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Imatinib is the standard treatment for unresectable and metastatic GIST. In the late stages, patients undergoing imatinib show drug resistance. Surgical intervention has been occasionally performed for resistant lesions. However, the clinical significance of such intervention remains unclear. Between 2006 and 2015, 37 patients were diagnosed with imatinib-resistant GISTs. We performed surgical intervention only for localized resistant lesions. We retrospectively investigated the background characteristics, data on surgical intervention and subsequent treatment, progression-free survival (PFS), and overall survival (OS). Eighteen patients diagnosed with localized resistance received surgical intervention (S-group) and 19 patients diagnosed with generalized resistance were received other TKIs (M-group). In S-group, no serious complications occurred, and all patients restarted imatinib after resection. The median PFS was 14.5 months. Five patients underwent surgical intervention multiple times followed by the continuation of imatinib, and the median duration of imatinib continuation was 22.2 months. Second-line TKIs were administered to 93% of the patients and the dose-intensity and outcome were similar in both groups. The median OS was 47.2 months after surgery. Surgical intervention could be performed safely and therefore could be followed by the continuation of TKI therapy. Surgical intervention based on the appropriate criteria of resistance might thus be useful for imatinib-resistant GISTs.

Surgery-induced factors such as postoperative infectious complications (PICs) and intraoperative blood loss (IBL) have a negative impact on the survival of patients undergoing surgery for gastric cancer. A recent study showed that neoadjuvant chemotherapy (NAC) could reduce the negative impact of PICs; hence, we conducted the present study to investigate if NAC can also reduce the negative prognostic impact of IBL. We reviewed 115 gastric cancer patients treated with NAC and radical gastrectomy. The cut-off for IBL predicting the long-term survival was assessed by a receiver operating characteristic curve. The Cox proportional hazard model was used to evaluate the association between patient characteristics including IBL, overall survival, and disease-free survival. The cut-off for IBL was set at 990 ml. Twenty-six patients had excessive IBL exceeding 990 ml (22.6%) and PICs developed in 33 patients (28.7%). The body mass index, IBL, ypT, and ypN were significant independent prognostic predictors, but PICs were not. NAC did not decrease the risk induced by excessive IBL. The prophylactic effect of NAC on surgery-induced risk was inconsistent.

This review introduces the definition, epidemiology and therapeutic challenges of rare cancers and describes the establishment of the Rare Cancer Center at the National Cancer Center, Japan. Rare cancers are defined as malignant tumors with an incidence rate of less than 6 cases per 100 000 individuals. Due to their low incidence rate, medical treatment for rare cancers is more challenging than for more common cancer types. Specifically, 190 types of cancers, including bone and soft tissue sarcomas, gastrointestinal stromal tumors (GISTs), neuroendocrine tumors and gliomas, are classified as rare cancers. Individually, each of the rare cancers accounts for less than 1% of all cancers, but collectively they account for 15% of all cancers. On the basis of their medical management, rare cancers can be subclassified into two types: Type I (rare cancers within cancer-rare organs) and Type II (rare cancers within cancer-common organs). Most importantly, the outcomes for rare cancers are poorer compared to those of common cancers. In 2014, the Rare Cancer Center was established at the National Cancer Center to address the various challenges related to rare cancers. The Rare Cancer Center has adopted a multifaceted approach for overcoming these challenges, including active sharing of information through a dedicated website and an online seminar series ‘Rare Cancer Meet the Expert’, providing medical support through telephone consultations via a ‘Rare Cancer Hotline’, supporting basic research and establishing the ‘MASTER KEY Project’ aimed at developing new treatments.

T1 gastric cancer is treated by endoscopic submucosal dissection (ESD) or surgery, considering the risk of lymph node metastasis. Additional gastrectomy is necessary when the pathological specimens after ESD show some risk of lymph node metastasis. Preoperative computed tomography (CT) after ESD sometimes reveals enlarged lymph nodes, which should prompt surgeons to select D2 over D1/D1+. However, whether or not CT after ESD is reliable remains unclear. Patients who underwent radical gastrectomy for clinical T1 between April 2015 and June 2019 were enrolled. The patients were classified into those who underwent CT after ESD (group A) and those who underwent CT before primary surgery or ESD (group B). The accuracy of the nodal diagnosis was compared between groups. A total of 650 patients (group A; 81, group B; 569) were examined. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value (group A vs. group B) were 77.8% vs. 84.2%, 0.0% vs. 15.9%, 84.0% vs. 95.7%, 0.0% vs. 38.2%, and 91.3% vs. 87.1%, respectively. The false-positive rate was 100% in group A and 61.8% in group B (p = 0.011). A nodal diagnosis by CT is unreliable for patients who need additional gastrectomy after ESD.

Aim We evaluated the efficacy and safety of TAS-116, a novel class of an orally active selective inhibitor of heat shock protein 90, in patients with advanced gastrointestinal stromal tumour (GIST) after failure of three or more lines of standard treatment with imatinib, sunitinib and regorafenib. Methods In this single-arm phase II study, patients received 160 mg/day oral TAS-116 for five consecutive days, followed by a 2-day rest. The primary end-point was centrally assessed progression-free survival (PFS). The secondary end-points were objective response rate, disease control rate, overall survival (OS), metabolic response rate, safety, pharmacokinetics and pharmacogenomics. Results Forty-one patients were enrolled in Japan, and 40 patients underwent efficacy and safety evaluation. At the cut-off date, the median PFS was 4.4 months (95% confidence interval [CI], 2.8–6.0) and 12-week progression-free rate was 73.4% (95% CI, 58.1–88.7). Thirty-four patients (85.0%) had stable disease for ≥ 6 weeks. The median OS was 11.5 months (95% CI, 7.0–not reached). All patients experienced at least one treatment-related adverse event (AE), including diarrhoea (80.0%), decreased appetite (45.0%) and increase in blood creatinine level (42.5%). Grade ≥3 AEs and treatment-related grade ≥3 AEs occurred in 23 (57.5%) and 21 (52.5%) patients, respectively. All AEs resolved after dose modification, and no TAS-116–related AEs led to treatment discontinuation. Conclusion TAS-116 showed significant activity in advanced GIST refractory to standard treatment. Further development of TAS-116 is warranted. Trial registration JapicCTI-163182.

Background A multidisciplinary approach based on guidelines and pathological diagnosis by specialized pathologists are important for improving the prognosis and QoL of GIST patients. This study examined the adherence to the guidelines and the concordance of the pathological diagnosis of high-risk GISTs. Patients and methods Among 541 patients with high-risk GISTs recruited to the prospective registry between Dec. 2012 and Dec. 2015, 534 patients were analyzed after central pathology with KIT and DOG1 IHC and genotyping of KIT and PDGFRA. Results Of the 534 patients, 432 (81%) received imatinib adjuvant therapy at a starting dose of 400 or 300 mg/day. Multivariate analysis indicated that age (HR 0.71; 95% CI 0.58–0.88), tumor size (HR for > 10 cm vs 10 vs

Background Advanced gastric cancer sometimes causes macroscopic serosal change (MSC) due to direct invasion or inflammation. However, the prognostic significance of MSC remains unclear. Methods A total of 1410 patients who had been diagnosed with deeper-than-pathological-T2 gastric cancer and undergone R0 gastrectomy with lymph node dissection at the National Cancer Center Hospital during January 2000 and December 2012 were restrospectively reviewed. Results MSC was not found in 108 of the 506 patients with pathological T4a (21.3%), whereas it was detected in 250 of the 904 patients with pathological T2-T3 (27.7%). The sensitivity, specificity and accuracy for diagnosing pathological serosa exposed (SE) by MSC were 78.7, 72.3 and 74.6%, respectively. The MSC-positive cases had a worse 5-year overall survival (OS) than the MSC-negative cases in pT3 (72.9% vs. 84.3%, p = 0.001), pT4a (56.2% vs. 73.4%, p = 0.001), pStageIIB (76.0% vs. 88.4%, p = 0.005), pStageIIIA (63.4% vs. 75.6%, p = 0.019), pStageIIIB (53.6% vs. 69.2%, p = 0.029) and pStage IIIC (27.6% vs. 50.0%, p = 0.062). A multivariate analysis showed that MSC was a significant independent predictor for the OS (hazard ratio [HR]: 1.587, 95%CI 1.209–2.083, p = 0.001) along with the tumor depth (HR: 7.742, 95%CI: 2.935–20.421, p p p Conclusions In this study, the MSC was one of the independent prognostic factors in patients with resectable locally advanced gastric cancer.

The use of patient‐derived xenografts (PDXs) has recently attracted attention as a drug discovery platform with a high predictive clinical efficacy and a preserved tumor heterogeneity. Given the racial differences in genetic variations, it would be desirable to establish a PDX library from Japanese cancer patients on a large scale. We thus tried to construct the Japanese PDX (J‐PDX) library with a detailed clinical information for further clinical utilization. Between August 2018 and May 2020, a total of 1126 cancer specimens from 1079 patients were obtained at the National Cancer Center Hospital and National Cancer Center Hospital East, Japan, and were immediately transplanted to immunodeficient mice at the National Cancer Center Research Institute. A total of 298 cross‐cancer PDXs were successfully established. The time to engraftment varied greatly by cancer subtypes, especially in the first passage. The engraftment rate was strongly affected by the clinical stage and survival time of the original patients. Approximately 1 year was needed from tumor collection to the time when coclinical trials were conducted to test the clinical utility. The 1‐year survival rates of the patients who were involved in establishing the PDX differed significantly, from 95.6% for colorectal cancer to 56.3% for lung cancer. The J‐PDX library consisting of a wide range of cancer subtypes has been successfully established as a platform for drug discovery and development in Japan. When conducting coclinical trials, it is necessary to consider the target cancer type, stage, and engraftment rate in light of this report., We have successfully established a PDX library derived from Japanese cancer patients. In less than 2 years, we have registered more than 1000 specimens and established nearly 300 PDXs. We will further enrich the library and use it as a platform to accelerate drug discovery in Japan.

The introduction of molecularly targeted drugs, including imatinib, has greatly improved the prognosis of gastrointestinal stromal tumor (GIST), and based on the different response image, the methods of response evaluation have been established for GISTs. Furthrmore, the best response evaluation using them has been reported to be associated with progression-free survival (PFS) in imatinib treatment. However, since it is more important to predict the clinical outcomes of imatinib treatment in “early treatment phase”, new predicting factor in earlier stage is desired to work out the whole strategy of each patient. Early morphological change (EMC) was previously reported as a predictive marker for molecularly targeted drugs in metastatic colorectal cancer. The purpose of the present study was to verify the efficacy of EMC in predicting the outcome in patients with GIST receiving imatinib at early evaluation. We retrospectively reviewed 66 patients. EMC in computed tomography (CT) image was evaluated, and the patients were categorized into two groups: active MR (morphological response) (+) group and active MR (−) group. We investigated the association between the presence of active MR and clinical outcomes. Forty-five patients had active MR ( +). The median progression-free survival (PFS) in patients with/without active MR was 49/23 months (P = 0.0039). The evaluation criteria based on EMC could be a sensitive method to predict the clinical outcome of imatinib treatment for patients with unresectable GIST.

PURPOSE: In Japan, for pharmaceutical products to be covered by public medical insurance, their efficacy and safety must first be confirmed in clinical trials. To our knowledge, this study is the first investigation into the off-label use of pharmaceutical products at a high-volume cancer treatment center in Japan. The objective of this study is to explore the framework necessary for future pharmaceutical development and regulatory approval in the field of oncology by surveying the frequency of and indications for off-label use of pharmaceutical products at the National Cancer Center Hospital in Tokyo, Japan. MATERIALS AND METHODS: The pharmaceutical products used off-label in daily practice from 2003 to 2015 at the National Cancer Center Hospital were retrospectively examined based on applications that had been submitted to an internal review committee requesting off-label use. RESULTS: A total of 1,390 applications were submitted during the study period. The most frequently used supporting documents were the results of phase II trials, followed by case series and phase III trials. The cancer most frequently treated with off-label drugs was sarcoma (15.1%), followed by urologic cancer (9.2%) and GI cancer (7.6%). CONCLUSION: As reported in previous studies, pharmaceutical products were generally used off-label for the treatment of rare cancers, for which large-scale clinical trials are difficult to conduct. Continued discussion of the types of frameworks that are needed to guide pharmaceutical development is necessary.

Background The surgical Apgar score (SAS) or modified SAS (mSAS) has been reported as a simple and easy risk assessment system for predicting postoperative complications in primary surgery for gastric cancer. However, few studies have described the SAS’s utility in gastric surgery after neoadjuvant chemotherapy (NAC). Methods One hundred and fifteen patients who received NAC and radical gastrectomy from 2008 and 2015 were included in this study. The SAS was determined by the estimated blood loss (EBL), lowest intraoperative mean arterial pressure, and lowest heart rate. The mSAS was determined by the EBL reassessed using the interquartile values. The predictive values of the SAS/mSAS for postoperative complications were assessed with univariate and multiple logistic regression analyses. Results Among the 115 patients, 41 (35.7%) developed postoperative complications. According to analyses with receiver operating characteristic curves of the SAS and mSAS for predicting postoperative complications, the cut-off value of the mSAS was set at 8. The rates of anastomotic leakage, pancreatic fistula, and arrhythmia in patients with high mSAS (> 8) values were higher than in those with low (0–3) and moderate [1–4] mSAS values. A multiple logistic regression analysis showed that the operation time, body mass index, and diabetes mellitus were independent risk factors for postoperative complications. The mSAS was not a significant predictor. Conclusion The predictive value of SAS or mSAS for morbidity may be limited in patients who undergo gastric cancer surgery after NAC. Future prospective studies with a large sample size will be needed to confirm the present results.

To investigate the efficacy and safety of Daikenchuto (DKT) for colorectal cancer patients undergoing surgery with the potential risk of postoperative ileus (POI). Colorectal cancer patients with abdominal pain and distention, scheduled for surgery, were randomly assigned to a DKT group or a control group. Patients assigned to the DKT group were given 15 g of DKT per day during the perioperative period. We then compared the perioperative gastrointestinal symptoms between the two groups. The aim for a sample size of 30 patients per group was not reached in time, so we conducted an analysis on 16 patients in each group. The visual Analogue Scale scores for abdominal pain and distention were similar in the two groups. The number of bowel movements per day on postoperative days (PODs) 1, 2, and 6 were significantly lower in the DKT group. The incidence of a sensation of incomplete bowel evacuation on PODs 3 and 28 was also significantly lower in the DKT group. There were no adverse events thought to be related to DKT. DKT could potentially inhibit diarrhea and reduce the number of bowel movements per day and the sensation of incomplete bowel evacuation after colorectal surgery. Thus, the perioperative use of DKT may be safe for colorectal cancer patients with abdominal pain and distention, who undergo surgery.

Background: Gastrointestinal stromal tumours (GISTs) with high-risk features have poor prognosis even if adjuvant treatment is given. Neoadjuvant imatinib may increase the cure rate by shrinking large GISTs and preserve organ function. Methods: We conducted an Asian multinational phase II study for patients with gastric GISTs ≥10 cm. Patients received neoadjuvant imatinib (400 mg/day) for 6–9 months. The primary end point was R0 resection rate. Results: A total of 56 patients were enroled in this study. In the full analysis set of 53 patients, neoadjuvant imatinib for ≥6 months was completed in 46 patients. Grade 3–4 neutropenia and rash occurred in 8% and 9%, respectively, but there were no treatment-related deaths. The response rate by RECIST was 62% (95% CI, 48–75%). The R0 resection rate was 91% (48/53) (95% CI, 79–97%). Preservation of at least half of the stomach was achieved in 42 of 48 patients with R0 resection. At the median follow-up time of 32 months, 2-year overall and progression-free survival rates were 98% and 89%, respectively. Conclusions: Neoadjuvant imatinib treatment for 6–9 months is a promising treatment for large gastric GISTs, allowing a high R0 resection rate with acceptable toxicity.

Splenectomy for dissecting splenic hilar lymph nodes (#10) should be avoided for most gastric cancer, considering the high morbidity and lack of any survival benefit, but it is often selected for scirrhous gastric cancer because this type frequently invades the whole stomach and lymph nodes. Splenectomy is necessary for dissecting #10; however, the survival benefit of dissecting #10 is unclear. Patients who had scirrhous gastric cancer and underwent D2 total gastrectomy with splenectomy at National Cancer Center Hospital, Japan, between 2000 and 2011 were retrospectively analyzed. The therapeutic value index was calculated by multiplying the metastatic rate of each nodal station and the 5-year survival of patients who had metastasis to each node. In total, 137 patients were eligible for the present study. The most frequent metastatic node was #3(58%), followed by #4d(46%), #1(35%), #4sb(23%), #6(22%), #7(21%), #4sa(18%), #10(15%), #2(14%), #11p(14%), #11d(13%), #9(13%), and #8a(11%). These lymph nodes had a metastatic rate of more than 10%. The node station with the highest index was #3(18.9), followed by #4d(14.1), #1(10.8), #4sa(6.11), #4sb(6.06), #10(5.09), #7(4.39), #11d(4.36), #11p(4.06), #2(2.93), #8a(2.18), and #9(1.45). The index of #10 exceeded that of #2, #7, #8a, and #9, which are the key nodes dissected in D2. The metastatic rate of the splenic hilar lymph nodes was relatively high, and the therapeutic index was the sixth highest among the 15 regional lymph nodes included in D2 dissection. Splenectomy for dissecting splenic hilar lymph nodes would be justified for scirrhous gastric cancer.

Whether or not surgery alone is sufficient for treating patients with pathological stage T1N2M0 (Stage IIA), T1N3a/bM0 (Stage IIB/IIIB), and T3N0M0 (Stage IIA) gastric cancer who were not indicated for adjuvant treatment according to the Japanese gastric cancer treatment guideline remains unclear. We retrospectively reviewed the clinical records of 236 patients who had been diagnosed with pT1N2-3b/pT3N0 gastric cancer and undergone R0 gastrectomy with lymph node dissection between January 2000 and December 2012 at the National Cancer Center Hospital, Japan. The 5-year recurrence-free survival (RFS) rates (95% confidence interval [CI]) of the patients with pathological (p) T1N2-3b and T3N0 cancer were 73.9% (63.1–84.7) and 89.5% (84.0–95.0), respectively. The only significant prognostic factors for the survival identified by a multivariate Cox regression analysis in patients with pT1N2-3 cancer were the pN stage (N3a/N2: hazard ratio [HR] 2.940, 95% CI 1.314–5.577; N3b/N2: HR 8.688, 95% CI 3.096–24.382) and tumor diameter (

The correct name of the corresponding author should be "Takaki Yoshikawa", and not "Takaki Yoshiaki" as given in the original publication of the article.

Simple Summary Gastrointestinal stromal tumors (GIST) are potentially malignant tumors and require evidence-based surgical and/or medical treatment. Laparoscopy has similar safety and prognostic outcomes to those of laparotomy and is currently a standard procedure for localized GISTs. However, surgery for gastric GISTs less than 2 cm may be re-evaluated due to the indolent nature of the GIST and other competing risks among GIST patients. A work-up with endoscopy and endoscopic ultrasonography as well as endoscopic or percutaneous biopsy is important for the preoperative diagnosis of GISTs. Medical treatment with tyrosine kinase inhibitors is the mainstay for recurrent/metastatic GISTs. The activity of an individual drug is well correlated with gene alterations, and, in the era of precision medicine, cancer genome profiling should be considered before medical treatment. Abstract Gastrointestinal stromal tumors (GISTs) are the most frequent malignant mesenchymal tumors in the gastrointestinal tract. The clinical incidence of GISTs is estimated 10/million/year; however, the true incidence is complicated by frequent findings of tiny GISTs, of which the natural history is unknown. The initial work-up with endoscopy and endoscopic ultrasonography plays important roles in the differential diagnosis of GISTs. Surgery is the only modality for the permanent cure of localized GISTs. In terms of safety and prognostic outcomes, laparoscopy is similar to laparotomy for GIST treatment, including tumors larger than 5 cm. GIST progression is driven by mutations in KIT or PDGFRA or by other rare gene alterations, all of which are mutually exclusive. Tyrosine kinase inhibitors (TKIs) are the standard therapy for metastatic/recurrent GISTs. Molecular alterations are the most reliable biomarkers for TKIs and for other drugs, such as NTRK inhibitors. The pathological and genetic diagnosis prior to treatment has been challenging; however, a newly developed endoscopic device may be useful for diagnosis. In the era of precision medicine, cancer genome profiling by targeted gene panel analysis may enable potential targeted therapy even for GISTs without KIT or PDGFRA mutations.

11524 Background: Pimitespib (PIM) is a novel class of orally active selective HSP90 inhibitors. KIT and PDGFRA are clients of HSP90 for their functional stability; therefore, HSP90 is a rational therapeutic target on GIST in pts with acquired resistance, such as secondary mutation in KIT, to approved tyrosine kinase inhibitors. A phase II trial showed clinical activity of PIM in pts with advanced GIST refractory to standard treatments whose medical need remains unmet. This phase III trial evaluated the efficacy and safety of PIM for this unmet clinical need. Methods: Eligible pts had histologically confirmed advanced GIST refractory to IM, SU, and REG, ≥1 measurable lesion, and ECOG performance status 0 or 1. Pts were randomized 2:1 to receive either PIM 160 mg once daily on a 5-days-on/ 2-days-off schedule or PL. Pts eligible for unblinding at the time of progressive disease were allowed to crossover to open-label PIM. The primary endpoint was progression-free survival (PFS) by blinded central radiological review based on modified RECIST 1.1. Secondary endpoints included overall survival (OS), PFS in the pts crossed over to PIM (secondary PFS), and safety. Crossover-adjusted OS was derived using the rank preserving structural failure time (RPSFT) model. Exploratory endpoints included pharmacogenomics (PGx). Results: From Oct 2018 to Apr 2020, 86 pts were randomized to receive either PIM (n = 58) or PL (n = 28). Baseline characteristics were well balanced between the two arms. Median PFS was 2.8 months (mo) (95% CI: 1.6–2.9) for PIM vs. 1.4 mo (95% CI: 0.9–1.8) for PL. The hazard ratio (HR) for PFS was 0.51 (95% CI: 0.30–0.87) ( p = 0.006, stratified log-rank test). Median OS was 13.8 mo (95% CI: 9.2–not reached) for PIM vs. 9.6 mo (95% CI: 5.5–not reached) for PL (HR for OS 0.63; p = 0.081), with 60.7 % of PL pts crossed over to PIM; secondary PFS was 2.7 mo (95% CI: 0.7–4.1). The RPSFT-adjusted median OS of PL was 7.6 mo (adjusted HR for OS 0.42; p = 0.007). Furthermore, the results of PGx analysis suggested that PIM was also effective in pts with secondary KIT mutation detected from blood samples. The most common ( > 5%) grade 3 or higher adverse events (AEs) in PIM/PL were diarrhea (13.8%/0%), anemia (6.9%/10.7%), decreased appetite (6.9%/0%), and tumor hemorrhage (5.2%/0%). AEs leading to PIM/PL study discontinuation were observed in 4/2 pts (6.9%/7.1%), respectively. Conclusions: This randomized trial demonstrated that PIM significantly improved PFS with OS prolongation in pts with advanced GIST refractory to IM, SU, and REG, as a HSP90 inhibitor for the first time. PIM was tolerated and AEs were manageable. With a mechanism of action different from that of standard therapies, PIM has the potential to be a new standard treatment in GIST. Clinical trial information: JapicCTI-184094.

Gastrointestinal stromal tumors (GISTs) are considered to be potentially malignant mesenchymal tumors of the gastrointestinal tract. Clinically relevant GISTs are rare; however, subclinical GISTs (mini-GISTs) (1-2 cm) and pathologic GISTs (micro-GISTs) (

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors originating in the gastrointestinal tract. With the introduction of molecular-targeted therapy for GISTs which has yielded remarkable outcomes, these tumors have become a model of multidisciplinary oncological treatment. Although Western clinical guidelines are available for GISTs, such as those published by the National Comprehensive Cancer Network (NCCN) and the European Society of Medical Oncology (ESMO), the clinical situations in Asian countries are different from those in Western countries in terms of diagnostic methods, surgical approach, and availability of new targeted agents. Accordingly, we have reviewed current versions of several GIST guidelines published by Asian countries (Japan, Korea, China, and Taiwan) and the NCCN and ESMO and discussed the areas of dissensus. We here present the first version of the Asian GIST consensus guidelines that were prepared through a series of meetings involving multidisciplinary experts in the four countries. These guidelines provide an optimal approach to the diagnosis and management of GIST patients in Asian countries.

Endoscopic submucosal dissection is recommended for early gastric cancer with a low risk of lymph node metastasis. When the pathological findings do not meet the curative criteria; then, an additional gastrectomy with lymph node dissection is recommended. However, most cases have neither lymph node metastasis nor a local residual tumor during an additional surgery.This was a single-institutional retrospective cohort study, analyzing 200 patients who underwent an additional gastrectomy after non-curative endoscopic submucosal dissection from January 2005 to October 2015. We reviewed the patients' clinicopathological data and evaluated the predictors for the presence of a residual tumor.Histopathology revealed lymph node metastasis in 15 patients (7.5 %) and a local residual tumor in 23 (11.5 %). A multivariable analysis revealed macroscopic findings (flat/elevated type) (p = 0.011, odds ratio = 4.63), lymphatic invasion (p 0.0001, odds ratio = 14.2), and vascular invasion (p = 0.04, odds ratio = 4.00) to be predictors for lymph node metastasis. A positive vertical margin (p = 0.0027, odds ratio = 3.26) and horizontal margin (p = 0.0008, odds ratio = 5.74) were predictors for a local residual tumor. All cases with lymph node metastasis had lymphovascular invasion with at least one other non-curative factor.The risk of a residual tumor can, therefore, be estimated based on the histopathology of endoscopic submucosal dissection samples. Lymphovascular invasion appears to be a pivotal predictor of lymph node metastasis.

Postoperative infectious complications (ICs) are associated with a poor prognosis following gastric cancer surgery. Neoadjuvant chemotherapy (NAC) targeting scirrhous-type or bulky nodal disease reportedly exerts a prophylactic effect on the negative impact of ICs. However, a recent study clearly showed that NAC for scirrhous-type disease had no survival benefit. We investigated this prophylactic effect and significant interactions among subgroups of histological response, macroscopic type, and bulky nodal disease. We examined 115 patients who received NAC followed by radical gastrectomy between January 2008 and December 2015. The overall survival (OS) and disease-free survival (DFS) were compared between those with and without ICs. Our cohort included 62 with type 4/giant type 3, 44 with bulky nodal disease/para-aortic nodal disease, and 25 with other diseases. A histological response was observed in 80 patients (69.5%). Thirty three (28.7%) developed ICs. There was no significant difference in the OS [hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.47–1.99, p = 0.920] or DFS (HR 0.74; 95% CI 0.40–1.38, p = 0.342) by the presence of ICs. The HR was 1.00 in patients who had no response to NAC (grade 0/1a) and 0.95 in those who responded to NAC (grade 1b/2/3). No subgroups showed significant interactions for the OS. NAC may cancel out the negative impact of morbidity on the survival in advanced gastric cancer patients. The prophylactic effects by NAC do not depend on the tumor type or histological response.

The Japan Clinical Oncology Group phase 3 study confirmed the survival non-inferiority of spleen-preserving surgery against splenectomy for advanced proximal gastric cancer not invading the greater curvature. However, the efficacy of #10 lymph node (LN) dissection for tumors that involve the greater curvature remains unclear. Data from patients who underwent D2-total gastrectomy with splenectomy between January 2000 and December 2012 were retrospectively reviewed. The study included 593 patients. The patients were split into two groups, with 212 patients in the tumor invasion of the greater curvature (Gre) group and 381 patients in the non-Gre group. Survival curves and the state of LN metastasis and the index of estimated benefit from LN dissection of each station were evaluated. The incidence of #10 LN metastasis was 8.1% (48/593): 15.1% in the Gre group and 4.2% in the non-Gre group. The 5-year overall survival rates for the patients with and without #10 metastasis were respectively 46.9 and 50.2% (P = 0.829) in the Gre group and 49.6 and 62.3% (P = 0.074) in the non-Gre group. The indices for #10 LN dissection were 7.1 in the Gre group and 2.3 in the non-Gre group. In the Gre group, the node station with the highest index was #3, followed by #4d, #1, #4sb, #4sa, #7, #2, #10 (index > 7). The splenic hilar nodes should be prioritized as a component of D2 lymphadenectomy for advanced gastric cancer invading the greater curvature based on its high metastatic rate and index.

Background Regorafenib improved the overall survival (OS) of patients with metastatic colorectal cancer (mCRC) who progress after standard therapies in two phase III trials. The present large-scale prospective observational study evaluated the safety and effectiveness of regorafenib administered to Japanese patients with mCRC in real-life setting. Materials and methods Patients with mCRC were prospectively registered and initially received ≤160 mg oral regorafenib daily, at the investigator's discretion, for weeks 1-3 of each 4-week cycle. The study's primary aim was to assess safety, particularly unexpected clinically significant adverse drug reactions (ADRs). A Cox's proportional hazards model was used to evaluate the association between OS, hand-foot skin reaction (HFSR), and baseline characteristics. Results We evaluated 1,227 of 1,301 patients (enrolled from March 2013 to May 2015). ADRs occurred in 89.3% of patients (mostly within the first 4 weeks) and were a major reason for discontinuing treatment. The most frequent ADRs were HFSR, liver injury, and hypertension. The cumulative incidence of HFSR and liver injury was higher in patients who initially received 160 mg than in those who received ≤120 mg. The incidence of hypertension and fatigue was similar between groups. Median OS was 6.9 months (95% confidential interval, 6.4-7.4). OS was associated with early onset of HFSR and good performance status (PS) but not with the initial dose. Conclusion The outcomes of this study were consistent with those of clinical trials. There were no new safety concerns. Regorafenib treatment would not be recommended for patients with higher PS. Implications for practice Previous clinical trials demonstrated regorafenib improved overall survival in patients with metastatic colorectal cancer who progress after standard chemotherapies. Because the eligibility criteria of the trials were restricted compared with a real-world setting, the data from the trials may not fully represent the profiles of regorafenib in clinical practice. This large-scale observational study showed that the safety and effectiveness of regorafenib in clinical practice were generally consistent with previous trials. The majority of patients reported adverse drug reactions within the first 4 weeks, most commonly hand-foot skin reaction. Regorafenib treatment would not be recommended for patients with higher performance status.

Background: Duodenal gastrointestinal stromal tumors (GISTs) are a rare subset of GISTs (3-5%), and their clinicopathological features have not been fully described. The purpose of this retrospective study was to examine these characteristics and compare the operative procedures. Methods: Twenty-five patients with duodenal GIST underwent complete resection, local resection (LR) or pancreaticoduodenectomy (PD) from 1990 to 2014 at our 2 hospitals. We analyzed patient characteristics, treatments, histological examinations, postoperative complications and survival outcomes. Results: Twelve patients (48%) with no symptoms were incidentally diagnosed for unrelated reasons. Sixteen patients (64%) had c-kit mutations while 6 (24%) were wild-type, including 4 with a history of neurofibromatosis type 1. Comparing LR (n = 16) and PD (n = 9), the recurrence-free survival rate was significantly worse for PD. On multivariate analysis, however, tumor size was an independent and significant prognostic factor, but not operative procedure. There was no body weight change with LR, but body weight decreased by 7% with PD. Conclusion: Duodenal GISTs had different characteristic genetic mutations compared to other GISTs. LR for duodenal GISTs appears to be oncologically and nutritionally feasible.

Background Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal sarcomas. This global, prospective registry followed patients with advanced or localised GIST (2007–2011). Methods Current and evolving diagnostics, treatments and outcome measures in patients with GIST were assessed. Eligible patients were diagnosed with advanced or localised GIST within 15months of registry entry. No treatment plan was prescribed, and no visit schedule was mandated. Treating physicians recorded patient information, including tumour response, diagnostic methods, medications, surgeries performed, mutation status and adverse events leading to dose/medication changes. Survival outcomes were estimated using the Kaplan–Meier method. Other data were analysed using descriptive statistics. Results The registry included 1663 patients (advanced GIST, n =1095; localised GIST, n =537). Medications (e.g. tyrosine kinase inhibitor use and dosing), disease progression or recurrence and physician assessment of response to treatment in registry patients were consistent with controlled trials and prevailing clinical recommendations. In advanced GIST, estimated 30-month progression-free survival (PFS) (59.8%) and overall survival (OS) (82.7%) were higher than results from previously reported trials (≈40% and ≈70%, respectively). Consistent with treatment guidelines, the most common initial treatments were imatinib for advanced GIST, and complete surgical resection for localised GIST. Computed tomography scans were the most common imaging technique used at diagnosis and follow-up. Mutation analysis was performed at diagnosis in only 15.3% and 14.5% of patients with advanced and localised GIST, respectively. Conclusions In this real-world GIST registry, patients with advanced GIST were treated with imatinib and patients with localised GIST received surgical resection, in accordance with prevailing clinical recommendations.

Objective: This study was conducted to expand the sunitinib safety database in Japanese imatinibresistant/-intolerant gastrointestinal stromal tumor patients. Retrospective analyses investigated common adverse events as potential prognostic markers. Methods: Four hundred and seventy patients who received sunitinib between June 2008 and November 2009 were analyzed for safety, progression-free survival and overall survival; 386 for objective response rate; 88% received sunitinib on Schedule 4/2 starting at 50 mg/day. Results: No unexpected safety issues occurred. Grade ≥ 3 adverse events occurred in 70%, most commonly thrombocytopenia (33%), neutropenia (22%) and leukopenia (15%). Objective response rate was 20% (95% confidence interval 16–24). Median progression-free survival was 22.4 weeks (95% confidence interval, 21.7–24.0). The overall survival rate at 24 weeks was 91% (95% confidence interval, 88–94). Higher relative dose intensity (≥70 vs.

International audience; Although gastrointestinal stromal tumors (GISTs) are a rare type of cancer, they are the commonest sarcoma in the gastrointestinal tract. Molecularly targeted therapy, such as imatinib therapy, has revolutionized the treatment of advanced GIST and facilitates scientific research on GIST. Nevertheless, surgery remains a mainstay of treatment to obtain a permanent cure for GIST even in the era of targeted therapy. Many GIST guidelines have been published to guide the diagnosis and treatment of the disease. We review current versions of GIST guidelines published by the National Comprehensive Cancer Network, by the European Society for Medical Oncology, and in Japan. All clinical practice guidelines for GIST include recommendations based on evidence as well as on expert consensus. Most of the content is very similar, as represented by the following examples: GIST is a heterogeneous disease that may have mutations in KIT, PDGFRA, HRAS, NRAS, BRAF, NF1, or the succinate dehydrogenase complex, and these subsets of tumors have several distinctive features. Although there are some minor differences among the guidelines-for example, in the dose of imatinib recommended for exon 9-mutated GIST or the efficacy of antigen retrieval via immunohistochemistry-their common objectives regarding diagnosis and treatment are not only to improve the diagnosis of GIST and the prognosis of patients but also to control medical costs. This review describes the current standard diagnosis, treatment, and follow-up of GISTs based on the recommendations of several guidelines and expert consensus

BACKGROUND: Patients with gastrointestinal stromal tumour (GIST) are often followed up after surgery with longitudinally repeated imaging examinations to detect recurrence early. Studies on follow-up of GIST patients are few, the optimal follow-up methods are unknown and the recommendations for follow-up vary in guidelines. METHODS: We reviewed the current evidence for follow-up of patients treated with surgery alone and of patients who were treated with adjuvant or neoadjuvant imatinib. RESULTS: Imaging of the abdomen and the pelvis with computerised tomography (CT) or magnetic resonance imaging (MRI) usually suffices, since metastases are uncommon at other sites. The frequency of imaging may be adjusted with the risk of recurrence with time. Very low risk GISTs are very frequently cured with surgery and usually require no regular follow-up after complete surgery, and annual CT of the abdomen and the pelvis for 5 years suffices for most patients with a low to intermediate risk for recurrence. Most high-risk patients are treated with imatinib for at least 3 years after surgery. CT or MRI may be carried out 6-monthly during adjuvant imatinib, 3 to 4-monthly during the 2 years that follow discontinuation of imatinib when the risk of recurrence is high, and then at 6-12 month intervals to complete 10 years of follow-up. Recurrence after the first 10 years of follow-up is infrequent. CONCLUSIONS: The follow-up schedules are best tailored with the risk of recurrence. The risk of recurrence should be estimated with the prognostic tools that consider the most relevant prognostic factors. ispartof: European Journal of Cancer vol:51 issue:12 pages:1611-1617 ispartof: location:England status: published

Background: Suppressor of cytokine signaling1 (SOCS1) is a negative regulator of various cytokines. Recently, it was investigated as a therapeutic target in various cancers. However, the observed antitumour effects of SOCS1 cannot not be fully explained without taking inhibition of proliferation signalling into account. Our aim was to discover a new mechanism of antitumour effects of SOCS1 for gastric cancer (GC). Methods: We analysed the mechanism of antitumour effect of SOCS1 in vitro. In addition, we evaluated antitumour effect for GC using a xenograft peritoneal carcinomatosis mouse model in preclinical setting. Results: We confirmed that SOCS1 suppressed proliferation in four out of five GC cell lines. SOCS1 appeared to block proliferation by a new mechanism that involves cell cycle regulation at the G2/M checkpoint. We showed that SOCS1 influenced cell cycle-associated molecules through its interaction with ataxia telangiectasia and Rad3-related protein. The significant difference in therapeutic effects was noted in terms of the post-treatment weight and total photon count of the intra-abdominal tumours. Conclusion: Forced expression of SOCS1 revealed a heretofore-unknown mechanism for regulating the cell cycle and may represent a novel therapeutic approach for the treatment of peritoneal carcinomatosis of GC.

The efficacy and feasibility of laparoscopic surgery (LAP) for gastric GISTs5 cm has not been adequately assessed. Here we investigated the clinical outcomes of these patients.Twenty-seven consecutive patients who underwent resection for gastric GISTs5 cm were enrolled in this retrospective study. We assessed the tumor characteristics, surgical outcomes, tumor recurrence, and patient survival in the open surgery (OPEN) group and in the LAP group.The tumor size in the OPEN group was larger than that in the LAP group, but there were no differences in the mitotic count. There were no differences in operative complications. Finally, there were no differences in the disease-free and no patients in the LAP group died.In patients with gastric GISTs5 cm, LAP can be performed with outcomes equivalent to those of OPEN if patient selection and intraoperative judgment are appropriate.

e22510 Background: Ruptured GIST has poor prognosis and patients (pts) with ruptured GISTs are recommended for imatinib adjuvant therapy, however, their clinicopathological features and the prognosis in the era of imatinib are unknown. Using data obtained from two different registry studies in Japan, we examined ruptured GIST patients in clinical practice. Methods: The study cohort registered 665 pts (339 male and 326 female; median age 66 yrs) with histologically-proven primary GISTs who underwent R0 or R1 surgery between 2003 and 2007. The validation cohort included 172 pts (100 and 72; median age 62.5) between 2000 and 2014. Pathological Dx was done with H&E, KIT- and DOG1-IHC. Results: Disease located in the stomach (n = 506), small intestine (n = 119), large intestine (n = 26), or others (n = 14) in the study cohort and it was 120, 37, 14 or 2 in the validation, respectively. Median tumor size was 4.0 and 5.0 cm, median mitosis 2.6 and 5.0 /50HPF, and tumor rupture was seen in 21 pts (3.2%) and 5 pts (2.9%) in the study and validation cohorts, respectively. Rupture occurred preoperatively in 12 pts and intraoperatively in 9 of the study cohort. Ruptured GISTs showed high mitotic activities (median mitosis 13.0 vs 2.5 /50HPF; P < 0.0001), larger tumor (median size 9.6 vs 4.0 cm; P = 0.0008), and were more symptomatic than non-ruptured in the study cohort. Ruptured GIST pts had more frequent relapses (P < 0.0001) and showed shorter RFS (estimated RFS = 2.4 yrs; P < 0.0001) than non-ruptured (8.4 yrs). There were no difference in age, gender, location, surgical approach, cell type, preoperative and postoperative imatinib use between two groups.These results were confirmed in the validation cohort. Ruptured GISTs showed more frequnent relapses in the peritoneum. Multivariate analysis indicated that location (HR = 1.6), size (1.07), mitosis (1.01), and rupture (4.5) were independent prognostic factors of RFS. Rupture was not always prognostic for OS, and age (1.03), gender (2.3), and mitosis (1.01) were independent prognostic factors of OS. Conclusions: Ruptured GISTs were symptomatic larger tumors with high mitotic activity and showed frequent relapses, however, it was not independently prognostic for OS in the era of imatinib.

There are some disparities between the clinical practice and profiles of cancer in Asia and those in Europe & North America. In Asia, surgical oncologists still have a major role in the multidisciplinary therapy of gastrointestinal stromal tumor (GIST), whereas medical oncologists hold this status in the West. Although the incidence of clinical GIST is considered similar between the two areas, small gastric GISTs are more frequently treated by surgery in East Asia compared with Europe & North America. The diagnosis and treatment of small submucosal tumors (SMTs), including GIST, is important in Asian clinical practice guidelines for GIST. Most items of Asian and Western GIST guidelines are very similar. There are slight differences between the two guidelines in the degree of recommendation, which may come from disparities of clinical practice and available medicines. Importantly, most clinical evidence in the GIST guidelines has been established by clinical trials conducted in Western countries, and the number of clinical trials is still limited in Asia, suggesting that Asian GIST patients may have limited access to investigational drugs after standard therapy. Finally, both Asian and Western GIST guidelines are well-harmonized in some parts, and their contents may reflect the medical circumstances of each region.

The randomized, double-blind, placebo-controlled GRID trial tested the oral multikinase inhibitor regorafenib in 199 patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib, and showed a significant improvement in progression-free survival (PFS) versus placebo [hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.19–0.39; p

This study aimed to assess the efficacy of daikenchuto (DKT), a commonly prescribed, traditional Japanese herbal medicine, on postoperative intestinal dysfunction after gastric cancer surgery. Patients with gastric cancer scheduled for a total gastrectomy were randomly assigned before surgery to receive either no treatment (n = 40; control group) or DKT (7.5 g/day, t.i.d.) for 3 months (n = 41) postoperatively. We examined gastrointestinal motility, stool attributes, the quantity of bowel gas, the quality of life, and the incidence of postoperative ileus. During the hospital stay, significant differences were observed between the DKT group and controls in the number of stools per day (1.1 ± 0.6 vs 0.8 ± 0.4, respectively; P = 0.037) and stool consistencies (Bristol scale ratings were 3.7 ± 0.8 vs 3.1 ± 0.8, respectively; P = 0.041). The DKT group showed significant reductions in gas volume scores, calculated from abdominal radiographs, at 7 days, 1 month, and 3 months after surgery. The groups did not show significant differences in quality of life scores (based on the Gastrointestinal Symptom Rating Scale) or in the incidence of postoperative ileus. DKT improved bowel movements, stool properties, and bowel gas. These results suggested that DKT promoted early postoperative bowel functions after total gastrectomy.

Gastrointestinal stromal tumor (GIST) is the most common and potentially-malignant mesenchymal tumor in the gastrointestinal tract (1,2). GIST may arise at any age although it is frequently reported around the 60s. GISTs are found most often in the stomach, followed by the small intestine, but GISTs may occur at any sites of the gastrointestinal tract and peritoneal cavity including the colon and esophagus. The proliferation of most GISTs (80% to 90%) is driven by gain-of-function mutations either in the KIT or platelet-derived growth factor receptor alpha ( PDGFRA ) gene, which are mutually exclusive. Surgery is the only potentially-curative treatment for primary GIST. Nearly 40% of GIST patients, however, have had disease recurrence even after complete resection (3). Imatinib mesylate (Gleevec, Novartis Pharmaceuticals, Basel, Switzerland) has revolutionized treatment of advanced and recurrent GISTs by inhibiting the KIT and PDGFRA signaling pathways (4).

Although dysregulation of microRNAs (miRNAs/miRs) is a common feature of human malignancies, its involvement in gastrointestinal stromal tumors (GISTs) is not fully understood. The present study aimed to identify the miRNAs that perform a role in GIST metastasis. miRNA expression profiles from a series of 32 primary GISTs were analyzed using microarrays, and miR-186 was observed to be downregulated in tumors exhibiting metastatic recurrence. Reverse transcription-quantitative polymerase chain reaction analysis of an independent cohort of 100 primary GISTs revealed that low miR-186 expression is associated with metastatic recurrence and a poor prognosis. Inhibition of miR-186 in GIST-T1 cells promoted cell migration. Gene expression microarray analysis demonstrated that miR-186 inhibition upregulated a set of genes implicated in cancer metastasis, including insulin-like growth factor-binding protein 3, AKT serine/threonine kinase 2, hepatocyte growth factor receptor, CXC chemokine receptor 4 and epidermal growth factor-containing fibulin-like extracellular matrix protein 1. These results suggest that the downregulation of miR-186 is involved in the metastatic recurrence of GISTs, and that miR-186 levels could potentially be a predictive biomarker for clinical outcome.

288 Background: D2 surgery is required for clinical T1 gastric cancer with nodal swelling, however, D2 has a higher risk for morbidity than D1/D1+. Moreover, previous study demonstrated that the false positive rate for nodal diagnosis in clinical T1 was very high. To select optimal surgery with high probability, we explored risk factors for false positivity in clinical T1 disease. Methods: Patients who underwent radical gastrectomy for clinical T1 gastric cancer between April 2015 and June 2019 were enrolled. Accuracy, sensitivity, specificity, positive predictive value, and negative predictive values for nodal diagnosis were retrospectively investigated. The risk factors for false positivity were also analyzed by the following factors; age, sex, histological type, tumor size, tumor depth, location, tumor type, presence of ulcer, and timing of CT that is (1) the patients who underwent primary endoscopic mucosal dissection (ESD) but resulted in non-curative resection, then received CT to proceed to surgery (delayed CT group) or (2) the other patients who had received CT before primary surgery or before non-curative ESD (primary CT group). Results: A total of 679 patients were examined in the present study. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 83.5% (567/679), 14.3% (13/91), 94.2% (554/588), 27.7% (13/47), and 87.7% (554/632), respectively. The false positive rate was 72.3% (34/47). In univariate analysis, differentiated tumor ( p= 0.012) and delayed CT (p < 0.001) were associated with the false positivity. Multivariate analysis revealed that delayed CT (OR, 4.534; p < 0.001) was a sole significant risk factor for false positivity. False positive rate was 100% (13/13) in the delayed CT group and 61.8% (21/34) in the primary CT group ( p= 0.009). Conclusions: False positive rate was high in clinical T1 disease, especially when the patients received delayed CT after non-curative ESD. D2 surgery would be unnecessary even though nodal swelling was detected in CT after non-curative ESD.

359 Background: Splenectomy for dissecting splenic hilar nodes (#10) should be avoided for most gastric cancer considering high morbidity and no survival benefit, while that is often selected in scirrhous type of gastric cancer because this special type frequently invades the whole stomach and the #10 nodes. Splenectomy is necessary for dissecting #10, however, survival benefit of dissecting #10 is unclear. Methods: Patients who had scirrhous gastric cancer and underwent D2 total gastrectomy with splenectomy in National Cancer Center Hospital, Japan, between 2000 to 2011 were retrospectively analyzed. The therapeutic value index was calculated by multiplying the metastatic rate of each nodal station and the 5-year survival of patients who had metastasis to each node. Results: In total, 144 patients were eligible for the present study. The most frequent metastatic site was the nodes along the lessar curvature (#3, 57%), followed by the nodes along the right gastro-epiploic artery (#4d, 45%), the right nodes located at the cardia (#1, 34%), the nodes along the left gastro-epiploic artery (#4sb, 23%), the inferior nodes at the pyloric ring (#6, 22%), the nodes along the left gastric artery (#7, 21%), the nodes along the short gastric artery (#4sa, 18%), the nodes along the cardiac branched artery (#2, 15%), the nodes around the spleen (#10, 15%), the distal nodes along the splenic artery (#11d, 15%), the proximal nodes along the splenic artery (#11p, 13%), the nodes around the celiac artery (#9, 13%), and the nodes along the common hepatic artery (#8a, 10%). These lymph nodes had a metastatic rate of more than 10%. The node with the highest index was #3(18), followed by #4d(13.4), #1(9.59), #4sa(5.85), #4sb(5.75), #10(4.86), #7(4.16), #11d(4.16), #11p(3.87), #2(3.07), #8a(2.08), and #9(1.39). The index of #10 was exceeded that of #2, #7, #8a, and #9 which are the key nodes dissected in D2. Conclusions: The metastatic rate of splenic hilar nodes was relatively high, and the therapeutic index was the sixth highest in the fifteen regional lymph nodes included in D2 dissection. Splenectomy for dissecting splenic hilar nodes would be justified in scirrhous type of gastric cancer considering its survival benefit.

Introduction Laparoscopic partial gastrectomy has become a common procedure for gastric submucosal tumors because of its accepted feasibility, safety, and oncologic outcomes. However, long-term postoperative outcomes have not been determined, especially based on the location of submucosal tumors. Methods We reviewed 52 consecutive gastric submucosal tumor patients who underwent laparoscopic partial gastrectomy between 1999 and 2009. They were divided into a lesser curvature group (LC group, n = 23) and a greater curvature group (GC group, n = 26) according to tumor location. We compared the following postoperative data about gastric function between the two groups: (i) body weight change during the first postoperative year; (ii) gastrointestinal symptoms (e.g. abdominal pain/discomfort, bloating, heartburn, and dyspepsia); (iii) the amount of food residue at endoscopy; and (iv) the need for medications such as histamine H2-receptor antagonists, proton pump inhibitors, and prokinetic drugs. Results Only a few patients – one in the LC group and two in the GC group – showed body weight loss (over 10%). Compared to the GC group (n = 0 in all three categories), the LC group showed significantly higher frequency of prolonged postoperative abdominal symptoms (n = 4, P = 0.042), food residue at endoscopic follow-up (n = 4, P = 0.036), and postoperative medication use (n = 5, P = 0.016). Conclusion Patients who received laparoscopic partial gastrectomy did not have severe body weight loss, which suggests dysfunction of the gastric remnant. However, patients in the LC group should receive special attention, as they have a higher risk of developing postoperative gastrointestinal symptoms.

A substantial number of localized gastrointestinal stromal tumor (GIST) patients have recurrences even after complete resection. The risk of recurrence after complete resection should be estimated when considering adjuvant therapy. In this study, we evaluated prognostic factors of GIST recurrence and compared several reported risk-stratification schemes for defining risk of recurrence to guide the use of adjuvant therapy using data from a large Japanese GIST population.We analyzed clinicopathological data collected retrospectively and prospectively from 712 GISTs with complete resection from 1980-2010. We evaluated possible prognostic factors and compared the National Institutes of Health consensus criteria, the Armed Forces Institute of Pathology criteria, Joensuu's modified NIH classification (J-NIHC), the American Joint Committee on Cancer staging system (AJCCS), and the Japanese modified NIH criteria for prediction of tumor recurrence in adjuvant settings.Univariate analysis suggested that the following factors were prognostic: tumor size, mitotic count, site, clinically malignant features of rupture and/or invasion, and gender. In multivariate analysis, size 5 cm, mitotic count 5/50 HPF, non-gastric location, and the presence of rupture and/or macroscopic invasion were independent adverse prognostic factors. When adjuvant therapy is considered for patients with high-risk GIST, the J-NIHC was the most sensitive classification system, while the AJCCS appeared to be the most accurate for predicting recurrence.Tumor size, mitotic count, tumor site, and clinical features of rupture and/or invasion were important prognostic factors for GIST recurrence. Joensuu's classification appeared to best identify candidates for adjuvant therapy.

Background The difficulty in obtaining the latest information on diseases is a challenge of rare cancer care. Rare Cancer Center began to hold seminar sessions entitled: "Meet the Expert on Rare Cancer (MtE)" through collaboration with CancerNet Japan and Oncolo since 2017. During these sessions, doctors with expertise as lecturers explain each type of rare cancer, with the latest information. Each session is video-recorded and shared through video-streaming on a website. A total of 35 MtE sessions were held with cooperation from more than 20 patient support groups. Methods A questionnaire survey was conducted to examine the details of the 35 MtE sessions held within the 2-year period between 2017 and 2018. The study items included: the contents of lectures, number and types of participants, sex ratio, and satisfaction with the seminar. Results The total number of participants during the study period was 1,230. The mean number of participants was 35/session (range: 17 to 53). Participants were mainly patients (41%) and their families (35%). The most frequent reason for participating in the seminar was "to learn about the newest treatment method (66%)", followed by "to obtain accurate information (65%)", and then "to collect information regarding rare cancers, which is not sufficiently available (65%)" Among all participants, 92% were satisfied with the seminar. The total number of views of the videos (31 sessions) already published online was 54,107 as of December 2018. Conclusion The results confirmed that the seminar providing information on rare cancers is markedly needed. As the number of video-streaming views was nearly 50 times larger than that of participants, there may also be a marked potential need for such seminars. As a future perspective, measures to effectively transmit more beneficial and useful information regarding rare cancers will be examined by analyzing responses to this questionnaire and video-streaming view frequencies.

Background Standard first line treatment for metastatic/recurrent gastrointestinal stromal tumor (GIST) is imatinib; however eventually almost all the GISTs become resistant to imatinib. Secondary mutation in KIT is the most relevant cause of imatinib-resistant, as high as 70% of cases. Sunitinib is the current standard second line treatment for imatinib-resistant GIST with median progression-free survival (PFS) of 24.6 weeks; however, in a preclinical study sunitinib is not active for approximately half of secondary mutant GIST. Regorafenib is active for some secondary mutations resistant to sunitinib in the preclinical study. Therefore, we conducted a prospective phase II study of regorafenib as second line therapy for imatinib-resistant GIST. Method Patients with imatinib-resistant metastatic/recurrent GIST were eligible for the current study. Other key inclusion criteria included patients with ECOG performance status of 0-1 and adequate organ function. Patients treated with sunitinib were excluded. The primary endpoint was PFS rate at 24 weeks. Tumor response, safety, and biomarkers were also analyzed. Results A total of 38 patients were enrolled as planned. Median age was 64.5 (39 - 80). Twenty-five patients were male. Primary site was stomach in 17, small intestine in 16. Best overall response was PR for 5 (13%), SD for 24 (63%) and PD for 6 (16%) patients, with response rate of 13%. Grade 3 or more adverse events (AE) were observed in 25 (66%) patients. Common grade 3 or more AE were hand-foot syndrome (n = 9), hypertension (n = 9), hepatotoxicity (n = 4), thrombocytopenia (n = 2), and proteinuria (n = 2). There was one treatment-related death (cerebral attack). The primary endpoint of PFS will be presented at the conference. Conclusion Regorafenib demonstrated promising activity in patients with imatinib-resistant GIST as second line therapy with acceptable toxicity.

Background Rare cancers have had a challenge in establishing standard therapies for patients compared to major cancers, due to the lack of basis for clinical studies and investigations. We started a biomarker driven basket/umbrella trial using a “master protocol”, called the MASTER KEY Project, which aims to find more efficient ways to evaluate treatments for rare cancers. Methods The project opened in April 2017 and consists of a prospective registry study part and a multiple clinical trials part. Patients with advanced rare cancers (annual incidence Results As of Feb. 2019, 515 patients were enrolled in the project, and 493 were available for their backgrounds. Most frequent cancer types were: soft tissue sarcomas (33.7%), neuroendocrine tumors (7.3%), tumors of CNS (5.9%), salivary gland tumors (4.5%), etc. 346 patients had next generation sequencing testing results. The most common alterations were TP53 (32.4%), KRAS (10.4%), PIK3CA (9.5%), MDM2 (5.2%), CDK42 (4.9%), CDKN2A (4.9%), and RB1 (4.9%). 278 patients already had 6 months follow-up, and 116 patients received 181 systemic chemotherapy regimens after enrollment. Of those regimens, 25 were biomarker-based therapies, and median progression free survival was 8.1 months compared to 4.8 months with other cytotoxic chemotherapy regimens (Hazard ratio 0.61; 95% confidential interval 0.32-1.07). Conclusions MASTER KEY Project is one of the largest platform trials focused only on rare cancers. The project provided the chance for rare cancer patients to receive biomarker-based treatment, and it showed better prognosis. This is a continuous project aimed to accelerate treatment development for rare cancers, with clinical trials directed towards new drug approvals. Clinical trial identification UMIN000027552. Legal entity responsible for the study The authors. Funding Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Kyorin Pharmaceutical, Novartis Parma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Taiho Pharmaceutical and Takeda Pharmaceutical. Disclosure All authors have declared no conflicts of interest.

e14532 Background: In April 2017, MASTER KEY Project, composed of a prospective registry study part and a multiple clinical trials part, was established to promote treatment development for rare cancers, which is lacking standard or investigational therapeutic options. Circulating tumor DNA (ctDNA) analysis by next-generation sequencing (NGS) has provided new insight into personalized medicine in a more accessible, non-invasive manner; however, most reports are focused on common cancers. We report genetic alterations detected by ctDNA NGS analysis in rare solid cancers. Methods: Prospectively consented patients (pts), also enrolled in MASTER KEY registry study, had ctDNA NGS testing at a CLIA-certified lab (Guardant360) for point mutations, indels, copy number amplifications, fusions, and microsatellite instability. Alterations were assessed for incidence according to cancer type, functional impact, therapeutic implications, and comparison with tissue NGS. Main inclusion criteria: 1) age ≥16, 2) histological diagnosis of rare cancer (annual incidence less than 6 cases per 100,000 population), cancer of unknown primary (CUP), or rare tissue subtypes of common cancers, 3) active metastatic / unresectable cancer, 4) a written consent. Results: From Nov. 2018 to Jan 2019, 50 pts had Guardant360 testing. Diseases included: soft tissue sarcoma (28), ovarian carc. (7), CUP (4), salivary gland tumor (3), thyroid carc. (2), GIST (1), adrenal cortical carc. (1), rare subtype of GI tract (1), malignant mesothelioma (1), nephroblastoma (1), NET (1), NUT carc. (1). All Japanese, male/female = 14/36, median age 61, ECOG performance status 0/1/2/3 = 30/19/0/1. 76% of pts (38/50) had ≥1 alteration detected, with median number of 2 alterations (range: 0-9), with VAF(0.1-60.3%); 87%(33/38) of those pts had a variant most likely pathogenic; 61% (20/33) of those pts had a variant potential for clinical action. Mean TAT was 10.3 days. 19 pts had tissue NGS testing and in 3 pts, alterations were detected by ctDNA NGS but not by tissue NGS. Updated results of 100 patients will be presented at the conference. Conclusions: Most rare cancer patients with advanced disease had a detectable genomic alteration by Guardant360. Clinical trial information: UMIN000034394.

The intracorporeal anastomosis is one of the most difficult procedures in single-incision laparoscopic gastrectomy for gastric cancer. We describe a simple technique for intracorporeal triangular Billroth I anastomosis in transumbilical single-port surgery. After adequate lymphadenectomy, the stomach and duodenum were staple-transected. Small incisions were made to the remnant stomach and the duodenum. The anvil of a linear stapler and a staple compartment were inserted through the holes, and then both ends were stitched up together by stapler. This staple line would be the bottom of the triangular anastomosis. The second and third lines were created by closure of the common hole and with simultaneous removal of three staple lines (stumps of the stomach and duodenum and the ventral side of the first anastomosis) using two linear staplers, respectively, completing the triangular anastomosis. We performed this technique in 45 patients between March and December 2011. All procedures were completed in single-port approaches. There were no postoperative anastomotic complications such as anastomotic leak and stricture. The median postoperative hospital stay was 7 days. Our technique for intracorporeal Billroth I reconstruction is safe and feasible. This technique could be a useful surgical option in all laparoscopic reconstructive procedures using linear stapling devices.

Background and Objectives Any gastrointestinal stromal tumors (GISTs) larger than 10 cm are classified as “high risk” according to the modified National Institutes of Health consensus criteria. We conducted a multicenter study to identify a subgroup with moderate prognosis even within the “high-risk” group. Methods We retrospectively collected data on 107 patients with tumors ≥10 cm from a multicenter database of GIST patients. Patients with macroscopic residual lesions or tumor rupture were excluded. The relationship between recurrence-free survival (RFS) and clinicopathological factors was analyzed. Results The median tumor size and mitotic count were 12.5 cm and 8/50 HPF. The RFS rate was 58.5% at 3 years, 52.1% at 5 years. Only mitotic count was an independent prognostic factor of RFS in the multivariate analysis (P = 0.001). The hazard ratio for recurrence in the subgroup with mitotic count >5/50 HPF was 2.91 (95% confidence interval, 1.53 to 5.56). The subgroup with mitotic count ≤5/50 HPF showed significantly better RFS than the mitotic count >5/50 HPF subgroup (P