A radiation-related second primary gastrointestinal stromal tumor in the bladder.

A 69-year-old man underwent 78 Gy/39 Fr of intensity-modulated radiation therapy for prostate cancer. Seven years after radiotherapy, a nonpapillary bladder tumor was identified. Transurethral resection of the bladder tumor was performed, and the pathological diagnosis was spindle cell sarcoma. Immunostaining revealed KIT-, DOG1++, CD34-, Actin++, Cytokeratin-, Desmin-, S100 protein-, and Vimentin++. No tumor recurrence was observed until 17 months after tumor resection. DOG1 is strongly and specifically expressed in gastrointestinal stromal tumors. This was a rare case of bladder gastrointestinal stromal tumor as a radiation-related second primary tumor.

Structural Analysis of the Colony-Stimulating Factor 3 Gene of Granulocyte Colony-Stimulating Factor-Producing Urothelial Cancer.

Background Granulocyte colony-stimulating factor (G-CSF) is a member of the CSF family of glycoproteins that regulate the proliferation, differentiation, and mobilization of neutrophils. G-CSF-producing malignant cancers have been reported to occur in various organs and are mostly associated with poor clinical prognosis. Here, we analyzed the structure of the CSF3 gene encoding the G-CSF protein to delineate the mechanism of G-CSF production by the cancer cells. Methodology Two cases of G-CSF-producing urothelial cancers and three cases of G-CSF-nonproducing bladder cancers were enrolled for genetic analysis. Results In one case of G-CSF-producing bladder cancer, six somatic mutations were detected in the 5'- upstream region of the CSF3 gene. No somatic mutations in the CSF3 gene were detected in another case of G-CSF-producing renal pelvic cancer and G-CSF-nonproducing bladder cancers. Copy numbers of the CSF3 gene were not increased in G-CSF-producing urothelial cancers. Conclusions Somatic mutations in the 5'- upstream region of the CSF3 gene may cause G-CSF protein overproduction.

Combination therapy with anti-programmed cell death 1 antibody plus angiokinase inhibitor exerts synergistic antitumor effect against malignant mesothelioma via tumor microenvironment modulation.

Malignant pleural mesothelioma (MPM) is an asbestos-related fatal malignant neoplasm. Although there has been no reliable chemotherapeutic regimen other than combination therapy of cisplatin and pemetrexed for two decades, combination of ipilimumab plus nivolumab brought about a better outcome in patients with MPM. Thus, cancer immunotherapy using immune checkpoint inhibitor (ICI) is expected to play a central role in the treatment of MPM. To maximize the antitumor effect of ICI, we evaluated whether nintedanib, an antiangiogenic agent, could augment the antitumor effect of anti-programmed cell death 1 (PD-1) antibody (Ab). Although nintedanib could not inhibit the proliferation of mesothelioma cells in vitro, it significantly suppressed the growth of mesothelioma allografts in mice. Moreover, combination therapy with anti-PD-1 Ab plus nintedanib reduced tumor burden more dramatically compared with nintedanib monotherapy via inducing remarkable necrosis in MPM allografts. Nintedanib did not promote the infiltration of CD8+ T cells within the tumor when used alone or in combination with anti-PD-1 Ab but it independently decreased the infiltration of tumor-associated macrophages (TAMs). Moreover, immunohistochemical analysis and ex vivo study using bone marrow-derived macrophages (BMDMs) showed that nintedanib could polarize TAMs from M2 to M1 phenotype. These results indicated that nintedanib had a potential to suppress protumor activity of TAMs both numerically and functionally. On the other hand, ex vivo study revealed that nintedanib upregulated the expression of PD-1 and PD-ligand 1 (PD-L1) in BMDMs and mesothelioma cells, respectively, and exhibited the impairment of phagocytic activity of BMDMs against mesothelioma cells. Co-administration of anti-PD-1 Ab may reactivate phagocytic activity of BMDMs by disrupting nintedanib-induced immunosuppressive signal via binding between PD-1 on BMDMs and PD-L1 on mesothelioma cells. Collectively, combination therapy of anti-PD-1 Ab plus nintedanib enhances the antitumor activity compared with respective monotherapy and can become a novel therapeutic option for patients with MPM.

Membrane-Fluidization-Dependent and -Independent Pathways Are Involved in Heat-Stress-Inducible Gene Expression in the Marine Red Alga Neopyropia yezoensis.

Heat stress responses are complex regulatory processes, including sensing, signal transduction, and gene expression. However, the exact mechanisms of these processes in seaweeds are not well known. We explored the relationship between membrane physical states and gene expression in the red alga Neopyropia yezoensis. To analyze heat-stress-induced gene expression, we identified two homologs of the heat-inducible high temperature response 2 (HTR2) gene in Neopyropia seriata, named NyHTR2 and NyHTR2L. We found conservation of HTR2 homologs only within the order Bangiales; their products contained a novel conserved cysteine repeat which we designated the Bangiales cysteine-rich motif. A quantitative mRNA analysis showed that expression of NyHTR2 and NyHTR2L was induced by heat stress. However, the membrane fluidizer benzyl alcohol (BA) did not induce expression of these genes, indicating that the effect of heat was not due to membrane fluidization. In contrast, expression of genes encoding multiprotein-bridging factor 1 (NyMBF1) and HSP70s (NyHSP70-1 and NyHSP70-2) was induced by heat stress and by BA, indicating that it involved a membrane-fluidization-dependent pathway. In addition, dark treatment under heat stress promoted expression of NyHTR2, NyHTR2L, NyMBF1, and NyHSP70-2, but not NyHSP70-1; expression of NyHTR2 and NyHTR2L was membrane-fluidization-independent, and that of other genes was membrane-fluidization-dependent. These findings indicate that the heat stress response in N. yezoensis involves membrane-fluidization-dependent and -independent pathways.

Selection of AVP-Shortage Patients as Candidates for Low-Dose Oral Desmopressin Administration.

OBJECTIVE: We herein attempted to select male patients with an elevated nocturnal urinary frequency possibly due to a shortage of AVP. These patients may be good candidates for low-dose oral desmopressin administration. PATIENTS AND METHODS: Serum and spot urine osmolality, electrolytes, serum creatinine, casual blood glucose, plasma brain natriuretic polypeptide (BNP), and plasma AVP were measured at the same time in 97 elderly male patients with urinary symptoms under free water drinking. RESULTS: A binary plot of plasma AVP and serum osmolality indicated a region at which patients had relatively lower AVP considering higher serum osmolality. It was tentatively named the desmopressin region. Twenty out of 97 (20.6%) patients were in the desmopressin region. Daily urine output did not exceed 3 L in any patient. Urine osmolality was slightly lower in patients in the desmopressin region. No significant differences were observed in urine volume, urinary frequency, or urination questionnaire scores between both groups. CONCLUSION: AVP-shortage patients may be selected for treatment with oral desmopressin based on measurements of serum osmolality and plasma AVP.

Delayed Intracystic Hemorrhage after Percutaneous Drainage and Sclerotherapy for a Symptomatic Giant Hepatic Cyst: A Case Report.

Herein, we have reported a rare case of intracystic hemorrhage due to rupture of a right hepatic artery pseudoaneurysm in a 76-year-old female patient who underwent drainage and 3% polidocanol sclerotherapy for a symptomatic giant hepatic cyst. One month after sclerotherapy, the patient presented to the emergency room with acute and severe abdominal pain. Non-contrast T1-weighted magnetic resonance imaging findings showed high hepatic cyst fluid signal intensity and abdominal arteriography findings revealed a right hepatic artery pseudoaneurysm surrounding the hepatic cystic wall. Therefore, the patient was diagnosed with intracystic hemorrhage due to a ruptured pseudoaneurysm. Embolization, using a detachable coil, was successful. Interventional radiologists should be aware of potential vascular injuries during drainage and sclerotherapy for giant hepatic cysts.

Tumor-associated macrophage-derived inflammatory cytokine enhances malignant potential of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an asbestos-related aggressive malignant neoplasm. Due to the difficulty of achieving curative surgical resection in most patients with MPM, a combination chemotherapy of cisplatin and pemetrexed has been the only approved regimen proven to improve the prognosis of MPM. However, the median overall survival time is at most 12 mo even with this regimen. There has been therefore a pressing need to develop a novel chemotherapeutic strategy to bring about a better outcome for MPM. We found that expression of interleukin-1 receptor (IL-1R) was upregulated in MPM cells compared with normal mesothelial cells. We also investigated the biological significance of the interaction between pro-inflammatory cytokine IL-1ß and the IL-1R in MPM cells. Stimulation by IL-1ß promoted MPM cells to form spheroids along with upregulating a cancer stem cell marker CD26. We also identified tumor-associated macrophages (TAMs) as the major source of IL-1ß in the MPM microenvironment. Both high mobility group box 1 derived from MPM cells and the asbestos-activated inflammasome in TAMs induced the production of IL-1ß, which resulted in enhancement of the malignant potential of MPM. We further performed immunohistochemical analysis using clinical MPM samples obtained from patients who were treated with the combination of platinum plus pemetrexed, and found that the overexpression of IL-1R tended to correlate with poor overall survival. In conclusion, the interaction between MPM cells and TAMs through a IL-1ß/IL-1R signal could be a promising candidate as the target for novel treatment of MPM (Hyogo College of Medicine clinical trial registration number: 2973).

Irregularly branched microvessels as visualized by magnifying endoscopy: a reliable marker for predicting deep submucosal invasion of superficial esophageal squamous cell carcinoma.

Background and study aims Magnifying endoscopy with narrow-band imaging (M-NBI) is reported to be useful in diagnosing invasion depth of superficial esophageal squamous cell carcinoma (SCC), but accurate diagnosis of deep submucosal invasion (SM2) has remained difficult. However, we discovered that irregularly branched microvessels observed with M-NBI are detected in SM2 cancers with high prevalence. Thus, this retrospective study aimed to investigate the diagnostic performance of irregularly branched microvessels as visualized by M-NBI for predicting SM2 cancers. Patients and methods Patients with superficial esophageal SCC lesions that were endoscopically or surgically resected at our hospital between September 2005 and December 2014 were included. Endoscopic findings by M-NBI of these lesions were presented to an experienced endoscopist who was unaware of the histopathological diagnosis and who then judged whether irregularly branched microvessels were present. Using the invasion depth according to postoperative histopathological diagnosis as the gold standard, we determined the diagnostic performance of the presence of irregularly branched microvessels as an indicator for SM2 cancers. Results A total of 302 superficial esophageal SCC lesions (228 patients) were included in the analysis. When irregularly branched microvessels were used as an indicator of SM2 cancers, the diagnostic accuracy was 94.0 % (95 % confidence interval [CI]: 91.1-96.1 %), sensitivity was 79.4 % (95 % CI: 66.6-88.4 %), specificity was 95.9 % (95 % CI: 94.3-97.0 %), positive predictive value was 71.1 % (95 % CI: 59.6-79.1 %), and negative predictive value was 97.3 % (95% CI: 95.7-98.5 %). Conclusions Irregularly branched microvessels may be a reliable M-NBI indicator for the diagnosis of cancers with deep submucosal invasion.

[Renal Cancer Tissue after Nivolumab/Ipilimumab Combination Therapy for Metastatic Renal Cell Carcinoma].

Antibodies that inhibit the function of PD-1, PD-L1, and CTLA4 increase the tumor immune response and suppress tumor growth. These immune checkpoint inhibitors have also been introduced into the treatment of metastatic renal cancer. We report combination therapywith nivolumab and ipilimumab in a case of renal cancer with bone metastasis and subsequent removal of the primarytumor. The patient was a 67-year-old male. Computed tomography (CT) revealed a 6.5×5.6 cm renal tumor in the left kidney, with osteolytic metastasis to the left 11th rib and thoracic spine. Irradiation of 30 Gy was performed for the thoracic spine tumors. Then, nivolumab+ipilimumab combination therapywas continued for a total of 4 courses. In addition, 4 courses of nivolumab monotherapywere added. CT after therapyrevealed a 15. 4% decrease in the length-wise diameter and increase in internal necrosis in the left kidneytumor, as well as shrinkage, absorption reduction, and appearance of a hardened border in the bone metastasis. Therefore, transabdominal left nephrectomywas performed. The histopathological diagnosis was clear cell carcinoma pT1bN0, grade 2. The renal cancer tissue was mostlyinternal necrosis, and the viable tumor comprised approximately10%. Marked infiltration of predominantlyCD8-positive lymphocytes to the primarytumor site was observed. Postoperatively, nivolumab was discontinued and the patient is under observation. In the specimens from 2 patients treated using pazopanib, a tyrosine kinase inhibitor, prior to renal cell cancer removal, there were fewer CD8- and CD4-positive cells infiltrating the renal cancer than after the combination therapy.

EphA2 inhibition suppresses proliferation of small-cell lung cancer cells through inducing cell cycle arrest.

Small-cell lung cancer (SCLC) is characterized by one of neuroendocrine tumors, and is a clinically aggressive cancer due to its rapid growth, early dissemination, and rapid acquisition of multidrug resistance to chemotherapy. Moreover, the standard chemotherapeutic regimen in SCLC has not changed for three decades despite of the dramatic therapeutic improvement in non-SCLC. The development of a novel therapeutic strategy for SCLC has become a pressing issue. We found that expression of Eph receptor A2 (EphA2) is upregulated in three of 13 SCLC cell lines and five of 76 SCLC tumor samples. Genetic inhibition using siRNA of EphA2 significantly suppressed the cellular proliferation via induction of cell cycle arrest in SBC-5 cells. Furthermore, small molecule inhibitors of EphA2 (ALW-II-41-27 and dasatinib) also exclusively inhibited proliferation of EphA2-positive SCLC cells by the same mechanism. Collectively, EphA2 could be a promising candidate as a therapeutic target for SCLC.

[A Case of Unclassified Sex Cord-Stromal Tumor Containing hCG-Positive Cells].

We present a case of unclassified sex cord-stromal testicular tumor with lung metastasis. A 48-year-old man consulted our hospital for left testicular enlargement that began 3 years ago. Computed tomography revealed a heterogeneously enhanced left testicular tumor 11 cm in diameter and a 5 mm metastatic lung tumor. The human chorionic gonadotropin (hCG) level was elevated (141.6 mU/ml), whereas the levels of α-fetoprotein (AFP) and LDH were normal. The external genitalia were normal and gynecomastia was not observed. Left high orchiectomy followed by 3 cycles of BEP chemotherapy (bleomycin, etoposide, and cisplatin) every 4 weeks was performed. The pathology of the excised specimen was unclassified sex cordstromal testicular tumor containing hCG-positive cells. On immunohistochemistry, the tumor cells were partly positive for AE1/AE3, hCG, and calretinin. Vimentin was diffusely positive, but OCT3/4, SALL4, GATA3, and CK7 were negative. After BEP treatment, the metastatic lung lesion disappeared. Unclassified sex cord-stromal testicular tumor is a rare disease and its treatment has not been established. Thus, further accumulation of cases is needed.

Analysis of Pleiotropic Effects of Nivolumab in Pretreated Advanced or Recurrent Non-small Cell Lung Cancer Cases.

BACKGROUND/AIM: Nivolumab is an immune checkpoint inhibitor for advanced non-small cell lung cancer (NSCLC). We investigated the safety and efficacy of nivolumab by analyzing the response factor, adverse effects (AE), and the post-treatment condition of pretreated advanced or recurrent NSCLC patients. PATIENTS AND METHODS: Nivolumab (3 mg/kg) was administered to 79 pre-treated NSCLC patients from December 2015 to January 2018. Nivolumab efficacy and AE were assessed using the Response Evaluation Criteria in Solid Tumors and the Common Terminology Criteria, respectively. RESULTS: Progression-free survival (PFS) was significantly prolonged in cases where the therapeutic effect of the pretreatment was a partial response (p=0.0004). Five cases (6.3%) experienced grade 3-4 AEs. PFS was significantly prolonged in the skin rash group versus the non-skin rash group, and in patients where nivolumab treatment was discontinued. CONCLUSIONS: Long-term survival was observed in patients with skin rash. Therapeutic effect of nivolumab immediately following its administration appears to be favorable for survival.

Prediction of prostate cancer by deep learning with multilayer artificial neural network.

INTRODUCTION: To predict the rate of prostate cancer detection on prostate biopsy more accurately, the performance of deep learning using a multilayer artificial neural network was investigated. METHODS: A total of 334 patients who underwent multiparametric magnetic resonance imaging before ultrasonography guided transrectal 12-core prostate biopsy were enrolled in the analysis. Twenty-two non-selected variables, as well as selected ones by least absolute shrinkage and selection operator (Lasso) regression analysis and by stepwise logistic regression analysis, were input into the constructed multilayer artificial neural network (ANN) programs; 232 patients were used as training cases of ANN programs and the remaining 102 patients were for the test to output the probability of prostate cancer existence, accuracy of prostate cancer prediction, and area under the receiver operating characteristic (ROC) curve with the learned model. RESULTS: With any prostate cancer objective variable, Lasso and stepwise regression analyses selected 12 and nine explanatory variables, respectively, from 22. Using trained ANNs with multiple hidden layers, the accuracy of predicting any prostate cancer in test samples was about 5-10% higher compared to that with logistic regression analysis (LR). The area under the curves (AUC) with multilayer ANN were significantly larger on inputting variables that were selected by the stepwise LR compared with the AUC with LR. The ANN had a higher net benefit than LR between prostate cancer probability cutoff values of 0.38 and 0.6. CONCLUSIONS: ANN accurately predicted prostate cancer without biopsy marginally better than LR. However, for clinical application, ANN performance may still need improvement.

Early-stage Clinical Characterization of Malignant Pleural Mesothelioma.

BACKGROUND/AIM: A strategy for improving survival of malignant pleural mesothelioma (MPM) patients is earlier diagnosis paired with earlier stage implementation of therapeutic interventions. This study aimed to determine the clinical signs of early-stage MPM to aid an earlier diagnosis and earlier-stage intervention. MATERIALS AND METHODS: Out of the 72 cases in our institution, 40 cases with 18F-FDG-PET/CT-negative MPM were retrospectively identified between 2007 and 2015. Overall survival rates were determined and compared with pathological features, histology, and treatment. RESULTS: The biphasic histological type of early-stage MPM was characterized by poor prognosis (p=0.0006). Additionally, the cytology-negative group (Class III and below) showed significantly shorter survival times (p=0.0290). There was no significant difference in survival between patients who received pleurectomy and those who received chemotherapy only (p=0.6991). Bimodal therapy resulted in a longer survival rate than trimodal therapy. CONCLUSION: In early-stage PET-negative MPM cases, biphasic histology and pleural effusion of Class III and below correlated with a poor prognosis. Surgical treatment using pleurectomy/decortication resulted in higher patient survival outcomes than therapy with extrapleural pneumonectomy.

Double cancer comprising malignant pleural mesothelioma and squamous cell carcinoma of the lung treated with radiotherapy: A case report.

Pleurectomy/decortication (P/D) is the surgical treatment of choice for early malignant mesothelioma, but it remains unclear whether radiotherapy along with P/D should be used as multimodal treatment for this disease. We herein present the case of a 76-year-old man with a history of asbestos exposure who was diagnosed with left-sided malignant pleural mesothelioma in February 2010. The patient underwent chemotherapy with a combination of cisplatin and pemetrexed and achieved stable disease, after which time he was kept under observation. A positron emission tomography/computed tomography scan performed in February 2011 revealed nodular shadows with fluorodeoxyglucose uptake in S3 of the left lung; using bronchoscopy, the patient was diagnosed with stage IIB (cT3N0M0) primary squamous cell carcinoma. Chemoradiotherapy with vinorelbine and 60 Gy/20 fr radiotherapy was performed, and a partial response was obtained, suggesting that the radiotherapy used to treat the carcinoma of the lung may have also helped control the disease activity of the pre-existing mesothelioma. The present case indicates the value of radiotherapy in the treatment of malignant mesothelioma. The aim of the present study was to examine the possibility of new multimodal treatments for mesothelioma, along with a discussion of the relevant literature.

Successful Treatment of Pulmonary Pleomorphic Carcinoma with Nivolumab: A Case Report.

Pulmonary pleomorphic carcinoma (PPC) has a poor prognosis due to the poor results of treatment with systemic chemotherapy. We report the case of a 73-year-old woman with PPC who showed a favorable response to nivolumab. As first-line treatment for postoperative recurrence, she received carboplatin and nanoparticle albumin-bound paclitaxel. However, 12 months later, a new metastatic lymph node appeared. Nivolumab was administered as second-line treatment, and the patient showed a favorable prolonged response. The effects of treatment of PPC with nivolumab seem promising. The results of a future prospective study are expected to identify indicators for the treatment of PPC.

The presence of free d-aspartate in marine macroalgae is restricted to the Sargassaceae family.

The presence of d-aspartate (d-Asp), a biologically rare amino acid, was evaluated in 38 species of marine macroalgae (seaweeds). Despite the ubiquitous presence of free l-Asp, free d-Asp was detected in only 5 species belonging to the Sargassaceae family of class Phaeophyceae (brown algae) but not in any species of the phyla Chlorophyta (green algae) and Rhodophyta (red algae). All other members of Phaeophyceae, including 3 species classified into the section Teretia of Sargassaceae did not contain d-Asp. These results indicate that the presence of free d-Asp in marine macroalgae is restricted only to the Sargassaceae family, excluding the species in the section Teretia.

Gastrectomy with limited surgery for elderly patients with gastric cancer.

BACKGROUND/OBJECTIVE: Elderly patients with gastric cancer can receive standard gastrectomy or gastrectomy with reduced nodal dissection, i.e., limited surgery, in order to prevent postoperative complications. This study evaluated the feasibility of gastrectomy with limited surgery for elderly patients with gastric cancer. METHODS: A total of 267 elderly patients (≥70 years old) were divided into two groups according to the level of nodal dissection: patients who received nodal dissection according to guidelines were included in the standard surgery group (standard group), and those who received reduced nodal dissection were included in the limited surgery group (limited group). The surgical outcomes of the two groups were compared. RESULTS: There were 170 patients in the standard group and 97 patients in the limited group. The limited group had significantly poorer nutrition status and a significantly higher proportion with comorbidities. Morbidity and mortality were similar in both groups. Multivariate analysis showed that the overall survival rates were significantly worse in patients with advanced age, male gender, low body mass index, low prognostic nutrition index, and higher tumor stage. The disease-specific survival rate was significantly lower in the limited group than in the standard group (p<0.001). CONCLUSION: Gastrectomy according to the gastric treatment guidelines for elderly patients with gastric cancer is recommended. Elderly male patients with poor nutrition have poor prognosis; prognostic nutrition index <40. Limited surgery is a treatment option for such patients.

Anorectal cancer surveillance in Crohn's disease.

OBJECTIVES: One of the characteristics of colorectal cancer complicating Crohn's disease (CD) in the Japanese population is that it frequently occurs in the lower anorectal site. This study aimed to examine CD patients biopsied in the lower anorectal sites to investigate the significance and problems associated with this method of cancer surveillance. METHODS: Among 116 patients with CD duration of ≥10 years, we examined patients diagnosed with cancer using histological examination of the lower anorectal site (287 times). We also evaluated the detection rates of cancer and atypical cells using this method. RESULTS: Of the 116 patients, neoplastic lesions were detected through biopsy in 22 (19.0%), of which 18 had carcinomas and 4 had atypical cells. The clinicopathological traits of the cancer patients were early-age onset and chronic disease duration of CD before cancer diagnosis. Histologic findings were characterized by a high frequency of poorly differentiated adenocarcinoma and mucinous carcinoma. The 18 patients with cancer were assigned to groups A and B depending on the presence or absence of cancer-related symptoms, and their characteristics were compared. Of these, 5 patients whose cancer was detected without symptoms (group A) had better prognosis than those detected with symptoms (group B) based on survival curves. We next examined 103 patients for surveillance after excluding 13 patients who were diagnosed with cancer-related symptoms from the 116 patients and found a 5.8% (6 patients) detection rate of cancer and atypical cells. CONCLUSIONS: Our results suggest the effectiveness of transanal histological testing for the surveillance of anorectal cancer with CD.

Expansion of lymph node metastasis in mixed-type submucosal invasive gastric cancer.

BACKGROUND/OBJECTIVE: Mixed-type early gastric cancer (differentiated and undifferentiated components) incurs a higher risk of lymph node metastasis than pure-type early gastric cancer (only differentiated or only undifferentiated components). Therefore, we investigated the expansion of lymph node metastasis in mixed-type submucosal invasive gastric cancer in order to establish the most appropriate treatment for mixed-type cancer. METHODS: We retrospectively analyzed 279 consecutive patients with submucosal invasive gastric cancer who underwent curative gastrectomy for gastric cancer between 1996 and 2015. We classified the patients into the mixed-type and pure-type groups according to histologic examination and evaluated the expansion of lymph node metastasis. RESULTS: The rate of lymph node metastasis was 23.7% (66/279) in the total patients, 36.4% (36/99) in the mixed-type group, and 16.6% (30/180) in the pure-type group. The significant independent risk factors for lymph node metastasis were tumor size ≥2.0 cm (P = 0.014), mixed-type gastric cancer (P < 0.001), and lymphatic invasion (P < 0.001). Lymphatic invasion and lymph node metastasis had a strong relationship in mixed-type group. The rates of no. 7 lymph node metastasis in the total patients and mixed-type group were 2.9% (8/279) and 5.1% (5/99), respectively; the rates of no. 8a lymph node metastasis were 1.4% (4/279) and 4.0% (4/99), respectively. CONCLUSION: Mixed histological type is an independent risk factor for lymph node metastasis. Lymph node metastasis in mixed-type gastric cancer involves expansion to the no. 7 and no. 8a lymph nodes. Therefore, lymphadenectomy for mixed-type submucosal invasive gastric cancer requires D1+ or D2 dissection.