combination chemotherapy of fluoropyrimidine and platinum between 2007 and 2018 and divided them into three groups: Groups A (2007-10), B (2011-14), and C (2015-2018), respectively. We compared the clinicopathological features, treatment details, and clinical outcomes among the three groups. RESULTS: In total, 1004 consecutive patients were enrolled (A; n = 254, B; n = 300, and C; n = 450). The number of patients with poor performance status, older age, esophagogastric junction adenocarcinoma, and primary tumor increased during the study period. All groups had similar median overall survival (OS); ~16 months) without any statistical difference but steady prolongation of survival was observed in the adjusted with imbalance prognostic factors among groups (B/A; hazard ratio, HR 0.82, 95% C.I 0.68-0.98, C/A; HR 0.72, 95% CI 0.60-0.86); OS of HER2-positive AGC patients was clearly improved (HER2-positive vs HER2-negative in Group B, HR 0.80, 95% CI 0.60-1.06; Group C, HR 0.68, 95% CI 0.51-0.90) but that of diffuse-type AGC patients remained dismal. CONCLUSIONS: The increasing availability of chemotherapy options potentially contributed to improved survival of AGC patients, but expanded chemotherapeutic indications made the survival benefit inconspicuous in the whole population. Future therapeutic development for the AGC subset not adequately receiving benefit from previous clinical trials is warranted.

Clinical Usefulness of Postoperative Serum Carcinoembryonic Antigen in Patients with Colorectal Cancer with Liver Metastases.

BACKGROUND: Colorectal cancer with liver metastasis (CLM) has high postoperative recurrence rates; therefore, optimizing perioperative treatment is imperative. Postoperative carcinoembryonic antigen (CEA) can aid in detecting minimal residual disease in colon cancer following curative resection. This study aimed to identify the potential role of serum CEA following liver resection in patients with CLM. METHODS: This retrospective study was conducted at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from 2004 to 2018 and enrolled patients with CLM who underwent complete resection of primary tumors and CLM. Associations between perioperative CEA levels and characteristics of recurrence were investigated. RESULTS: Recurrence was detected during a median follow-up period of 90.1 months in 343 (54.2%) out of 633 analyzed patients. Patients in the postoperative CEA level > 5 ng/ml group had a significantly higher recurrence rate (75.7% versus 50.0%, p < 0.01) and shorter time until recurrence (4.4 versus 36.9 months, p < 0.01) than those in the postoperative CEA level ≤ 5 ng/ml group. Multivariate analysis revealed that postoperative CEA level > 5 ng/ml was an independent predictor, with hazard ratios of 2.77 (p < 0.01) for recurrence-free survival (RFS) and 3.18 (p < 0.01) for overall survival (OS). Additionally, RFS was significantly shorter among patients in the postoperative CEA level > 5 ng/ml group who did not have normalized CEA levels following adjuvant chemotherapy than among those in the normalized CEA group. CONCLUSIONS: The postoperative and post-adjuvant chemotherapy CEA levels in the CEA level > 5 ng/ml group may be predictors of RFS and OS.

Effect of DNA methylation status on first-line anti-epidermal growth factor receptor treatment in patients with metastatic colorectal cancer.

PURPOSE: The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer (CRC). However, there is a lack of consensus on CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patients with metastatic CRC (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors. METHODS: We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment. We analyzed the incidence and clinicopathological characteristics of highly methylated CRC (HMCC) and associations between genome-wide DNA methylation status and response rate (RR), progression-free survival (PFS), and overall survival (OS). RESULTS: In total, 169 patients were included in the final analyses. The frequency of HMCC was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAF V600E mutation (P < 0.0001). Patients with HMCC showed worse clinical outcomes than those with low-methylated CRC in terms of RR (P = 0.017), PFS (P = 0.004), and OS (P = 0.019). In the multivariate analysis, peritoneal metastasis (P = 0.017), methylation status (P = 0.037), and BRAF V600E mutations (P = 0.0001) were independent factors for shorter PFS. CONCLUSIONS: Genome-wide DNA methylation status is an independent factor associated with PFS in patients with mCRC treated with first-line EGFR inhibitors.

Managing a gastrointestinal oncology practice in Japan during the COVID-19 pandemic: single institutional experience in The Cancer Institute Hospital of Japanese Foundation for Cancer Research.

Coronavirus disease 2019 (COVID-19) was declared to be a global pandemic by the World Health Organization on March 11, 2020. On April 7, 2020, a state of emergency was declared in Japan, as had been by other nations worldwide. This unprecedented crisis has profound implications for patients undergoing chemotherapy and for practicing healthcare professionals. Various reports have shown data indicating that cancer patients with COVID-19 have high morbidity and mortality rates. In order to reduce the use of medical resources to avoid the risk of COVID-19 infections in both cancer patients and health care providers, oncologists now have to draw the line for cancer treatments by maintaining their efficacy while avoiding severe adverse events. In this article, we outlined the decisions made regarding the practice of gastrointestinal oncology in our institution during the COVID pandemic.

[A Practical Approach to the Management of Patients with Gastrointestinal Cancer during the Novel Coronavirus Disease 2019(COVID-19)Pandemic-What Can Medical Oncologists Do?]

The SARS-CoV-2 was first identified in December 2019 in Wuhan, China. Since then, the ongoing COVID-19 pandemic has drastically changed the healthcare system, including cancer treatments worldwide. Since March 2020 in Japan, cancer patients faced a crisis; they suffered from delays or restrictions in cancer treatment during the initial outbreak. At present, we can perform cancer treatment as usual. Most of the treatments depend on continuous infection control by cancer patients and their families. However, the need to recognize cancer treatment management during the COVID-19 pandemic is crucial. Cancer treatment practice, purpose, risk factors, and the evidence during clinical trials should be comprehensively evaluated and adapted for each patient. Moreover, there is a need to discuss care planning between healthcare professionals, patients, and their families in advance. The COVID-19 vaccine could be essential for cancer patients. In this article, we review cancer treatment points for implementing whole-person care, including advanced care planning for patients with gastrointestinal malignancies, during the COVID-19 pandemic.

[Position of the Japanese Subgroup Data from Global Trial in Advanced Gastric Cancer].

Global studies have been planned to achieve early approval of the new agent especially in cancer chemotherapy. On the other hand, it is important to consider the difference in efficacy among each region. As medical approval in Japan means reimbursement of medical cost, new drug is required to show its effectiveness in the medical situation in Japan, and the Japanese subgroup data is important. Especially in the gastric cancer field, where there is a large difference in survival time and surgical outcome between Japan and outside Japan need to consider Japanese domestic data. But characteristic of Japanese subgroup is the number of target patients is small, high censored case due to longer survival and the background factors are not even. So the interpretation of the data requires caution because of these robustness.

Neoadjuvant Chemoradiotherapy with Cisplatin Plus Fluorouracil for Borderline Resectable Esophageal Squamous Cell Carcinoma.

BACKGROUND: The optimal treatment strategy for patients with borderline resectable (BR) esophageal squamous cell carcinoma (ESCC), in which tumors grow very close to the adjacent vital organs, remains unclear. This study evaluated the efficacy of neoadjuvant chemoradiotherapy (NACRT) with cisplatin plus fluorouracil (CF) and irradiation (40 Gy) for these patients. METHODS: The study cohort included 50 patients with BR-ESCC who received NACRT as the initial treatment and were allocated to one of two groups: patients who achieved curative resection (R0 group) or those who did not (Non-R0 group). The overall survival (OS), relapse-free survival (RFS), and pre-therapeutic predictive factors for Non-R0 were evaluated. RESULTS: Among the 50 patients, 22 (44%) achieved curative resection clinically. The median OS was significantly better in the R0 group than in the Non-R0 group (2.4 vs 0.8 years; hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.12-0.67; p < 0.01). The independent predictive factors before NACRT for Non-R0 were higher serum SCC antigen level (p < 0.01) and clinical nodal involvement (p = 0.02). In addition, OS was significantly worse for the patients with higher levels of serum SCC antigen than for those with lower levels (p < 0.01). CONCLUSIONS: Curative resection was achieved for about 40% of the patients who received NACRT for BR-ESCC. Therefore, NACRT could be a useful neoadjuvant treatment option for BR-ESCC. However, a higher serum SCC antigen level before NACRT is predictive of treatment failure and poor survival.