A case of an unreported point mutation in promoter 1B of the adenomatous polyposis coli gene, which is responsible for gastric adenocarcinoma and proximal polyposis of the stomach.

A 35-year-old woman of Asian descent with epigastralgia was referred to our hospital. Esophagogastroduodenoscopy revealed gastric cancer in the upper body and carpeting fundic gland polyposis in the fornix and body. Computed tomography revealed no metastases. Total colonoscopy and capsule endoscopy revealed no polyposis, except in the stomach. The patient was diagnosed with advanced gastric cancer and underwent open total gastrectomy. We speculated that her gastric cancer was a hereditary tumor due to its early onset and accompanying fundic gland polyposis. Germline multi-gene panel testing identified a single-nucleotide variant, c.-191 T > G, in exon 1B of the adenomatous polyposis coli gene, which can cause gastric adenocarcinoma and proximal polyposis of the stomach. To our knowledge, this is the first manuscript to report the variant (c.-191 T > G) in promoter 1B of the adenomatous polyposis coli gene, which is related to a predisposition to gastric adenocarcinoma and proximal polyposis of the stomach.

Protocol of a phase II study investigating the efficacy and safety of trifluridine/tipiracil plus ramucirumab as a third-line or later treatment for advanced gastric cancer.

In Japan, systemic chemotherapy is the standard treatment for unresectable, advanced, or recurrent gastric cancer. However, numerous patients with gastric cancer do not receive late-line treatment because of the rapid progression of gastric cancer. Additionally, late-line treatments, such as nivolumab, trifluridine tipiracil (FTD/TPI), or irinotecan, have limited effects on improving clinical symptoms and delaying the onset of symptoms associated with cancer progression. Recently, a combination of FTD/TPI and ramucirumab was reported to have a high response rate in late-line treatment; however, owing to patient selection bias and a high rate of hematologic toxicity in that previous study, this regimen may not be feasible in real-world clinical applications. Our objective is to conduct a single-arm phase II study to assess the safety and efficacy of FTD/TPI plus ramucirumab combination therapy for gastric cancer after third-line treatment under real-world clinical conditions. This study will recruit 32 patients according to eligibility criteria and administer FTD/TPI (35 mg/m2) and intravenous ramucirumab (8 mg/kg). The primary endpoint will be the time to treatment failure. The secondary endpoints will include the overall survival time, progression-free survival time, overall response rate, disease control rate, relative dose intensity, and incidence of adverse events. The results will add new insights for improving the late-line treatment of advanced gastric cancer.

Combination of oligo-fractionated irradiation with nivolumab can induce immune modulation in gastric cancer.

BACKGROUND: Tumor-associated antigen (TAA)-specific CD8(+) T cells are essential for nivolumab therapy, and irradiation has been reported to have the potential to generate and activate TAA-specific CD8(+) T cells. However, mechanistic insights of T-cell response during combinatorial immunotherapy using radiotherapy and nivolumab are still largely unknown. METHODS: Twenty patients included in this study were registered in the CIRCUIT trial (ClinicalTrials.gov, NCT03453164). All patients had multiple distant metastases and were intolerance or had progressed after primary and secondary chemotherapy without any immune checkpoint inhibitor. In the CIRCUIT trial, eligible patients were treated with a total of 22.5 Gy/5 fractions/5 days of radiotherapy to the largest or symptomatic lesion prior to receiving nivolumab every 2 weeks. In these 20 patients, T-cell responses during the combinatorial immunotherapy were monitored longitudinally by high-dimensional flow cytometry-based, multiplexed major histocompatibility complex multimer analysis using a total of 46 TAAs and 10 virus epitopes, repertoire analysis of T-cell receptor ß-chain (TCRß), together with circulating tumor DNA analysis to evaluate tumor mutational burden (TMB). RESULTS: Although most TAA-specific CD8(+) T cells could be tracked longitudinally, several TAA-specific CD8(+) T cells were detected de novo after irradiation, but viral-specific CD8(+) T cells did not show obvious changes during treatment, indicating potential irradiation-driven antigen spreading. Irradiation was associated with phenotypical changes of TAA-specific CD8(+) T cells towards higher expression of killer cell lectin-like receptor subfamily G, member 1, human leukocyte antigen D-related antigen, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain, CD160, and CD45RO together with lower expression of CD27 and CD127. Of importance, TAA-specific CD8(+) T cells in non-progressors frequently showed a phenotype of CD45RO(+)CD27(+)CD127(+) central memory T cells compared with those in progressors. TCRß clonality (inverted Pielou's evenness) increased and TCRß diversity (Pielou's evenness and Diversity Evenness score) decreased during treatment in progressors (p=0.029, p=0.029, p=0.012, respectively). TMB score was significantly lower in non-progressors after irradiation (p=0.023). CONCLUSION: Oligo-fractionated irradiation induces an immune-modulating effect with potential antigen spreading and the combination of radiotherapy and nivolumab may be effective in a subset of patients with gastric cancer.

Early endpoints of a randomized phase II trial of preoperative chemotherapy with S-1/CDDP with or without trastuzumab followed by surgery for HER2-positive resectable gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1301C (Trigger Study).

BACKGROUND: This randomized phase II study explored the superiority of trastuzumab plus S-1 plus cisplatin (SP) over SP alone as neoadjuvant chemotherapy (NAC) for HER2-positive resectable gastric cancer with extensive lymph node metastasis. METHODS: Eligible patients with HER2-positive gastric or esophagogastric junction cancer and extensive lymph node metastasis were randomized to receive three or four courses of preoperative chemotherapy with SP (arm A) or SP plus trastuzumab (arm B). Following gastrectomy, adjuvant chemotherapy with S-1 was administered for 1 year in both arms. The primary endpoint was overall survival, and the sample size was 130 patients in total. The trial is registered with the Japan Registry of Clinical Trials, jRCTs031180006. RESULTS: This report elucidates the early endpoints, including pathological findings and safety. The study was terminated early due to slow patient accruals. In total, 46 patients were allocated to arm A (n = 22) and arm B (n = 24). NAC was completed in 20 patients (91%) in arm A and 23 patients (96%) in arm B, with similar incidences of grade 3-4 hematological and non-hematological adverse events. Objective response rates were 50% in arm A and 84% in arm B (p = 0·065). %R0 resection rates were 91% and 92%, and pathological response rates (≥ grade 1b in Japanese classification) were 23% and 50% (p = 0·072) in resected patients, respectively. CONCLUSIONS: Trastuzumab can be safely added to platinum-containing doublet chemotherapy as NAC, and it has the potential to contribute to higher antitumor activity against locally advanced, HER2-positive gastric or esophagogastric junction cancer with extensive nodal metastasis.

S-1 as an alternative treatment after 5-fluorouracil-induced coronary vasospasm in a patient with small bowel adenocarcinoma: a case report.

5-Fluorouracil (5-FU) is a chemotherapeutic agent used worldwide to treat various solid tumors. It may cause adverse cardiotoxic events, the most common of which is coronary vasospasm. Recently, the 2022 European Society for Medical Oncology guidelines for metastatic colorectal cancer recommended S-1 as an alternative therapy after 5-FU-induced cardiotoxicity; however, only limited data on Asian patients are available. Here, we report a case of safe administration of S-1 to a 72-year-old Japanese female patient with metastatic small bowel adenocarcinoma who developed 5-FU-induced coronary vasospasm. While receiving modified FOLFOX6 (5-FU plus leucovorin and oxaliplatin) as palliative chemotherapy, she experienced chest pain with electrocardiographic ST elevation. Chemotherapy was temporarily suspended, but treatment was resumed by switching from modified FOLFOX6 to SOX (S-1 plus oxaliplatin) as the tumor began to worsen. Owing to the adverse event of enteritis, the patient's treatment was switched to S-1 monotherapy after cycle 3, and S-1 monotherapy was continued without any cardiotoxicity. S-1 may be a promising alternative therapy after 5-FU-induced cardiotoxicity.

Phase I/II clinical trial of nivolumab in combination with oligo-fractionated irradiation for unresectable advanced or recurrent gastric cancer.

BACKGROUND: Although immune checkpoint inhibitors (ICI) targeting for PD-1 axis is a promising approach for advanced gastric cancer (GC) patients, the response rate is still limited. Induction of synergistic effect of irradiation with ICI targeting for the PD-1 axis can be an attractive strategy. The aim of this study was to assess the effect of the combination of irradiation with anti-PD-1 therapy for advanced GC. METHODS: We conducted a single-arm, phase I/II trial in GC patients treated with a combination of nivolumab and oligo-fractionated irradiation (22.5 Gy/5 fractions/5 days) (NCT03453164). Eligible patients (n = 40) had unresectable advanced or recurrent GC which progressed after primary and secondary chemotherapy with more than one lesion. The primary endpoint is the disease control rate (DCR) of non-irradiated target lesions and the secondary endpoints are the median survival time (MST), safety, and DCR of irradiated lesions. RESULTS: We observe that the DCR for the non-irradiated target as the abscopal effect is 22.5% (90% confidence interval (CI), 12.3-36.0), and the DCR for the irradiated lesion is 40.0% (90% CI, 26.9-54.2). The median survival time is 230 days (95% CI, 157-330), and grade 3 and higher adverse events (AEs) are observed in 16 patients (39 %) with no obvious additional AEs when adding irradiation. CONCLUSIONS: The present study suggests that the combination of nivolumab with oligo-fractionated irradiation has the potential to induce a promising anti-tumor effect for advanced GC.

Immunotherapy is a type of treatment that triggers the immune system to kill cancers. Combining immunotherapy with radiotherapy may enhance its effects. We evaluated this in a clinical trial in which we treated patients with advanced or recurrent cancers of the stomach (gastric cancer) with a combination of immunotherapy and radiotherapy. The combination was able to control disease in a subset of patients and was safe, with no obvious additional adverse effects when adding radiotherapy. The median survival time­at which point half of the patients treated are still alive­was 230 days. While these results are promising, larger, more rigorous studies are needed to determine whether this combination therapy is better than alternative approaches to treating advanced or recurrent gastric cancers.

Clinical Effect of the C-Reactive Protein to Serum Albumin Ratio in Patients with Metastatic Gastric or Gastroesophageal Junction Cancer Treated with Trifluridine/Tipiracil.

Trifluridine/tipiracil (FTD/TPI) is an oral anticancer agent used as a third- or later-line treatment for patients with metastatic gastric cancer/gastroesophageal junction cancer (mGC/GEJC). The C-reactive protein-to-serum albumin ratio (CAR) is an inflammation-based prognostic marker in gastric cancer. This retrospective study evaluated CAR's clinical significance as a prognostic factor in 64 patients with mGC/GEJC administered FTD/TPI as a third- or later-line therapy. Patients were categorized into high- and low-CAR groups based on pre-treatment blood data. This study evaluated associations between CAR and overall survival (OS), progression-free survival (PFS), clinicopathological features, treatment efficacy, and adverse events. The high-CAR group had significantly worse Eastern Cooperative Oncology Group performance status, a higher prevalence of patients administered with a single course of FTD/TPI, and a higher rate of patients not administered chemotherapy after FTD/TPI therapy than the low-CAR group. Median OS and PFS were significantly poorer in the high-CAR group than in the low-CAR group (113 vs. 399 days; p < 0.001 and 39 vs. 112 days; p < 0.001, respectively). In multivariate analysis, high CAR was an independent prognostic factor for OS and PFS. The overall response rate was not significantly different between the high- and low-CAR groups. Regarding adverse events, the high-CAR group had a significantly lower incidence of neutropenia and a higher incidence of fatigue than the low-CAR group. Therefore, CAR may be a potentially useful prognostic factor for patients with mGC/GEJC treated with FTD/TPI as third- or later-line chemotherapy.

Evaluation of Irinotecan and Trifluridine/Tipiracil as Fourth-line Treatments After Third-line Nivolumab for Advanced Gastric Cancer.

BACKGROUND/AIM: Irinotecan and trifluridine/tipiracil (FTD/TPI) are fourth-line treatment options after third-line nivolumab for advanced gastric cancer (AGC). However, the efficacy and safety of irinotecan and FTD/TPI in the fourth-line setting after third-line nivolumab remains unclear. This study aimed to evaluate the efficacy and safety of irinotecan and FTD/TPI in the fourth-line setting after third-line nivolumab. PATIENTS AND METHODS: We identified 137 AGC patients treated with nivolumab as third-line treatment in our institute between October 2017 and July 2021. Of these, we recruited 19 AGC patients who initiated irinotecan and 23 AGC patients who initiated FTD/TPI in the fourth-line setting until September 2021. RESULTS: The median overall survival was 5.83 months for irinotecan and 6.31 months for FTD/TPI. Median time-to-treatment failure was 2.07 months for irinotecan and 1.64 months for FTD/TPI. While the frequency of all-grade diarrhea was higher in irinotecan (36% vs. 17%), grade ≥3 neutropenia tended to be higher in FTD/TPI (21% vs. 35%). CONCLUSION: Irinotecan and FTD/TPI may be clinically useful as fourth-line treatments after nivolumab.

Efficacy of Pembrolizumab Monotherapy in Japanese Patients with Advanced Gastric or Gastroesophageal Junction Cancer.

PURPOSE: Pembrolizumab demonstrated antitumor activity in programmed death ligand 1 positive (combined positive score (CPS) ≥ 1) gastric/gastroesophageal junction cancer in KEYNOTE-059 (third line or beyond), KEYNOTE-061 (second line), and KEYNOTE-062 (first line). We characterized efficacy and safety of pembrolizumab monotherapy in Japanese patients across several lines of therapy in these studies. METHODS: This analysis was conducted in 34 patients from KEYNOTE-059 cohort 1 (all pembrolizumab), including 13 patients with CPS ≥ 1, 65 patients with CPS ≥ 1 from KEYNOTE-061 (pembrolizumab, n = 27; chemotherapy, n = 38), and 70 patients with CPS ≥ 1 from KEYNOTE-062 (pembrolizumab, n = 38; chemotherapy, n = 32). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were evaluated. RESULTS: In KEYNOTE-059, ORR with pembrolizumab was 9%, median PFS was 2 months, and median OS was 10 months. In KEYNOTE-061, median OS was 12 months with pembrolizumab versus 10 months with chemotherapy (hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.39-1.15). Median PFS (pembrolizumab vs. chemotherapy) was 2 months versus 4 months (HR, 1.21; 95% CI, 0.69-2.13); ORR was 7% versus 18%. In KEYNOTE-062, median OS was 20 months with pembrolizumab versus 18 months with chemotherapy (HR, 0.76; 95% CI, 0.43-1.33). Median PFS (pembrolizumab vs. chemotherapy) was 6 months versus 7 months (HR, 1.03; 95% CI, 0.61-1.74); ORR was 29% versus 34%. CONCLUSIONS: The current analysis provides valuable information that anti-PD-1 therapies are worthy of further assessment for gastric cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02335411 (KEYNOTE-059), NCT02370498 (KEYNOTE-061), and NCT02494583 (KEYNOTE-062).

Clinical Significance of Neutrophil-to-Lymphocyte Ratio/Serum Albumin Ratio in Patients With Metastatic Gastric or Gastroesophageal Junction Cancer Administered Trifluridine/Tipiracil.

BACKGROUND/AIM: Trifluridine/tipiracil (FTD/TPI) is an anticancer-agent that is administered as third-line or later chemotherapy for metastatic gastric/gastroesophageal junction cancer (mGC/GEJC). Although inflammatory and nutritional statuses have attracted attention as prognostic factors for patients with mGC/GEJC in this therapy, their usefulness has not been fully clarified. Thus, this study investigated the clinical significance of prognostic nutritional index (PNI), neutrophil/lymphocyte ratio (NLR), and NLR/serum albumin (Alb) ratio in patients administered FTD/TPI. PATIENTS AND METHODS: This retrospective study included 64 patients who underwent FTD/TPI treatment for mGC/GEJC at Kanagawa Cancer Center, Kanagawa, Japan, between October 2019 and June 2022. Patients were divided into high and low PNI, NLR, and NLR/Alb groups according to their pretreatment blood data. This study evaluated the associations between the inflammatory and nutritional indexes and survivals. RESULTS: Overall survival (OS) and progression-free survival (PFS) of patients with low PNI were significantly poorer than those with high PNI. However, low PNI was not an independent prognostic factor for OS and PFS. There was no significant association between NLR and OS or PFS. In contrast, the OS of patients with high NLR/Alb was significantly poorer than those with high PNI and low NLR/Alb. Furthermore, multivariate analysis showed that high NLR/Alb was an independent prognostic factor for OS. CONCLUSION: The NLR/Alb may be a useful prognostic factor in patients with mGC/GEJC being administered FTD/TPI as third-line or later chemotherapy.

Phase I Study of the Liposomal Formulation of Eribulin (E7389-LF): Results from the Advanced Gastric Cancer Expansion Cohort.

PURPOSE: In the dose-expansion part of this open-label, phase I study, we explored the efficacy and safety of E7389-LF (liposomal formulation of eribulin) in Japanese patients with advanced gastric cancer. PATIENTS AND METHODS: Patients with advanced gastric cancer who had been previously treated with ≥2 lines of chemotherapy received E7389-LF 2.0 mg/m2 every 3 weeks (the previously determined maximum tolerated dose, the primary objective of Study 114). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), and safety; exploratory objectives included disease control rate (DCR) and clinical benefit rate (CBR), as well as pharmacodynamic measurements of serum biomarkers. RESULTS: As of June 24, 2021, 34 patients were enrolled and treated (10 from the original dose-expansion cohort, expanded to include 24 additional patients). Six patients had partial responses, for an ORR of 17.6% [95% confidence interval (CI), 6.8-34.5], and the median PFS was 3.7 months (95% CI, 2.7-4.8). The DCR was 79.4% (95% CI, 62.1-91.3), and the CBR was 32.4% (95% CI, 17.4-50.5). Overall, 32 patients (94.1%) experienced treatment-related adverse events, and 26 patients (76.5%) experienced grade ≥3 events, most commonly neutropenia (41.2%) and leukopenia (29.4%). Of the 8 endothelial cell/vasculature markers tested in this study, 7 were significantly increased among patients treated with E7389-LF; these changes were generally consistent regardless of best overall response. CONCLUSIONS: E7389-LF 2.0 mg/m2 every 3 weeks was tolerable and showed preliminary activity for the treatment of patients with gastric cancer.

Effectiveness of Etoposide and Cisplatin vs Irinotecan and Cisplatin Therapy for Patients With Advanced Neuroendocrine Carcinoma of the Digestive System: The TOPIC-NEC Phase 3 Randomized Clinical Trial.

Importance: Etoposide plus cisplatin (EP) and irinotecan plus cisplatin (IP) are commonly used as community standard regimens for advanced neuroendocrine carcinoma (NEC). Objective: To identify whether EP or IP is a more effective regimen in terms of overall survival (OS) in patients with advanced NEC of the digestive system. Design, Setting, and Participants: This open-label phase 3 randomized clinical trial enrolled chemotherapy-naive patients aged 20 to 75 years who had recurrent or unresectable NEC (according to the 2010 World Health Organization classification system) arising from the gastrointestinal tract, hepatobiliary system, or pancreas. Participants were enrolled across 50 institutions in Japan between August 8, 2014, and March 6, 2020. Interventions: In the EP arm, etoposide (100 mg/m2/d on days 1, 2, and 3) and cisplatin (80 mg/m2/d on day 1) were administered every 3 weeks. In the IP arm, irinotecan (60 mg/m2/d on days 1, 8, and 15) and cisplatin (60 mg/m2/d on day 1) were administered every 4 weeks. Main Outcomes and Measures: The primary end point was OS. In total, data from 170 patients were analyzed to detect a hazard ratio (HR) of 0.67 (median OS of 8 and 12 months in inferior and superior arms, respectively) with a 2-sided α of 10% and power of 80%. The pathologic findings were centrally reviewed following treatment initiation. Results: Among the 170 patients included (median [range] age, 64 [29-75] years; 117 [68.8%] male), median OS was 12.5 months in the EP arm and 10.9 months in the IP arm (HR, 1.04; 90% CI, 0.79-1.37; P = .80). The median progression-free survival was 5.6 (95% CI, 4.1-6.9) months in the EP arm and 5.1 (95% CI, 3.3-5.7) months in the IP arm (HR, 1.06; 95% CI, 0.78-1.45). A subgroup analysis of OS demonstrated that EP produced more favorable OS in patients with poorly differentiated NEC of pancreatic origin (HR, 4.10; 95% CI, 1.26-13.31). The common grade 3 and 4 adverse events in the EP vs IP arms were neutropenia (75 of 82 [91.5%] patients vs 44 of 82 [53.7%] patients), leukocytopenia (50 of 82 [61.0%] patients vs 25 of 82 [30.5%] patients), and febrile neutropenia (FN) (22 of 82 [26.8%] patients vs 10 of 82 [12.2%] patients). While incidence of FN was initially high in the EP arm, primary prophylactic use of granulocyte colony-stimulating factor effectively reduced the incidence of FN. Conclusions and Relevance: Results of this randomized clinical trial demonstrate that both EP and IP remain the standard first-line chemotherapy options. Although AEs were generally manageable, grade 3 and 4 AEs were more common in the EP arm. Trial Registration: Japan Registry of Clinical Trials: jRCTs031180005; UMIN Clinical Trials Registry: UMIN000014795.

Successful resection of gastric cancer arising from a heterotopic gastric gland in the submucosa by endoscopic submucosal dissection.

Heterotopic gastric gland (HGG)-originating early gastric cancer was endoscopically resected. We resected the HGG, widely marked the perimeter outside the submucosal tumor-like area, injected from outside the markings into the submucosa, dissected the muscular layer, and used fine-tip hood. HGG removal and ensuring negative horizontal and vertical margins are critical.

Endoscopic mucosal resection using a ligation device for duodenal neuroendocrine tumors: a simple method.

Introduction: Duodenal neuroendocrine tumors (DNETs) smaller than 1 cm in diameter, without invasion to the muscularis propria, have a low risk of metastasis. Therefore, DNETs are frequently resected endoscopically. However, among the various procedures, the best fit for DNET in terms of feasibility, effectiveness, and simplicity is unclear. Methods: Patients with DNET who underwent endoscopic submucosal resection using a ligation device (ESMR-L) at Kanagawa Cancer Center between May 2003 and December 2020 were studied retrospectively to evaluate clinical characteristics and short-term and long-term outcomes. Results: Eleven consecutive patients with 12 lesions were treated with 12 sessions of ESMR-L. Lesions were discovered in patients at a median age of 68 (range, 50-83) years. One patient had two lesions at the time of the initial ESMR-L session. Eleven of the 12 lesions (91.7%) existed in the duodenal bulb, of which 10 (83.3%) were in the anterior wall, and the remaining one (8.3%) existed in the descending part of the duodenum. The en bloc and R0 resection rates were 100% and 75%, respectively. The rates of bleeding and perforation were both 0%. Among the four patients who had non-curative resections, two patients underwent additional surgery after ESMR-L. One patient had a local remnant tumor, and the other had lymph node metastasis. In cases of local remnant tumors, the vertical margin was positive in the ESMR-L specimen. In that case, ligation by the O-ring was insufficient, retrospectively. All patients had no recurrence during the median follow-up period of 5.7 years. Discussion: ESMR-L was the best fit for DNET within the indications for endoscopic resection. It is a simple procedure that enables easy and complete resection of DNETs without complications.

Feasibility, efficacy, and cautionary note of endoscopic resection for gastric tube cancer after esophagectomy.

BACKGROUND: Gastric tube cancer (GTC), whose usual histology is adenocarcinoma, occurs frequently as a result of improved survival after esophagectomy. Whether endoscopic resection (ER) for GTC is safe and suitable and guidelines for treatment and follow-up remains unclear. METHODS: Patients with GTC who underwent ER at Kanagawa Cancer Center Hospital between 1997 and 2020 were studied retrospectively to evaluate clinical characteristics and short- and long-term outcomes. RESULTS: Twenty-two consecutive patients with 43 lesions were treated in 42 sessions of ER. Lesions were discovered at a median of 9.0 (0-21.8) years after esophageal surgery. Nine (40.9%) patients had multiple lesions at the time of the initial ER session. However, six (54.5%) of the 11 co-existing lesions were overlooked. The location of the middle third was an estimated risk factor for overlooking (p = 0.028). In endoscopic submucosal dissection (ESD) cases, the en bloc dissection rate was as high as 97.1%, and the rates of bleeding, perforation, and aspiration pneumonitis were 17.6%, 0%, and 2.9%, respectively. The bleeding rate was relatively higher than that in usual gastric ESD. Twelve patients (54.5%) experienced synchronous and/or metachronous multiple GTCs during their life span. Thirteen (61.9%) patients died during the median follow-up period of 5.9 (0.7-15.5) years. One patient (7.7%) died of GTC recurrence, 15.4 years after the initial non-curative ER date; 3 (23.1%) patients died of esophageal cancer recurrence, and 3 (23.1%) died of other organ malignancies. The 5-year overall survival rate was 85.0%, and the 5-year disease-specific survival rate was 100%. CONCLUSIONS: ER is feasible for GTCs. However, the rate of bleeding was high in ESD cases. Life-long endoscopic screening of metachronous lesions is desirable. Care should be taken not to overlook lesions in the middle third of the gastric tube. Early detection of esophageal cancer recurrence and other organ malignancies may improve prognosis.

Feasibility of gastric endoscopic submucosal dissection in elderly patients aged ≥ 80 years.

BACKGROUND: Endoscopic resection, especially endoscopic submucosal dissection (ESD), is increasingly performed in elderly patients with early gastric cancer, and lesions beyond the expanded indications are also resected endoscopically in some patients. It is essential to assess whether gastric ESD is safe and suitable for elderly patients and investigate what type of lesions carry an increased risk of ESD-related complications. AIM: To assess the efficacy and feasibility of gastric ESD for elderly patients, and define high-risk lesions and prognostic indicators. METHODS: Among a total of 1169 sessions of gastric ESD performed in Kanagawa Cancer Center Hospital from 2006 to 2014, 179 sessions (15.3%) were performed in patients aged ≥ 80 years, and 172 of these sessions were done in patients with a final diagnosis of gastric cancer. These patients were studied retrospectively to evaluate short-term outcomes and survival. The short-term outcomes included the rates of en bloc resection and curative resection, complications, and procedure-related mortality. Curability was assessed according to the Japanese Gastric Cancer Treatment Guidelines 2010. Fisher's exact test was used to statistically analyze risk factors. Clinical characteristics of each group were compared using Fisher's exact test and Mann-Whitney U test. Survival rates at each time point were based on Kaplan-Meier estimation. Overall survival rates were compared between patients with gastric cancer in each group with use of the log-rank test. To identify prognostic factors that jointly predict the hazard of death while controlling for model overfitting, we used the least absolute shrinkage and selection operator (LASSO) Cox regression model including factors curative/ noncurative, age, gender, body mass index, prognostic nutritional index, Charlson comorbidity index (CCI), Glasgow prognostic score, neutrophil-to-lymphocyte ratio, and antithrombotic agent use. We selected the LASSO Cox regression model that resulted in minimal prediction error in 10-fold cross-validation. P < 0.05 was considered statistically significant. RESULTS: The en bloc dissection rate was 97.1%, indicating that a high quality of treatment was achieved even in elderly patients. As for complications, the rates of bleeding, perforation and aspiration pneumonitis were 3.4%, 1.1% and 0.6%, respectively. These complication rates indicated that ESD was not associated with a particularly higher risk in elderly patients than in nonelderly patients. A dissection incision > 40 mm, lesions associated with depressions, and lesions with ulcers were risk factors for post-ESD bleeding, and location of the lesion in the upper third of the stomach was a risk factor for perforation in elderly patients (P < 0.05). Location of the lesion in the lower third of the stomach tended to be associated with a higher risk of bleeding. The overall survival (OS) did not differ significantly between curative and noncurative ESD (P = 0.69). In patients without additional surgery, OS rate was significantly lower in patients with a high CCI (≥ 2) than in those with a low CCI (≤ 1) (P < 0.001). CONCLUSION: Gastric ESD is feasible even in patients aged ≥ 80 years. Observation without additional surgery after noncurative ESD is reasonable, especially in elderly patients with CCI ≥ 2.

Prognostic Impact of Immune-related Adverse Events in Gastric Cancer Patients Treated With Nivolumab.

BACKGROUND/AIM: To evaluate the impact of development of nivolumab monotherapy-induced immune-related adverse events (irAEs) and continuing nivolumab with irAEs on the survival of patients with gastric cancer (GC). PATIENTS AND METHODS: Patients with unresectable advanced GC and recurrence after curative resection who received nivolumab monotherapy were included in the study. Survival was compared between patients who did and did not develop irAEs, and between those who continued and discontinued treatment due to irAEs. RESULTS: Of 110 GC patients, 22 developed irAEs. Grade ≥3 IrAEs included rash and diarrhoea associated with enteritis. Progression-free and overall survival (OS) were significantly better in patients with irAEs than in those without. The overall survival of patients who continued treatment despite irAEs was better than that of those who discontinued treatment. CONCLUSION: irAE development was associated with better survival in patients with GC who received nivolumab monotherapy. Continuing nivolumab with appropriate treatment in GC patients with irAEs may improve survival.

Association of renal function with the safety and efficacy of cisplatin plus S-1 therapy and docetaxel plus cisplatin plus S-1 therapy in patients with advanced gastric cancer: an exploratory analysis of JCOG1013.

BACKGROUND: Although cisplatin and 5-chloro-2,4-dihydropyrimidine (dihydropyrimidine dehydrogenase inhibitor contained in S-1) are excreted into the urine, it remains unknown how creatinine clearance (CrCl) affects the safety and efficacy of cisplatin plus S-1 and docetaxel plus cisplatin plus S-1 in patients with advanced gastric cancer. METHODS: Among the 741 participants in JCOG1013 comparing cisplatin plus S-1 with docetaxel plus cisplatin plus S-1, 723 with serum creatinine levels ≤1.2 mg/dL were categorized into A1 (CrCl ≥ 80 mL/min), A2 (60 ≤ CrCl <80) and A3 (CrCl < 60) in the cisplatin plus S-1 arm and similarly B1, B2 and B3 in the docetaxel plus cisplatin plus S-1 arm. The initial dose modification by CrCl was pre-specified in the docetaxel plus cisplatin plus S-1 arm but not in the cisplatin plus S-1 arm. RESULTS: The numbers of patients categorized as A1/A2/A3 and B1/B2/B3 were 169/136/57 and 170/138/53, respectively. In the cisplatin plus S-1 arm, a lower CrCl was associated with higher incidences of grade 4 leukopenia (P = 0.006), neutropenia (P = 0.002), and grade 3/4 anorexia (P = 0.004) and febrile neutropenia (P = 0.049), whereas there was no association in the docetaxel plus cisplatin plus S-1 arm. No significant differences were observed according to CrCl in the overall survival [median: 15.4/15.5/15.4 months in A1/A2/A3 (P = 0.886) and 15.3/13.7/13.7 months in B1/B2/B3 (P = 0.719)], progression-free survival [median: 7.1/6.8/6.2 months in A1/A2/A3 (P = 0.884) and 7.5/7.2/7.8 months in B1/B2/B3 (P = 0.851)] and response rates [58.9/57.8/46.9% in A1/A2/A3 (P = 0.311) and 62.0/61.5/51.5% in B1/B2/B3 (P = 0.362)]. CONCLUSIONS: Renal impairment was associated with severe adverse events in cisplatin plus S-1 therapy but not with the efficacy in cisplatin plus S-1 and docetaxel plus cisplatin plus S-1 therapy.

A case of esophageal granular cell tumor diagnosed by mucosal incision-assisted biopsy.

For an esophageal submucosal mass suspicious of granular cell tumor (GCT) based on gross appearance and endoscopic ultrasound findings, a sufficient number of biopsy specimens is required for a definite diagnosis using immunohistochemical examination. When the specimen obtained by forceps biopsy is insufficient, endoscopic ultrasound-fine needle aspiration (EUS-FNA) is believed to be an useful alternative. However, it may be difficult to obtain an adequate amount of tumor material using EUS-FNA. Mucosal incision-assisted biopsy (MIAB) is a simple method that can collect larger amounts of specimens. This procedure is helpful for physicians who encounter the problem of obtaining an adequate amount of biopsy material from esophageal tumors suspicious for GCT. We present a case of esophageal GCT that was successfully diagnosed through MIAB.

Successful Conversion Surgery for Stage IV Gastric Cancer after Nivolumab Monotherapy as Third-Line Chemotherapy.

There are few reports of conversion surgery (CS) after nivolumab monotherapy because it is considered as a third-line standard chemotherapy for unresectable or recurrent gastric cancer. Here, we report a rare case of stage IV gastric cancer effectively treated with CS after nivolumab monotherapy as a third-line chemotherapy. A 73-year-old man was referred to our hospital with loss of appetite and abdominal discomfort. Stage IV gastric cancer with liver metastasis was diagnosed via upper gastrointestinal endoscopy and CT. Twelve courses of capecitabine, cisplatin, and trastuzumab were administered as the first-line treatment, 25 courses of paclitaxel plus ramucirumab as the second-line treatment, and 31 courses of nivolumab monotherapy as the third-line treatment. After 31 courses of nivolumab monotherapy, CT showed that the primary tumor shrank with no liver metastasis or ascites. Diagnostic laparoscopy was performed with no peritoneal dissemination (P0), and the peritoneal lavage cytology was negative (CY0). CS was performed with total gastrectomy and D2 lymph node dissection (R0 resection). The pathological diagnosis was U, Ant-Less, Type 2, 70 × 63 mm, poorly differentiated adenocarcinoma (ypT3N0M0 ypStage IIA). R0 resection was performed, and the histological response was grade 1a. The patient did not show recurrence for 9 months after CS.