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Background: Glucose transporters (GLUTs) are highly expressed in various cancers. However, the implications of these variable expression patterns are unclear. This study aimed to clarify the correlation between class I GLUT expression patterns and clinical outcomes in non-small cell lung cancer (NSCLC), including their potential role in inflammatory signaling., Methods: Biopsy tissues from 132 patients with NSCLC (92 adenocarcinomas [ADC] and 40 squamous cell carcinomas [SQCC]) were analyzed. mRNA expression levels of class I GLUTs (solute carrier 2A [SLC2A]1, SLC2A2, SLC2A3, and SLC2A4) and inflammation-related molecules (toll-like receptors TLR4, RelA/p65, and interleukins IL8 and IL6) were measured. Cellular localization of GLUT3 and GLUT4 was investigated using immunofluorescence., Results: Single, combined, and negative GLUT (SLC2A) expression were observed in 27/92 (29.3%), 27/92 (29.3%), and 38/92 (41.3%, p < 0.001) of ADC and 8/40 (20.0%), 29/40 (72.5%, p < 0.001), and 3/40 (7.5%) of SQCC, respectively. In ADC, the single SLC2A3-expressed group had a significantly poorer prognosis, whereas the single SLC2A4-expressed group had a significantly better prognosis. The combined expression groups showed no significant difference. SLC2A expression was not correlated with SQCC prognosis. SLC2A4 expression correlated with lower IL8 expression. GLUT3 and GLUT4 expressions were localized in the tumor cytoplasm., Conclusions: In lung ADC, single SLC2A3 expression correlated with poor prognosis, whereas single SLC2A4 expression correlated with better prognosis and lower IL8 expression. GLUT3 expression, which is increased by IL8 overexpression, may be suppressed by increasing the expression of GLUT4 through decreased IL8 expression., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background/aim: Clinical staging in the eighth edition of the Union for International Cancer Control TNM classification (TNM8) is reported to predict the prognosis of patients with gastric cancer. However, there have been no reports on using the TNM8 for prognostic stratification of patients with adenocarcinoma of the esophagogastric junction (AEG). This study aimed to investigate whether it was possible to stratify the prognosis of patients who underwent curative surgery for Siewert type II/III AEG according to the TNM8 clinical stage (cStage)., Patients and Methods: This study included patients with Siewert type II/III AEG who underwent curative surgery between 2000 and 2019 at Kanagawa Cancer Center. Those who received neoadjuvant chemotherapy were excluded. We investigated the survival of patients with AEG of each TNM8 cStage., Results: This study included 138 patients, among whom 102 (74%) had Siewert type II and 36 (26%) had Siewert type III AEG. A total of 50, 38, 43, and seven patients were classified with cStage I, II, III, and IV, respectively. The median duration of follow-up of the survivors was 54.7 months. The 5-year overall survival rate of the entire cohort was 65.8%, whereas for patients with cStage I, II, III and IV was 81.6%, 69.0%, 54.3% and 14.3%, respectively. The hazard ratio with reference to cStage I was 1.83, 3.07, and 8.13 for cStage I, III, and IV, respectively, increasing in a stepwise manner., Conclusion: TNM8 Clinical staging is able to stratify the prognosis of patients with Siewert type II/III AEG., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Most human malignant neoplasms show loss of primary cilia (PC). However, PC are known to be retained and involved in tumorigenesis in some types of neoplasms. The PC status in lung carcinomas remains largely uninvestigated. In this study, we comprehensively assessed the PC status in lung carcinomas. A total of 492 lung carcinomas, consisting of adenocarcinomas (ACs) (n = 319), squamous cell carcinomas (SCCs) (n = 152), and small cell lung carcinomas (SCLCs) (n = 21), were examined by immunohistochemical analysis using an antibody against ARL13B, a marker of PC. The PC-positive rate was markedly higher in SCLCs (81.0%) than in ACs (1.6%) and SCCs (7.9%). We subsequently performed analyses to characterize the PC-positive lung carcinomas further. PC-positive lung carcinomas were more numerous and had longer PC than normal cells. The presence of PC in these cells was not associated with the phase of the cell cycle. We also found that the PC were retained even in metastases from PC-positive lung carcinomas. Furthermore, the hedgehog signaling pathway was activated in PC-positive lung carcinomas. Because ARL13B immunohistochemistry of lung carcinoids (n = 10) also showed a statistically significantly lower rate (10.0%) of PC positivity than SCLCs, we searched for a gene(s) that might be upregulated in PC-positive SCLCs compared with lung carcinoids, but not in PC-negative carcinomas. This search, and further cell culture experiments, identified HYLS1 as a gene possessing the ability to regulate ciliogenesis in PC-positive lung carcinomas. In conclusion, our findings indicate that PC are frequently present in SCLCs but not in non-SCLCs (ACs and SCCs) or lung carcinoids, and their PC exhibit various specific pathobiological characteristics. This suggests an important link between lung carcinogenesis and PC., (Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Splenic hilar lymphadenectomy is not recommended for advanced proximal gastric cancer that does not invade the greater curvature according to the results of the previous studies. The efficacy of splenic hilar lymphadenectomy for type II and type III adenocarcinomas of the esophagogastric junction and easy spread to the greater curvature of the stomach remains unclear. This study aimed to investigate the efficacy of splenic hilar lymphadenectomy and identify the risk factors for metastasis to splenic hilar nodes., Methods: We examined patients who underwent R0/1 gastrectomy for Siewert types II and III at a single high-volume center in Japan. We analyzed the metastatic incidence, therapeutic value index, and risk factors for splenic hilar lymph node metastasis., Results: We examined 126 patients (74, type II; 52, type III). Splenectomy was performed in 76 patients. Metastatic incidence and the therapeutic value index of splenic hilar lymph nodes in patients with type II and type III tumors were 4.5% and 0, and 21.9% and 9.4, respectively. In the patients who underwent splenectomy, we identified Siewert type III tumors (odds ratio: 6.93, 95% confidence interval: 1.24-38.8, p = 0.027) and tumor location other than the lesser curvature (odds ratio: 7.36, 95% confidence interval: 1.32-41.1, p = 0.023) to be independent risk factors. The metastatic incidence (46.2%) and therapeutic value index (15.4) were high in patients with both risk factors., Conclusions: Splenic hilar lymphadenectomy may contribute to the survival of patients with Siewert type III tumors, especially when the predominant location is not the lesser curvature., Competing Interests: Declaration of competing interest Yasushi Rino has received speaker honorariums and research grants from Daiichi Sankyo, Johnson & Johnson, Otsuka, Lilly, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Abbott Nutrition, Asahi Kasei, Tsumura & Co., Covidien, Zeria Pharmaceutical and EA Pharma. The other authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: There are two distinct etiologies of esophago-gastric junctional adenocarcinomas (EGJACs): one associated with extensive gastric mucosal atrophy (GA), resembling non-cardiac gastric cancers; and the other related to gastro-esophageal reflux disease, resembling esophageal adenocarcinoma. In this study, we investigated the associations between the visceral fat area (VFA) and EGJACs separately in the two subtypes of EGJACs, depending on the extent of background GA., Methods: Sixty-four consecutive patients with EGJACs (Siewert type 2) were enrolled from a population-based database in Akita Prefecture, Japan, between 2014 and 2019. Two age- and sex-matched healthy controls were randomly assigned to each EGJAC case. The extents of GA were evaluated endoscopically, and the VFA values were measured based on computed tomography images. Logistic regression analyses were performed to investigate the associations between EGJACs and the VFA., Results: Study subjects were classified into 2 subgroups depending on the extent of endoscopic GA: 29 (45.3%) without and 35 (54.7%) with extensive GA. Multivariable regression analyses revealed that a VFA of ≥100 cm 2 was significantly associated with EGJACs in subjects without extensive GA [odds ratio (95% confidence interval): 2.65 (1.08-6.54)], while there was no such association in subjects with extensive GA [odds ratio (95% confidence interval): 1.52 (0.60-3.83)]., Conclusions: The contribution of the VFA to the etiology of EGJACs seems to differ depending on the extent of background GA, with the VFA more prominently associated with EGJACs in subjects without extensive GA than in those with it, providing further rationale concerning the heterogeneous nature of EGJAC etiology.

Introduction: This study explored the predictors of a histological aggressive component in ground glass opacity-containing lung adenocarcinoma., Methods: Of the 2388 patients who underwent resection for lung cancer at our institute between 2017 and 2020, we collected data on the 501 patients with ground glass opacity-containing adenocarcinoma with a total diameter of ≤2 cm. Using a historical cohort, we identified histological aggressive components that were related to a poor prognosis in early-stage adenocarcinoma. A multivariable analysis was conducted to identify predictors for the presence of a histological aggressive component., Results: Lymphovascular invasion and predominant micropapillary or solid patterns were identified as histological aggressive components by a prognostic analysis using a historical cohort. Of the 501 patients included, 36 (7.2%) had at least one histological aggressive component. A multivariate analysis showed that a consolidation/tumour ratio > 0.5 (P < 0.01), maximum standardized uptake value on positron emission tomography ≥1.5 (P = 0.01) and smoking index >20 pack-years (P = 0.01) were predictors of the presence of a histological aggressive component. A total of 98% of cases without any of the above factors did not have a histological aggressive component., Conclusions: Approximately 7% of ground glass opacity-containing small adenocarcinomas contained histological aggressive component. A consolidation/tumour ratio > 0.5, maximum standardized uptake value ≥ 1.5 and smoking index >20 pack-years were predictors for such cases. These predictors may be useful for screening patients with a potentially high risk of a poor prognosis and for prioritizing resection without delay., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: While an association between esophago-gastric junctional adenocarcinomas (EGJACs) and obesity, especially visceral obesity, has been suggested in Western countries, the association remains unclear in Asia, including Japan. In this population-based case-control study, we investigated the association between EGJACs and obesity., Methods: To perform near-population-based data collection for all early-stage EGJACs occurring in Akita Prefecture from 2014 to 2019, clinical data, including endoscopic and computed tomography (CT) findings, were collected from 11 cancer treatment base hospitals in the area. Age- and gender-matched controls were extracted at a case-to-control ratio of 1:2 from healthy subjects who received health checkups in the same area. The visceral fat area (VFA) was calculated using CT images. Logistic regression analyses were performed to investigate the associations between EGJACs and obesity-related parameters., Results: In total, 74 EGJAC cases (62 males, median age of 70 years old) and 148 controls were extracted. Multivariable analyses showed a significantly negative association between the BMI and EGJACs and a significantly positive association between the VFA and EGJACs with odds ratios (ORs) (95% confidence intervals [CIs]) of 0.65 (0.53-0.80) and 1.01 (1.01-1.02), respectively. These findings were confirmed in another dataset (40 EGJACs and 80 controls). In addition, as a categorical variable, VFA ≥ 100 cm 2 showed a significantly positive association with EGJACs (OR [95% CI] 1.96 [1.02-3.76])., Conclusions: We found paradoxical associations between EGJACs and obesity-related parameters (BMI vs. VFA) in a Japanese population, suggesting a potentially pivotal role of the VFA rather than the BMI as a risk factor for EGJACs., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: The current WHO classification proposed high-grade biliary intraepithelial neoplasm (BilIN) and intracholecystic papillary neoplasm (ICPN) as precursors of the gallbladder carcinoma (GBC). Herein, conventional GBCs (cGBCs) were pathologically examined with respect to these two precursors., Methods: Forty-seven cases of GBC with grossly visible invasions were collected from Fukui Saiseikai Hospital. The association of two precursors was analyzed referring to pathologic features of cGBCs and post-operative survival., Results: 20 cGBCa (42.6%) were associated with either of two precursors in the surrounding mucosa: high-grade BilIN in 15 cases (31.9%) or ICPN in 5 cases (10.6%). Association of precursors was not related to gross types of and histological differentiation of cGBC. cGBCs without precursors showed frequent vascular/perineural invasion and lymph node metastasis, though cGBCs with and without precursors presented a similar post-operative survival. High-grade BilIN and ICPN associated with cGBCs showed more complicated cytoarchitectural features compared with those with no or focal invasion., Conclusion: More than 40% of cGBCs were associated with high-grade BilIN or ICPN, and the former was a frequent precursor. cGBCs without precursors showed aggressive pathologic features. Clinical detection of these precursors may make early treatment of cGBCs possible., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: The new grading system proposed by the Pathology Committee of the International Association for the Study of Lung Cancer in 2020 was based on the combination of the histologically predominant subtype and high-grade component. Because the predominant subtypes are associated with characteristic subsets, unique subsets can be identified by this grading system., Methods: We analyzed the clinicopathologic, genotypic, and prognostic features of a cohort of 781 consecutive patients with invasive nonmucinous adenocarcinoma of the lung., Results: Grade 3 tumors were associated with younger age, male sex, a higher smoking dose, and aggressive features (tumor size, lymph node metastasis, stage, lymphovascular invasion, and pleural invasion). Recurrence-free survival and 3-year overall survival were well-stratified according to tumor grade, and the differences were confirmed with multivariate analysis using the Cox proportional hazard model. Radiologically, most grade 3 tumors exhibit a solid nodular pattern on computed tomography images and a high maximum standardized uptake value with positron emission tomography. Genotypically, 43% of the grade 3 adenocarcinomas lacked any driver mutations, although one of the driver mutations was detected in 79% of grade 1 or 2 tumors. Patient age, positive smoking history, solid nodule on computed tomography image, and higher maximum standardized uptake value were identified as significant preoperative predictive factors of grade 3 tumors, with a prediction rate greater than 90%., Conclusions: Besides stratifying the patient outcomes, the new grading system characterized unique clinicopathologic subsets and this study suggested that grade 3 tumors could be predicted using the preoperative variables., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Invasive gallbladder carcinoma generally presents as nodular-sclerosing growth. Recently, "polypoid invasive carcinoma (PICA)" showing grossly visible polypoid neoplasm and histologically invasive carcinoma with no adenomatous components was proposed as a neoplastic polyp of the gallbladder., Methods: We herein report five cases of PICA collected from 49 cases of invasive gallbladder carcinoma in comparison with another polypoid preinvasive neoplasm of gallbladder, intracholecystic papillary neoplasm (ICPN)., Results: Polypoid invasive carcinomas were composed of four males and one female with an average age of 74 years. Polypoid lesions were sessile (height ranging from 6 to 10 mm and the largest diameter ranging from 12 to 40 mm), and histologically, polypoid neoplasms presented papillary configuration containing tubular and cribriform components with thin inflammatory, fibrotic stroma. Polypoid carcinoma invaded directly and continuously into the gallbladder wall with destruction of the muscle layer. These patterns of PICA were different from ICPN, showing papillary patterns containing tubular components with fine fibrovascular stalks and with occasional focal stromal invasion but with preserved muscle layer. Post-operative outcome was not favorable in PICA but was favorable in ICPN., Conclusions: Polypoid invasive carcinoma shared several pathological features with ICPN, such as intraluminal polypoid pattern with papillary configurations, but PICAs were invasive adenocarcinoma with destruction of muscle layer while ICPNs were preinvasive neoplasm with occasional focal stromal invasion, thus both should be differentiated from each other., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Pulmonary carcinoid tumors rarely coexist with non-small cell lung carcinoma, and only nine cases have been reported previously. The pathogenesis and origin of these combined tumors remain unclear because of its rarity., Case Presentation: We examined two cases of adenocarcinoma coexisting with a typical or atypical carcinoid tumor: Case 1 was a 77-year-old woman and Case 2 was an 83-year-old woman. Both of these cases had no respiratory symptoms, and underwent pulmonary lobectomies due to incidentally detected lung nodules. Recurrence and metastases were not detected after the surgery. Histologically, carcinoid and adenocarcinoma components were present in both cases. The two components coexisted without mixing with each other. Next-generation sequencing was performed on the two components in these cases. In each case, no common genetic variants were detected., Conclusion: We considered that our cases could histologically and genetically represent collision tumors that did not share common progenitor cells. Comprehensive analyses such as whole genome sequencing could provide important information for elucidating the pathogenesis of adenocarcinoma and carcinoid components., (© 2022. The Author(s).)

Introduction: Because several articles have reported a prognostic association with the radiologic features of ground-glass opacity, we explored whether the histologic presence of a lepidic component had similar significance., Methods: We retrospectively evaluated 380 consecutive surgically resected lung adenocarcinomas (ADCs) of pathologic (p)stage IA. The tumors were classified into lepidic-positive and lepidic-negative ADCs. Clinicopathologic characteristics, radiographic ground-glass opacity status, and disease-free survival were compared between lepidic-positive and lepidic-negative ADCs and between part-solid and solid nodules on computed tomography images., Results: Of the 380 cases, 176 (46.3%) were lepidic-positive ADCs. Of the overall patients with pT1, lepidic-positive ADCs were found to have significantly better recurrence-free survival (5 y, 95.4% versus 87.0%, p = 0.005), but this significance was not reproduced in pT1 subcategories (pT1a, pT1b, and pT1c). Furthermore, the presence of the lepidic component was not an independent prognostic factor in the multivariate analysis (hazard ratio = 0.46 [95% confidence interval: 0.19-1.14], p = 0.09). We also analyzed the extent of the lepidic component with 10% incremental valuables. Although we found that a 10% or greater extent of lepidic component made the recurrence-free survival difference the largest, a clear prognostic impact was not obtained with this cutoff point., Conclusions: Although lepidic-positive ADCs tended to have a favorable outcome, the lepidic component was not a clear independent prognostic factor in pstage I ADC., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: We aimed to examine the characteristics of imaging findings of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) in the lungs of smokers compared with those of non-smokers., Materials and Methods: We included seven cases of AIS and 20 cases of MIA in lungs of smokers (pack-years ≥ 20) and the same number of cases of AIS and MIA in lungs of non-smokers (pack-years = 0). We compared the diameter of the entire lesion and solid component measured on computed tomography (CT) images, pathological size and invasive component diameter measured from pathological specimens, and CT values of the entire lesion and ground-glass opacity (GGO) portions between the smoker and non-smoker groups., Results: The diameters of AIS and MIA on CT images and pathological specimens of the smoker group were significantly larger than those of the non-smoker group (p = 0.036 and 0.008, respectively), whereas there was no significant difference in the diameter of the solid component on CT images or invasive component of pathological specimens between the two groups. Additionally, mean CT values of the entire lesion and GGO component of the lesions in the smoker group were significantly lower than those in the non-smoker group (p = 0.036 and 0.040, respectively)., Conclusion: AIS and MIA in smoker's lung tended to have larger lesion diameter and lower internal CT values compared with lesions in non-smoker's lung. This study calls an attention on smoking status in CT-based diagnosis for early stage adenocarcinoma., (© 2021. The Author(s).)

Introduction: Laparoscopic gastrectomy has become a standard procedure for treatment of gastric cancer, and hence, the opportunity for trainees to perform open gastrectomies may decrease. We investigated whether laparoscopic distal gastrectomy, performed by surgical trainees without sufficient experience performing open gastrectomies, was feasible and safe., Patients and Methods: We compared short-term outcomes in patients when laparoscopic distal gastrectomies were performed by experienced trainees (ET group; n = 124) and inexperienced trainees (IT group; n = 98) from 2013 to 2019., Results: The operation time was significantly shorter in the ET group (median time: 253 minutes vs 286 minutes, P < 0.001). The incidence of grade ≥ 2 postoperative complications did not differ significantly between the groups. In the multivariate analysis, experience performing open gastrectomies was not an independent predictor of postoperative complications., Conclusion: Laparoscopic distal gastrectomies performed by trainees, with insufficient experience performing open gastrectomies, are as feasible and safe as that performed by ET., (© 2020 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Background/aim: Stanniocalcin2 (STC2) is associated with proliferation, invasion, and metastasis in various cancers. We examined the clinical significance of STC2 mRNA expression in patients with colorectal cancer (CRC)., Patients and Methods: Relative expression levels of STC2 mRNA in CRC tissues and corresponding normal mucosa obtained from 202 patients were measured using quantitative real-time reverse transcriptase-polymerase chain reaction., Results: Expression of STC2 mRNA was higher in the cancer tissue than in the adjacent normal mucosa. STC2 mRNA expression in cancer tissues was associated with tumour size, liver metastasis, venous invasion, and lymph node metastasis. High expression of STC2 mRNA was significantly associated with poorer postoperative survival (p=0.0003). Multivariate analysis showed that high expression of STC2 mRNA was an independent predictor of postoperative survival., Conclusion: High expression of STC2 mRNA in CRC tissue may be a useful prognostic marker in patients with CRC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

KRAS -driven lung cancers frequently inactivate TP53 and/or STK11/LKB1 , defining tumor subclasses with emerging clinical relevance. Specifically, KRAS - LKB1 (KL)-mutant lung cancers are particularly aggressive, lack PD-L1, and respond poorly to immune checkpoint blockade (ICB). The mechanistic basis for this impaired immunogenicity, despite the overall high mutational load of KRAS -mutant lung cancers, remains obscure. Here, we report that LKB1 loss results in marked silencing of stimulator of interferon genes (STING) expression and insensitivity to cytoplasmic double-strand DNA (dsDNA) sensing. This effect is mediated at least in part by hyperactivation of DNMT1 and EZH2 activity related to elevated S-adenylmethionine levels and reinforced by DNMT1 upregulation. Ectopic expression of STING in KL cells engages IRF3 and STAT1 signaling downstream of TBK1 and impairs cellular fitness, due to the pathologic accumulation of cytoplasmic mitochondrial dsDNA associated with mitochondrial dysfunction. Thus, silencing of STING avoids these negative consequences of LKB1 inactivation, while facilitating immune escape. SIGNIFICANCE: Oncogenic KRAS -mutant lung cancers remain treatment-refractory and are resistant to ICB in the setting of LKB1 loss. These results begin to uncover the key underlying mechanism and identify strategies to restore STING expression, with important therapeutic implications because mitochondrial dysfunction is an obligate component of this tumor subtype. See related commentary by Corte and Byers, p. 16 . This article is highlighted in the In This Issue feature, p. 1 ., (©2018 American Association for Cancer Research.)

A 63-year-old man was pointed out with a mediastinal tumor on chest computed tomography (CT). On positron emission tomography-CT, fluorodeoxyglucose accumulation with a maximum standardized uptake value of 12.70 was seen in this tumor. Scar-like nodule was found in the apex of the right lung, but no abnormal accumulation was observed in this nodule. The level of carcinoembryonic antigen was abnormally elevated. We performed mediastinal tumorectomy under thoracoscopic surgery. Since arterial oxygen saturation fell during intraoperative one-lung ventilation, we finished the surgery without resection of right apex nodule. Histologically, mediastinal tumor was diagnosed as metastatic adenocarcinoma in lymph node. Because immunohistochemical staining suggested lung adenocarcinoma as the primary site, the right apex nodule was resected. Pathological diagnosis of this nodule was scar fibrosis. No other malignant lesions were detected, and therefore we finally diagnosed this tumor as mediastinal lymph node carcinoma of unknown primary site. The patient was given adjuvant chemotherapy, and at present, 37 months after surgery, the patient remains free of the disease.

Background/aim: To date, there have not been any established biomarkers predicting the efficacy of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). The objective of this study was to evaluate the significance of the aspartate aminotransaminase (AST)/alanine aminotransaminase (ALT) ratio (De Ritis ratio) as a biomarker for mCRPC patients receiving cabazitaxel., Patients and Methods: This study included 74 consecutive docetaxel-refractory mCRPC patients treated with cabazitaxel. It assessed the impact of the pretreatment De Ritis ratio, in addition to conventional clinicopathological parameters, on the oncological outcomes in these patients., Results: After treatment with cabazitaxel, 22 (29.7%) of the 74 patients achieved a prostate-specific antigen (PSA) response; however, there was no significant difference in the PSA response rate between patients with a low De Ritis ratio (<1.35) and those with a high ratio (≥1.35). In this series, the median periods of PSA progression-free survival (PFS) and overall survival (OS) after the introduction of cabazitaxel were 4.2 and 14.7 months, respectively. No significant difference was noted in PSA PFS between the low and high De Ritis ratio groups, whereas OS in the high De Ritis ratio group was significantly poorer compared with that in the low De Ritis ratio group. Univariate analysis showed the significant impact of the De Ritis ratio on OS, but not PFS, in these 74 patients. Furthermore, the De Ritis ratio, in addition to the performance status and lactate dehydrogenase level, was shown to be independently associated with OS on multivariate analysis., Conclusion: Assessment of the De Ritis ratio may provide useful prognostic, but not predictive, information on cabazitaxel therapy in mCRPC patients., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

We report 2 resected cases of patients with non-isolated splenic metastasis of colon cancer. Case 1: A 67-year-old man who underwent partial transverse colectomy and partial hepatectomy for transverse colon cancer and liver metastasis. Approximately 18 months after the operation, splenectomy and partial hepatectomy were performed for metastasis to the spleen and liver. After partial hepatectomy for another recurrence, no signs of new recurrence have been observed for 42 months after splenectomy. Case 2: A 53-year-old woman who presented with bloating. CT and MRI scans revealed masses of the ileocecum, both ovaries, and spleen. We performed right hemicolectomy, total hysterectomy, bilateral salpingo-oophorectomy, pelvic lymphadenectomy, para-aortic lymphadenectomy, omentectomy, and splenectomy. Histological findings showed cecal cancer metastasizing to the bilateral ovaries and spleen. Metastatic splenic tumor is relatively rare(0.3-7.3%). Splenectomy was reported to be an effective treatment modality for isolated splenic metastasis, while that for non-isolated metastasis is uncertain. Surgical resection should be considered even in non-isolated splenic metastasis cases because of the evidence of long-term survival in case 1.

Cancer-associated fibroblast (CAF)-dependent local invasion is the process by which cancer cells invade the extracellular matrix using tracks that have been physically remodeled by CAFs. In the present study, we investigated the process by which the epithelial-mesenchymal transition (EMT) of cancer cells affect CAF-dependent local invasion. Using an in vitro collagen invasion assay, we showed cancer cells undergoing EMT to promote the matrix-remodeling ability of CAFs and thereby enhance CAF-dependent local cancer cell invasion. Platelet-derived growth factor (PDGF)-BB secretion was significantly elevated in cancer cells undergoing EMT, and this induced an increase in the invasion ability of both CAFs and cancer cells. Conversely, knockdown of PDGF-B expression in cancer cells undergoing EMT, or treatment with a PDGF-receptor inhibitor, decreased the invasion ability of both CAFs and cancer cells. By analyzing the gene expression profiles of 442 patients with lung adenocarcinomas, we established that high expression of PDGF-B and presentation of mesenchymal-like tumors were significantly associated with a high rate of disease recurrence and poor patient prognosis. Thus, cancer cells undergoing EMT may accelerate their own ability to invade local tissues via PDGF-BB secretion to promote CAF matrix remodeling. Therefore, targeting PDGF signaling between cancer cells undergoing EMT and CAFs is a promising therapeutic target to inhibit cancer progression and improve patient prognosis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours.

Purpose: To determine the iodine load per body weight (ILPBW) that is minimally required for the detection of pancreatic adenocarcinoma for 80kVp CT imaging., Material and Methods: Institutional review board approval and written informed consent were obtained. Fifty-seven consecutive patients with histopathologically-proven pancreatic adenocarcinoma were assigned to three groups at random according to iodine load (0.5, 0.4, and 0.3gI/kg) and underwent CT at 80kVp. Enhancement of the pancreas and visualization of the tumor were assessed during the pancreatic parenchymal-phase and compared among the three groups. The relationship between the iodine load and tumor conspicuity was also analyzed., Results: The mean CT number of the pancreas (HUpancreas) was higher in the 0.5gI/kg group (158.8HU) than in the 0.4 (121.7HU) and 0.3 (106.6HU) gI/kg groups (P<0.05). Tumor-to-pancreas contrast (HUtumor-to-pancreas) was also higher in 0.5gI/kg group (88.9HU) than in 0.4 (62.2HU) and 0.3 (54.5HU) gI/kg groups (P<0.05). Linear regression between HUpancreas or HUtumor-to-pancreas and ILPBW were expressed as HUpancreas=23.3+263.9×ILPBW (r=0.74, P<0.0001) and HUtumor-to-pancreas=-1.24+174.3×ILPBW (r=0.56, P<0.0001), respectively. The iodine load estimated to achieve an acceptable HUpancreas (>100HU) and HUtumor-to-pancreas (>50HU) were 0.29 and 0.30gI/kg, respectively., Conclusion: An iodine load of 0.3gI/kg was the least amount required for the detection of pancreatic adenocarcinoma at 80kVp CT., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: As one form of tumor invasion, cancer cells can invade the extracellular matrix (ECM) through tracks that have been physically remodeled by cancer-associated fibroblasts (CAFs). However, CAFs are a heterogeneous population with diverse matrix-remodeling capacities. The purpose of this study was to investigate how CAFs with various matrix-remodeling capacities influence cancer cell invasion., Methods: We established single-cell-derived clones from three primary cultures of CAFs from lung adenocarcinoma patients (Case 1, 5 clones; Case 2, 5 clones; and Case 3, 7 clones). Using a co-culture model, we evaluated the correlations between the number of invaded cancer cells and the remodeling areas generated by CAF clones in each case., Results: When A549 lung adenocarcinoma cells and CAF clones were co-cultured, both the numbers of invaded cancer cells and the remodeling areas generated by the CAF clones varied greatly. The number of invaded cancer cells was moderately and strongly correlated with the remodeling areas generated by each CAF clone originating from Cases 1 and 2 (R(2) value = 0.53 and 0.68, respectively), suggesting that the remodeling areas in the ECM may determine the number of invaded cancer cells. In contrast, the number of invaded cancer cells was not correlated with the remodeling areas generated by CAF clones originating from Case 3, suggesting that factors other than the remodeling areas might determine the number of invading cancer cells., Conclusions: These findings showed two types of fibroblast-dependent cancer cell invasion that are dependent on and independent of the remodeling areas generated by CAFs.

Purpose: To evaluate the contributory value of Fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography/computed tomography (PET/CT) in the prediction of lymphovascular tumor invasion in patients with lung adenocarcinoma., Materials and Methods: We evaluated F-18 FDG-PET/CT images in 84 patients with histopathologically proven lung adenocarcinoma (37 men and 47 women, age range 39-83 years, mean age 67.0 ± 8.9 years). The maximum standardized uptake values (SUVmax) of the carcinomas were measured from the PET images. The Mann-Whitney U test was conducted to compare the median SUVmax between the tumor groups with and without lymphovascular invasion. In the subgroup patients with no lymph-node metastasis, we also compared the median SUVmax between the tumor groups with and without lymphatic invasion., Results: The tumors with lymphovascular invasion had a significantly (P < 0.0001) greater median SUVmax than those without invasion. In the subgroup patients with no lymph-node metastasis, the median SUVmax was higher in tumors with lymphatic invasion than those without (P = 0.0004). The sensitivity, specificity, and area under the receiver operating characteristic curve for the detection of tumors with lymphovascular invasion were 89, 75 %, and 0.82, respectively, with a cutoff SUVmax value of 2.32., Conclusion: The SUVmax of lung adenocarcinoma is a potential imaging biomarker for predicting tumor lymphovascular invasion.

Meningiomas show a diverse histopathologic appearance, often referred to as metaplastic changes; however, adenocarcinoma-like metaplasia is an extremely rare condition. Here, we present a novel case. A dura-based bulky mass located in the right frontotemporal region was identified radiologically in an 83-year-old woman. The tumor, yellow to ash-gray in color, was subtotally removed. Histopathological examination revealed robust adenocarcinoma-like structures within a conventional meningothelial neoplasm. Meningioma elements showed a WHO grade I to III histology. Morphological and immunophenotypic transition between meningothelial and columnar epithelial cells was confirmed on detailed observation. It was of note that the adenocarcinomatous components shared an immunophenotype with intestinal epithelium, expressing CDX2, MUC2 and cytokeratin 20. The present case could be differentiated from secretory meningioma based on distinct cellular atypia, lack of intracytoplasmic lumina and pseudosammoma bodies, and the intact status of the KLF4 gene. In addition, the morphological and immunophenotypic transition excluded the possibility of metastatic carcinoma within meningioma. This is the first reported case of meningioma with adenocarcinoma-like metaplasia harboring an intestinal immunophenotype., (© 2014 Japanese Society of Neuropathology.)

Lung cancer is the leading cause of cancer death worldwide. Although disruption of normal proliferation and differentiation is a vital component of tumorigenesis, the mechanisms of this process in lung cancer are still unclear. A transcription factor, C/EBPβ is a critical regulator of proliferation and/or differentiation in multiple tissues. In lung, C/EBPβ is expressed in alveolar pneumocytes and bronchial epithelial cells; however, its roles on normal lung homeostasis and lung cancer development have not been well described. Here we investigated whether C/EBPβ is required for normal lung development and whether its aberrant expression and/or activity contribute to lung tumorigenesis. We showed that C/EBPβ was expressed in both human normal pneumocytes and lung adenocarcinoma cell lines. We found that overall lung architecture was maintained in Cebpb knockout mice. Neither overexpression of nuclear C/EBPβ nor suppression of CEBPB expression had significant effects on cell proliferation. C/EBPβ expression and activity remained unchanged upon EGF stimulation. Furthermore, deletion of Cebpb had no impact on lung tumor burden in a lung specific, conditional mutant EGFR lung cancer mouse model. Analyses of data from The Cancer Genome Atlas (TCGA) revealed that expression, promoter methylation, or copy number of CEBPB was not significantly altered in human lung adenocarcinoma. Taken together, our data suggest that C/EBPβ is dispensable for development of lung adenocarcinoma.

Purpose: To perform volumetric analysis of stage I lung adenocarcinomas by using an automated computer program and to determine value of volumetric computed tomographic (CT) measurements associated with prognostic factors and outcome., Materials and Methods: Consecutive patients (n = 145) with stage I lung adenocarcinoma who underwent surgery after preoperative chest CT were enrolled. By using volumetric automated computer-assisted analytic program, nodules were classified into three subgroups: pure ground glass, part solid, or solid. Total tumor volume, solid tumor volume, and percentage of solid volume of each cancer were calculated after eliminating vessel components. One radiologist measured the longest diameter of the solid tumor component and of total tumor with their ratio, which was defined as solid proportion. The value of these quantitative data by examining associations with pathologic prognostic factors and outcome measures (disease-free survival and overall survival) were analyzed with logistic regression and Cox proportional hazards regression models, respectively. Significant parameters identified at univariate analysis were included in the multiple analyses., Results: All 22 recurrences occurred in patients with nodules classified as part solid or solid. Multiple logistic regression analysis revealed that percentage of solid volume of 63% or greater was an independent indicator associated with pleural invasion (P = .01). Multiple Cox proportional hazards regression analysis revealed that percentage of solid volume of 63% or greater was a significant indicator of lower disease-free survival (hazard ratio, 18.45 [95% confidence interval: 4.34, 78.49]; P < .001). Both solid tumor volume of 1.5 cm(3) or greater and percentage of solid volume of 63% or greater were significant indicators of decreased overall survival (hazard ratio, 5.92 and 9.60, respectively [95% confidence interval: 1.17, 30.33 and 1.17, 78.91, respectively]; P = .034 and .036, respectively)., Conclusion: Two volumetric measurements (solid volume, ≥1.5 cm(3); percentage of solid volume, ≥63%) were found to be independent indicators associated with increased likelihood of recurrence and/or death in patients with stage I adenocarcinoma.

A 73-year-old man with atrial fibrillation and previous left pneumonectomy was admitted with pleural effusion. Anticoagulant therapy was discontinued because of chest tube drainage. Six days later, the patient experienced chest discomfort. Echocardiography showed a pedunculated thrombus with swaying motion in the left pulmonary artery (PA) stump. Contrast-enhanced computed tomography of the chest revealed filling defects in not only the left PA stump but also the right PA, implying contralateral pulmonary embolism. Anticoagulants were resumed, and thrombolysis was successful 3 days later. Patients undergoing pneumonectomy in whom anticoagulant therapy is discontinued should be recognized as being at high risk for PA stump thrombosis and subsequent contralateral pulmonary embolism., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The work by Cheung and colleagues, in this issue of Cancer Cell, demonstrates another example of how lineage-specific transcriptional regulators of differentiation, GATA6 and HOPX, can control the fate of lung adenocarcinoma progression., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Tissue-specific differentiation programs become dysregulated during cancer evolution. The transcription factor Nkx2-1 is a master regulator of pulmonary differentiation that is downregulated in poorly differentiated lung adenocarcinoma. Here we use conditional murine genetics to determine how the identity of lung epithelial cells changes upon loss of their master cell-fate regulator. Nkx2-1 deletion in normal and neoplastic lungs causes not only loss of pulmonary identity but also conversion to a gastric lineage. Nkx2-1 is likely to maintain pulmonary identity by recruiting transcription factors Foxa1 and Foxa2 to lung-specific loci, thus preventing them from binding gastrointestinal targets. Nkx2-1-negative murine lung tumors mimic mucinous human lung adenocarcinomas, which express gastric markers. Loss of the gastrointestinal transcription factor Hnf4α leads to derepression of the embryonal proto-oncogene Hmga2 in Nkx2-1-negative tumors. These observations suggest that loss of both active and latent differentiation programs is required for tumors to reach a primitive, poorly differentiated state., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The NKX2-1 transcription factor, a regulator of normal lung development, is the most significantly amplified gene in human lung adenocarcinoma. To study the transcriptional impact of NKX2-1 amplification, we generated an expression signature associated with NKX2-1 amplification in human lung adenocarcinoma and analyzed DNA-binding sites of NKX2-1 by genome-wide chromatin immunoprecipitation. Integration of these expression and cistromic analyses identified LMO3, itself encoding a transcription regulator, as a candidate direct transcriptional target of NKX2-1. Further cistromic and overexpression analyses indicated that NKX2-1 can cooperate with the forkhead box transcription factor FOXA1 to regulate LMO3 gene expression. RNAi analysis of NKX2-1-amplified cells compared with nonamplified cells demonstrated that LMO3 mediates cell survival downstream from NKX2-1. Our findings provide new insight into the transcriptional regulatory network of NKX2-1 and suggest that LMO3 is a transcriptional signal transducer in NKX2-1-amplified lung adenocarcinomas.

Background: The cation channels of the transient receptor potential (TRP) superfamily are implicated in cancer formation; in particular, TRPC3 has been shown to contribute to the progression of human ovarian cancer. However, the relationship between TRP expression and the clinicopathological characteristics of lung cancer and patient prognosis is not well understood. Therefore, we investigated the relationship between TRP expression and the prognosis of patients with adenocarcinoma of the lung., Methods: We used semiquantitative real-time reverse transcription polymerase chain reaction to assess the expression of TRP mRNA in tumor samples from 95 patients with adenocarcinoma of the lung. We then correlated the TRP mRNA levels with clinicopathological factors. We also used immunohistochemical staining to determine the localization of expressed TRP., Results: The 5-year overall and disease-free survival rates among patients expressing higher levels of TRPC3 mRNA were significantly better than the corresponding rates among patients expressing lower levels (P=0.004, P=0.002, respectively, by log-rank test). Multivariate Cox proportional hazard analyses revealed that tumor size (hazard ratio, 2.46; 95% confidence interval [CI], 1.06 to 5.79; P=0.036), n2 (hazard ratio, 3.81; 95% CI, 1.29 to 11.77; P=0.015) and TRPC3 (hazard ratio, 2.71; 95% CI, 1.33 to 5.59; P=0.006) were independent factors affecting the 5-year overall survival rate. Immunohistochemistry showed that the cytoplasm of tumor cells were stained positively for TRPC3., Conclusions: Higher levels of TRPC3 expression in tumor cells are an independent predictor of a better prognosis in patients with adenocarcinoma of the lung.

Purpose: To compare (11)C-choline positron emission tomography (C-PET), (18)F-fluorodeoxyglucose PET (FDG-PET), and MR imaging in the preoperative detection of prostate cancer., Materials and Methods: C-PET, FDG-PET, and MR images were obtained in 43 consecutive patients with suspected prostate cancer, and prostate cancers were histopathologically confirmed in 26 patients. Unenhanced T1-weighted, T2-weighted, and gadolinium-enhanced MR images were obtained. C-PET and FDG-PET were conducted 1.5 and 60 minutes after injection of 5.5 and 5.0 MBq/kg tracers, respectively. A nuclear and a genitourinary radiologist retrospectively reviewed PET and MR images at random, respectively, and assigned a confidence level for the presence of prostate cancer using a four-point scale. Diagnostic performance was tested using the McNemar test and receiver operating characteristic curve analysis., Results: The sensitivity was greater (P < 0.05) with MR (88%) and C-PET (73%) images than with FDG-PET images (31%). The accuracy was greater (P < 0.05) with MR images (88%) than with C-PET (67%) and FDG-PET (53%) images. The area-under-curve value with MR (0.90) was greater than those with C-PET (0.53) and FDG-PET (0.54) images (P < 0.01)., Conclusion: MR imaging should be primarily performed in the preoperative detection of prostate cancer. C-PET and FDG-PET did not improve the detection., (Copyright 2010 Wiley-Liss, Inc.)

Cucurbitacin B (cucB) is a triterpenoid constituent of Cucurbitaceae vegetables and a promising phytochemical for cancer prevention. However, the mechanism of anti-tumor activity of cucB remains unknown, especially in colon cancers. Here, we demonstrate for the first time that cucB inhibited growth of human colon cancer SW480 cells through a reactive oxygen species (ROS)-dependent mechanism. CucB induced G(2) phase arrest and apoptosis in a dose-dependent manner. At the molecular level, cucB reduced the expression of cyclin B1 and cdc25C proteins and activated caspases in SW480 cells. On the other hand, the state of phosphorylation of signaling transducer and activator of transcription 3 (STAT3) was unchanged. We found that cucB increased intracellular ROS levels, and N-acetylcysteine, a well-known antioxidant, reduced the changes in expression of the molecules, and suppressed both G(2) arrest and apoptosis. These results suggested that cucB induced G(2) arrest and apoptosis through a STAT3-independent but ROS-dependent mechanism in SW480 cells.

Objective: Panitumumab, a fully human monoclonal antibody targeting epidermal growth factor receptor (EGFR), has antitumor activity and an acceptable safety profile in patients with metastatic colorectal cancer (mCRC). This Phase 2 study evaluated efficacy, pharmacokinetics and safety of panitumumab in Japanese patients with mCRC who developed progressive disease during or after fluoropyrimidine, irinotecan and oxaliplatin chemotherapy., Methods: Eligible patients had histologically proven colorectal adenocarcinoma and EGFR tumor expression in > or =1% of tumor cells by immunohistochemistry. Patients received panitumumab 6 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per modified Response Evaluation Criteria in Solid Tumors (RECIST) by independent central review. Secondary endpoints included progression-free survival (PFS), overall survival (OS), pharmacokinetic parameters and incidence of adverse events., Results: Fifty-two patients received at least one dose of panitumumab. Seven patients had partial responses for a confirmed ORR of 13.5% (95% CI: 5.6, 25.8). Median PFS was 8.0 weeks (95% CI: 7.4, 11.4) and median OS was 9.3 months (95% CI: 7.1, 12.8). Panitumumab pharmacokinetics were consistent with prior studies in Japanese and non-Japanese patients. The most common treatment-related adverse events (all, worst grade 3) were acne (81%, 2%), dry skin (62%, 0%), rash (46%, 2%), paronychia (33%, 2%), pruritus (33%, 0%) and hypomagnesemia (33%, 0%). No adverse event of infusion reaction was reported by the investigators., Conclusions: Panitumumab monotherapy was active in Japanese patients with chemotherapy-refractory mCRC, with pharmacokinetic and safety profiles similar to those seen in prior studies.

The prognostic value of histologic classifications of gastric adenocarcinoma is controversial, although they have been commonly used. The clinical significance of the mucin phenotype has not been clarified. This study was conducted to determine the clinical significance of mucin phenotype as a possible prognostic factor. Mucin histochemistry by paradoxical concanavalin A (Con A) staining and immunostaining for 45M1, MUC2 glycoprotein and CD10 of mucin was performed in surgically obtained paraffin-embedded specimens from 106 gastric adenocarcinomas. We determined their mucin phenotypes and analyzed their relationships with clinical and histopathologic variables and survival rates. Among 106 gastric adenocarcinomas, 37 (34.9%), 35 (33.0%), 22 (20.8%) and 12 (11.3%) expressed the intestinal (I-), the gastric (G-), mixed (M-), and undetermined (U-) phenotypes, respectively. Although the mucin phenotype correlated well with histologic differentiation (p=0.000) and Lauren's classification of a tumor (p=0.003), it did not accord completely with them. There was no relationship between mucin phenotype and other patient clinicopathologic variables. No statistically significant difference in survival was observed among mucin phenotypes on univariate (p=0.089) and multivariate (p=0.088) analyses. However, the patients with I-phenotype tumor had a significantly better outcome than those with non-I-phenotype tumor on univariate (p=0.023) and multivariate (p=0.049) analyses. In conclusion, the mucin phenotype did not accord completely with histologic differentiation and Lauren's classification of gastric adenocarcinoma, despite a well-defined correlation between them. I-phenotypic expression, but not the histologic differentiation and Lauren's classification, was found to be an independent good prognostic factor of gastric cancers.

Matrix-producing carcinoma of the breast is a well-established entity in the group of metaplastic carcinoma, which is histologically characterized by myxochondroid matrix formation and is extremely rare. We describe here four additional cases of matrix-producing carcinoma of the breast. All cases of matrix-producing carcinoma show nest-like, sheet-like, and cord-like growth of tumor cells with cellular atypia, in addition to scattered cancer cells within myxoid or myxohyalinous stroma. Three of four cases showed an acellular or oligocellular matrix-rich zone in the center of the tumor. Immunohistochemically, cancer cells of all cases were positive for cytokeratins and epithelial membrane antigens and partially positive for sox9 and p63. Aggrecan and type II collagen, which are cartilage-specific matrix molecules, were deposited in the stroma of all cases. Type I and type IV collagens were also deposited on the stroma of all cases. These findings suggest that, although cancer cells of matrix-producing carcinoma of the breast are epithelial, they transdifferentiate to chondrocyte-like cells and produce cartilage-specific matrix molecules, which are useful markers for diagnosing matrix-producing carcinoma.

Context: Mass-forming pancreatitis can be divided into two distinct types: alcoholic and autoimmune. There have been some cases of an ambiguous diagnosis although care was taken to differentiate between alcoholic mass-forming pancreatitis, focal type autoimmune pancreatitis and pancreatic cancer., Case Report: We report a case of pancreatic cancer mimicking alcoholic or autoimmune pancreatitis with the formation of a mass in a 32-year-old man with a history of heavy drinking. Although both serum immunoglobulin G and immunoglobulin G4 levels were normal, many serum auto-antibodies, including the antinuclear antibody, were detected. After he stopped drinking, abdominal computed tomography showed a pancreatic head mass 28 mm in diameter with little and weak enhancement in the early and delayed phases, respectively. Endoscopic retrograde cholangiopancreatography showed an obstruction of the main pancreatic duct in the pancreatic head and marked stenosis of the lower common bile duct. Although a percutaneous ultrasound-guided pancreatic biopsy demonstrated no evidence of autoimmune pancreatitis, he was treated with prednisolone to test the efficacy of steroid therapy. However, the pancreatic mass became enlarged after steroid therapy, and he underwent surgery during which the mass was found to be pancreatic cancer. Although the patient was treated with gemcitabine, he died 5 months after surgery. We retrospectively assessed DNA hypermethylation in the patient's pure pancreatic juice obtained on admission. We observed hypermethylation of the cancer-specific gene tissue factor pathway inhibitor 2 (TFPI2)., Conclusion: This finding suggests that if the DNA hypermethylation of pure pancreatic juice had been assayed before steroid therapy, it would have supported the diagnosis of pancreatic cancer, and steroid therapy could have been avoided.

The mammalian SWI/SNF chromatin remodeling complex, an essential epigenetic regulator, contains either a single Brm or BRG1 molecule as its catalytic subunit. We observed frequent loss of Brm expression but not of BRG1 in human gastric cancer cell lines. Treatment with histone deacetylase inhibitor rescued Brm expression, indicating epigenetic regulation of this gene, and an RNA interference-based colony formation assay revealed antioncogenic properties of Brm. Brm immunostaining of 89 primary gastric cancers showed an obvious reduction in 60 cases (67%) and a severe decrease in 37 cases (42%). Loss of Brm is frequent in the major gastric cancer types (well- or moderately-differentiated tubular adenocarcinoma and poorly-differentiated adenocarcinoma) and positively correlates with the undifferentiated state. Among the minor gastric cancer types, Brm expression persists in signet-ring cell carcinoma and mucinous adenocarcinoma, but a marked decrease is observed in papillary adenocarcinoma. Intestinal metaplasia never shows decreased expression, indicating that Brm is a valid marker of gastric oncogenesis. In contrast, BRG1 is retained in most cases; a concomitant loss of BRG1 and Brm is rare in gastric cancer, contrary to other malignancies. We further show that Brm is required for villin expression, a definitive marker of intestinal metaplasia and differentiation. Via regulating such genes important for gut differentiation, Brm should play significant roles in determining the histologic features of gastric malignancy.

Objective: The aggressiveness of small adenocarcinomas has not been fully evaluated using integrated positron emission tomography/computed tomography. We investigated malignant aggressiveness according to positron emission tomography/computed tomography, high-resolution computed tomographic findings, and the proportions of pathologically defined bronchioloalveolar carcinomas in cT1N0M0 lung adenocarcinoma., Methods: Sixty consecutive patients with cT1N0M0 lung adenocarcinomas of 3 cm or less in diameter underwent fluorodeoxyglucose-positron emission tomograph/computed tomography, and high-resolution computed tomography, followed by complete tumor resection. Correlations between the proportion of bronchioloalveolar carcinoma and maximum standardized uptake value on positron emission tomographic scan/computed tomographic scan, ground-glass opacity, and tumor shadow disappearance rate were investigated and the findings were compared with clinicopathologic features., Results: Lymphatic and vascular invasion occurred in 18 (30%) and 13 (22%) patients, respectively, whereas hilar or mediastinal lymph nodes occurred in 8 patients (13%). Maximum standardized uptake value generally seemed the most valuable predictor of lymphatic invasion, vascular invasion, and nodal metastasis compared with ground-glass opacity, tumor shadow disappearance rate, and bronchioloalveolar carcinoma ratios. Although the association was significant between the bronchioloalveolar carcinoma ratio versus maximum standardized uptake value, ground-glass opacity ratio, and tumor shadow disappearance rate (all P < .0001), maximum standardized uptake value (R2 = 0.245) was less correlated with the bronchioloalveolar carcinoma ratio than was the ground-glass opacity ratio (R2 = 0.554) and tumor shadow disappearance rate (R2 = 0.671)., Conclusions: The malignant behavior of small adenocarcinomas with a lower maximum standardized uptake value and a greater proportion of ground-glass opacity, tumor shadow disappearance rate, and bronchioloalveolar carcinoma was less aggressive. Maximum standardized uptake value was a more powerful clinical predictor of biologic tumor performance, independent of pathologic bronchioloalveolar carcinoma proportion. Preoperative assessment of maximum standardized uptake value on positron emission tomographic/computed tomographic findings, in addition to the ground-glass opacity ratio and tumor shadow disappearance rate on high-resolution computed tomographic scans, might be useful to guide treatment strategies for small adenocarcinomas.

Background: Recently, the right gastroepiploic artery (RGEA) has been used in coronary artery bypass grafting (CABG) as an alternative arterial graft. Unfortunately, an increased incidence of gastric cancers has been reported after CABG using the RGEA. Handling of the RGEA during gastrectomy in these patients may cause lethal complications, which sometimes reduces the feasibility of curative dissection of lymph nodes at the base of the graft., Case Presentations: We describe two cases of gastric cancer undergoing gastrectomy after CABG with the use of RGEA. To avoid the potentially fatal coronary event during gastrectomy, safe handling of the conduit including preparations for injuries and prevention of vessel spasm was performed in both cases, accompanied by an adequate monitoring of the systemic circulation. Intraoperative frozen section examination showed no lymph node metastasis around the graft in any of the cases; therefore, complete lymph node dissection at the base of the graft was not undertaken. No complications occurred during the operation. In addition to these two cases, twenty-four cases reported in the literatures were reviewed (a total of 26 cases). Ten early and 16 advanced gastric cancers were included. Among the 16 advanced gastric cancer cases, an alternative graft was employed in 8 due to the resection of an original graft to complete lymph node dissection. Mere handling of a graft often caused lethal complications suggesting that the operation should be completed by isolation of the graft. A pedicled graft harvesting via the ante-gastric route was popular. However, a skeletonized harvesting with resection of the pyloric branches of the RGEA would be better because this would interrupt the original lymph flow, which could eliminate the need for lymph node dissection and graft isolation. Among the 10 cases having early gastric cancers, 6 were found within 1.5 years after CABG. Early detection in these 6 cases was possible due to the use of gastric fiberscopic examination before and after CABG, which gave them opportunities to receive a less extensive operation such as endoscopic mucosal resection., Conclusion: Adequate intraoperative care as well as an optimal lymph node dissection considering the graft harvesting method at the first CABG leads to successful gastrectomy after CABG using the RGEA graft. Therefore, this operation should be carried out with careful management by both gastrointestinal and cardiovascular surgeons.

Aim: This study was performed to investigate the range of optimal concentration and mechanisms of paclitaxel (PXL) radio-enhancement in gastrointestinal cancer cell lines HT29 and MKN45., Methods: Cell growth inhibition by PXL pretreatment at various concentrations (0-10 microM) followed by irradiation was investigated using a modified MTT assay. To investigate the mechanisms of the observed radio-enhancement, flow cytometry was conducted to define the cell cycle distributions. Furthermore, the alterations in expression of a DNA repair molecule [excision repair cross-complementation group1 (ERCC1)] and an angiogenesis factor [vascular endothelial growth factor (VEGF)] induced by PXL were investigated., Results: Cytotoxic concentrations of PXL (0.1-10 microM) that cause accumulation of cells in the G2/M phase have strong radio-enhancing effects and inhibit total cell growth. The maximal non-cytotoxic concentration of PXL (0.01 microM) also had a radio-enhancing effect. The expression of the genes of ERCC1 and VEGF induced by radiation was suppressed by PXL pretreatment. The protein secretion of VEGF induced by radiation was suppressed at cytotoxic doses of PXL, and the induced protein secretion of ERCC1 was also suppressed even at maximal non-cytotoxic doses of PXL., Conclusion: The range of optimal concentration for PXL pretreatment was 0.01-0.1 microM in these cells. Two major mechanisms of radio-enhancement are suggested: (1) PXL induces G2/M arrest leading to increased DNA damage after radiation, which results in mitotic death, and (2) PXL suppresses the expression of radiation-induced DNA repair molecules and angiogenesis factors, resulting in inhibition of cell growth and cell death.

This is a first pediatric case about the efficacy of octreotide for improving symptoms of malignant bowel obstruction. A 12-year-old boy was referred to our hospital for treatment of transverse colon cancer with peritoneal dissemination. A transverse colectomy was undertaken with postoperative adjuvant chemotherapy. Seven months later, severe abdominal symptoms occurred caused by incomplete bowel obstruction owing to tumor progression. The patient's quality of life decreased with a resultant disturbed mental condition. His parents sought to stop chemotherapy and for him to receive palliative care at home. We suggested nasogastric tube placement, but this was rejected. After obtaining informed consent, octreotide was administered intravenously. After 1 week, abdominal symptoms improved and the boy's complaints stopped. He had a good appetite and was able to eat small amounts of food. He was able to spend his final 2 months at home without nausea and in his family surroundings.

A water-soluble extract from the culture medium of Ganoderma lucidum (Rei-shi) mycelia (MAK) has been shown to exert a potent chemopreventive effect. The present study was designed to investigate the effects of dietary MAK supplementation on the development of lung tumors initiated by N-nitrosobis (2-hydroxypropyl) amine (BHP) in male Slc:Wistar rats. A total of 77 animals, 6 weeks of age, were divided into 5 groups and given BHP (2,000 ppm) in their drinking water for 10 weeks. The normal controls were not supplied with BHP. After treatment with the carcinogen, the rats were fed a normal control MF solid diet, or the same diet containing MAK (1.25%, 2.5% or 5%) for 12 weeks. Macroscopically, all the doses of MAK reduced the number of nodules, and the effect of 5% MAK was found to be especially significant. Microscopically, an increase in the number of proliferating cell nuclear antigen (PCNA)-negative tumors and a decrease in the number of tumors strongly positive for PCNA were observed in the tissue sections from the rats that had received all the doses of MAK. The present results thus indicate that dietary supplementation with MAK inhibits the development of lung tumors, suggesting that MAK may be a potent chemopreventive agent against lung carcinogenesis.

A 45-year-old man was admitted to our hospital because of chronic hepatitis C and a large liver tumor accompanied by increased serum levels of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), the tumor markers for hepatocellular carcinoma. Endoscopic examination revealed advanced gastric cancer. Biopsy specimens of the stomach and liver showed gastric adenocarcinoma and its metastasis to the liver. Immunohistochemical studies demonstrated that adenocarcinoma cells both of the stomach and liver, were positive for the antibodies against AFP as well as DCP. Expression of AFP mRNA was shown in the cancer cells of the stomach. Accordingly, we diagnosed this patient with AFP- and DCP-producing adenocarcinoma of the stomach together with liver metastasis.

90K/Mac-2 Binding Protein (M2BP) plays a role in regulation of immune responses and cell adhesive ability in patients with cancer and infectious diseases. We previously reported that M2BP was highly expressed in lung cancer and that immune responses to M2BP were increased in many patients with lung cancer. To determine the involvement of M2BP in metastatic processes of cancer progression, we examined the ability of M2BP DNA-transduced lung carcinoma cell lines to adhere to extracellular matrices. Although expressions of cell-surface integrins were not modulated in the M2BP transfectants, they showed increased adhesiveness to fibronectin and collagen IV. We next analyzed the serum levels of M2BP in patients with lung cancer and normal donors and the relationships between M2BP expression and clinicopathological factors in the patients. The M2BP level was markedly elevated in the patients and was strongly correlated with nodal involvement and clinical staging. To determine whether expression of M2BP by cancer cells is modulated in the environment of tumor-bearing hosts, M2BP expression in M2BP-positive QG56 cells following exposure of the cells to pro-inflammatory cytokines was examined. The M2BP expression in QG56 cells was up-regulated by many of the cytokines that activate host protective immunity. The findings in this study suggest that M2BP plays a role in cancer metastasis by increased adhesiveness of cancer cells and that M2BP is increasingly produced even in a state of exposure to the host immune system. This molecule may be useful as a predictive factor of disease progression in lung cancer.

Adenocarcinoma arising from short-segment Barrett's esophagus (SSBE) is rare in Japan, although the incidence of this condition is increasing in Western countries. Four cases of early adenocarcinoma arising from SSBE were diagnosed and treated at Niigata-prefectural Yoshida Hospital. All patients were male, variously 55, 71, 73 and 79 years of age. All four patients had long-term gastroesophageal reflux disease, although one patient had erosive esophagitis and three patients did not have erosive esophagitis. Three patients were diagnosed as having Helicobacter pylori-free stomach. All adenocarcinomas occurred close to the squamocolumnar junction. Patients with SSBE should undergo detailed endoscopic examination of the squamocolumnar junction in order to detect early adenocarcinoma arising from SSBE.