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Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the human gastrointestinal tract, differentiating toward the interstitial cell of Cajal (ICC), arises predominantly in the stomach and small intestine. Small intestinal GISTs appear to have worse prognosis than gastric GISTs. In a pilot study of a cDNA expression chip using several GISTs, we found that Cell Adhesion Molecule 1 (CADM1), which could contribute to tumor growth and infiltration, is expressed more strongly in small intestinal GISTs than gastric GISTs. In the present study, we examined CADM1 expression in GISTs of different sites and with different gene abnormalities using a large number of gastric and small intestinal GISTs. First, immunoblotting confirmed significantly higher CADM1 expression in small intestinal GISTs with exon 11 c-kit mutation than gastric GISTs with exon 11 c-kit mutation. Real-time PCR also revealed that small intestinal GISTs with exon 11 c-kit mutation showed significantly higher CADM1 mRNA than gastric GISTs with exon 11 c-kit mutation. Although most small intestinal GISTs showed high CADM1 mRNA expression regardless of gene abnormality types, different CADM1 expression was detected between gastric GISTs with c-kit mutation and those with PDGFRA mutation. Immunohistochemistry showed that many small intestinal GISTs were CADM1-positive but most gastric GISTs CADM1-negative or -indefinite. In the normal gastric and small intestinal walls, immunoreactivity of CADM1 was detected only in nerves, but neither in gastric ICCs nor small intestinal ICCs, indicating that the high CADM1expression in small intestinal GISTs might be acquired during tumorigenesis. Different CADM1 expression between gastric and small intestinal GISTs might be related to different prognoses between them. Further functional experiments are needed to elucidate the role of CADM1 on GIST biology, and there is a possibility that targeting therapy against CADM1 has a preventive effect for tumor spreading in small intestinal GISTs.

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.

FMS-like tyrosine kinase 3 (FLT3) in hematopoietic cells binds to its ligand at the plasma membrane (PM), then transduces growth signals. FLT3 gene alterations that lead the kinase to assume its permanently active form, such as internal tandem duplication (ITD) and D835Y substitution, are found in 30–40% of acute myelogenous leukemia (AML) patients. Thus, drugs for molecular targeting of FLT3 mutants have been developed for the treatment of AML. Several groups have reported that compared with wild-type FLT3 (FLT3-wt), FLT3 mutants are retained in organelles, resulting in low levels of PM localization of the receptor. However, the precise subcellular localization of mutant FLT3 remains unclear, and the relationship between oncogenic signaling and the mislocalization is not completely understood. In this study, we show that in cell lines established from leukemia patients, endogenous FLT3-ITD but not FLT3-wt clearly accumulates in the perinuclear region. Our co-immunofluorescence assays demonstrate that Golgi markers are co-localized with the perinuclear region, indicating that FLT3-ITD mainly localizes to the Golgi region in AML cells. FLT3-ITD biosynthetically traffics to the Golgi apparatus and remains there in a manner dependent on its tyrosine kinase activity. Tyrosine kinase inhibitors, such as quizartinib (AC220) and midostaurin (PKC412), markedly decrease FLT3-ITD retention and increase PM levels of the mutant. FLT3-ITD activates downstream in the endoplasmic reticulum (ER) and the Golgi apparatus during its biosynthetic trafficking. Results of our trafficking inhibitor treatment assays show that FLT3-ITD in the ER activates STAT5, whereas that in the Golgi can cause the activation of AKT and ERK. We provide evidence that FLT3-ITD signals from the early secretory compartments before reaching the PM in AML cells.

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.

Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the human gastrointestinal tract, differentiating toward the interstitial cell of Cajal (ICC), arises predominantly in the stomach and small intestine. Small intestinal GISTs appear to have worse prognosis than gastric GISTs. In a pilot study of a cDNA expression chip using several GISTs, we found that Cell Adhesion Molecule 1 (CADM1), which could contribute to tumor growth and infiltration, is expressed more strongly in small intestinal GISTs than gastric GISTs. In the present study, we examined CADM1 expression in GISTs of different sites and with different gene abnormalities using a large number of gastric and small intestinal GISTs. First, immunoblotting confirmed significantly higher CADM1 expression in small intestinal GISTs with exon 11 c-kit mutation than gastric GISTs with exon 11 c-kit mutation. Real-time PCR also revealed that small intestinal GISTs with exon 11 c-kit mutation showed significantly higher CADM1 mRNA than gastric GISTs with exon 11 c-kit mutation. Although most small intestinal GISTs showed high CADM1 mRNA expression regardless of gene abnormality types, different CADM1 expression was detected between gastric GISTs with c-kit mutation and those with PDGFRA mutation. Immunohistochemistry showed that many small intestinal GISTs were CADM1-positive but most gastric GISTs CADM1-negative or -indefinite. In the normal gastric and small intestinal walls, immunoreactivity of CADM1 was detected only in nerves, but neither in gastric ICCs nor small intestinal ICCs, indicating that the high CADM1expression in small intestinal GISTs might be acquired during tumorigenesis. Different CADM1 expression between gastric and small intestinal GISTs might be related to different prognoses between them. Further functional experiments are needed to elucidate the role of CADM1 on GIST biology, and there is a possibility that targeting therapy against CADM1 has a preventive effect for tumor spreading in small intestinal GISTs.

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.

Most gastrointestinal stromal tumours (GISTs) are caused by constitutively active mutations in Kit tyrosine kinase. The drug imatinib, a specific Kit inhibitor, improves the prognosis of metastatic GIST patients, but these patients become resistant to the drug by acquiring secondary mutations in the Kit kinase domain. We recently reported that a Kit mutant causes oncogenic signals only on the Golgi apparatus in GISTs. In this study, we show that in GIST, 2-methylcoprophilinamide (M-COPA, also known as "AMF-26"), an inhibitor of biosynthetic protein trafficking from the endoplasmic reticulum (ER) to the Golgi, suppresses Kit autophosphorylation at Y703/Y721/Y730/Y936, resulting in blockade of oncogenic signalling. Results of our M-COPA treatment assay show that Kit Y703/Y730/Y936 in the ER are dephosphorylated by protein tyrosine phosphatases (PTPs), thus the ER-retained Kit is unable to activate downstream molecules. ER-localized Kit Y721 is not phosphorylated, but not due to PTPs. Importantly, M-COPA can inhibit the activation of the Kit kinase domain mutant, resulting in suppression of imatinib-resistant GIST proliferation. Our study demonstrates that Kit autophosphorylation is spatio-temporally regulated and may offer a new strategy for treating imatinib-resistant GISTs.

A drug delivery system (DDS) is a method for delivering a drug to its site of action in the body, with the goal of achieving therapeutic benefits while reducing adverse effects. Pharmacokinetics (PK) and pharmacodynamics (PD) studies have been conducted to evaluate drug delivery, but these approaches are rarely used in the early stages of drug discovery and development. We demonstrated that the tumor stromal barrier inhibits drug distribution within tumor tissue, especially in refractory cancers such as pancreatic cancer. This poses an obstacle to the discovery of new drugs, and is difficult to overcome using conventional in vitro drug discovery methods. In addition, we are also developing new DDS drugs and antibody-drug conjugates (ADCs). These agents act via four steps: Systemic circulation, the enhanced permeability and retention (EPR) effect, penetration within the tumor tissue, and action on cells including controlled drug release. Most of these activities can be evaluated by conventional biological or pharmacological assays. However, it is difficult to examine drug distribution and controlled drug release within targeted tissues. Recent advances in mass spectrometry imaging (MSI) allow examining drug delivery much more conveniently with the off-labeling. A mass microscope, a new type of matrix-associated laser desorption/ionization (MALDI)-MSI analyzer, is a microscope coupled with an atmospheric MALDI and quadruple ion trap time-of-flight (TOF) mass spectrometer, and can provide imaging data with enhanced resolution and high sensitivity. Using a mass microscope, we succeeded in visualizing the EPR effect of a polymeric micelle drug and controlled drug release by an ADC. Currently, we are developing a new drug imaging method using electrospray ionization (ESI)-MSI. Here, we review the use of MSI in early stages of drug discovery and development, as well as our related recent work.

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.

Gastrointestinal stromal tumors (GISTs) are caused by gain-of-function mutations in the Kit receptor tyrosine kinase. Most primary GIST patients respond to the Kit inhibitor imatinib, but this drug often becomes ineffective because of secondary mutations in the Kit kinase domain. The characteristic intracellular accumulation of imatinib-sensitive and -resistant Kit protein is well documented, but its relationship to oncogenic signaling remains unknown. Here, we show that in cancer tissue from primary GIST patients as well as in cell lines, mutant Kit accumulates on the Golgi apparatus, whereas normal Kit localizes to the plasma membrane (PM). In imatinib-resistant GIST with a secondary Kit mutation, Kit localizes predominantly on the Golgi apparatus. Both imatinib-sensitive and imatinib-resistant Kit (Kit(mut)) become fully auto-phosphorylated only on the Golgi and only if in a complex-glycosylated form. Kit(mut) accumulates on the Golgi during the early secretory pathway, but not after endocytosis. The aberrant kinase activity of Kit(mut) prevents its export from the Golgi to the PM. Furthermore, Kit(mut) on the Golgi signals and activates the phosphatidylinositol 3-kinase–Akt (PI3K–Akt) pathway, signal transducer and activator of transcription 5 (STAT5), and the Mek–Erk pathway. Blocking the biosynthetic transport of Kit(mut) to the Golgi from the endoplasmic reticulum inhibits oncogenic signaling. PM localization of Kit(mut) is not required for its signaling. Activation of Src-family tyrosine kinases on the Golgi is essential for oncogenic Kit signaling. These results suggest that the Golgi apparatus serves as a platform for oncogenic Kit signaling. Our study demonstrates that Kit(mut)’s pathogenicity is related to its mis-localization, and may offer a new strategy for treating imatinib-resistant GISTs.

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.

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.

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.

823 Background: Imatinib is a standard first line treatment for advanced gastrointestinal stromal tumor (GIST); 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 standard of care 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 mutations. Regorafenib is active for some secondary mutations resistant to sunitinib in the preclinical study. Therefore, we conducted a phase II study evaluating regorafenib for imatinib-resistant GIST. Methods: Patients with imatinib-resistant advanced GIST were enrolled. Key eligibility criteria were ECOG PS of 0-1 and adequate organ function. Prior exposure of sunitinib was not allowed. The primary endpoint was PFS rate at 24 weeks. ctDNA for KIT was evaluated prior to regorafenib administration. 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. Median PFS was 36.3 weeks and PFS rate at 24 weeks was 47.4% (primary endpoint was not met). Best overall response was PR for 6 (16 %), SD for 25 (63 %) and PD for 5 (13 %) patients. Grade 3 or more adverse events (AE) were observed in 25 (66 %) patients. Common grade 3 or more AE were hand-foot-skin reaction (n = 9), hypertension (n = 9), hepatotoxicity (n = 4). ctDNA was evaluated in 32 patients and among them secondary mutations were observed in 15 patients (47%). PFS was shorter (15.6 weeks) in patients with exon 13 mutation than that in patients without second mutation (49.3 weeks, not statistically significant). Conclusions: Regorafenib demonstrated favorable activity in patients with imatinib-resistant GIST as second line therapy with acceptable toxicity. Secondary mutation in KIT might be a predictor of the efficacy of regorafenib. Clinical trial information: UMIN000016115.

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.

The frameworks providing cancer genome medicine in the real world have been implemented under the government initiatives. In April 2018, 11 Designated Core Hospitals for Cancer Genomic Medicine and 100 Cooperative Hospitals for Cancer Genomic Medicine were designated. In the Cooperative Hospitals, the specimens may be submitted to the genetic testing after informed consent from cancer patients who wishes to have cancer genome medicine. On completion of the genetic testing, attending physicians should participate in the expert panel held at the Designated Core Hospitals to decide the recommended treatment, which may be done under patients' consent. The Designated Core Hospitals, in addition, are required to conduct multiple-gene panel testing(outsourcing is acceptable), to hold the regular expert panel to decide the recommended treatment based on annotation information, to mainly conduct investigator-initiated clinical trial and advanced medical care B, to nurture specialized human resources involved in cancer genome medicine, and to provide clinical support for the Cooperative Hospitals to conduct cancer genome medicine when necessary. Genomic and clinical information may be centralized from these hospitals and institutes to the Center for Cancer genomics and Advanced Therapeutics(C-CAT)to develop new knowledge databases of Japanese cancer patients as well as to develop brand new medicines in future.

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.

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.

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.

After the revelation of kinase targeting with orally available small molecules, the use of imatinib in chronic myelogenous leukemia and in gastrointestinal stromal tumor (GIST) has now become commonplace and just two of many examples of the use of kinase inhibitors in cancer. In this article, we discuss important practice points that may impact upon questions of therapy of primary and metastatic GIST, with the hope that the questions addressed in this rare solid tumor can serve as examples of what can be achieved with kinase-directed therapies in other cancers. We present cases that highlight some of the key issues in GIST management and afterward discuss both points of consensus and controversial issues in what is now recognized as one of the most common forms of sarcoma. Implications for Practice: The treatment of gastrointestinal stromal tumor (GIST) has become sophisticated with the availability of three approved agents in many countries and 15 years of experience with primary and metastatic disease. Important lessons from tyrosine-kinase inhibitors in GIST can be gleaned from this experience and will impact implementation of similar agents for other cancers.

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.

Purpose Mutated KIT and platelet-derived growth factor alpha gene (PDGFRA) drive GI stromal tumor (GIST) oncogenesis, but the clinical significance of their single mutations is known incompletely. Patients and Methods We identified 11 population-based series of patients with GIST through a literature search and pooled individual data from 3,067 patients treated with macroscopically complete tumor excision. Mutation analysis was done from 1,505 tumors. We analyzed associations between KIT and PDGFRA mutations and recurrence-free survival (RFS) in the subsets in which patients were treated with surgery alone. Results We identified 301 different single mutations in KIT and 33 in PDGFRA. Patients with PDGFRA mutations had more favorable RFS than those with KIT mutations (hazard ratio, 0.34; P = .004). Only one of the 35 GISTs with KIT exon 11 duplication mutations recurred. Patients with deletions of only one codon of KIT exon 11 had better RFS than those with another deletion type, and some KIT exon 11 substitution mutations (Trp557Arg, Val559Ala, and Leu576Pro) were also associated with favorable RFS. Patients with an identical mutation had greatly variable outcomes depending on the standard prognostic factors, notably, mitotic count. Commonly used risk stratification schemes tended to overestimate the risk for recurrence in subgroups with prognostically favorable mutations. Conclusion GISTs with an identical KIT or PDGFRA mutation may have widely varying risks for recurrence. Most of the patients with PDGFRA mutations and those with KIT exon 11 duplication mutation or deletion of one codon have favorable RFS with surgery alone and are usually not candidates for adjuvant therapy.

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.

Most of the gastrointestinal stromal tumors (GIST) have mutations in the KIT gene, encoding a receptor tyrosine kinase. Imatinib, a receptor tyrosine kinase inhibitor, is the first-line therapy for unresectable and metastatic GISTs. Despite the revolutionary effects of imatinib, some patients are primarily resistant to imatinib and many become resistant because of acquisition of secondary mutations in KIT. This study investigated the antitumor effects of SOCS1 gene therapy, which targets several signaling pathways. We used GIST-T1 (imatinib-sensitive) and GIST-R8 (imatinib-resistant) cells. We infected both cell lines with an adenovirus expressing SOCS1 (AdSOCS1) and examined antitumor effect and mechanisms of its agent. The latter harboured with secondary KIT mutation and had imatinib resistance > 1000-fold higher than the former cells. We demonstrated that AdSOCS1 significantly decreased the proliferation and induced apoptosis in both cell lines. Moreover, SOCS1 overexpression inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), AKT, and focal adhesion kinase (FAK) in both of them. Inhibition of JAK signaling did not affect the proliferation enough. However, inhibition of the FAK signaling with an FAK inhibitor or RNA interference significantly showed inhibitory effect on cell growth and suppressed the phosphorylation of AKT, indicating a cross-talk between the AKT and FAK pathways in both the imatinib-sensitive and imatinib-resistant GIST cells. Our results indicate that the activation of FAK signaling is critical for proliferation of both imatinib-sensitive and -resistant GIST cells and the interference with FAK/AKT pathway might be beneficial for therapeutic target.

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.

The characteristics of patients with gastrointestinal stromal tumor(GIST)who need long-term surveillance after resection remain unclear. We investigated the characteristics of 14 patients with GIST who developed recurrence over 5 years after resection. The most common primary tumor site was the stomach, followed by the rectum and small intestine. We found that 58% of patients had low-risk tumors, and 29% of patients developed recurrence over 10 years after resection. The most common first recurrence site was local, followed by the liver and peritoneum. All 4 patients with rectal GIST underwent local resection and developed local recurrence. Late recurrence could be observed even in low-risk tumors. Particularly, patients with rectal GIST frequently developed local recurrence. Thus, postoperative surveillance should be considered depending on operative or pathological findings.

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.