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BackgroundRegorafenib improves overall survival (OS) of patients with advanced progressive gastrointestinal stromal tumors (GISTs) after standard chemotherapy in phase III trials in the 3rd-line setting. This large-scale, prospective observational study evaluated the safety and effectiveness of regorafenib in Japanese patients with GIST in a real-world clinical setting.MethodsPatients with GIST received oral regorafenib at a maximum daily dose of 160 mg for weeks 1–3 of each 4-week cycle (dose could be modified at investigator’s discretion). The primary objective was to assess safety, particularly significant adverse drug reactions (ADRs), as well as the frequency of occurrence of ADRs, hand and foot syndrome (HFS), discontinuation of treatment due to disease progression and adverse events. A Cox proportional hazards model was used to evaluate associations between OS or time to treatment failure (TTF) and baseline characteristics or HFS.ResultsBetween August 2013 and March 2021, 143 evaluable patients were enrolled. ADRs occurred in 90.2% of patients and led to treatment discontinuation in 28.3%. The most frequent ADRs were HFS, hypertension, and liver injury. The overall response rate was 11.3% and disease control rate 56.5% (RECIST) based on investigators’ assessments. Median OS was 17.4 months (95% CI 14.24–23.68). Median TTF was 5.3 (95% CI 4.0–6.5) months. Improved OS and TTF responses occurred in patients with an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1.ConclusionThe outcomes in this real-world study were consistent with those seen in clinical trials. No new safety concerns were identified.Clinical trial registrationhttps://clinicaltrials.gov, identifier NCT01933958.

Abstract Aim Tumor rupture has been indicated as a risk factor for recurrence of gastrointestinal stromal tumors (GISTs). The universal definition of tumor rupture was proposed. This study evaluated whether the universal definition was more accurate in identification of GISTs with high recurrent risk than subjective judgment. Methods The study included 507 patients with high‐risk GISTs who underwent complete resection between December 2012 and December 2015. We conducted a questionnaire survey in participating institutes to re‐diagnose tumor rupture based on the universal definition according to their surgical and pathological findings. We compared the clinical outcomes of tumor rupture based on the definition to those based on the surgeon's judgment and clarified the clinical importance of the rupture. Results Sixty‐four patients were initially registered to have tumor rupture by surgeon's judgment, and it became 90 patients who had tumor rupture after reevaluation. Although there were significant differences in recurrence‐free survival (RFS) between no rupture and rupture for both initial registration and reevaluation (p = 0.002,

Abstract Background Familial gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the digestive tract caused by germline gain-of-function mutations in the KIT gene or platelet-derived growth factor receptor alpha gene (PDGFRA). These mutations cause not only multiple GISTs but also diffuse hyperplasia of interstitial cells of Cajal (ICCs), which is related to esophageal motility disorder. Case presentation A 53-year-old man was referred to our hospital because of anemia and dysphagia. Fifteen years earlier, he had undergone a laparoscopic partial gastrectomy for multiple gastric GISTs with a germline mutation in exon 17 of the KIT gene. An upper gastrointestinal endoscopy revealed that the patient had multiple gastric GISTs and a large esophageal diverticulum directly above the esophagogastric junction. The largest gastric tumor was 7 cm, with a delle that might cause bleeding. Because the patient presented with dysphagia, we performed video-assisted thoracic esophagectomy and laparoscopic-assisted proximal gastrectomy simultaneously. The patient had survived without metastasis for 4 years after surgery and dysphagia had improved. Conclusions This is the first report of successful laparoscopic–thoracoscopic surgery for a patient with familial gastric GISTs accompanied with a large esophageal diverticulum.

Abstract Tyrosine kinase inhibitors (TKIs) improve the prognosis of patients with gastrointestinal stromal tumors (GISTs). We conducted a retrospective cohort study using cancer registries linked with health utilization data in Japan and Taiwan to assess TKI usage in older and non-older patients. Patients diagnosed with GIST (2012–2014) were categorized into the following: adjuvant and advanced/metastatic settings. The duration and patterns of imatinib therapy were compared between the older (aged ≥ 75 years) and non-older (

Summary: Most gastrointestinal stromal tumors (GISTs) develop due to gain-of-function mutations in the tyrosine kinase gene, KIT. We recently showed that mutant KIT mislocalizes to the Golgi area and initiates uncontrolled signaling. However, the molecular mechanisms underlying its Golgi retention remain unknown. Here, we show that protein kinase D2 (PKD2) is activated by the mutant, which causes Golgi retention of KIT. In PKD2-inhibited cells, KIT migrates from the Golgi region to lysosomes and subsequently undergoes degradation. Importantly, delocalized KIT cannot trigger downstream activation. In the Golgi/trans-Golgi network (TGN), KIT activates the PKD2-phosphatidylinositol 4-kinase IIIβ (PKD2-PI4KIIIβ) pathway through phospholipase Cγ2 (PLCγ2) to generate a PI4P-rich membrane domain, where the AP1-GGA1 complex is aberrantly recruited. Disruption of any factors in this cascade results in the release of KIT from the Golgi/TGN. Our findings show the molecular mechanisms underlying KIT mislocalization and provide evidence for a strategy for inhibition of oncogenic signaling.

Abstract Background Most gastrointestinal stromal tumors (GIST) harbor a mutation in KIT or platelet‐derived growth factor receptor alfa (PDGFRA). Although genotyping is a useful predictive marker of tyrosine kinase inhibitors, whether it can predict prognosis remains controversial. Methods Data on 402 patients with GIST who underwent macroscopically complete surgery and received no neoadjuvant/adjuvant therapy were selected from a prospective GIST database at the three, participating hospitals. The types and locations of KIT and PDGFRA mutations were analyzed by direct sequencing of the amplified genes. The association between the genotypic characteristics and prognosis was then examined. Results Tumor genotypes were analyzed in 398 of 402 (99%) patients, and 120 mutation patterns were identified. KIT mutations had broad malignancy potential which differed according to the type of mutation. Deletion and deletion‐insertion type mutations were associated with worse RFS while duplication and substitution type mutations were associated with favorable RFS KIT deletion/deletion‐insertion, including codons 557 and 558, were especially associated with worse RFS on multivariate analysis both of all the patients and those with KIT mutations. Conclusions Specific GIST genotypes were significantly associated with a risk of recurrence. Genotype analysis may be useful for predicting the prognosis and determining the indications for adjuvant imatinib in patients with GIST.

Abstract 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.

Abstract 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

Abstract 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.

Abstract Background KIT tyrosine kinase is expressed in mast cells, interstitial cells of Cajal, and hematopoietic cells. Permanently active KIT mutations lead these host cells to tumorigenesis, and to such diseases as mast cell leukemia (MCL), gastrointestinal stromal tumor (GIST), and acute myeloid leukemia (AML). Recently, we reported that in MCL, KIT with mutations (D816V, human; D814Y, mouse) traffics to endolysosomes (EL), where it can then initiate oncogenic signaling. On the other hand, KIT mutants including KITD814Y in GIST accumulate on the Golgi, and from there, activate downstream. KIT mutations, such as N822K, have been found in 30% of core binding factor-AML (CBF-AML) patients. However, how the mutants are tyrosine-phosphorylated and where they activate downstream molecules remain unknown. Moreover, it is unclear whether a KIT mutant other than KITD816V in MCL is able to signal on EL. Methods We used leukemia cell lines, such as Kasumi-1 (KIT N822K , AML), SKNO-1 (KIT N822K , AML), and HMC-1.1 (KIT V560G , MCL), to explore how KIT transduces signals in these cells and to examine the signal platform for the mutants using immunofluorescence microscopy and inhibition of intracellular trafficking. Results In AML cell lines, KITN822K aberrantly localizes to EL. After biosynthesis, KIT traffics to the cell surface via the Golgi and immediately migrates to EL through endocytosis in a manner dependent on its kinase activity. However, results of phosphorylation imaging show that KIT is preferentially activated on the Golgi. Indeed, blockade of KITN822K migration to the Golgi with BFA/M-COPA inhibits the activation of KIT downstream molecules, such as AKT, ERK, and STAT5, indicating that KIT signaling occurs on the Golgi. Moreover, lipid rafts in the Golgi play a role in KIT signaling. Interestingly, KITV560G in HMC-1.1 migrates and activates downstream in a similar manner to KITN822K in Kasumi-1. Conclusions In AML, KITN822K mislocalizes to EL. Our findings, however, suggest that the mutant transduces phosphorylation signals on lipid rafts of the Golgi in leukemia cells. Unexpectedly, the KITV560G signal platform in MCL is similar to that of KITN822K in AML. These observations provide new insights into the pathogenic role of KIT mutants as well as that of other mutant molecules.

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.

Although complications including graft thrombosis, graft pancreatitis, and rejection have been well documented after pancreas transplantation, the occurrence of graft duodenal perforation is uncommon. In this article, we report a case of graft duodenal perforation due to internal hernia after simultaneous pancreas-kidney transplantation (SPK). A patient with type I diabetes mellitus and diabetic nephropathy had undergone SPK from a cadaveric donor. One year later, she was admitted to our hospital for severe lower abdominal pain with preshock status. She was immediately examined by abdominal computed tomography and both peripancreas graft fluid accumulation and severe dilatation of the ileum were detected. On emergency operation, two punched holes located at the graft duodenal side near the suture line and an obstruction of herniated bowel behind the graft pancreas were detected. These holes were repaired and the internal hernia was reduced. However, a control of the intraabdominal infection was very difficult despite intensive treatment with antibiotics and additional abdominal drainage. Finally, a graft pancreatectomy was unavoidably required. When complications, including symptomatic intraabdominal infection, require re-laparotomy after pancreas transplantation, the therapeutic focus should be switched from salvaging the graft to the preservation of life.

Although inflammatory polyposis is one of the common complications in patients with inflammatory bowel disease, it is rare that each poly grows up to more than 1.5 cm. We describe a case of localized giant inflammatory polyposis of the ileocecum associated with Crohn’s disease. A 40-year-old man who had been followed for 28 years because of Crohn’s disease was hospitalized for right lower abdominal pain after meals. Barium enema and colonoscopy showed numerous worm-like polyps in the ascending colon which grew up to the hepatic flexure of the colon from the ileocecum, causing an obstruction of the ileocecal orifice. Since histology of a biopsy specimen taken from the giant polyps showed no dysplasia, he was diagnosed with ileus due to the localized giant inflammatory polyposis. A laparoscopically assisted ileocecal resection was performed. The resected specimen showed that the giant polyps grew up into the ileocecum. Histological examination revealed inflammatory polyposis without neoplasm. Generally, conservative treatment is indicated for localized giant inflammatory polyposis because this lesion is regarded as benign. However, occasionally serious complications arise, requiring surgical treatment.

Dysregulation of microRNA (miRNA) has been implicated in gastrointestinal stromal tumors (GISTs) but the mechanism is not fully understood. In this study, we aimed to explore the involvement of epigenetic alteration of miRNA genes in GISTs.GIST-T1 cells were treated with 5-aza-2'-deoxycytidine (5-aza-dC) and 4-phenylbutyric acid (PBA), after which miRNA expression profiles were analyzed using TaqMan miRNA arrays. DNA methylation was then analyzed using bisulfite pyrosequencing. The functions of miRNAs were examined using MTT assays, wound-healing assays, Boyden chamber assays and Matrigel invasion assays. Gene expression microarrays were analyzed to assess effect of ectopic miRNA expression in GIST-T1 cells.Of the 754 miRNAs analyzed, 61 were significantly upregulated in GIST-T1 cells treated with 5-aza-dC plus PBA. Among those, 21 miRNA genes were associated with an upstream CpG island (CGI), and the CGIs of miR-34a and miR-335 were frequently methylated in GIST-T1 cells and primary GIST specimens. Transfection of miR-34a or miR-335 mimic molecules into GIST-T1 cells suppressed cell proliferation, and miR-34a also inhibited migration and invasion by GIST-T1 cells. Moreover, miR-34a downregulated a number of predicted target genes, including PDGFRA. RNA interference-mediated knockdown of PDGFRA in GIST-T1 cells suppressed cell proliferation, suggesting the tumor suppressive effect of miR-34a is mediated, at least in part, through targeting PDGFRA.Our results suggest that miR-34a and miR-335 are candidate tumor suppressive miRNAs in GISTs, and that they are frequent targets of epigenetic silencing in GISTs.

Purpose. This retrospective, nonrandomized study investigated the effect of imatinib rechallenge plus best supportive care (BSC) on overall survival after imatinib and sunitinib treatment for patients with locally advanced or metastatic gastrointestinal stromal tumor (GIST). Methods. Twenty-six patients who had previously been exposed to both imatinib and sunitinib were enrolled in this study. The treatment regimen was BSC with or without imatinib, based on the patient’s choice after discussion with his or her physician. The primary endpoint was overall survival, and secondary endpoints were time to treatment failure, clinical response rate assessed by Choi criteria, and safety. Results. Fourteen patients were treated with imatinib plus BSC and 12 received BSC alone. Median overall survival was greatly improved for the imatinib group, although differences were not significant (22 months for imatinib plus BSC versus 4 months for BSC; P=0.058). Three patients (21%) had a clinical response in the imatinib group, and one had a clinical response in the BSC alone group. Imatinib was well tolerated. Conclusions. Rechallenge with imatinib may be associated with improvement in overall survival without deteriorating performance status in patients who failed imatinib and sunitinib. A prospective study should be considered to confirm the efficacy of rechallenge with imatinib.

Histological diagnosis of sarcomas (malignant bone and soft tissue tumors) is challenging due to their rarity, morphological diversity, and constantly evolving diagnostic criteria. In this study, we aimed to assess the concordance in histological diagnosis of bone and soft tissue tumors between referring hospitals and a tertiary sarcoma center and analyzed the clinical impact of the diagnostic alteration. We analyzed 628 consecutively accessioned specimens from 624 patients who visited a specialized sarcoma center for treatment. The diagnoses at referring hospitals and those at the sarcoma center were compared and classified into four categories: agreed, disagreed, specified, and de‐specified. Of the 628 specimens, the diagnoses agreed in 403 (64.2%) specimens, whereas some changes were made in 225 (35.8%) specimens: disagreed in 153 (24.3%), specified in 52 (8.3%), and de‐specified in 20 (3.2%) cases. The benign/intermediate/malignant judgment changed for 92 cases (14.6%). The diagnostic change resulted in patient management modification in 91 cases (14.5%), including surgical and medical treatment changes. The main inferred reason for the diagnostic discrepancies was a different interpretation of morphological findings of the tumor, which accounted for 48.9% of the cases. This was followed by the unavailability of specialized immunohistochemical antibodies and the unavailability of genetic analysis. In summary, our study clarified the actual clinical impact of diagnostic discrepancy in bone and soft tissue tumors. This may underscore the value of pathology consultation, facilitating access to specialized diagnostic tools, and continued education. These measures are expected to improve diagnostic precision and ultimately benefit patients. [ABSTRACT FROM AUTHOR]