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A paradigm shift has occurred in cancer chemotherapy from tumor-specific treatment with cytotoxic agents to personalized medicine with molecular-targeted drugs. Thus, it is essential to identify genomic alterations and molecular features to recommend effective targeted molecular medicines regardless of the tumor site. Nevertheless, it takes considerable expertise to identify treatment targets from primary-sequencing data in order to provide drug recommendations. The Molecular Tumor Board (MTB) denotes a platform that integrates clinical and molecular features for clinical decisions.This study retrospectively analyses all the cases of discussion and decision at the MTB in Tohoku University Hospital and summarizes genetic alterations and treatment recommendations.The MTB discussed 1003 comprehensive genomic profiling (CGP) tests conducted in patients with solid cancer, and the resulting rate of assessing treatment recommendations was approximately 19%. Among hundreds of genes in the CGP test, only 30 genetic alterations or biomarkers were used to make treatment recommendations. The leading biomarkers that led to treatment recommendations were tumor mutational burden-high (TMB-H) (n = 32), ERBB2 amplification (n = 24), BRAF V600E (n = 16), and BRCA1/2 alterations (n = 32). Thyroid cancer accounted for most cancer cases for which treatment recommendation was provided (81.3%), followed by non-small cell lung cancer (42.4%) and urologic cancer (31.3%). The number of tests performed for gastrointestinal cancers was high (n = 359); however, the treatment recommendations for the same were below average (13%).The results of this study may be used to simplify treatment recommendations from the CGP reports and help select patients for testing, thereby increasing the accuracy of personalized medicine.

PDF file 3876K, The association between histone mRNA and miR-760 in GC cells

Purpose: Recent studies revealed that both disseminated tumor cells and noncancerous cells contributed to cancer progression cooperatively in the bone marrow. Here, RNA-seq analysis of bone marrow from gastric cancer patients was performed to identify prognostic markers for gastric cancer.Experimental Design: Bone marrow samples from eight gastric cancer patients (stages I and IV: n = 4 each) were used for RNA-seq analysis. Results were validated through quantitative real-time PCR (qRT-PCR) analysis of HIST1H3D expression in 175 bone marrow, 92 peripheral blood, and 115 primary tumor samples from gastric cancer patients. miR-760 expression was assayed using qRT-PCR in 105 bone marrow and 96 primary tumor samples. Luciferase reporter assays were performed to confirm whether histone mRNAs were direct targets of miR-760. miR-760 expression was also evaluated in noncancerous cells from gastric cancer patients.Results: RNA-seq analysis of bone marrow samples from gastric cancer patients revealed higher expression of multiple histone mRNAs in stage IV patients. HIST1H3D expression in the bone marrow, peripheral blood, and primary tumor of stage IV patients was higher than that in stage I patients (P = 0.0284, 0.0243, and 0.0006, respectively). In contrast, miR-760 was downregulated in the bone marrow and primary tumor of stage IV patients compared with stage I patients (P = 0.0094 and 0.0018, respectively). Histone mRNA and miR-760 interacted directly. Furthermore, miR-760 was downregulated in noncancerous mucosa in stage IV gastric cancer patients.Conclusion: Histone mRNA was upregulated, whereas miR-760 was downregulated in the bone marrow and primary tumor of advanced gastric cancer patients, suggesting that the histone mRNA/miR-760 axis had a crucial role in the development of gastric cancer. Clin Cancer Res; 19(23); 6438–49. ©2013 AACR.

XLS file 26K, Genes with higher expression in the BM from Stage IV patients compared to that from Stage I patients

PDF file 146K, Supplementary Data

Supplementary Tables S1-S2 PDF file - 41K, CRC Patient characteristics in training set (2000-2004) and validation set (2005-2008) (S1); Gene list of GSEA analysis (S2).

Supplementary Figure Legends PDF file - 49K, Legend for Supplementary Figures S1-S9

Circulating tumor cells (CTC) in blood have attracted attention both as potential seeds for metastasis and as biomarkers. However, most CTC detection systems might miss epithelial–mesenchymal transition (EMT)-induced metastatic cells because detection is based on epithelial markers. First, to discover novel markers capable of detecting CTCs in which EMT has not been repressed, microarray analysis of 132 colorectal cancers (CRC) from Japanese patients was conducted, and 2,969 genes were detected that were overexpressed relative to normal colon mucosa. From the detected genes, we selected those that were overexpressed CRC with distant metastasis. Then, we analyzed the CRC metastasis-specific genes (n = 22) to determine whether they were expressed in normal circulation. As a result, PLS3 was discovered as a CTC marker that was expressed in metastatic CRC cells but not in normal circulation. Using fluorescent immunocytochemistry, we validated that PLS3 was expressed in EMT-induced CTC in peripheral blood from patients with CRC with distant metastasis. PLS3-expressing cells were detected in the peripheral blood of approximately one-third of an independent set of 711 Japanese patients with CRC. Multivariate analysis showed that PLS3-positive CTC was independently associated with prognosis in the training set (n = 381) and the validation set [n = 330; HR = 2.17; 95% confidence interval (CI) = 1.38–3.40 and HR = 3.92; 95% CI = 2.27–6.85]. The association between PLS3-positive CTC and prognosis was particularly strong in patients with Dukes B (HR = 4.07; 95% CI = 1.50–11.57) and Dukes C (HR = 2.57; 95% CI = 1.42–4.63). PLS3 is a novel marker for metastatic CRC cells, and it possesses significant prognostic value. Cancer Res; 73(7); 2059–69. ©2012 AACR.

Supplementary Figures S1-S9 PDF file - 984K, Representative photomicrographs of tissue sections immunostained for PLS3 (S1); The clinical significance of PLS3 expression in a second independent set of 110 primary colorectal cancer samples (S2); PLS3 expression profiles in various tissues, including peripheral blood-derived cells (S3); EMT induction in CaR-1 cells by TGF-beta1 (S4); PLS3 mRNA expression in LoVo cells expressing stem cell makers (S5); Immunocytochemical staining of PLS3 in rectal cancer cell line CaR-1 and peripheral blood mononuclear cells (S6); Validation of PLS3 expression in PB after recurrence (S7); Survival curves of Dukes stage B CRC patients based on the level of CK19/CK20 mRNA expression in PB (S8); PLS3 expression profiles in several cancer cell lines (S9)

The aim of this study was to clarify whether PET with 11C-methyl-l-methionine (11C-met PET) can predict consequential outcomes at the time of discontinuing temozolomide (TMZ)-adjuvant chemotherapy in patients with residual isocitrate dehydrogenase gene (IDH)-mutant lower-grade glioma.Among 30 patients showing residual lesions of IDH-mutant lower-grade glioma, we compared the tumor-to-normal brain tissue ratio of standardized uptake values (SUVT/N) from 11C-met PET at the time of discontinuing TMZ-adjuvant chemotherapy with putative predictive factors including age, Karnofsky Performance Scale, number of courses of adjuvant therapy, residual tumor size, and promotor methylation status of O6-methylguanine-DNA methyl-transferase gene (MGMT). For each factor, progression-free survival (PFS) was compared between groups divided by cutoff values, determined to predict tumor relapse using receiver operating characteristic curves for each factor. Univariate and multivariate analyses were conducted using log-rank testing and Cox regression analysis, respectively. In addition, PFS was compared between patients grouped by combined findings from multiple predictors identified from univariate and multivariate analyses.Univariate and multivariate analyses identified SUVT/N from 11C-met PET and MGMT methylation status as independent predictors of outcomes after TMZ discontinuation. When comparing 3 groups assigned by the combination of MGMT and SUVT/N findings, PFS differed significantly among groups.The present study suggested that 11C-met PET at the time of discontinuing TMZ-adjuvant chemotherapy allows prediction of outcomes at least comparable to MGMT methylation status in patients with residual IDH-mutant lower-grade glioma. Further, 11C-met PET allows more precise prediction of outcomes by assessment in combination with MGMT findings.

PurposeWe investigated whether early circulating tumor DNA (ctDNA) changes, measured using digital PCR (dPCR), can predict later chemotherapy responses in esophageal squamous cell cancer (ESCC).DesignWe compared the dynamics of ctDNA and tumor volumes during chemotherapy in 42 ESCC. The accuracy of predictions of later chemotherapy responses were evaluated by the ratio of the variant allele frequency (VAF) of ctDNA (post-/pre-ctDNA) and the total tumor volume (post-/pre-volume) before and after an initial chemotherapy cycle using a receiver-operating characteristic curve analysis. Total positive and negative objective responses (ORs) were defined as either >50% or ≤50% reductions, respectively, in the total tumor volume at the end of first-line chemotherapy.ResultsMutation screening of 43 tumors from 42 patients revealed 96 mutations. The pretreatment dPCR-ctDNA data were informative in 38 patients, using 70 selected mutations (1–3 per patient). The areas under the curve (AUCs) for the post-/pre-volume and post-/pre-ctDNA levels used in predicting the total OR were 0.85 and 0.88, respectively. The optimal cutoff value of post-/pre-ctDNA was 0.13. In 90% (18/20) of patients with a post-/pre-volume ≥50%, the total OR could be predicted by the post-/pre-ctDNA with high accuracy; the AUC by post-/pre-ctDNA was higher than that by post-/pre-volume (0.85 vs 0.76, respectively). Patients with low post-/pre-ctDNA (n = 18) had a significantly better overall survival rate than those with high post-/pre-ctDNA (n = 20; P = 0.03).ConclusionsEarly ctDNA changes after an initial cycle of chemotherapy predict later responses to treatment with high accuracy in ESCC patients.

BACKGROUND & AIMSThis study investigated whether a circulating tumor DNA (ctDNA) assay using digital PCR (dPCR) could provide early relapse detection and disease-free corroboration at molecular level during postoperative surveillance of colorectal cancer (CRC).METHODSThe ctDNA dynamics of 52 patients with CRC measured by dPCR targeting 87 individual tumor-specific mutations (1-5 per patient) were compared with results for conventional surveillance using serum tumor markers and computed tomography scanning (CTS). The data were collected between March 2016 and June 2018.RESULTSA total of 1,526 prospectively collected plasma samples from 867 timepoints were analyzed. The average number of ctDNA assays per patient was 16.4 and the median follow-up was 1,503 days (range 322-1,951 days). Among patients with Stage II or higher disease who underwent curative resection as their initial surgery (n=47), patients who were ctDNA-positive during the postoperative period (n= 9) showed a higher risk of relapse than those who had sustained ctDNA-negative results (n=38) (hazard ratio 56.3, 95%CI 7.8–407.0, P < 0.0001). Elevated ctDNA levels were observed in nine of 10 clinical-relapse patients (11 of 13 events) with an average lead time from a ctDNA-positive time-point to clinical relapse of 191.9 days (range 0-376 days). Given periodic CTS surveillance with ctDNA, 218 (57.1%) CTSs were presumed to be unnecessary for clinical relapse detection and a ctDNA assay would still provide a lead time of 307 days (range 45–582 days).CONCLUSIONOur findings suggest that the ctDNA assay can reduce the frequency of CTS for relapse diagnosis during postoperative surveillance of CRC. UMIN Clinical Trial Registry number, UMIN000045114

Background Circulating tumour DNA (ctDNA) is known as a tumour-specific personalised biomarker, but the mutation-selection criteria from heterogeneous tumours remain a challenge. Methods We conducted multiregional sequencing of 42 specimens from 14 colorectal tumours of 12 patients, including two double-cancer cases, to identify mutational heterogeneity to develop personalised ctDNA assays using 175 plasma samples. Results “Founder” mutations, defined as a mutation that is present in all regions of the tumour in a binary manner (i.e., present or absent), were identified in 12/14 tumours. In contrast, “truncal” mutations, which are the first mutation that occurs prior to the divergence of branches in the phylogenetic tree using variant allele frequency (VAF) as continuous variables, were identified in 12/14 tumours. Two tumours without founder and truncal mutations were hypermutators. Most founder and truncal mutations exhibited higher VAFs than “non-founder” and “branch” mutations, resulting in a high chance to be detected in ctDNA. In post-operative long-term observation for 10/12 patients, early relapse prediction, treatment efficacy and non-relapse corroboration were achievable from frequent ctDNA monitoring. Conclusions A single biopsy is sufficient to develop custom dPCR probes for monitoring tumour burden in most CRC patients. However, it may not be effective for those with hypermutated tumours.

Background: Circulating tumor DNA (ctDNA), a new class of tumor marker, has been demonstrated the clinical validity of: 1) early relapse prediction, 2) therapeutic efficacy evaluation, and 3) relapse-free corroboration in the context of cancer treatment. Variant allele frequencies (VAFs) of ctDNA were under 0.1% even in most advanced cancer patients. Since the detection limit of next-generation sequencing (NGS) is above 1%, higher sensitivity is needed for sensitive ctDNA monitoring. Digital PCR (dPCR) offers excellent sensitivity at an affordable cost compared with NGS. A mutation-specific primer/probe (P/P) is required for the dPCR assay, but a limited number of P/Ps are commercially available. Materials and Methods: To provide essential probes for the rapid monitoring of sensitive ctDNA, we developed an off-the-shelf (OTS) dPCR P/P library (OTS-Probes) that includes probes that can detect >1,000 mutations found in human cancer. The majority of the mutations to be detected by these P/P sets have been selected using an originally developed statistical scoring from hot spot mutations reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. To evaluate the coverage of OTS-Probes in human cancer specimens, the Cancer Genome Atlas (TCGA) and the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) datasets were used. TCGA is an international landmark cancer genomic program in the U.S., and C-CAT is a Japanese cancer genome profiling database. Results: At least one mutation was matched to the OTS-Probes for ctDNA monitoring in lung, colorectum, stomach, liver, pancreas, breast, uterus, and prostate from TCGA and C-CAT cancer specimens, reflecting 63% and 77% of corresponding tumor types, respectively. The mutation coverage of the OTS-Probes tends to be lower in TCGA than in C-CAT, partially due to the fact that information about the TERT promoter mutation is absent in TCGA. We found that some ARID1A deletion mutations that have a high count in COSMIC were not observed in either the TCGA or the C-CAT database. We also analyzed the coverage of the OTS-Probes in different organs and driver genes. Currently, more than 250 P/P sets have been designed, synthesized, and validated with human tumor DNA or synthesized DNA fragments. Importantly, nearly 98% of P/P sets work with the same PCR condition. With our proprietary oligo synthesis method with modified bases, only a small percentage of P/P sets required optimization of the annealing temperature. Conclusion: We developed a dPCR P/P library called OTS-Probes. Our analysis suggests that 60-80% of cancer patients could immediately apply at least one P/P set for sensitive ctDNA monitoring by dPCR. A quarter of the P/P library has already been validated by tumor DNA or synthesized DNA fragments. OTS-Probes is a great tool for ctDNA- related studies and for clinical use when a higher sensitivity than NGS can offer is required. Citation Format: Hayato Hiraki, Akiko Yashima-Abo, Takeshi Iwaya, Satoshi S. Nishizuka. A digital-PCR primer/probe library for pan-cancer ctDNA monitoring established from public databases for somatic mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6704.

Background: Many patients undergo a next generation sequencing (NGS)-based cancer genome profiling (CGP) test, but it often does not aid in choosing an optimal therapeutic regimen. Therefore, the genomic information should be used for minimal residual disease (MRD) detection, which directly leads to improved post-treatment cancer patient management. Circulating tumor DNA (ctDNA) is a small fraction of DNA present in blood that carries somatic mutations in cancer patients. Our previous studies demonstrated the clinical validity of ctDNA as a tumor marker for MRD detection. However, the variant allele frequency (VAF; reflecting the fraction of somatic mutations) of ctDNA is less than 1%, at which stable detection is difficult for NGS. Instead of NGS, we have established a highly sensitive ctDNA monitoring system for MRD detection using an originally developed library of >1000 digital PCR (dPCR) probes. Patients and Methods: Using a Clinical Institutional Review Board approval from the Iwate Medical University Hospital, we initiated a dPCR assay system, called off-the-shelf (OTS)-Assay, in April 2022 under a partnership with Quantdetect, Inc (Tokyo, Japan). The OTS-Assay has three main components: OTS-Scan, OTS-Select, and OTS-Monitor. The OTS-Scan can provide an original CGP if a patient comes with no CGP results. The OTS-Select chooses matched somatic mutations from our dPCR probe library. The OTS-Monitor quantifies VAFs of ctDNA periodically in the patient plasma with a sensitivity of 0.05% VAF. There is no strict patient eligibility criteria other than the requirement of previous therapy for treatment of an advanced cancer. Results: Between April and November 2022, 26 patients visited Iwate Medical University Hospital for the OTS-Assay. Twenty-five patients were referred from other Departments of Iwate Medical University Hospital. The primary cancer types include esophagus (n=21), colorectal (n=2), pancreas (n=2), and breast (n=1). Twenty patients had CGP results at their first visit. OTS-Select were used for 13 patients and picked an average of 11.4 mutations per patient. Among those, each of eight patients were immediately able to start ctDNA monitoring with one of the 1000 dPCR probes. As of November 2022, there are four patients who received OTS-Monitor more than one time. Any unexpected VAF increase of ctDNA has not been noted, although a substantial decrease of ctDNA VAF was found in one patient who received one cycle of chemotherapy. Conclusion: The OTS-Assay is a practical introduction of our previous clinical research products based on a core technology, which uses an originally developed library of >1000 dPCR probes. The potential of early and accurate MRD detection will improve post-treatment cancer patient management. Citation Format: Satoshi S. Nishizuka, Hayato Hiraki, Masakazu Abe, Akiko Yashima-Abo, Takeshi Iwaya. An introduction of a highly sensitive circulating tumor DNA monitoring system for minimal residual disease detection using a library of 1000 digital PCR probes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5599.

Background Pylorus-preserving gastrectomy (PPG) has been accepted as a function-preserving surgery for the treatment of early gastric cancer in East Asian countries. Therefore, this study aimed to evaluate the feasibility and safety of totally laparoscopic PPG (TLPPG) with intracorporeal anastomosis. Methods A total of 43 patients with early gastric cancer underwent laparoscopy-assisted PPG (LAPPG) with extracorporeal anastomosis between May 2006 and November 2012. The operative outcomes of 22 patients who underwent TLPPG between November 2012 and February 2019 were evaluated, and data were compared with that of the LAPPG group. Results No significant difference in the operative time was observed between the two groups. Blood loss was lower in the TLPPG group (18.5 mL) than in the LAPPG group (30.7 mL, p = 0.008), and the length of abdominal incision was shorter in the TLPPG group (3.8 cm) than in the LAPPG group (4.7 cm, p < 0.001). No significant difference in the complication rate was observed between the two groups (13.6% in the TLPPG vs. 9.3% in the LAPPG group, p = 0.594). No anastomosis-related complications occurred in either group. No significant between-group difference was observed in the delayed gastric emptying (TLPPG, 9.1 vs. LAPPG, 7%, p = 0.762). The initiation of postoperative fluid (TLPPG, 1.0 day vs. LAPPG, 3.0 days, p < 0.001) and meal (TLPPG, 3.0 days vs. LAPPG, 4.0 days, p < 0.001) intake was earlier in the TLPPG group than in the LAPPG group. No significant between-group difference was observed in the postoperative hospital stay. Conclusions The findings of this study suggest that TLPPG with intracorporeal reconstruction not only is as feasible and safe as LAPPG for the treatment of patients with early gastric cancer but also provides certain advantages such as reduced blood loss and wound size.

Introduction Recent studies have reported that induction chemotherapy with docetaxel plus cisplatin and 5-fluorouracil (DCF) is an effective treatment for unresectable, locally advanced esophageal cancer. The aim of this study was to investigate the safety and feasibility of thoracoscopic esophagectomy (TE) after DCF for initially unresectable esophageal squamous cell carcinoma (ESCC). Methods Twenty-three patients with initially unresectable T4 thoracic ESCC underwent TE after induction DCF. Results The neighboring organs with tumors were the tracheobronchus in nine patients, thoracic aorta in 13, and pericardium and diaphragm in three each (concurrent overlapping invasion occurred in five patients). The mean total operation time was 556.3 ± 107.2 minutes, and the mean time of the thoracic procedure was 258.9 ± 83.9 minutes. The mean total blood loss was 166.2 ± 117.8 mL, and the loss during the thoracic procedure was 33.5 ± 24.6 mL. All patients achieved complete R0 resection under TE. No conversions to open thoracotomy were performed. The postoperative morbidity rate was 34.8%. The postoperative hospital stay was 24.3 (range, 13-38) days. Five patients had recurrence: four had distant metastasis (lung, two; liver, three; and one with overlap), and one had mediastinal lymph node recurrence. No local recurrence was noted at the site of the primary T4 tumor. Conclusions TE was safely performed in 23 patients after DCF therapy for locally advanced unresectable ESCC. Induction DCF, followed by TE, could be an alternative treatment for unresectable T4 ESCC.

Highlights • ECS is a rare tumor often treated in the same manner as esophageal cancer. • ECS often presents as a polypoid tumor continuous with the superficial lesion. • We encountered an ECS case in which a polypoid lesion sloughed off before surgery. • Polypoid tumor exfoliation in ECS may lead to an incorrect diagnosis., Introduction Most esophageal carcinosarcoma (ECS) tumors present as a polypoid tumor that is continuous with the superficial lesion and suspended by a pedicle. Here, we report a case of ECS in which a polypoid lesion sloughed off before surgery. Presentation of case A 76-year-old man with dysphagia was admitted to our hospital. Esophagogastroscopy revealed a 20-mm polypoid tumor continuous with a superficial lesion and attached to the lesion by a thin pedicle in the mid-thoracic esophagus. Histopathological examination of the endoscopic biopsy showed that the superficial lesion was a moderately differentiated squamous cell carcinoma and that the polypoid tumor contained a sarcomatous element. He was diagnosed with ECS and underwent radical esophagectomy with three-field lymph node dissection. In the resected specimen, no polypoid tumor was found, and only a superficial lesion was observed. The histopathological findings revealed only squamous cell carcinoma, and the pathological diagnosis was esophageal squamous cell carcinoma, pT1bN0M0, pathological stage I. The patient was discharged from the hospital 22 days after surgery and did not experience any complications. He is currently alive and remained cancer-free for three years since surgery was performed. Discussion Due to the distinctive configuration in which the polypoid lesion was connected to the superficial cancerous lesion by a very thin pedicle, researchers suggested that the polypoid tumor, which consisted of a sarcomatous element, was sloughed off before surgery. Conclusion We encountered a rare case of ECS in which the sarcomatous element sloughed off prior to surgical resection.

Highlights • Primary malignant melanoma of the esophagus (PMME) is a rare disease with a poor prognosis. • There are few reports of treatment with the anti-programmed cell death 1 antibody, nivolumab for PMME. • We report a case of retroperitoneal recurrence of PMME successfully treated with nivolumab., Introduction Primary malignant melanoma of the esophagus (PMME) is a rare disease with a poor prognosis. Here, we report a case of retroperitoneal recurrence of PMME successfully treated with the anti-programmed cell death 1 antibody, nivolumab. Presentation of case A 70-year-old male with dysphagia was referred to our hospital. Esophagogastroscopy showed an elevated tumor in the lower thoracic esophagus. A histopathological examination of the biopsy revealed poorly differentiated squamous cell carcinoma. The patient was diagnosed with clinical T3N1M0 stage III esophageal squamous cell carcinoma and was treated with neoadjuvant chemotherapy followed by radical esophagectomy. A postoperative histopathological examination revealed that atypical cells with a brown pigment were scattered in the tumor. Immunohistochemical staining demonstrated positive expression of human melanoma black 45, melan A, and S100. A pathological diagnosis of PMME was confirmed. Sixteen months after surgery, abdominal computed tomography revealed solitary retroperitoneal recurrence in the lateral portion of the ascending colon. Fluorine-18 fluorodeoxyglucose positron emission tomography (PET) showed hypermetabolic accumulation with a maximum standardized uptake value of 5.8. The patient was treated with nivolumab (240 mg) every two weeks. After eight courses of nivolumab, abnormal accumulation of the retroperitoneal mass disappeared on PET, and this therapeutic effect continued for 20 months. Conclusions Nivolumab was effective for recurrence of PMME in our case. There are few reports of treatment with nivolumab for PMME. Further studies are necessary to establish the usefulness of nivolumab for PMME in the future.

Highlights • Super-late pulmonary recurrence of esophageal squamous cell carcinoma. • Successfully resection and long survive after pulmonary metastasectomy. • Surgical indication of pulmonary oligometastasis of esophageal cancer., Introduction Pulmonary metastases from esophageal squamous cell carcinoma (ESCC) are often detected bilateral and multiple lesions and are often accompanied by metastases to other sites. The concept of oligometastasis has been developed, and limited distant metastases have been considered as indications for surgical resection for the purpose of extending overall survival. We herein present a long-surviving case of super-late pulmonary recurrence of ESCC, seven years after radical esophagectomy. Presentation of case A 71-year-old woman who underwent radical subtotal esophagectomy with three-field lymph node dissection with a diagnosis of an advanced poorly differentiated ESCC with cT3N1M0 seven years ago visited our hospital. Chest X-ray and computed tomography at the 7-year follow-up revealed a solitary pulmonary tumor, 1.5 cm in diameter, at the right middle lobe without any extrapulmonary metastases; however, we could not diagnose whether primary lung cancer or pulmonary metastasis of ESCC was present. Therefore, we performed thoracoscopic partial resection of the right middle lobe. A histopathological examination including immunohistochemical staining revealed that the tumor was not derived from both alveolar epithelium and neuroendocrine cells and was diagnosed as pulmonary oligometastasis of ESCC. She has been followed for four years without re-recurrence. Conclusion Pulmonary oligometastases of ESCC should be considered as surgical indications if the tumor is detected after a long disease-free interval without any extrapulmonary recurrences.

BackgroundParadoxically,Helicobacter pylori-positive (HP+) advanced gastric cancer patients have a better prognosis than those who are HP-negative (HP-). Immunologic and statistical analyses can be used to verify whether systematic mechanisms modulated by HP are involved in this more favorable outcome.MethodsA total of 658 advanced gastric cancer patients who underwent gastrectomy were enrolled. HP infection, mismatch repair, programmed death-ligand 1 (PD-L1), and CD4/CD8 proteins, and microsatellite instability were analyzed. Overall survival (OS) and relapse free survival (RFS) rates were analyzed after stratifying clinicopathological factors. Cox proportional hazards regression analysis was performed to identify independent prognostic factors.ResultsAmong 491 cases that were analyzed, 175 (36%) and 316 (64%) cases were HP+and HP−, respectively. Analysis of RFS indicated an interaction of HP status among the subgroups for S-1 Dose (P=0.0487) and PD-L1 (P=0.016). HP+patients in the PD-L1 group had significantly higher five-year OS and RFS than HP-patients (81% vs. 68%;P=0.0011; HR 0.477; and 76% vs. 63%;P=0.0011; HR 0.508, respectively). The five-year OS and RFS was also significantly higher for HP+compared to HP-patients in the PD-L1-/S-1-reduced group (86% vs. 46%;p=0.0014; HR 0.205; 83% vs. 34%;p=0.001; HR 0.190, respectively). Thus, HP status was identified as one of the most potentially important independent factors to predict prolonged survival.ConclusionModulation of host immune system function by HP may contribute to prolonged survival in the absence of immune escape mechanisms of gastric cancer.

Background Paradoxically, Helicobacter pylori–positive (HP+) advanced gastric cancer patients have a better prognosis than those who are HP–negative (HP-). Immunologic and statistical analyses can be used to verify whether systemic mechanisms modulated by HP are involved in this more favorable outcome. Methods A total of 658 advanced gastric cancer patients who underwent gastrectomy were enrolled. HP infection, mismatch repair, programmed death–ligand 1 (PD-L1) and CD4/CD8 proteins, and microsatellite instability were analyzed. Overall survival (OS) and relapse-free survival (RFS) rates were analyzed after stratifying clinicopathological factors. Cox proportional hazards regression analysis was performed to identify independent prognostic factors. Results Among 491 patients that were analyzed, 175 (36%) and 316 (64%) patients were HP+ and HP−, respectively. Analysis of RFS indicated an interaction of HP status among the subgroups for S-1 dose (Pinteraction = .049) and PD-L1 (P = .02). HP+ patients in the PD-L1- group had statistically higher 5-year OS and RFS than HP- patients (81% vs 68%; P = .0011; hazard ratio [HR] = 0.48, 95% confidence interval [CI] = 0.303 to 0.751, and 76% vs 63%; P = .001; HR = 0.508, 95% CI = 0.335 to 0.771, respectively). The 5-year OS and RFS was also statistically higher for HP+ compared with HP- patients in the "PD-L1- and S-1–r educed" group (86% vs 46%; P = .001; HR = 0.205, 95% CI = 0.07 to 0.602, and 83% vs 34%; P = .001; HR = 0.190, 95% CI = 0.072 to 0.498, respectively). Thus, HP status was identified as one of the most potentially important independent factors to predict prolonged survival. Conclusion This retrospective study suggests that an HP-modulated host immune system may contribute to prolonged survival in the absence of immune escape mechanisms of gastric cancer.

Aim Laparoscopic liver resection (LLR) is increasingly carried out worldwide. However, there are concerns regarding ischemia‐reperfusion injury caused by pneumoperitoneum and the Pringle maneuver. It is not clear whether perioperative use of glucocorticoids lowers the risk of ischemia‐reperfusion hepatic injury in LLR as has been reported for open liver resection. The aim of the present study was to investigate the role of perioperative glucocorticoid use in improving hepatic function and surgical outcomes after LLR. Methods In this double‐blind, randomized controlled trial (UMIN000013823), we enrolled 130 patients who presented to our institution for LLR between April 2014 and October 2018. Six patients were excluded, resulting in 124 patients being randomized to either the glucocorticoid or the control group. Preoperatively, patients in the glucocorticoid group received 500 mg methylprednisolone in saline solution, patients in the control group saline solution only. Surgical outcomes and blood parameters were compared between the two groups. Results The Pringle maneuver could not be carried out in 24 patients, resulting in 50 patients in each group being included in the analysis. Postoperatively, total, direct and indirect bilirubin, and C‐reactive protein and interleukin‐6 levels were significantly lower, albumin levels were significantly higher, and prothrombin time was significantly shorter in the glucocorticoid than in the control group. Surgical outcomes were not significantly different between the groups. Conclusion This first report on preoperative glucocorticoid use in LLR showed that it significantly improved postoperative liver function and thus might enhance the safety of LLR., In this single‐center, double‐blind, randomized controlled trial, we show the effect of a single bolus of methylprednisolone on hepatic function as evidenced by postoperative bilirubin and albumin levels, and prothrombin time after laparoscopic liver resection. We conclude that perioperative glucocorticoid use may enhance the safety of this procedure.

ObjectiveTo evaluate long-term whole blood (WB) storage at room temperature (RT), plasma and peripheral blood mononuclear cell (PBMC) DNA was collected simultaneously using BD Vacutainer® CPTTM Mononuclear Cell Preparation Tubes (CPT) and Streck Cell-Free DNA Blood Collection Tubes (BCT®).MethodsPlasma DNA was isolated from both types of tubes at various time points at RT. DNA from PBMCs was extracted using CPT from WB stored in BCT. The extracted DNA was used to monitor esophageal cancer treatment.ResultsBCT maintained steady levels of plasma DNA for up to nine days. After transfer of BCT-stored WB to CPT, PBMC-DNA were yielded with suitable quality for up to seven days. ctDNA from esophageal cancer patients carrying TP53 mutations reflected treatment efficacy.ConclusionBCT/CPT combinatory procedure allows storage of blood samples for up to seven days at RT for valid clinical assays using ctDNA.

Background Indications for laparoscopic liver resection (LLR) are continuously expanding. The Japanese Society of Hepato-Biliary-Pancreatic Surgery defines highly difficult hepatectomy as a procedure involving one or more sections (except for left lateral sectionectomy) or anatomical segmentectomy. This study aimed to assess the outcomes of complex LLR procedures and compare their technical difficulties, about which only a little is known to date. Methods We performed a retrospective review of the operative outcomes of 118 consecutive patients who underwent pure laparoscopic complex hepatectomy. The surgical outcomes, including operative times, blood loss amounts, and postoperative morbidity rates, were compared among complex LLR procedures. Results The overall median operative time was 280 minutes, and the median intraoperative blood loss was 86 mL. Two patients required conversion to open laparotomy (1.7%). The postoperative major morbidity rate was 11.0% Posterosuperior segmentectomy, right hemihepatectomy, and anterior sectionectomy required the longest operative times. Anterior and posterior sectionectomy resulted in the highest blood loss, and right hemihepatectomy and anterior sectionectomy resulted in the most complications. Conclusions The surgical difficulties associated with complex LLR procedures vary. It is critical to recognize the specific risks and cautionary points to ensure patient safety and provide proper systemic training to surgeons.

PurposeCirculating tumor DNA (ctDNA) analysis has been proposed as an approach for prediction of post-treatment patient outcomes. However, whether a single platform will provide optimal information in all patients or alternatively a patient-specific monitoring approach based on assessment of mutations in the primary tumor from that patient remains an urgent question. Experimental Design: We conducted multiregional sequencing of 42 specimens of 14 colorectal tumors (Stage III and more) from 12 patients, including two double cancer cases, to identify the full spectrum of mutational heterogeneity and identify aberrations that could be used to develop personalized ctDNA assays.Results“Founder” mutations that occur in all regions of the sample were identified in 12/14 (85.7%) tumors. Subsequent phylogenetic analysis of each tumor showed that 12/14 tumors (85.7%) carried at least one “truncal” mutation. Most founder and truncal mutations exhibited higher variant allele frequency (VAF) than “non-founder” and “branch” mutations. In addition, both founder and truncal mutations were more likely to be detected as ctDNA than non-founder and branch mutations. Synchronized ctDNA dynamics of multiple mutations suggested those mutations from the same clonal origin. For 10/12 patients (83.3%) with nearly 1,000 days of post-operative observation, the validity of frequent personalized ctDNA monitoring was confirmed in terms of early relapse prediction, treatment efficacy, and non-relapse corroboration.ConclusionsPersonalized ctDNA monitoring based on aberrations with a high VAF in the primary tumor site should be explored in larger prospective clinical trials to determine the full clinical validity.Translational relevanceCirculating tumor DNA (ctDNA) has been reported to be a new class of tumor-specific personalized biomarkers, but the selection criteria of index gene mutations from heterogeneous tumors as well as the achievement of sufficient sensitivity remain a challenge. Among mutations detected by multiregional sequencing, we monitored mutations with high variant allele frequencies (VAFs) from advanced colorectal cancers. Clinical validity of longitudinal ctDNA monitoring using highly-sensitive digital PCR was evaluated in terms of: (a) early relapse prediction; (b) treatment efficacy evaluation; and (c) no relapse corroboration. We found that ctDNA from high VAF mutations of a tumor are likely to be founder/truncal mutations. Based on rigorous longitudinal monitoring, our results suggest that sensitivity required the VAF to be 0.01-0.1%. The ctDNA from high VAF mutations strongly reflects tumor burden in a timely manner, thereby establishing clinical validity as a new class of tumor-specific personalized biomarkers.

BackgroundCirculating tumor DNA (ctDNA) test has not yet been an established tool for monitoring cancer. Sensitive, yet affordable methods should allow frequent ctDNA monitoring that can assist in clinical management.Patients and MethodsThis prospective observational study was conducted in a total of 36 patients with Stage I to IV esophageal squamous cell cancer (ESCC) were enrolled between September 1, 2015 and February 28, 2018. We investigated whether frequent ctDNA monitoring during treatment followed by routine surveillance by digital PCR (dPCR) using tumor-specific mutations offers clinical validity in daily practice for ESCC patients.ResultsMutation screening of tumors from analyzable 35 patients using a specifically-designed "SCC panel" revealed 221 mutations with variant allele frequency (VAF) >2%. VAF of ctDNA was informative in 34 patients surveillance by dPCR using 58 mutations (1-3 per patient). A total of 569 plasma samples at 332 time points for ctDNA testing were evaluated. In pretreatment plasma, the average VAF was higher in advanced stages than earlier stages (P < .0001); tumor volume was also higher for higher VAF (r = 0.71). The ctDNA-positive rate in the pretreatment plasma of stage II or higher was 85.2% (23/27) whereas 85.7% (6/7) stage I were below the detection limit. Ninety-one % (10/11) patients whose ctDNA increased during chemotherapy showed disease progression. Among patients who recurred, ctDNA elevated with a median lead time of 149 days to the imaging diagnosis. Patients with decreased ctDNA within 3 months of initial treatment (n = 10) showed significantly better outcomes than did patients with ctDNA-positive (n = 11; P < .0001, HR 0.10, 95% CI, 0.03-0.30).ConclusionsOur results indicate that frequent tumor burden monitoring using a small number of tumor-specific ctDNAs by dPCR enables prediction of relapse and chemotherapeutic efficacy, as well as relapse-free corroboration in management of ESCC patients.

Several studies have demonstrated that prehabilitation helps reduce the incidence of postoperative complications. In this study, we investigated the safety and efficacy of enhanced prehabilitation (EP) in the hospital for patients with esophageal cancer. We retrospectively reviewed the data of 48 consecutive patients who underwent radical esophagectomy with gastric tube reconstruction between September 2015 and June 2019. EP program had been introduced in August 2017. In the EP group, patients received the EP program during hospitalization 7 days before surgery in addition to conventional perioperative rehabilitation. The EP program consisted of aerobic exercise and muscle strength training in the morning and afternoon. Operative outcomes were compared between patients who received EP (EP group; 23 patients) and patients who did not receive EP (control group; 25 patients). The preoperative (EP group vs. control group, 492.9 ± 79.7 vs. 418.9 ± 71.8 m, p