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脳出血を発症したvon Recklinghausen病(以下R病)患者に褐色細胞腫の合併をみた1例を経験した.症例は52歳の女性.脳出血にて開頭術を受け入院中,精査で左副腎腫瘤を認め当科へ紹介された. R病の家系を有し,全身に神経線維腫, cafe-au-lait spotを認めた.血中,尿中カテコールアミン検査, 131I-MIBG シンチグラムで左副腎褐色細胞腫と診断,左副腎摘出術を施行し高血圧の改善を認めた. R病は神経線維腫, cafe-au-lait spotを特徴とする常染色体優性の遺伝性疾患である.一方,褐色細胞腫はカテコールアミン産生による多彩な臨床症状を呈する疾患で,本症例のごとくときに脳出血などの重篤な合併症が生じる.以前よりこれら両疾患の合併が知られているが,因果関係については未だ明らかにされていない.遺伝子学的考察を中心に若干の文献的考察を加えて報告する.

[Background] Promising efficacy of the immunotherapy with anti-PD-1 antibody for esophageal squamous cell carcinoma (ESCC) is expected. Tumor-infiltrating lymphocytes (TILs)have been found to be associated with favorable outcome of patients in many cancers including ESCC. However, the contributing factor of TILs in the primary tumor remains unclear. Dendritic cells (DCs) are the most potent antigen-presenting cells to induce cytotoxic T lymphocytes. [Purpose] The aim of this study was to examine the correlation of mature dendritic cells with CD8+ cells in the tumor in order to clarify the impact of DCs on locally infiltrated lymphocytes in ESCC. [Object and Methods] Formalin-fixed, paraffin-embedded blocks of primary lesions were collected from 80 patients with ESCC who underwent surgical treatment at Osaka City University Hospital. Immunohistochemical analysis using anti-LAMP-3 antibody and CD8 antibody was used to evaluate intratumoral DCs and TILs. The number of LAMP-3+DCs and TILs were counted at ×400 magnification. We divided the 80 cases into two groups according to the median number of intratumoral DCs and TILs to examine the clinicopathological features. [Results] LAMP-3+DCs were predominantly observed in peritumoral area and sparsely found in intratumoral area, whereas CD8+T cells distributed between both peritumoral and intratumoral areas. The number of DCs was significantly associated with increasing TNM stage. For example, the median number of DCs was 59.9 in pathological T1, 34.2 in T2/3, 62.4 in pN1, 34.1 in pN1/2/3. In addition, many patients with high infiltaraion of DCs had positive lymphatic invasion (Ly). The number of intratumoral DCs was significantly correlated with the number of TILs which were observed in intratumoral regions. Patients in the high infiltration of DCs group showed a significant better prognosis than patients in the low infiltration group. Double staining showed that LAMP3+DC-CD8+T cell clusters were seen in peritumoral area. Citation Format: Junya Nishimura, Hiroaki Tanaka, Yuichiro Miki, Tatsuro Tamura, Tatsunari Fukuoka, Go Ohira, Masatsune Shibutani, Sadaaki Yamazoe, Kenjiro Kimura, Takahiro Toyokawa, Hisashi Nagahara, Ryosuke Amano, Kazuya Muguruma, Kiyoshi Maeda, Kosei Hirakawa, Masaichi Ohira. Impact of intratumoral mature dendritic cells on prognosis of the patients with esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2945. doi:10.1158/1538-7445.AM2017-2945

It has been reported that the examination of circulating tumor cells (CTCs) is beneficial for predicting tumor stage or treatment response. The epitherial cell adhesion molecule (EpCAM) and cytokeratin has been used as epithelial markers for the identification of CTCs. Since the epithelial-mesenchymal transition is one of malignant phenotype of cancer cells, it is necessary to investigate other markers which might detect mesenchymal CTCs. This study aims to clarify the clinical significance of EpCAM negative and CEA positive CTCs in patients with gastric cancer. Forty patients who underwent operation for gastric cancer were enrolled in this study. A total of 10ml peripheral blood samples were obtained preoperatively. Informed consent to participate in this study was obtained from all of the patients before their surgery. This study was approved by the Human Ethics Review Committee of our University. After collection of mononuclear cell fraction, these cells were stained by PAPI, anti-CD45, anti-EpCAM, anti-cytokeratin, and anti-CEA (CD66e) antibody. We enumerated the number of cells which showed EpCAM, cytokeratin, and CEA positive expression among CD45 negative cells. ROC analyses were performed for investigating predictive value of these cell counts for distant metastasis. We examined association between these cell counts and clinicopathological features. ROC analyses revealed that the AUC for predicting distant metastasis using EpCAM, Cytokeratin, and CEA positive cell counts were 0.583, 0.638, and 0.769, respectively. The median number of EpCAM negative and CEA positive cells was 231 (range: 0-61897). The cell counts of EpCAM negative and CEA positive cells were significantly associated with Tumor depth (p=0.0084), lymph node metastasis (p=0.0107), and tumor size (p=0.023). CEA might be useful marker for detecting high risk of recurrence in patients with gastric cancer. Citation Format: Yuichiro Miki, Masakazu Yashiro, Tomohisa Okuno, Kishu Kitayama, Tatsuro Tamura, Takahiro Toyokawa, Hiroaki Tanaka, Kazuya Muguruma, Kosei Hirakawa, Masaichi Ohira. Clinical significance of EpCAM-negative and CEA-positive circulating tumor cells in gastric carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3791. doi:10.1158/1538-7445.AM2017-3791

Background:Recent evidence shows that neutrophils often migrate into the tumor and are associated with tumor progression. These tumor associated neutrophils (TANs) neutrophils have potential to induce angiogenesis, lymphangiogensesis and immunosuppression by inhibiting cytotoxic T lymphocytes. Immune status is one of the important prognostic factor of gastric cancer. We previously reported that lymphangiogenesis was augmented in the primary tumor of gastric carcinoma. Aim:The aim of this study was to investigate the correlation between CD15+ TANs and clinicopatological features of patients with gastric cancer. Materials and Methods: We investigated the association of the density of TANs in primary tumor with clinicopathological features by immunohistochemistry. We used specimens from a total of 143 primary tumor and 497 lymph nodes from 120 patients underwent gastrectomy between 2007 and 2008 in our department. We examined prognostic value of TANs identified as positive CD15 cells in both of the primary tumor and tumor draining lymph nodes. Results:The median number of TANs in primary tumor and tumor draining lymph nodes were 18.4 and 23 cells/HPF, respectively. High TANs in both of the primary tumor and lymph nodes had correlation with depth of invasion (primary tumor P Conclusion: Our results showed that patients with high CD15+TANs infiltration in gastric cancer tissues had poorer prognosis because of increasing lymph nodes metastasis. These findings suggested the TANs might have important role of tumor lymphangiogenesis in microenvironment of gastric carcinoma. Citation Format: Hiroaki Tanaka, Soichiro Hiramatsu, Tatsuro Tamura, Hisashi Nagahara, Kenjiro Kimura, Masatsune Shibutani, Go Ohira, Takahiro Toyokawa, Sadaaki Yamazoe, Ryosuke Amano, Kazuya Muguruma, Kiyoshi Maeda, Kosei Hirakawa, Masaichi Ohira. Infiltration of neutrophils in the tumor was associated with poor prognosis of patients with gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4001. doi:10.1158/1538-7445.AM2017-4001

Background Recently, the preoperative immune-nutritional status has been reported to correlate with the survival rate in patients with colorectal cancer (CRC). However, there have been no reports on the relationship between the controlling nutritional status (CONUT) score and the clinical outcome after curative surgery for CRC. We herein evaluated the prognostic significance of the CONUT score in patients with CRC, and then compared the accuracy of the CONUT score and the prognostic nutritional index (PNI) as a predictor of survival. Methods We retrospectively reviewed a database of 204 patients who underwent curative surgery for Stage II/III CRC. Patients were divided into two groups according to the CONUT score and the PNI. Results The five-year cancer-specific survival (CSS) rate was significantly higher at 92.7% in the low CONUT group, compared to a rate of 81.0% in the high CONUT group (p=0.0016). The five-year CSS was 71.2% in the low PNI group and 92.3% in the high PNI group, which showed a significant difference (p=0.0155). A multivariate analysis showed that lymph node metastasis and the CONUT score were independent risk factors for CSS. Conclusion This study suggested that the CONUT score is a strong independent predictor of the survival among CRC patients.

BACKGROND/AIM: Recent evidence indicates that inflammation is a hallmark of cancer. Tumor-associated neutrophils (TANs) contribute to tumor invasion. However, whether TANs and lymph node metastasis are related is unknown. Intranodal lymphatic vessel density (LVD) is significantly correlated with tumor progression, lymph node metastasis in gastric cancer. Herein, we investigated the effects of TANs in regional lymph nodes.We investigated the association of the density of TANs in regional lymph nodes with clinicopathological features by immunohistochemistry. Furthermore, we examined the prognostic value of TANs in lymph nodes.The number of TANs in regional lymph nodes was positively correlated with intranodal LVD and micrometastases. Patients with higher cluster of differentiation 15(+) TAN counts had significantly poorer prognosis than those with lower counts.Our results suggest that TANs in regional lymph nodes promote the invasion of lymph nodes by cancer cells via augmentation of lymphangiogenesis and thereby contribute to tumor progression.

Lymph node metastasis is one of the most important prognostic factors in patients with esophageal squamous cell carcinoma (ESCC). Neoadjuvant treatment can reduce micrometastasis in lymph nodes to enable curative resection by down staging. The aim of this study was to evaluate the histological effect of neoadjuvant therapy on lymph node metastasis of ESCC by performing immunohistochemistry for cytokeratin staining.A total of 3061 lymph nodes were examined from 62 patients who received neoadjuvant treatment followed by esophagectomy with lymphadenectomy.We observed positive staining for cytokeratin in 276 (9.0%) lymph nodes, which included overt metastasis, micrometastasis and hyalinized cytokeratin particles (HCP). Patients with HCPs in lymph nodes had better outcomes than patients without HCPs in lymph node. A significant prognostic difference between the patients with HCPs and without HCPs was observed in a subgroup of patients with nodal metastasis.Our findings suggest that HCP might reflect a degenerative change of cancer cells in lymph nodes and can predict the response to neoadjuvant therapy.

Background The aim of this study was to clarify the operative mortality and long‐term survival of gastrectomy for elderly patients with gastric cancer. Methods A total of 461 patients who underwent gastrectomy for gastric cancer in our hospital were classified as elderly group (≥80 years‐old, 95 patients) and control group (60–69 years‐old, 366 patients). Results The frequency of comorbidities was significantly (P

Tumor-associated macrophages (TAMs) correlate with lymphangiogenesis in primary lesions and with lymph node (LN) metastasis of several cancers. However, the association of TAMs in regional LNs with lymphatic spread of cancer remains unclear. The purpose of this study was to evaluate the distribution of TAMs in draining LNs and the impact of TAMs on the establishment of LN metastasis of gastric cancer.The number and distribution of TAMs in regional LNs that were obtained from 49 patients who underwent radical surgery for gastric cancer at Osaka City University Hospital in 2011 were assessed. TAMs were defined as immunohistochemically CD163 positive cells. The association of the TAM density with lymph node metastasis and the lymphatic drainage route of the stomach were investigated.A high density of TAMs was significantly associated with pathologically positive lymph nodes and pathological TNM stage. The density of TAMs was increased in LNs with micro metastasis compared with those without metastasis. There was a significant, positive correlation between TAM number and lymphatic vessel density in LNs. In nonmetastatic LNs, TAMs were likely to accumulate in the neighborhood of the primary lesion. In addition, the density of TAMs in distant LNs was significantly increased in patients in whom LN metastasis was observed in perigastric LNs.Accumulated TAMs may induce lymphangiogenesis and prepare an environment that facilitates cancer proliferation in LNs. Our findings might provide a conceptual framework for understanding the lymphatic spreading of cancer and for designing future therapeutic strategies for gastric cancer.

The purpose of this study was to evaluate the significance of the combination of the carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels as a prognostic indicator and for monitoring for recurrence and metastasis after potentially curative surgery for patients with stage II colorectal cancer.A total of 238 patients with stage II colorectal cancer who underwent potentially curative surgery were enrolled in the study. A high CEA level was defined as a level exceeding 5 ng/ml and a high CA19-9 level was defined as a level exceeding 37 U/ml.Out of these 238 patients, 92 (38.7%) patients had high CEA levels, 23 (9.7%) patients had high CA19-9 levels and 15 (6.3%) patients had both high CEA and CA19-9 levels. The disease-free and overall survival rates were significantly worse in patients with both a high CEA level and high CA19-9 level. Tumor marker(s) elevated before the operation tended to be elevated again at the time of relapse.The combination of preoperative CEA and CA19-9 levels was useful for predicting the prognosis and for monitoring recurrence and metastasis after potentially curative surgery in patents with stage II colorectal cancer.

Prostaglandin D2 (PGD2) has been demonstrated to have antitumor effects on cancer cells. PGD2 acts through two major receptors of DP1 and DP2, as well as through the peroxisome proliferator-activated receptor γ (PPARγ) via the PGD2 metabolite, 15-deoxy-Δ12-14-PGJ2. The expression levels of DP1, DP2, and PPARγ were analyzed by immunohistochemistry on 277 primary gastric carcinomas. Either DP1- or DP2-positive cases were regarded as DP-positive. DP-Positive tumour was significantly associated with lymph mode metastasis, lymphatic invasion, and venous invasion. PPARγ positivity was not associated with any clinicopathological factors of gastric cancer. DP-Negative and PPARγ-positive cases were significantly associated with T category, lymph metastasis, and lymphatic invasion. The prognosis of DP-negative and PPARγ-positive cases was better than that of the other cases. These findings suggest that DP and PPARγ signaling influence the invasiveness of cancer cells. DP and PPARγ can be used as a potential marker for gastric cancer progression.

Pulmonary complications (PCs) after esophagectomy for patients with esophageal cancer have been correlated with prolonged hospital stays and in-hospital mortality. Previous studies have shown that minimally-invasive esophagectomy (MIE) is associated with a lower rate of PCs compared to conventional open surgery. Although PCs were reportedly associated with many factors, including surgical approaches, patients' demographics, and perioperative variables, the predictive factors for PCs including MIE, have not been fully evaluated.A total of 209 patients with resectable esophageal cancer who underwent three types of esophagectomy were included in the present study; (i) 93 cases who underwent the combined thoracoscopic MIE and laparoscopic MIE; (ii) 42 cases who underwent the combined open thoracotomy and laparoscopic MIE; (iii) 74 cases who underwent the combined open thoracotomy and open laparotomy, which were defined as the total MIE group, hybrid MIE group, and total open group, respectively. We compared clinical outcomes of the three groups and identified postoperative predictive factors of PCs using multivariate analysis.The incidence of PCs was significantly reduced (p=0.015) in the total-MIE group (8/93: 8.5%) compared with the total-open group (16/74: 21.6%), but it was not significantly reduced in the hybrid MIE group (5/42: 11.9%) compared with the total open group (p=0.19). The multivariate analysis showed that the presence of cardiac comorbidity [odds ratio (OR)=5.90; p=0.013], lung comorbidity (OR=3.95; p=0.031), and anastomotic leakage (OR=6.00; p0.01) were independent risk factors for PCs after esophagectomy. In contrast, total MIE reduced the risk of PCs (OR=0.328; p=0.036).The combination of thoracoscopic and laparoscopic MIE presents as an excellent surgical procedure for the reduction of PCs after esophagectomy.

We report a patient who underwent 2-term surgery to treat focal progression of a huge liver metastasis and peritoneal dissemination from a gastric gastrointestinal stromal tumor(GIST)during imatinib mesylate treatment. A 59-year-old man underwent an emergency surgery for perforative peritonitis caused by gastric GIST in June 2006 and a partial resection of the stomach in September 2006. Four years later, abdominal computed tomography(CT)detected a huge liver tumor that occupied the entire right lobe. We initiated imatinib mesylate treatment(400mg/day), and the patient maintained stable disease for several months. However, focal progression of the huge liver tumor and a peritoneal tumor at the splenic hilum were revealed by CT; therefore, an extended right hepatic resection was performed in August 2011 and a distal pancreatectomy, splenectomy, and partial resection of the stomach were performed in February 2012. The patient died of the primary disease at 16 months after the hepatic resection for focal progression.

AIM Thoracoscopic esophagectomy (TE) in the prone position for patients with esophageal cancer has received a great deal of attention. We retrospectively compared clinical outcomes and surgical stress of TE in the prone position (TE-P) and in the lateral position (TE-L) at our institution. METHODS A total of 58 consecutive patients (28 in the TE-L group and 30 in the TE-P group) were studied. Between the 2 groups, clinical outcomes and various parameters were compared. RESULTS There were no hospital deaths in both TEL and TEP groups. Blood loss during the thoracoscopic part of the surgery were significantly (P

Background and Aim: The neutrophil to lymphocyte ratio (NLR) may be related to progression in several cancers. The aim of this study was to investigate the impact of pretreatment NLR in advanced gastric cancer on the prognosis of the patients stratified by metastatic pattern. Methods: We retrospectively investigated clinical data from 191 patients with stage IV gastric cancer who had undergone surgery for primary gastric cancer between 1997 and 2010 at the Department of Surgical Oncology of Osaka City University. Results: All patients had unresectable metastatic factors including peritoneal metastasis (P) and liver metastasis (H). Sixty-one (32%) patients had more than two unresectable factors. We determined a cutoff value of 2.5 for the NLR to be optimal to discriminate the patient's characteristics and divided patients into low (2.5) NLR group for subsequent analysis. In the low NLR group, long survival was found in patients with H, P, or multiple site metastases. Conclusion: Our results suggest that NLR well reflects the progression of critical metastasis and surgical resection might improve prognosis for patients with low NLR. In conclusion, NLR might be used as a predictive marker to decide on surgical therapy for patients with Stage IV gastric cancer. i 2014 S. Karger AG, Basel

The right non-recurrent inferior laryngeal nerve (NRILN) is a rare nerve anomaly that communicates the laryngeal nerve to the right vagal nerve trunk directly in the neck, which is usually accompanied by aberrant right subclavian artery (ARSA). We report on two cases of thoracic esophageal carcinoma undertaken in patients with these abnormalities: a 73-year-old woman with progressive dysphagia and a 63-year-old asymptomatic man. Although there have been 10 cases of thoracic esophageal carcinomas associated with ARSA and NRILN in literature, as far as we are aware of, this is the first report to describe successful resection using video-assisted thoracoscopic surgery (VATS). We found that the combination of preoperative recognition of the ARSA using three-dimensional computed tomography (3D-CT) and VATS in the prone position allowed for visual magnification with an excellent thoracoscopic view and facilitated successful tumor resection and preservation of NRILN.

A 61-year-old man presented to our hospital with hypercalcemia and elevated C reactive protein (CRP). Evaluation revealed renal cell carcinoma (RCC) with metastasis to lung, bone, and brain. He underwent partial resection of the right kidney and a left nephrectomy. Histopathologic findings of resected tumors were consistent with clear cell RCC. Whole-brain irradiation was performed for management of brain metastasis. Postoperatively, he was treated with molecularly targeted therapy using a mammalian target of rapamycin inhibitor. Approximately 14 months later, he suffered an episode of upper gastrointestinal bleeding with secondary anemia and melena. Upper gastrointestinal endoscopy revealed a distinctly protruding lesion in the gastric body. Biopsy of the gastric lesion showed metastatic clear cell RCC. He underwent partial gastrectomy. His postoperative course was uneventful. However, 4 months after surgery, he died from brain metastasis. Metastatic RCC to the stomach, although rare, should be suspected in any patient with a history of RCC who presents with gastrointestinal symptoms.

We examined the clinical results of 15 patients treated with imatinib mesylate for metastatic or recurrent gastrointestinal stromal tumors(GIST)at the Osaka City General Hospital. Treatment with imatinib was initiated at 400 mg daily; however, in case of severe adverse events, the dose was gradually reduced to 300 mg or 200 mg to reach a tolerable dose so that administration could be continued for as long as possible. Assessments were performed according to the Response Evaluation Criteria in Solid Tumors(RECIST)and Choi criteria. According to the assessment by the RECIST criteria, clinical response(CR)was observed in 1 patient; partial response(PR), in 5 patients; stable disease(SD), in 6 patients; and progressive disease(PD), in 3 patients; the response rate was 40%. However, as per the Choi criteria, CR was observed in 1 patient; PR, in 11 patients; SD, in 1 patient; and PD, in 2 patients; the response rate was 80%. The median period of progression-free survival was 2,031 days and the 5-year survival rate was 80.0%. Grade 3 or higher adverse reactions observed included leukopenia(1 case), neutropenia( 2 cases), and anemia(1 case). In 6 patients(40%), the dose of imatinib was reduced to 300 mg or less; however, no significant difference in progression-free survival was observed between the 200/300mg group and 400/800mg group. Choi criteria are useful in assessing the response of advanced GIST to imatinib mesylate, and reducing the dose of imatinib mesylate to 200/300mg daily might be sufficient for treating patients who experience severe adverse reactions.

The patient was a 68-year-old man who complained of hoarseness and dyspnea. Upper gastrointestinal endoscopy revealed a type 3 tumor located in the middle thoracic esophagus at 30 cm from the incisor tooth that involved one-fourth of the circumference of the esophagus. Histopathological examination revealed moderately differentiated squamous cell carcinoma. Chest computed tomography( CT) revealed severe tracheal stenosis due to compression by a metastatic lymph node along the left recurrent laryngeal nerve. The patient was diagnosed as having cT4( 106recL-trachea), N2( 101L, 106recL, 106recR), M0, Stage IVa unresectable esophageal carcinoma. After insertion of a tracheal stent tube( spiral Z stent: diameter, 18 mm; length, 80 mm) to improve dyspnea, combination chemotherapy with 5-fluorouracil( 5-FU) plus nedaplatin was administered. Subsequent CT and endoscopy showed that the main tumor and the metastatic lymph node had significantly reduced in size and that complete response (CR) had been achieved. Thirty months after the initial treatment, the patient showed no sign of disease recurrence, after completion of 19 cycles of chemotherapy. The patient did not experience any severe adverse events. We report a case of a patient with locally advanced squamous cell carcinoma of the esophagus successfully treated with 5-FU/nedaplatin combination chemotherapy following tracheal stent tube placement.

We report a case of a 72-year-old woman with breast cancer who developed significant stenosis due to gastric cardia metastasis. The patient had undergone radical mastectomy for breast cancer when she was 53 years old and had developed postoperative recurrent diseases in the sternum and lung when she was 62 years old. Nineteen years after mastectomy, computed tomography (CT) scans showed gastric cardia metastasis. As symptoms of cardiac stenosis gradually developed, we performed proximal gastrectomy. The specimen was histologically diagnosed as estrogen receptor( ER)-positive scirrhous carcinoma that had metastasized from the breast cancer. The patient resumed oral intake of food after surgery. Surgical treatment might be useful to improve the quality of life of patients with metastatic gastric tumor.

This study aimed to investigate the clinical significance of preoperative neutrophil-to-lymphocyte ratio(NLR)as a predictor of prognosis in patients with Stage IV colorectal cancer. A total of 130 patients who underwent operation for Stage IV colorectal cancer were enrolled in the study. Of the patients, 69 had an NLR of ≥ 3.0 and were defined as the high-NLR group. Patients who received preoperative therapy and underwent emergency operation for perforation were excluded from the analysis. The 2-year survival rate was 58.1% in the high-NLR group and 43.5% in the low-NLR group. The median survival time was 38.0 months in the high-NLR group and 22.3 months in the low-NLR group. The patient prognosis in the high-NLR group was significantly worse than that in the low-NLR group. A univariate analysis indicated that high NLR, peritoneal dissemination, curability C, histological type( non-differentiated), and number of organs involved in metastasis (more than 1 organ) were the risk factors of poor survival. All of these factors, except peritoneal dissemination, were independent risk factors for poor survival on multivariate analysis. A high preoperative NLR may be considered as a convenient biomarker to identify patients with a poor prognosis after operation for stage IV colorectal cancer.

We report a case of familial adenomatous polyposis( FAP) presenting with thyroid cancer. A 24-year-old woman, on histological examination, was diagnosed as having the cribriform-morular variant of papillary thyroid carcinoma, which is known to be associated with FAP. Therefore, she underwent colonoscopy, and FAP was diagnosed. In addition, abdominal computed tomography( CT) scans revealed a tumor, approximately 12 cm in diameter, in the right lower abdomen. After total thyroidectomy, total proctocolectomy and excision of the tumor arising from the mesentery of the small intestines were performed. The histological diagnosis was FAP with a desmoid tumor arising from the mesentery.

A 64-year-old man with a high serum level of cancer antigen 19-9 (CA19-9) was diagnosed with pancreatic head cancer by computed tomography. Because the tumor was found to have directly invaded the hepatic artery for long segment on laparotomy, we diagnosed it as an unresectable locally advanced pancreatic cancer. Radiation therapy( 50.4 Gy/28 Fr) with gemcitabine( GEM)( 1,000 mg/m2 on days 1, 8, and 15, every 4 weeks) for 3 courses was administered. Subsequently, additional systemic chemotherapy with GEM( 800 mg/m2 on days 1 and 15, every 3 weeks) and S-1( 100 mg/body on days 1-14, every 3 weeks) was administered for 4 courses. After the treatment, the main tumor shrunk without distant metastasis. Thus, we performed pancreaticoduodenectomy with resection of the common hepatic artery. An end-to-end microvascular anastomosis was made between the left gastric artery and the right hepatic artery. Pathological examination revealed that90% of the tumor cells had disappeared and confirmed a negative margin status (R0). Eight months postoperatively, the patient is healthy and shows no signs of recurrence.

Chemoradiotherapy( CRT) for esophageal cancer is a useful modality for both locally advanced and resectable cases. Among adverse events related to CRT, radiation pneumonitis( RP) requires special attention because it has been shown to be occasionally associated with a worse acute prognosis. We report 5 cases of severe RP after CRT. All patients were male, and their mean age was 72 years (range: 66-76 years). The clinical stage of esophageal cancer was I in 1 case, II in 2 cases, and IVa in 2 cases. The mean total radiation dose was 51.8 Gy (range: 43.4-61.4). Initial symptoms and first abnormal findings were a high fever in 4 cases and elevated serum C-reactive protein( CRP) levels in 1 case. No patients presented with respiratory symptoms, including dyspnea and coughing, as initial symptoms. All cases were diagnosed as RP by chest computed tomography examination, an average of 6.8 days after the completion of RT. Four patients required intensive care and were put on ventilator support. All patients received steroid pulse therapy. Two patients recovered from RP; however, 3 died( 1 attributable to multi-organ failure and 2 to respiratory failure). It is important to consider RP caused by CRT when patients present with high fever or elevated CRP levels after the completion of RT for esophageal cancer.

Laparoscopy-assisted total gastrectomy (LATG), esophagojejunostomy is an effective but difficult procedure to perform. We describe a simple modification that substantially facilitates insertion of the anvil into the esophagus and avoids oral injuries and complications. After mobilization of the stomach and esophagus, a semicircumferential esophagotomy is made at the anterior esophageal wall. An OrVil anvil (Orvil, Covidien, Norwalk, CT, USA) is delivered laparoscopically and secured with a POLYSORB (Covidien) suture to the esophagus. The suture is advanced anteriorly so that the center rod penetrates the esophageal wall. The esophagus is transected with the stapler at this point. A circular-stapled esophagojejunostomy is then performed using the hemidouble stapling technique. Laparoscopy-assisted total gastrectomies were performed for 40 patients with gastric cancers (T1N0M0). All procedures were completed laparoscopically without any complications. The time required to place the anvil averaged 5 min compared with 9 min reported by others. There were no major complications or mortality in this series. The major advantage of this technique is that circular stapling is much easier than linear stapling, allowing surgeons without advanced surgical skills in LATG to perform the procedure effectively and safely.

A meta-analysis was conducted to evaluate and compare the short- and long-term outcomes of laparoscopic and conventional open surgery for gastric gastrointestinal stromal tumors (GISTs).We searched MEDLINE, EMBASE, Science Citation Index, and the Cochrane Controlled Trial Register for relevant articles published between 2000 and July 2013 by using the search terms "laparoscopic", "laparoscopy-assisted", "surgery", "gastrointestinal tumor", "GIST" and "gastric".We identified 12 articles reporting results that compared laparoscopic surgery with open surgery for gastric GISTs. Our meta-analysis included 644 patients with GISTs; 312 had undergone laparoscopic surgery, and 332 had undergone open surgery. In the short-term period, 14 outcome variables were examined. In the long-term period, six oncological variables were analyzed. Laparoscopic surgery for gastric GIST was associated with a reduction in intraoperative blood loss, shorter period to flatus, earlier resumption of oral intake, and shorter duration of hospital stay over the short-term, and with a significantly lower rate of overall recurrence, metastatic recurrence and local recurrence in the long-term compared to open surgery.Laparoscopic surgery may be an acceptable surgical treatment option compared to open surgery for gastric GIST.

Endoscopic treatment has been increasingly used for T1 esophageal squamous cell carcinoma (ESCC). However, this therapy is sometimes incomplete if the depth of the T1 primary tumor reaches the muscularis mucosae or submucosal layer because these tumors have a relatively high incidence of lymph node metastasis. However, to our knowledge, no previous reports on the prediction of nodal metastasis determined by evaluating primary tumor specimens of patients with ESCC are available.A total of 55 patients with T1 ESCC invading as deep as the submucosal layer who underwent curative esophagectomy were examined. We investigated the significance of the immunohistochemical staining of Vascular endothelial growth factor-C (VEGF-C) and E-cadherin in the primary tumor and Tumor budding for prediction of nodal metastasis.Metastasis to the regional lymph nodes was observed in 26 cases (47.3%) in this setting. VEGF-C expression and reduced E-Cadherin expression in the primary tumor was observed in 32 (58.1%) and 38 cases (69.1%), respectively. High-grade tumor budding was observed in 29 cases (52.7%). E-cadherin expression and tumor budding were closely correlated with nodal metastasis (p=0.04 and0.01 respectively), whereas VEGF-C expression tended to correlate with lymph node metastasis (p=0.06). In addition, high-grade tumor budding was significantly correlated (p0.01) with reduced E-cadherin expression. The accuracy of tumor budding and E-cadherin expression for nodal metastasis were 67.3% and 65.4% respectively, comparable with the one of lymphatic involvement (63%). Tumor budding (p0.01), but not E-cadherin and VEGF-C expression, was significantly correlated with poor survival.After the endoscopic treatment, additional therapy, such as surgery or chemoradiotherapy, may be required if reduced E-cadherin expression and high-grade tumor budding are observed in primary tumor specimen.

Any gastrointestinal stromal tumors (GISTs) larger than 10 cm are classified as "high risk" according to the modified National Institutes of Health consensus criteria. We conducted a multicenter study to identify a subgroup with moderate prognosis even within the "high-risk" group.We retrospectively collected data on 107 patients with tumors ≥10 cm from a multicenter database of GIST patients. Patients with macroscopic residual lesions or tumor rupture were excluded. The relationship between recurrence-free survival (RFS) and clinicopathological factors was analyzed.The median tumor size and mitotic count were 12.5 cm and 8/50 HPF. The RFS rate was 58.5% at 3 years, 52.1% at 5 years. Only mitotic count was an independent prognostic factor of RFS in the multivariate analysis (P = 0.001). The hazard ratio for recurrence in the subgroup with mitotic count5/50 HPF was 2.91 (95% confidence interval, 1.53 to 5.56). The subgroup with mitotic count ≤5/50 HPF showed significantly better RFS than the mitotic count5/50 HPF subgroup (P 0.001).Mitotic count is closely associated with outcome in patients with large GISTs. This suggests that the subset of large GISTs with low mitotic counts may be considered as "intermediate-risk" lesions.

Background We retrospectively investigated prognostic factors to be used in selecting the patients with stage IV gastric cancer (GC) who have an unfavorable prognosis after palliative gastrectomy. Methods A total of 146 GC patients at stage IV who had undergone palliative gastrectomy were enrolled. Various clinicopathological parameters were evaluated for prognosis. Results Surgical morbidity and hospital mortality occurred in 35 (23.9 %) and 4 (2.7 %) patients, respectively. The overall 5-year survival rate and the median survival time were 11.2 % and 13.2 months, respectively. Of the 146 patients, 64 had uncomfortable symptoms associated with GC and 76 had no such symptoms. Of the 64 patients with uncomfortable symptoms, 60 (93.7 %) experienced relief of these symptoms after palliative surgery. Multivariate analysis for patients without uncomfortable symptoms associated with GC revealed that the number of incurable factors and serum SPan-1 level were independent prognostic factors. Conclusions Patients with stage IV GC who had multiple incurable factors and a high level of serum SPan-1 might not be candidates for palliative gastrectomy for the purpose of prognostic benefit.

74 Background: The adjuvant chemotherapy with S-1 is the standard treatment for Stage II/III gastric cancer in Japan. Immunological status of host is critical for treatment outcome. Several investigators showed that systemic immune-inflammaotry indexes including neutrophil lymphocyte ratio (NLR) and modified Glasgow Prognostic Score (mGPS) well reflected the tumor progression. Methods: We analyzed clinical data obtained from 170 patients with pathological stage II/III gastric cancer who underwent surgery followed by S-1 adjuvant chemotherapy at Osaka City University Hospital between 2006 and 2015. Tumor infiltrating cells were detected by immunohistochemistry. Results: We found recurrent diseases in 70 (41%) patients including 15 in stage II and 55 in stage III. In univariate analysis using Cox proportion model, 2 grade of mGPS, the increase value of post-operative CEA, CA19-9, number of lymphocytes and NLR were associated with recurrence. Post-operative elevation of CEA and NLR were identified as independent risk factors for recurrence in multivariate analysis. Increase value of pre-operative NLR and CEA was significantly associated with early recurrent within one year after surgery. Tumor infiltrating neutrophils and PD-1+ T cells had correlated with the increase of pre-operative NLR and CEA value, respectively. Patients with low PD-1+T cells and low neutrophils had better prognosis than those with high infiltration. Conclusions: Post-surgical elevation of CEA and NLR value were useful as a predictive marker for recurrence in patients treated with S-1 adjuvant chemotherapy after surgery for gastric cancer. Early recurrence had correlated with tumor infiltrating neutrophils and PD-1+T cells. Our results suggested that systemic and local immune suppression should be an important element to exacerbate prognosis after chemotherapy for resectable gastric cancer.

The loss of the adhesion molecules is reported to correlate with tumor invasion and metastasis in patients with various cancers. E-cadherin is an important molecule for cell-to-cell adhesion. While, CD44 is important for cell-to-extra cellular matrix adhesion. The aim of the present study is to evaluate the significance of the expression of E-cadherin and CD44 in patients with the unresectable metastatic colorectal cancer who are undergoing palliative chemotherapy. Formalin-fixed, paraffin-embedded samples were obtained from 49 patients who underwent primary tumor resection and who were receiving palliative chemotherapy for unresectable metastatic colorectal cancer. We evaluated the expression of E-cadherin and CD44 by immunohistochemistry. The expression of E-cadherin was not significantly associated with progression-free survival (PFS) or overall survival (OS). Although, the expression of CD44 did not correlate with PFS, it tended to correlate with the OS (p = 0.0699). According to the combination of CD44 and E-cadherin, both low expression group showed a significant poor PFS (p = 0.0101) and OS (p = 0.0009). Objective response rate and disease control rate were significantly decreased in both low expression group (p = 0.0076 and p = 0.0294, respectively). A univariate analysis to determine the variables that were associated with PFS indicated that the both low expression of E-cadherin and CD44 (p = 0.0474) and gender (p = 0.0330) were significantly associated with decreased survival. A multivariate analysis showed that the both low expression of E-cadherin and CD44 was an independent risk factor for decreased PFS (hazard ratio [HR]: 8.276, 95% confidence interval [CI]: 1.383-43.311; p = 0.0227). According to OS, the both low expression of E-cadherin and CD44 expression was revealed a prognostic factor by univariate and multivariate analysis(HR:15.118, 95%CI: 2.645-77.490; p = 0.0039). This study suggested that the combined low expression of both E-cadherin and CD44 was a strong independent predictor of decreased chemotherapeutic outcome and survival in patients with unresectable metastatic colorectal cancer. Citation Format: Yasuhito Iseki, Masatsune Shibutani, Kiyoshi Maeda, Hisashi Nagahara, Tatsuro Tamura, Go Ohira, Sadaaki Yamazoe, Katsunobu Sakurai, Kenjiro Kimura, Takahiro Toyokawa, Ryosuke Amano, Naoshi Kubo, Hiroaki Tanaka, Kazuya Muguruma, Masaichi Ohira, Kosei Hirakawa. The significance of the expression of E-cadherin and CD44 in patients with unresectable metastatic colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5050.

Background: Glypican1 (GPC1) is a cell surface heparan sulfate proteoglycan that acts as a co-receptor for heparin-binding growth factors, and it plays a crucial role in cancer growth. Recently, it has been reported that GPC1 enriched on cancer-derived exosomes, and GPC1-positive exosomes in the circulation was frequently found in the patients with early pancreatic cancer. However role of GPC1-positive exosomes derived from tumor stromal cells remains to be unclear. The aim of this study is to clarify the significance of GPC1 expression on stromal cells in gastric carcinoma. Methods: A total of 597 patients with gastric cancer was enrolled in this study. An anti-GPC1 antibody was used for immunohistochemical staining. GPC1 expression was scored by the intensity of staining and the percentage of positive cells. GPC1 expression on cancer cells or stromal cells was evaluated. The corelation between GPC1 expression and clinicopathological features was statistically analyzed. Results: GPC1 expression on cancer cells was found in 473 (79%) of 597 cases. GPC1 expression on stromal cells was found in 147 (75%) of 597 cases. A Kaplan-Meier survival curve showed that overall survival of patients with GPC1-positive stromal cells was significantly better (log-rank p = 0.0028) than that with GPC1-negative stromal cells (5-year survival rate; 72.5% vs 57.9%, respectively). In contrast, overall survival was not statistically different (log rank p = 0.090) between patients with GPC1-positive tumor cells and GPC1-negative tumor cells (5-year survival rate; 71.8% vs. 64.6%, respectively). GPC1 expression on stromal cells was significantly correlated with T stage, lymph node metastasis, lymphatic vessel invasion, and clinical stage. Conclusions: GPC1 expression on stromal cells was associated with the good prognosis of patients with gastric cancer. GPC1-positive exosomes in stromal cells might be correlated with the progression of gastric cancer. Citation Format: Yuichiro Miki, Masakazu Yashiro, Kishu Kitayama, Hiroaki Kasashima, Go Masuda, Naoshi Kubo, Katsunobu Sakurai, Takahiro Toyokawa, Hiroaki Tanaka, Kazuya Muguruma, Masaichi Ohira, Kosei Hirakawa. Significance of glypican-1 expression on tumor stromal cells in gastric carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4097.

Background: The host immune system is one of the key players of anti-tumor functions. High numbers of tumor infiltrating lymphocytes has been showed to be a predictor of favorable clinical outcome in several solid cancers. The role of B cells in tumor microenvironment is still unclear. Recent studies have reported a correlation between the densities of B cells and the favorable clinical outcome of cancer patients. Moreover, some studies considered the organization of tumor infiltrating B cells as criteria in addition to the cell density. Tertiary lymphoid structures (TLSs) are defined as transient ectopic lymphoid organizations that can develop in non-lymphoid tissues at the site of chronic inflammation, and are anatomically and functionally similar to secondary lymphoid organs. In the present study, we investigated the association between tumor infiltrating B cells and clinicopathological features in gastric cancer. Materials and Methods: Tumor blocks were obtained from 226 patients with stage Ib to stage IV gastric cancer who had undergone initial surgical resection. The density of CD20+ B cells within the tumor and invasive margin area was assessed by immunohistochemistry. We also evaluated CD3+ T cells, CD21+ follicular dendritic cells (FDCs), Bcl6 germinal center B cells, and PNAd+ high endothelial venules (HEVs) to show the presence of TLSs in gastric cancer. Results: Tumor infiltrating B cells mostly organized clusters surrounded by CD3+ T cells. B cell area contained FDCs and some clusters had Bcl6+ B cells. There were HEVs around follicles. We observed most of TLSs at the tumor invasive margin. Kaplan-Meier survival analysis showed that high number of CD20+ B cells was associated with significantly better survival (P Conclusion: We demonstrated that B cells mostly infiltrated as TLSs and were associated with better prognosis in patients with gastric cancer. Our results suggested that B cells, perhaps as the structure of TLSs, might play an important role for immune response against gastric cancer. Citation Format: Chie Sakimura, Hiroaki Tanaka, Tatsuro Tamura, Go Ohira, Masatsune Shibutani, Sadaaki Yamazoe, Katsunobu Sakurai, Hisashi Nagahara, Kenjiro Kimura, Takahiro Toyokawa, Ryosuke Amano, Naoshi Kubo, Kazuya Muguruma, Kiyoshi Maeda, Masaichi Ohira, Kosei Hirakawa. Intratumoral tertiary lymphoid structures are associated with favorable prognosis of patients with gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1468.

We report a patient who had a complete response by treatment with 200 mg of imatinib mesylate daily for peritoneal recurrences of gastrointestinal stromal tumor(GIST)of the stomach. On March 2007, a 68-year-old woman underwent distal gastrectomy for GIST of the stomach. On May 2007, peritoneal recurrences were recognized on CT scan, and treatment with 400 mg daily of imatinib mesylate was started. Because grade 2 systemic edema and rash developed one week later, the imatinib mesylate dose had to be reduced to 200 mg daily from July 2007. After reduction of imatinib mesylate, the adverse reactions resolved. Peritoneal dissemination disappeared on CT scan from April 2010, and complete response has been maintained for 18 months.

Primary histiocytic sarcoma of the spleen is a rare but potentially lethal condition. It can remain asymptomatic or only mildly symptomatic for a long time. An 81-year-old woman presented with an extremely enlarged spleen. She suffered from progressive anemia and required a red blood cell transfusion once a month. Although computed tomography, ultrasonography, and magnetic resonance imaging were performed for diagnosis, a confirmed diagnosis was not obtained. Her enlarged spleen compressed her stomach, and she suffered from gastritis and a sense of gastric fullness just after meals. She underwent laparoscopic splenectomy for therapeutic and diagnostic purposes. Her post-operative course was uneventful. After surgery, her red blood cell and platelet counts increased markedly. The tumor was diagnosed as splenic histiocytic sarcoma. Post-surgical chemotherapy was not performed, and the patient died of liver failure due to liver metastasis 5 mo after surgery. Laparoscopic splenectomy is minimally invasive and useful for the relief of symptoms related to hematological disorders. However, in cases of an enlarged spleen, optimal views and working space are limited. In such cases, splenic artery ligation can markedly reduce the size of the spleen, thus facilitating the procedure. The case reported herein suggests that laparoscopic splenectomy may be useful for the treatment of splenic malignancy.

Background Transforming growth factor β (TGFβ) receptor signaling is closely associated with the invasion ability of gastric cancer cells. Although Smad signal is a critical integrator of TGFβ receptor signaling transduction systems, not much is known about the role of Smad2 expression in gastric carcinoma. The aim of the current study is to clarify the role of phosphorylated Smad2 (p-Smad2) in gastric adenocarcinomas at advanced stages. Methods Immunohistochemical staining with anti-p-Smad2 was performed on paraffin-embedded specimens from 135 patients with advanced gastric adenocarcinomas. We also evaluated the relationship between the expression levels of p-Smad2 and clinicopathologic characteristics of patients with gastric adenocarcinomas. Results The p-Smad2 expression level was high in 63 (47%) of 135 gastric carcinomas. The p-Smad2 expression level was significantly higher in diffuse type carcinoma (p = 0.007), tumours with peritoneal metastasis (p = 0.017), and tumours with lymph node metastasis (p = 0.047). The prognosis for p-Smad2-high patients was significantly (p = 0.035, log-rank) poorer than that of p-Smad2-low patients, while a multivariate analysis revealed that p-Smad2 expression was not an independence prognostic factor. Conclusion The expression of p-Smad2 is associated with malignant phenotype and poor prognosis in patients with advanced gastric carcinoma.

Keratinocyte growth factor (KGF) from gastric fibroblasts have been reported to stimulate proliferation of scirrhous gastric cancer cells with K-samII amplification in a paracrine manner. The aim of this study was to evaluate the clinical significance of the co-expression of K-sam and KGF in gastric carcinomas. A total of 136 primary gastric tumors were investigated by staining with antibodies against K-sam and KGF. K-sam expression on cancer cells and KGF expression on fibroblasts was estimated. The relationship between the K-sam and/or KGF expression and the clinicopathological characteristics were analyzed. K-sam expression was positive in 42 (31%) of 136 gastric carcinomas. K-sam expression was positively correlated with scirrhous cancer (p

48 Background: Programmed cell death (PD) -1, one of immune checkpoint molecules, expresses on T cells and induces immune tolerances in tumor microenvironment by binding to the ligand PDL-1 on the cancer cells. The clinical effect of immune checkpoint inhibitors such as anti-PD-1/PDL-1 antibody was demonstrated in various cancer including malignant melanoma, lung cancer and gastric cancer. The development of biomarkers for case selection that these inhibitors are effective will be in urgent need. We previously showed that neutrophil-lymphocyte ratio (NLR), a marker for general immune response, was related with postoperative recurrence and advanced stage of gastric cancer. In this study, we report the association of pretreatment NLR with PD-1/PDL-1 expression in the primary tumor of gastric cancer. Methods: Using immunohistochemistry, we retrospectively examined the expression of PDL-1 and infiltration of PD-1+ cells in primary tumor from 180 patients who had undergone surgery for gastric cancer between 2007 and 2010 at the Department of Surgical Oncology of Osaka City University. Results: Positive expression of PDL-1 was observed in 78 (43%) patients. PDL-1 expression was correlated with tumor infiltrated PD-1+ cells and related poor prognosis of the patients with Stage II/III. NLR was correlated with pathological stage and lymph node metastasis. In the positive PDL-1 group, NLR was significantly increased compared with negative group. However, the number of infiltrated PD-1+ cells was not correlated with NLR. Conclusions: PDL-1 expression in gastric cancer tissues was associated with pretreatment NLR, indicating that local immune suppression could be reflected in the systemic immune responses. Our data also suggested that NLR might be one of surrogate marker for PD-1/PDL-1 blockade therapy for gastric cancer.

Remnant gastric cancer (RGC) and gastric stump cancer after distal gastrectomy (DG) are recognized as the same clinical entity. In this review, the current knowledges as well as the non-settled issues of RGC are presented. Duodenogastric reflux and denervation of the gastric mucosa are considered as the two main factors responsible for the development of RGC after benign disease. On the other hand, some precancerous circumstances which already have existed at the time of initial surgery, such as atrophic gastritis and intestinal metaplasia, are the main factors associated with RGC after gastric cancer. Although eradication of Helicobacter pylori (H. pylori) in remnant stomach is promising, it is still uncertain whether it can reduce the risk of carcinogenesis. Periodic endoscopic surveillance after DG was reported useful in detecting RGC at an early stage, which offers a chance to undergo minimally invasive endoscopic treatment or laparoscopic surgery and leads to an improved prognosis in RGC patients. Future challenges may be expected to elucidate the benefit of eradication of H. pylori in the remnant stomach if it could reduce the risk for RGC, to build an optimal endoscopic surveillance strategy after DG by stratifying the risk for development of RGC, and to develop a specific staging system for RGC for the standardization of the treatment by prospecting the prognosis.

Introduction: Anaplastic pancreatic cancer (APC) is a rare subtype of pancreatic ductal adenocarcinoma (PDA). The prognosis of APC is poorer than that of ordinary PDA. There is no established therapeutic strategy as well as PDA. In this study, we compared the expression of molecular markers in intratumoral different lesions which are undifferentiated lesion (UL) and ductal lesion (DL) to reveal progression pattern of APC and hold important clue for the therapy of APC. Materials & Methods: Formalin fixed paraffin embedded blocks were made from the primary APC tissues obtained from 6 patients. Each block was manipulated for staining with Hematoxylin and Eosin (H&E) and immunohistochemistry (IHC) for SOX9, E-cadherin, vimentin, ZEB-1, Snail, N-cadherin, CD24 and CD44. Using H&E slice, each sample was divided from cancerous lesion and non-cancerous lesion. Furthermore, cancerous lesion were divided from DL and UL. And then, for each marker, the intensity of staining of UL was compared with that of DL. The intensity was scored from 0 to 3. The relation between DL and UL was estimated based on the intensity score of each sample. Results: The proportion of DL to all cancerous lesion was 0.5% to 32%. The score of SOX9 was all 3 except one case in both lesions. Although the expression of E-cadherin was almost negative in UL, DL showed various scores. About vimentin, the intensity in UL was largely 2 and 3. In contrast, that of DL was very weak or none. The score of ZEB1 was 0 or 1 in DL and 1 or 3 in UL. Although Snail showed various scores in both regions, the score was mostly higher in UL than in DL. The score of N-cadherin expression was comparatively high in UL. CD24 and CD44 were not almost expressed in DL. In UL, the expression of these markers were various intensity. Disscusion: In the current study, it was suggested that APC might be derived from PDA by showing the expression of SOX9. Previous studies were reported from the view of KRAS mutation and cytokeratin expression about the origin of APC. However, recent studies were reported that these markers were often expressed even in other pancreatic neoplasm. Furthermore the expression of SOX9 is only identified in PDA among pancreatic neoplasms. Also, it was suggested that UL might change from DL through EMT by confirming the difference of the expression pattern of markers relating EMT in DL and UL. Because the expression of CD24 and CD44 varied in each case, it is unclear whether the stemness concerned with the progression to APC in our study. We also need to estimate the other stem cell markers including CD133, Oct3/4 or Nanog. Conclusion: It was suggested that EMT might induce the progression from PDA to APC. Citation Format: Kotaro Miura, Kenjiro Kimura, Ryosuke Amano, Sadaaki Yamazoe, Go Ohira, Kohei Nishio, Masatsune Shibutani, Katsunobu Sakurai, Hisashi Nagahara, Takahiro Toyokawa, Naoshi Kubo, Hiroaki Tanaka, Kazuya Muguruma, Hiroshi Otani, Masakazu Yashiro, Kiyoshi Maeda, Masaichi Ohira, Kosei Hirakawa. Epithelial mesenchymal transition may contribute to anaplastic change of pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5276. doi:10.1158/1538-7445.AM2015-5276

Background: Autophagy is an intracellular degradation system that is induced under starvation or hypoxia. Recently, autophagy has been reported to be associated with carcinogenesis and tumor progression. The significance of autophagy in gastric cancer progression remains controversial. Microtubule-associated protein light chain 3 (LC3) is a component of autophagosomes that stimulate autophagy. There are 3 types of LC3 gene family members, LC3A, LC3B and LC3C. LC3A and LC3B were recently reported to be associated with autophagy in LC3 members. The aim of this study was to evaluate the significance of an autophagy protein, LC3, in gastric cancer. Materials and Methods: A diffuse-type gastric cancer cell line, OCUM-2MD3, was used in this study. Effect of starvation on the expression level of LC3A and LC3B mRNA of OCUM-2MD3 cells was examined by RT-PCR under glucose free condition. A total of 528 patients who underwent resection of a primary gastric cancer were enrolled. The correlation between the clinicopathological features of 528 primary gastric carcinomas and LC3 expression was examined by immunohistochemistry. Results: Expression level of LC3A and LC3B mRNA significantly increased five and two times respectively in OCUM-2MD3 under glucose free conditions compared to that under high glucose conditions. Immunohistochemical study showed that LC3 expression was positive in 94 (17.8%) of 528 gastric cancers. There was a statistically significant correlation between LC3 positive-expression and histologic type (p = 0.002), lymphatic invasion (p Conclusion: LC3 might play an important role for autophagy of gastric cancer cells in starvation condition. LC3 is associated with progression of gastric cancer, and is a useful prognostic marker for patients with gastric cancer. Citation Format: Go Masuda, Masakazu Yashiro, Hiroaki Kasashima, Haruhito Kinoshita, Tatsunari Fukuoka, Tamami Morisaki, Tsuyoshi Hasegawa, Katsunobu Sakurai, Takahiro Toyokawa, Naoshi Kubo, Hiroaki Tanaka, Kazuya Muguruma, Masaichi Ohira, Kosei Chung. Significance of an autophagy protein, microtubule-associated protein light chain 3 (LC3), in gastric cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 992. doi:10.1158/1538-7445.AM2015-992

Background: Cancer-associated fibroblasts (CAF) have been suggested to be associated with the progression of gastric cancer cells. Hypoxic region was frequently found in cancer microenvironment of gastric cancer. The aim of our study was to clarify the interaction between CAF and gastric cancer cells under hypoxia. We found that hypoxia up-regulated the growth and interaction between the CAF and gastric cancer cells through SDF1α/CXCR4 dependent mechanism. Materials and Methods: Six gastric cancer cell lines and three fibroblasts cell lines were used. The expression level of CXCR4 under hypoxia was examined by RT-PCR, Western blot. SDF1 production from CAF under hypoxia wad examined by ELISA. The proliferation of diffuse type gastric cancer cells that were co-culture with CAF was examined under hypoxia, in comparison with that under normoxia. Proliferation activity of diffuse type gasitrc cancer cells was examined in the presence of CAF, CXCR4 inhibitor, FGFR2 inhibitor, HIF1α siRNA or CXCR4 siRNA under hypoxia, in comparison with that under normoxia. Results: The proliferation of diffuse type gastric cancer cells was significantly increased in the presence of CAF. The proliferation - stimulating effects by CAF were evident in hypoxia, in compared with normoxia. CXCR4 expression of diffuse type gastric cancer cells was significantly increased under hypoxia, but decreased FGFR2 expression under hypoxia. HIF1α siRNA significantly down-regulated CXCR4 expression level in hypoxia. SDF1 from CAF was increased under hypoxia, and was also decreased by HIF1α knockdown. FGFR2 inhibitor significantly decreased he proliferation-stimulating activity of CAF under normoxia, but not under hypoxia. Although, CXCR4 inhibitor significantly decreased the proliferation-stimulating activity of CAF under hypoxia, but not under normoxia. These findings suggested that the key signaling associated with the growth-interaction between CAF and gastric cancer cells in hypoxic condition might be different from those in normoxic condition. Conclusion: Hypoxic microenvironment switch the driver signaling from FGF7/FGFR2 to SDF-1/CXCR4 in diffuse type of gastric cancer. CXCR4/SDF1 axis might play an important role for the proliferation of gastric cancer in hypoxic tumor microenvironment. Citation Format: Haruhito Kinoshita, Masakazu Yashiro, Hiroaki Kasashima, Go Masuda, Tamami Morisaki, Tatsunari Fukuoka, Katsunobu Sakurai, Takahiro Toyokawa, Kenjiro Kimura, Naoshi Kubo, Hiroaki Tanaka, Kazuya Muguruma, Masaichi Ohira, Kosei Hirakawa. SDF1α / CXCR4 axis might be associated with growth-interaction between cancer-associated fibroblasts and gastric cancer cells in hypoxic tumor microenvironment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 436. doi:10.1158/1538-7445.AM2015-436

Purpose: Lysyl oxidase families are involved in a variety of pathological processes, including cancer progression. Lysyl oxidase-like 2 (LOXL2) in the tumor stroma was mainly expressed in fibroblasts, which are a major stromal compartment of gastric cancer. Significance of LOXL2 remains unclear in gastric carcinoma. The aim of this study was to clarify the role of fibroblast-derived LOXL2 in the development of gastric cancer. Methods: Two gastric cancer cell lines, OCUM-12 and NUGC-3, and cancer-associated fibroblasts (CAF) were used in this in vitro study. The effect of fibroblast-derived LOXL2 on the motility of gastric cancer cells was analyzed by wound-healing assay, double-chamber invasion assay, and western blot. The correlation between LOXL2 expression and the clinicopathological features of 548 primary gastric carcinomas was examined by immunohistochemistry. Results: LOXL2 mRNA expression of CAF, was significantly higher than that of normal fibroblasts. CAF significantly stimulated the migration and invasion of OCUM-12 and NUGC-3 cells. This motility-stimulating ability of CAF was inhibited by LOXL2 siRNA. Western blot analysis indicated that phosphorylation of focal adhesion kinase (FAK) in cancer cells was increased by the conditioned medium from CAF, and was not affected by the conditioned medium from LOXL2 siRNA-treated CAF. Immunohistochemical study indicated that LOXL2 expression in stromal cells was significantly associated with tumor invasion depth, lymph node metastasis, lymphatic invasion, venous invasion, and peritoneal dissemination. The overall survival of all patients with LOXL2-positive stromal cells was significantly poorer than those with LOXL2-negative stromal cells. Multivariable logistic regression analysis revealed that LOXL2 expression in stromal cells was an independent predictive parameter for the overall survival of patients with gastric cancer. Conclusion: LOXL2 from CAF may stimulate the motility of gastric cancer cells. LOXL2 expression in stromal cells may be a useful prognostic factor for patients with gastric cancer. Citation Format: Hiroaki Kasashima, Masakazu Yashiro, Kisyu Kitayama, Go Masuda, Haruhito Kinoshita, Katsunobu Sakurai, Takahiro Toyokawa, Naoshi Kubo, Hiroaki Tanaka, Kazuya Muguruma, Masaichi Ohira, Kosei Hirakawa. Lysyl oxidase-like 2 (LOXL2) from cancer-associated fibroblasts stimulates the progression of gastric carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5063. doi:10.1158/1538-7445.AM2015-5063

Background: Recently, the preoperative immune-nutritional status has been reported to correlate with the long-term survival in colorectal cancer (CRC) patients. Markers of the immune-nutritional status, such as the serum albumin concentration and prognostic nutritional index (PNI) were reported to have prognostic value. However, there have been no reports on the relationship between the controlling nutritional status (CONUT) score and the clinical outcome after curative surgery for CRC. We herein evaluated the prognostic significance of the CONUT score in patients with CRC, and compared the accuracy of the CONUT score and the PNI as a predictor of survival. Materials and methods: We retrospectively reviewed a database of 204 patients who underwent curative surgery for Stage II/III CRC between 2004 and 2009. Patients were divided into two groups according to the CONUT score and the PNI. Result: The low-CONUT group (N = 150) had two or fewer points, while the high-CONUT group (N = 54) had a score of three points or more. The low-PNI group (N = 27) had a PNI < 40, while the high-PNI group (N = 177) had a PNI of 40 or more. The five-year relapse-free survival (RFS) rate was 73.0% in the low-CONUT group and 53.6% in the high-CONUT group, which was significantly different (p = 0.0018). The five-year RFS was 51.5% in the low-PNI group and 70.4% in the high-PNI group, there was a significant difference between the low PNI group and the high PNI group (p = 0.0162). In a univariate analysis of the postoperative survival based on the clinicopathological factors, the sex, age, lymphatic vessel invasion, venous invasion, lymph node metastasis, preoperative CA19-9 level, the CONUT score and the PNI were associated with the RFS. A multivariate analysis showed that sex (Odds ratio (OR) = 2.012, 95%CI; 1.135-3.685, p = 0.0164) and the preoperative CA19-9 (OR = 2.194,95%CI; 1.054-4.271, p = 0.0364) were independently associated with the RFS. The five-year cancer-specific survival (CSS) rate was significantly higher at 92.7% in the low-CONUT group than that of 81.0% in the high-CONUT group (p = 0.0016). The five-year CSS was 71.2% in the low PNI group and 92.3% in the high PNI group, which was also significantly different (p = 0.0155). In a univariate analysis for the CSS, lymph node metastasis, the preoperative CA19-9 level, the CONUT score and the PNI were significantly associated with the CSS. A multivariate analysis showed that lymph node metastasis (OR = 4.080, 95%CI; 1.476-13.089, p = 0.0097) and the CONUT score (OR = 3.661, 95%CI;1.084-11.234, p = 0.0376) were independently associated with the CSS. Conclusion: This study suggested that the CONUT score is a strong independent predictor of the survival among CRC patients. The CONUT score is a more sensitive prognostic factor than the PNI. Citation Format: Yasuhito Iseki, Masatsune Shibutani, Kiyoshi Maeda, Hisashi Nagahara, Hiroshi Ohtani, Tetsuro Ikeya, Kenji Sugano, Sadaaki Yamazoe, Katsinobu Sakurai, Kenjiro Kimura, Takahiro Toyokawa, Ryosuke Amano, Naoshi Kubo, Hiroaki Tanaka, Kazuya Muguruma, Masaichi Ohira, Kosei Hirakawa. Impact of the preoperative Controlling Nutritional Status (CONUT) score on the clinical outcome after curative surgery for colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3418. doi:10.1158/1538-7445.AM2015-3418

Background: Markers of the systemic inflammatory response have been recognized to correlate with prognosis in patients with various types of cancers. The pretreatment albumin to globulin ratio (AGR) has been reported to correlate with the long-term survival in patients with various cancers. However, there are no reports regarding the correlation between the pretreatment AGR and chemotherapeutic outcomes in patients with unresectable metastatic colorectal cancer. The aim of this study was to evaluate the prognostic significance of the pretreatment AGR in patients with unresectable metastatic colorectal cancer. Methods: A total of 66 patients with unresectable metastatic colorectal cancer who underwent palliative chemotherapy for metastatic tumors were enrolled. The AGR was calculated as follows: Albumin/(Total protein - Albumin). Results: The median pretreatment AGR was 1.254 (range: 0.849-1.840); we set 1.25 as the cut-off according to this value. Based on the cut-off value of 1.25, 34 patients were classified into the high-AGR group and 32 patients were classified into the low-AGR group. The high-AGR group had a significantly higher chemotherapeutic disease control rate (p = 0.040) and better progression-free survival (p = 0.0171) and overall survival (p = 0.0360) rates than the low-AGR group. Among the clinicopathological factors, the AGR was identified to be the only prognostic factor for progression-free survival (Hazard Ratio: 2.527, 95% Confidence Interval: 1.152-5.545, p = 0.021) and overall survival (Hazard Ratio: 1.946, 95% Confidence Interval: 1.033-3.668, p = 0.039). Conclusions: The pretreatment AGR is a useful prognostic marker in patients with unresectable metastatic colorectal cancer who receive palliative chemotherapy. Citation Format: Masatsune Shibutani, Kiyoshi Maeda, Hisashi Nagahara, Hiroshi Ohtani, Yasuhito Iseki, Tetsuro Ikeya, Kenji Sugano, Katsunobu Sakurai, Sadaaki Yamazoe, Kenjiro Kimura, Takahiro Toyokawa, Ryosuke Amano, Naoshi Kubo, Hiroaki Tanaka, Kazuya Muguruma, Masaichi Ohira, Kosei Hirakawa. The albumin to globulin ratio predicts chemotherapeutic outcomes in patients with unresectable metastatic CRC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 577. doi:10.1158/1538-7445.AM2015-577

A 54-year-old woman with scirrhous gastric cancer in the upper third area was admitted to our hospital. She was diagnosed with advanced gastric cancer that was inoperable due to peritoneal metastasis, so weekly paclitaxel (PTX) therapy was carried out. After 2 courses, malignant ascites completely disappeared and bilateral hydronephrosis improved. After 4 courses, no ascites or hydronephrosis were seen. Only neutropenia (grade 2) and alopecia (grade 1) were observed as adverse events during the therapy, but no major adverse events were noted. We also investigated the concentration of paclitaxel in ascites. Two hours after intravenous injection of PTX, the concentration of PTX in ascites rose over the reported cytotoxic dose of PTX, and this available concentration was maintained after 48 hours. Weekly paclitaxel therapy is suggested to be one of the safe and useful treatments for advanced gastric cancer with malignant ascites.

45 Background: Tumor markers such as carcinoembryonic antigen (CEA) and CA 19-9 are both widely used in the follow up of patients with gastric cancer. However, there are no definitive predictive markers for postopetrative recurrence. It has been reported that preoperative neutrophil lymphocyte ratio (NLR) was associated with prognosis of patients with gastrointestinal cancer. The aim of this study was to examine the impact of postoperative NLR on prediction for postoperative recurrence of gastric cancer. Methods: We retrospective reviewed data from 318 patients with Stage II/III gastric cancer who underwent curative surgical resection followed by adjuvant chemotherapy for between 2006 and 2013. Patients treated with preoperative chemotherapy or multiple cancers were excluded. Results: We found 118 recurrent diseases which mainly included 47 cases with peritoneal dissemination, 27 with distant lymph node metastasis and 24 with liver metastasis. Postoperative NLR was calculated every 6 months and the data at the time of recurrence or last survival were used for analysis. In univariate analysis, histological diffuse type, mascroscopical type 4 cancer, regional lymph node metastasis, lymphatic invasion in primary tumor, tumor diameter, elevated CEA or CA19-9, and elevated NLR were associated with poor prognosis. In multivariate analysis, we found that elevated CA19-9 and NLR were independent predictive markers. Increased NLR was associated with diffuse type, peritoneal dissemination, elevated CEA and preoperative NLR but not with adverse effect of adjuvant chemotherapy. Conclusions: The postoperative NLR might be one of the surrogate markers for recurrence after curative surgery for patients with Stage II/III gastric cancer.

To evaluate the prognostic significance of the lymphocyte to monocyte ratio (LMR) in patients with unresectable metastatic colorectal cancer who received palliative chemotherapy.A total of 104 patients with unresectable metastatic colorectal cancer who underwent palliative chemotherapy were enrolled. The LMR was calculated from blood samples by dividing the absolute lymphocyte count by the absolute monocyte count. Pre-treatment LMR values were measured within one week before the initiation of chemotherapy, while post-treatment LMR values were measured eight weeks after the initiation of chemotherapy.The median pre-treatment LMR was 4.16 (range: 0.58-14.06). We set 3.38 as the cut-off level based on the receiver operating characteristic curve. Based on the cut-off level of 3.38, 66 patients were classified into the high pre-treatment LMR group and 38 patients were classified into the low pre-treatment LMR group. The low pre-treatment LMR group had a significantly worse overall survival rate (P = 0.0011). Moreover, patients who demonstrated low pre-treatment LMR and normalization after treatment exhibited a better overall survival rate than the patients with low pre-treatment and post-treatment LMR values.The lymphocyte to monocyte ratio is a useful prognostic marker in patients with unresectable metastatic colorectal cancer who receive palliative chemotherapy.

Background The endoscopic treatment has been increasingly used for T1 esophageal squamous cell carcinoma (ESCC). However, this therapy is sometimes incomplete if the depth of the T1 primary tumor reaches the muscularis mucosae (MM) or submucosal layer (SM) because these tumors have relatively high incidences of lymph node metastasis. However, no previous report on the predictive factor of nodal metastasis determined by evaluating primary tumor specimens of patients with ESCC is available. Patients and Methods A total of 55 patients with T1 ESCC invading as deep as the submucosal layer who underwent curative esophagectomy were examined. We investigated the significance of the immunohistochemical stainings of VEGF-C and E-cadherin in the primary tumor and tumor budding for prediction of nodal metastasis. Results Metastasis to the regional lymph nodes was observed in 26 cases (47.3%) in this setting. VEGF-C expression and reduced E-cadherin expression in the primary tumor was observed in 32 (58.1%) and 38 cases (69.1%), respectively. High-grade tumor budding was observed in 29 cases (52.7%). E-cadherin expression and tumor budding were closely correlated with nodal metastasis (p = 0.039 and Conclusion After the endoscopic treatment, additional therapy, such as surgery or chemoradiotherapy, may be required if reduced E-cadherin expression and high-grade tumor budding are observed in the primary tumor specimen. Citation Format: Naoshi Kubo, Masaichi Ohira, Katsunobu Sakurai, Takahiro Toyokawa, Hiroaki Tanaka, Kazuya Muguruma, Masakazu Yashiro, Kiyoshi Maeda, Naoyoshi Onoda, Kosei Hirakawa. Tumor budding and E-cadherin expression are useful predictors of nodal involvement in T1 esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3818. doi:10.1158/1538-7445.AM2014-3818