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Differentiated thyroid cancer (DTC) is the most prevalent endocrine malignancy worldwide and requires effective prognostic markers and therapeutic targets to optimize patient outcomes. This study investigated the potential of human serum albumin (HSA) cysteine-34 (Cys34) redox state as a prognostic indicator and therapeutic avenue for DTC. A retrospective cohort study of 99 patients with DTC undergoing radioactive iodine therapy found that higher concentrations of HSA with the reduced form of Cys34 (i.e., human mercaptalbumin [HMA]) were associated with improved progression-free survival in metastatic DTC. In vitro experiments using a DTC cell line revealed that HMA induced cytotoxic effects by triggering ferroptosis, characterized by lipid peroxidation, intracellular ROS accumulation, and decreased cell viability. Ferroptosis inhibitors rescued cell viability, confirming their role in cytotoxicity. These results implicate the HSA-Cys34 redox state is a promising avenue for precision medicine in DTC, shedding light on the prognostic relevance and therapeutic potential of HMA-induced ferroptosis. They emphasize the opportunity for personalized treatment strategies to advance the management of patients with DTC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

This study aimed to assess recurrence-free survival (RFS) rates and recurrence-related factors of patients who received adjuvant therapy (AT) with radioactive iodine (RAI) for differentiated thyroid cancer (DTC) following thyroidectomy. We evaluated 284 patients who underwent AT between January 2011 and July 2020 at our hospital. Recurrence was defined as visible recurrent lesions on image analysis or need for repeat surgery with pathologically confirmed recurrent lesions. RFS rate and prognostic factors were statistically evaluated. The median observation period was 30.2 months (range, 5.7-294 months). Overall, 192 patients were female and 92 were male, and the median age was 54 years (range, 9-85 years). Initial assessment revealed 39 recurrence cases. The 3-year RFS rate was 85.8% (95% confidence interval: 81.1-90.9%). Univariate analysis revealed that histology (except for papillary carcinoma), Tg level > 4 ng/dL before AT, and AT result significantly exacerbated the RFS rate. In multivariate analysis, histology and AT result were also important contributors to the worsening RFS rate. Results of AT can be determined relatively early and are important in predicting future recurrence in patients with DTC. Increasing the success rate of AT may lead to an improved prognosis., (© 2023. The Author(s).)

The effect of body mass index (BMI) on esophageal and gastric carcinogenesis might be heterogeneous, depending on subtype or subsite. However, findings from prospective evaluations of BMI associated with these cancers among Asian populations have been inconsistent and limited, especially for esophageal adenocarcinoma and gastric cardia cancer. We performed a pooled analysis of 10 population-based cohort studies to examine this association in 394,247 Japanese individuals. We used Cox proportional hazards regression to estimate study-specific hazard ratios (HRs) and 95% confidence intervals (CIs), then pooled these estimates to calculate summary HRs with a random effects model. During 5,750,107 person-years of follow-up, 1569 esophageal cancer (1038 squamous cell carcinoma and 86 adenocarcinoma) and 11,095 gastric (728 cardia and 5620 noncardia) cancer incident cases were identified. An inverse association was observed between BMI and esophageal squamous cell carcinoma (HR per 5-kg/m 2 increase 0.57, 95% CI 0.50-0.65), whereas a positive association was seen in gastric cardia cancer (HR 1.15, 95% CI 1.00-1.32). A nonsignificant and significant positive association for overweight or obese (BMI ≥25 kg/m 2 ) relative to BMI <25 kg/m 2 was observed with esophageal adenocarcinoma (HR 1.32, 95% CI 0.80-2.17) and gastric cardia cancer (HR 1.24, 95% CI 1.05-1.46), respectively. No clear association with BMI was found for gastric noncardia cancer. This prospective study-the largest in an Asian country-provides a comprehensive quantitative estimate of the association of BMI with upper gastrointestinal cancer and confirms the subtype- or subsite-specific carcinogenic impact of BMI in a Japanese population., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Perianal Paget's disease (PPD) is an intraepithelial invasion of the perianal skin and is frequently associated with underlying anorectal carcinoma. The relatively rare nature of this disease has made it difficult to develop treatment recommendations. This study aims to analyze the clinical and pathological features of perianal Paget's disease (PPD) and to explore rational treatment options and follow-up for this disease., Methods: The National Cancer Center Hospital database was searched for all cases of perianal Paget's disease diagnosed between 2006 and 2021. In the 14 patients identified, we reviewed the diagnosis, management, and outcomes of adenocarcinoma with pagetoid spread, including suspected or recurrent cases., Results: All 14 cases met the inclusion criteria. The median follow-up period after diagnosis was 4.5 (range, 0.1-13.0) years. Pagetoid spread before initial treatment was suspected in 12 cases (85.7%). Underlying rectal cancer was identified in 6 cases, and no primary tumor was detected in the other 6 cases. Seven patients had recurrent disease, with the median time to recurrence of 34.6 (range, 19.2-81.7) months. The time to the first relapse was 3 months, and that to the second relapse was 6 months. The overall 5-year survival rate was 90.0%., Conclusions: Endoscopic and radiologic evaluation, as well as immunohistologic examination, should be performed. is to differentiate PPD with and without underlying anorectal carcinoma. The time to first recurrence varies widely, and long-term and regular follow-up for more than 5 years is considered necessary for local recurrence and distant metastasis., (© 2023. The Author(s).)

Apico-basal polarity is a fundamental property of the epithelium that functions as a barrier, holds cells together, and determines the directions of absorption and secretion. Apico-basal polarity is regulated by extracellular matrix-integrin binding and downstream signaling pathways, including focal adhesion kinase, rouse-sarcoma oncogene (SRC), and RHO/RHO-associated kinase (ROCK). Loss of epithelial cell polarity plays a critical role in the progression of cancer cells. However, in differentiated carcinomas, polarity is not completely lost but dysregulated. Recent progress with a three-dimensional culture of primary cancer cells allowed for studies of the mechanism underlying the abnormality of polarity in differentiated cancers, including flexible switching of polarity status in response to the microenvironment. Invasive micropapillary carcinoma (MPC) is one of the histopathological phenotypes of adenocarcinoma, which is characterized by inverted polarity. Aberrant activation of RHO-ROCK signaling plays a critical role in the MPC phenotype. Establishing in vitro models will contribute to future drug targeting of the abnormal polarity status in cancer., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Blood-based biomarkers for gastric cancer risk stratification could facilitate targeting screening to people who will benefit from it most. The ABC Method, which stratifies individuals by their Helicobacter pylori infection and serum-diagnosed chronic atrophic gastritis status, is currently used in Japan for this purpose. Most gastric cancers are caused by chronic H. pylori infection, but few studies have explored the capability of antibody response to H. pylori proteins to predict gastric cancer risk in addition to established predictors., Methods: We used the least absolute shrinkage and selection operator (Lasso) to build a predictive model of noncardia gastric adenocarcinoma risk from serum data on pepsinogen and antibody response to 13 H. pylori antigens as well as demographic and lifestyle factors from a large international study in East Asia., Results: Our best model had a significantly (P < 0.001) higher AUC of 73.79% [95% confidence interval (CI), 70.86%-76.73%] than the ABC Method (68.75%; 95% CI, 65.91%-71.58%). At 75% specificity, the new model had greater sensitivity than the ABC Method (58.67% vs. 52.68%) as well as NPV (68.24% vs. 66.29%)., Conclusions: Along with serologically defined chronic atrophic gastritis, antibody response to the H. pylori proteins HP 0305, HP 1564, and UreA can improve the prediction of gastric cancer risk., Impact: The new risk stratification model could help target more invasive gastric screening resources to individuals at high risk., (©2022 American Association for Cancer Research.)

Objective Although Barrett's adenocarcinoma (BA) remains a minor disease in Japan, its incidence has been gradually increasing. We analyzed the characteristics of BA in Japanese populations. Methods We retrospectively reviewed medical records and analyzed the clinicopathological differences between short-segment Barrett's esophagus (SSBE) and long-segment Barrett's esophagus (LSBE), as well as metastasis. Local recurrence and metachronous lesions were analyzed only in patients who underwent endoscopic resection (ER). Patients Consecutive patients who had pathological T1 BAs resected by ER or surgery from January 2003 to December 2017. Results A total of 168 patients were analyzed, including 139 with SSBE and 29 with LSBE. In total, 67% of the SSBE lesions and 32% of the LSBE lesions were located between 0 and 3 o'clock (p=0.0014). No patients who achieved pathological margin-free resection (pR0) and 17% of patients who did not achieve pR0 experienced local recurrence (p=0.0131). None of the patients without lymphovascular involvement, a poorly differentiated component, lesion size of >30 mm, and submucosal invasion of >500 μm experienced metastasis. The 5-year cumulative incidence rate of metachronous BA after ER was 0% in patients with SSBE and 40% in patients with LSBE (p=0.0005). Conclusion Superficial BA was likely to be detected at the right anterior wall of SSBE in the Japanese population. The risk for metachronous BA after ER was high in Japanese patients with LSBE, as in Western patients.

Background: Body mass index (BMI) is inversely associated with lung cancer risk, while residual confounding by smoking or weight change is controversial. Evidence on height and lung cancer is scarce., Methods: We investigated the associations between anthropometrics, BMI, and height, and incidence of lung cancer among 92,098 study subjects (44,158 men and 47,940 women) in the Japan Public Health Center-based Prospective Study. Cox proportional hazards regression was performed with adjustment for potential confounders and by cancer subtypes and smoking status. Information on weight and height was self-reported at baseline, and validated using measured health check-up data., Results: During follow-up between 1990 and 2013 (average, 19.1 years), a total of 2,152 lung cancer cases were newly diagnosed. In a multivariate regression model, lower BMI was positively associated with overall lung cancer risk [<19 kg/m 2 HR = 1.48; 95% confidence interval (CI) = 1.18-1.85 and 19-22.9 kg/m 2 ; HR = 1.19; 95% CI = 1.05-1.35; P = <0.001] in men. The risk estimate was also elevated for adenocarcinoma in the BMI <19 kg/m trend category and for squamous cell carcinoma among men in the 19-22.9 kg/m 2 BMI category. An association was also observed between low BMI, weight decrease, and squamous cell carcinoma in women. No significant associations were observed for other weight categories, height, weight change and lung cancer, adenocarcinoma, squamous and small cell carcinoma.2 BMI category. An association was also observed between low BMI, weight decrease, and squamous cell carcinoma in women. No significant associations were observed for other weight categories, height, weight change and lung cancer, adenocarcinoma, squamous and small cell carcinoma., Conclusions: Our prospective study suggests that lower BMI may be associated with an increased risk of smoking-related lung cancer in Japan, irrespective of gender., Impact: This study highlights the association between lower BMI and the risk of lung cancer in men., (©2021 American Association for Cancer Research.)

Most colorectal cancers (CRCs) are differentiated adenocarcinomas, which maintain expression of both stemness and differentiation markers. This observation suggests that CRC cells could retain a regeneration system of normal cells upon injury. However, the role of stemness in cancer cell regeneration after irradiation is poorly understood. Here, we examined the effect of radiation on growth, stemness, and differentiation in organoids derived from differentiated adenocarcinomas. Following a sublethal dose of irradiation, proliferation and stemness markers, including Wnt target genes, were drastically reduced, but differentiation markers remained. After a static growth phase after high dose of radiation, regrowth foci appeared; these consisted of highly proliferating cells that expressed stem cell markers. Radiosensitivity and the ability to form foci differed among the cancer tissue-originated spheroid (CTOS) lines examined and showed good correlation with in vivo radiation sensitivity. Pre-treating organoids with histone deacetylase inhibitors increased radiation sensitivity; this increase was accompanied by the suppression of Wnt signal-related gene expression. Accordingly, Wnt inhibitors increased organoid radiosensitivity. These results suggested that only a small subset of, but not all, cancer cells with high Wnt activity at the time of irradiation could give rise to foci formation. In conclusion, we established a radiation sensitivity assay using CRC organoids that could provide a novel platform for evaluating the effects of radiosensitizers on differentiated adenocarcinomas in CRC., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Intradural extramedullary spinal metastasis is a relatively rare condition. Furthermore, there are few reports with the initial presentation being a neurological symptom from an intradural metastasis. We report a case of a patient with metastasis to the cauda equina from breast cancer found due to neurological symptoms as the initial presentation., Case Presentation: A 76-year-old Japanese woman who was previously healthy presented to our hospital with bilateral severe buttock and lower extremity pain without any history of injury. A solitary intradural cauda equina mass was found by magnetic resonance imaging at the L2/3 level, and we suspected a schwannoma initially. The patient hoped to undergo surgery due to the severe pain. However, the chest computed tomographic scan obtained to assess the patient's general status showed the suspected breast cancer of the left side and a lung metastasis. Hence, we considered the possibility of cauda equina tumor metastatic from the breast cancer. We performed an L1-3 laminectomy and tumor extirpation. The pathology revealed adenocarcinoma. After surgery, she had relief from pain, and her status remained satisfactory until she died 9 months after surgery., Conclusions: It is difficult to clarify whether the cauda equina tumor is benign or malignant based only on Magnetic resonance imaging findings. Clinicians should consider the possibility of metastasis when planning the surgery for intradural cauda equina tumor extirpation.

Background: Narrow-band imaging (NBI) classifications for Barrett's esophagus have been proposed for the detection of early esophageal adenocarcinoma. We developed a simplified classification system with demonstrated high diagnostic accuracy and reproducibility among experienced endoscopists, but the feasibility of this system among novice endoscopists was unclear., Methods: In the present study, eight novice endoscopists with no experience of magnification endoscopy were asked to review 248 images of Barrett's esophagus (72 dysplastic, 176 non-dysplastic) obtained using high-definition magnification endoscopy with NBI 6 weeks before (1st test), immediately after (2nd test), and 6 weeks after (3rd test) being taught the simplified classification system. The primary outcomes were differences in diagnostic accuracy for dysplasia among the three tests., Results: The specificity and overall accuracy improved significantly in the 2nd vs. 1st test [97% vs. 80% (p < 0.001) and 94% vs. 82% (p < 0.001), respectively], but sensitivity was comparable (87% in both tests; p = 0.42). In the 3rd test, the sensitivity and overall accuracy decreased significantly compared with the 2nd test [82% vs. 87% (p < 0.001) and 93% vs. 94% (p < 0.05), respectively], but there was no significant difference in specificity (97% in both tests; p = 0.16). The kappa values for interobserver agreement for the mucosal pattern, vascular pattern, and predicted histology were substantial, and improved significantly in the 2nd vs. 1st test (0.78 vs. 0.59, 0.70 vs. 0.53, and 0.79 vs. 0.66, respectively; p < 0.001 for all)., Conclusions: The simplified NBI classification system may be appropriate for novice endoscopists to use in providing high accuracy and reproducibility.

Background: Small bowel adenocarcinoma (SBA) is a rare malignancy that accounts for 1-2% of gastrointestinal tumours. We investigated the clinical characteristics, outcomes, and prognostic factors of primary SBA., Methods: We retrospectively analysed the characteristics and clinical courses of 205 SBA patients from 11 institutions in Japan between June 2002 and August 2013., Results: The primary tumour was in the duodenum and jejunum/ileum in 149 (72.7%) and 56 (27.3%) patients, respectively. Sixty-four patients (43.0%) with duodenal adenocarcinoma were asymptomatic and most cases were detected by oesophagogastroduodenoscopy (EGD), which was not specifically performed for the detection or surveillance of duodenal tumours. In contrast, 47 patients (83.9%) with jejunoileal carcinoma were symptomatic. The 3-year survival rate for stage 0/I, II, III, and IV cancers was 93.4%, 73.1%, 50.9%, and 15.1%, respectively. Multivariate analysis revealed performance status 3-4, high carcinoembryonic antigen, high lactate dehydrogenase (LDH), low albumin, symptomatic at diagnosis, and stage III/IV disease were independent factors for overall survival (OS). Ten patients (18.5%) with stage IV disease were treated with a combination of resection of primary tumour, local treatment of metastasis, and chemotherapy; this group had a median OS of 36.9 months., Conclusions: Although most SBA patients were diagnosed with symptomatic, advanced stage disease, some patients with duodenal carcinoma were detected in early stage by EGD. High LDH and symptomatic at diagnosis were identified as novel independent prognostic factors for OS. The prognosis of advanced SBA was poor, but combined modality therapy with local treatment of metastasis might prolong patient survival.

Adenocarcinoma (ADC) and squamous cell carcinoma (SqCC) are the two predominant subtypes of non-small cell lung cancer (NSCLC) and are distinct in their histological, molecular and clinical presentation. However, metabolic signatures specific to individual NSCLC subtypes remain unknown. Here, we perform an integrative analysis of human NSCLC tumour samples, patient-derived xenografts, murine model of NSCLC, NSCLC cell lines and The Cancer Genome Atlas (TCGA) and reveal a markedly elevated expression of the GLUT1 glucose transporter in lung SqCC, which augments glucose uptake and glycolytic flux. We show that a critical reliance on glycolysis renders lung SqCC vulnerable to glycolytic inhibition, while lung ADC exhibits significant glucose independence. Clinically, elevated GLUT1-mediated glycolysis in lung SqCC strongly correlates with high 18 F-FDG uptake and poor prognosis. This previously undescribed metabolic heterogeneity of NSCLC subtypes implicates significant potential for the development of diagnostic, prognostic and targeted therapeutic strategies for lung SqCC, a cancer for which existing therapeutic options are clinically insufficient.

The patient was a 73-year-old man who visited our department with black stools as the chief complaint. Upper digestive tract endoscopy revealed three type 2 lesions in the lesser curvature of the gastric antrum and the gastric angle and the posterior wall of the upper gastric body, which were diagnosed by biopsy as tub2, por, and sig, respectively. Total gastrectomy was performed. The final pathological diagnosis was quintuple gastric cancer with a main lesion of large-cell endocrine carcinoma and four adenocarcinoma sublesions. We report this extremely rare case of gastric endocrine cell carcinoma complicated by adenocarcinoma.

A 71-year-old man with anemia, weight loss, and loss of appetite was admitted. Ultrasound examination found thickening of the wall of the stomach. A type 3 gastric tumor was detected in the greater curvature of the gastric corpus via upper gastrointestinal endoscopy. Total gastrectomy, transverse colon resection, and Roux-en-Y anastomosis reconstruction was performed. In the postoperative pathological results, adenocarcinoma, tub2, and diffuse large B cell lymphoma collision was found. The patient underwent chemotherapy for malignant lymphoma and although it was a relatively advanced neoplasia, he is alive without a recurrence.

Aim: To clarify the biological feature contributing to gastric cancer with diffuse bone metastases at diagnosis., Methods: The participants visited the Department of Clinical Oncology, Akita University Hospital, from January 2014 to August 2015. The selection criterion for gastric cancer with diffuse bone metastases at diagnosis includes over 29 hot spots of bone scintigraphy. Circulating tumor cell were collected from 20 mL of peripheral venous blood drawn using a CellSearch kit and a CellTracks AutoPrep system by SRL, a clinical laboratory. The endpoints of this study were correlations between circulating tumor cells (CTC) count and therapeutic outcomes., Results: Among 39 patients with gastric cancer, 5 patients met the criterion. The incidence of this subtype was 12.8%. CTC counts ranged from 235 to 6440 cells/7.5 mL of peripheral blood (median of 1724). These values were much higher than common gastric cancers (2 cells). In chemo-sensitive cases, CTC counts decreased within 14 d (median) from 275, 235 and 1724 to 2, 7 and 66, respectively. On the other hand, CTC counts increased after treatment failure or insensitive case from 2, 7 and 6440 to 787, 513 and 7885, respectively. The correlation between CTC count and survival time showed a trend, but did not reach significance (Y = 234.6 - 0.03X, P = 0.085)., Conclusion: High CTC count is a biological hallmark of this subtype, and can be used as a direct and definitive indicator of therapeutic outcome.

Intestinal epithelial cells possess apical-basal polarity, which governs the exchange of nutrients and waste. Perturbation of cell polarity appears to be a general feature of cancers, although most colorectal cancers are differentiated adenocarcinomas, in which polarity is maintained to some extent. Little is known about the role of dysregulated polarity in cancer. The cancer tissue-originated spheroid method was applied to the preparation and culture of spheroids. Spheroids were cultured in suspension or in type I collagen gel. Polarity was assessed by IHC of apical markers and electron microscopy. Two types of polarity status in spheroids were observed: apical-in, with apical membrane located at cavities inside the spheroids in type I collagen gel; and apical-out, with apical membrane located at the outermost layer of spheroids in suspension. These polarities were highly interchangeable. Inhibitors of Src and dynamin attenuated the polarity switch. In patients, clusters of cancer cells that invaded vessels had both apical-in and apical-out morphologic features, whereas primary and metastatic tumors had apical-in features. In a mouse liver metastasis model, apical-out spheroids injected into the portal vein became apical-in spheroids in the liver within a few days. Inhibitors of Src and dynamin significantly decreased liver metastasis. Polarity switching was observed in spheroids and human cancer. The polarity switch was critical in an experimental liver metastasis model., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

A 71-year-old man who tested positive in a pepsinogen test also underwent upper gastrointestinal endoscopy. A 0-IIc lesion was identified at the posterior wall of the antrum. Biopsy findings indicated endocrine cell carcinoma. The patient underwent distal gastrectomy, and subsequent histopathological examination of the resected specimens showed a moderately differentiated adenocarcinoma (tub2) in the mucosa with transformation to small cell carcinoma in the submucosal and muscle layers. The final diagnosis was of a mixed adenoneuroendocrine carcinoma. We herein describe a case report of this patient with this rare form of gastric carcinoma.

We report a case of small intestinal adenocarcinoma treated with laparoscopic surgery. A 70-year-old woman had abdominal pain and epigastralgia. There were no abnormal findings on upper and lower endoscopy. The symptoms continued for 4 months after endoscopy, so she presented to our hospital. After CT examination, small bowel cancer with ileus was suspected. An ileus tube was inserted to relieve the bowel pressure and she was diagnosed with ileum cancer by enteroscopy. Laparoscopic surgery was performed and the pathological stage was determined as pStage Ⅲa. She was treated with oral chemotherapy (UFT plus LV) and had no recurrence 6 months after surgery.

Introduction: Using cell line-based assays, the secretion of erythroblastic leukemia viral oncogene homologue (ERBB) ligands has been reported to contribute to resistance against crizotinib in lung cancer with the echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase fusion gene. However, it is difficult to predict the role of the ligands in each patient. Here, we report an analysis of the mechanism of resistance behind crizotinib resistance using a primary culture of cancer cells from pleural effusion of an anaplastic lymphoma kinase-positive lung cancer patient who was clinically resistant to crizotinib., Methods: Primary cancer cells were prepared as cancer tissue-originated spheroids (CTOSs) according to previously described methods. CTOSs were maintained in StemPro medium, and a sensitivity assay was performed under growth factor-free conditions, or under stimulation with epidermal growth factor (EGF) or neuregulin-1/heregulin. The effect of treatment with crizotinib alone or a combination of crizotinib and erlotinib was examined., Results: Cancer cells (LB53) were established to be CTOSs from a patient who was clinically resistant to crizotinib. The CTOSs were sensitive to crizotinib under growth factor-free conditions in vitro, whereas resistant under stimulation with EGF or neuregulin-1. These ligands rescued the inhibition of intracellular signaling by crizotinib. Pleural effusion from the patient also activated EGF receptor signaling to the similar extent of EGF stimulation. The resistance to crizotinib by EGF was reversed by blocking EGF receptor signaling by erlotinib in vitro., Conclusion: Stimulation by ERBB ligands is suggested to be responsible for resistance to crizotinib in this patient. The CTOS method may enable analysis of resistance mechanism for targeted therapy in individual patients.

A 77-year-old-woman, whose chief complaint was anemia, was referred to our hospital and diagnosed with advanced gastric cancer with liver metastasis and lymph node metastasis.Gastrointestinal endoscopy showed a tumor on the lesser curvature of the gastric corpus.Histologically, biopsy specimens indicated adenocarcinoma with genetic amplification of human epidermal growth factor receptor type 2.Computed tomography and magnetic resonance imaging showed lymph node metastasis and liver metastasis.The patient received a total gastrectomy and a partial liver resection after combination chemotherapy consisting of capecitabine, cisplatin, and trastuzumab.Histopathological examination of a resected specimen showed a minute residual cancer nest at the subserosa of the stomach and lymph node metastasis, but no liver metastasis. This combined modality therapy can be considered an effective treatment for gastric cancer with liver metastasis, and we hope that it will be established as a standard therapy.

Background: The International association for the study of cancer (IASLC)/American thoracic society (ATS)/European respiratory society (ERS) has established a new subclassification of lung adenocarcinoma, especially for the lepidic pattern component, formerly called bronchioloalveolar adenocarcinoma (BAC). According to the new classification, BAC has been classified into the following 4 main subtypes: adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), invasive adenocarcinoma (IA), and variants of invasive adenocarcinoma (VIA). An observational study was conducted to validate this classification in patients with pathological stage IA pulmonary adenocarcinoma., Patients and Methods: 147 patients treated for pathological stage IA lung adenocarcinoma by complete resection at Osaka University Medical Hospital from January 1993 to December 2002 were assessed. The tumor specimens of the cohort were classified into the 4 subgroups. In addition, these groups were compared for various prognostic factors., Results: Adenocarcinoma in situ was observed in 30 patients, MIA in 8, IA in 104, and VIA in 5 patients, with 5-year survival rates of 100, 100, 85.5, and 60.0 %, respectively. The relationship between the histological classification and K-ras mutation was significant (p < 0.001), especially when comparing the VIA group with the others (p ≪ 0.001). Ki67-labeling indices were significantly different between the AIS and IA groups (p = 0.040)., Conclusions: This study validated the proposed IASLC/ATS/ERS classification for pulmonary adenocarcinoma in patients with pathological stage IA pulmonary adenocarcinoma. The difference between AIS and IA may depend on the proliferation of the carcinoma. In addition, the difference between VIA and the other adenocarcinoma types may depend on genetic factors, especially K-ras mutations.

Background/aims: To evaluate the clinicopathological features and results of surgery for gastric cancer in elderly patients aged ˃80 years relative to those aged ˂79 years, and to recommend the appropriate surgical treatment for elderly patients., Methodology: A total of 332 patients with gastric cancer who underwent gastrectomy in our department between 2002 and 2012 were evaluated. Of these, 81 were aged ˃80 years (Group A) and 251 were aged ˂79 years (Group B). We compared surgical outcomes and survival in these two groups. RESULTS; Postopeartive complications were associated with preoperative cormorbid disease(p<0.01). D2 and R0 resection was common in GroupB (p<0.01). Respiratory complications and hospital deaths were higher in Group A than in Group B. Overall survival (OS) was significantly lower in Group A than in Group B. Regarding Stage I disease, OS was significantly lower in Group A; however, cause-specific survival was similar between the two groups. Multivariate analysis showed that radicality and postoperative complications were independent prognostic factors for OS in elderly gastric cancer patients., Conclusions: These results indicate that postoperative respiratory complications and other causes of death worsened the prognosis of elderly. Preoperative accurate judgment of co-morbid disease, meticulous postoperative management and follow up might be improved survival of gastric cancer in elderly.

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.

Background/aim: Carcinomas of unknown primary origin (CUPs) account for 3%-5% of all malignancies. The majority of CUPs have unfavorable prognosis and are chemoresistant. Predictive biomarkers should be established to improve therapeutic outcomes. Metastatic ability of CUPs may be related to the existence of circulating tumor cells (CTCs)., Patients and Methods: Ten patients diagnosed with CUP visiting the Akita University Hospital participated in this study. CTCs were calculated by the CellSearch system., Results: The present observational study indicates that CTCs were detected in 50% of CUPs, and in 80% chemotherapeutically-naïve cases. Furthermore, decrease in CTC count between the pre-treatment and post-treatment phases were observed in chemosensitive cases., Conclusion: Rapid assessment of the efficacy of chemotherapy by CTC count may become a useful predictive biomarker of CUPs., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Although alcohol and smoking have not been established as risk factors for prostate cancer, they are important risk factors for other human cancers and potentially major avoidable factors. Alcohol drinkers and smokers might be less likely to get screening, which might lead to attenuation of the positive association. Here, we investigated the association of alcohol drinking and smoking and prostate cancer according to stage, as well as prostate cancer detected by subjective symptoms, in a large prospective study among Japanese men. The Japan Public Health Center-based prospective study (JPHC study) was established in 1990 for Cohort I and in 1993 for Cohort II. Subjects were 48,218 men aged 40-69 years who completed a questionnaire, which included their alcohol and smoking habits at baseline, and who were followed until the end of 2010. During 16 years of follow-up, 913 men were newly diagnosed with prostate cancer; of whom 248 had advanced cases, 635 were organ-localized and 30 were of an undetermined stage. Alcohol consumption was dose-dependently associated with advanced prostate cancer [nondrinkers: reference, 0-150 g/week: hazard ratio (HR) = 1.23, 95% confidence interval (CI) = 0.83-1.82; 150-300 g/week: HR = 1.51, 95% CI = 1.04-2.19; ≥ 300 g/week: HR = 1.41, 95% CI = 0.97-2.05, p for trend = 0.02]. The positive association was not substantially changed among cancers detected by subjective symptoms. Smoking was inversely associated with prostate cancer among total subjects, but tended to increase the risk of advanced prostate cancer detected by subjective symptoms. In conclusion, abstinence from alcohol and prohibition of smoking might be important factors in the prevention of advanced prostate cancer., (© 2013 UICC.)

Objective: The clinicopathological characteristics and surgical results of young lung cancer patients were investigated., Materials and Methods: Seven hundred and four (6.0%) patients with lung cancer, aged up to 50 years, were enrolled from among the 11,663 patients registered in the Japanese Lung Cancer Registry Study 2004, and their clinical data were compared with those of 10,959 patients older than 50 years. This epidemiological study is based on the single year registration of surgically treated patients in the major institutes in Japan., Results: The 5-year overall survival rate (5Y-OS) and the 5-year lung cancer-related survival rate was 79.2%/69.0% (p<0.001) and 81.3%/76.6% (p=0.005) in the young/old groups, respectively. In the young/old groups, lobectomy and pneumonectomy was performed in 76.9%/78.0% and 5.7%/3.2%, respectively; adjuvant therapies were given preoperatively in 10.4%/4.7% (p<0.001) and postoperatively in 31.4%/24.5% (p<0.001). The proportions of patients with p-stage IIIA (18.2%) and adenocarcinoma histology (78.7%) were higher in the young group. The 5Y-OS was 94.8%/86.2% for p-stage IA (p<0.001), 87.0%/73.2% for p-stage IB (p=0.001), 61.0%/61.6% for p-stage IIA (p=0.595), 71.0%/48.4% for p-stage IIB (p=0.003), 49.6%/39.4% for p-stage IIIA (p=0.020), and 80.0%/24.8% for p-stage IIIB (p=0.012); it was 83.5%/80.7% for females (p=0.106) and 75.1%/62.3% for males (p<0.001) in the young/old groups. The postoperative survival was significantly better with all operative procedures in the young group. The 5Y-OS after recurrence was 17.9%/13.4% in the young/old groups (p=0.016). In the young group, the 5Y-OS was better in females (83.5%) than in males (75.1%, p=0.002), and for patients with adenocarcinoma (80.3%) than for those with squamous cell carcinoma (68.5%, p=0.013). Age up to 50 years was identified as an independent better prognostic factor on multivariate analysis., Conclusions: The postoperative survival in lung cancer patients aged up to 50 years was better than that in patients older than 50 years., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objectives: A new pathological classification for pre- and minimally invasive adenocarcinoma has been established, with distinction prior to surgery crucial because of the extremely good prognosis., Methods: Of 412 patients who underwent surgery for lung cancer from 2008 to 2011, 110 classified as c-stage I had each of the following four parameters assessed for predictive power for pre- or minimally invasive adenocarcinoma and relapse-free survival (RFS): (i) whole tumour size (WS) shown by computed tomography (CT) , (ii) size of the solid (SS) component in CT findings, (iii) maximum standard uptake value in fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan images (SUVmax) and (iv) serum level of carcinoembryonic antigen., Results: For prediction of pre- or minimally invasive adenocarcinoma, the area under the receiver-operating curve was >0.7 for all the four parameters, while only SS was found to be an independent factor in multivariate logistic regression analysis. In Cox proportional hazard model analysis, SS and SUVmax were statistically significant, and SS was exclusively independent in multivariate analysis. Differences in RFS between T1a and T1b were more pronounced when using SS compared with WS. In the sub-classification of T1a, we used a breakpoint of 1.0 cm in SS (T1a-α and T1a-β), which resulted in a 2-year RFS rate of 1.00 for T1a-α (n=21), 0.89 for T1a-β (n=27) and 0.68 for T1b (n=26) (P=0.002 between T1a-β and T1b)., Conclusions: The SS parameter was useful to distinguish pre- and minimally invasive adenocarcinoma from other types of lung cancer, and set a T1a sub-classification.

In preparation for a collaborative multidisciplinary study of the pathogenesis of esophageal cancer, the authors reviewed the published literature to identify similarities and differences between Japan and China in esophageal cancer epidemiology. Esophageal squamous cell carcinoma (ESCC) is the predominant histologic type, while the incidence of esophageal adenocarcinoma remains extremely low in both countries. Numerous epidemiologic studies in both countries show that alcohol consumption and cigarette smoking are contributing risk factors for ESCC. There are differences, however, in many aspects of esophageal cancer between Japan and China, including cancer burden, patterns of incidence and mortality, sex ratio of mortality, risk factor profiles, and genetic variants. Overall incidence and mortality rates are higher in China than in Japan, and variation in mortality and incidence patterns is greater in China than in Japan. During the study period (1987-2000), the decline in age-adjusted mortality rates was more apparent in China than in Japan. Risk factor profiles differed between high- and low-incidence areas within China, but not in Japan. The association of smoking and drinking with ESCC risk appears to be weaker in China than in Japan. Genome-wide association studies in China showed that variants in several chromosome regions conferred increased risk, but only genetic variants in alcohol-metabolizing genes were significantly associated with ESCC risk in Japan. A well-designed multidisciplinary epidemiologic study is needed to examine the role of diet and eating habits in ESCC risk.

A sublobar resection is currently recognized as an option for early small-sized non-small cell lung cancer (NSCLC), and intraoperative rapid and accurate lymph node assessment is required for a complete resection. To solve this issue, we investigated the clinical utility of one-step nucleic acid amplification (OSNA) assay, an automated rapid molecular diagnostic method and its optimal mRNA marker for detection of lymph node metastasis in lung cancer. We extracted 16 target candidate mRNA markers with high expression in lung cancer from a genetic database, and then quantified their expression levels by quantitative RT-PCR using surgically dissected lymph nodes with or without metastasis. Cytokeratin 19 (CK19), cytokeratin 7 (CK7), stratifin (SFN), and anterior gradient homolog 2 (AGR2) showed significant differences for mRNA expression between metastasis-negative and -positive lymph nodes in quantitative-RT-PCR screening. CK19 and CK7 were finally selected as potential target markers and were quantified using OSNA assay findings of 165 dissected lymph nodes obtained from 49 lung cancer patients. The OSNA assay with CK19 and CK7 were completed within 40 min and their positive predictive value, negative predictive value, and accuracy comparing to pathological diagnosis with hematoxylin-eosin staining and immunohistochemistry were shown to be 95.0%, 99.3%, and 98.8%, and 85.0%, 97.9%, and 96.4%, respectively, using a cut-off value of 250 copies/μL. Among the 165 lymph nodes tested, 1 false negative result was due to massive necrosis of cancer cells and 1 false positive was caused by the allocation bias of cancer cells in the sampling in patient with pleural dissemination. The best performance was observed when CK19 was used as a marker, while the addition of CK7 mRNA as a marker did not increase sensitivity or specificity. In conclusion, an OSNA assay using CK19 could be effective for molecular diagnosis of lymph node metastasis in lung cancer. This is the first report suggesting the potential clinical utility of OSNA assay for intraoperative rapid diagnosis of nodal status in lung cancer., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Video-assisted thoracic surgery is useful during a typical lobectomy procedure, though challenging in complicated cases. We report successful video-assisted thoracic surgery lobectomy procedures performed after coronary artery bypass grafting in two lung cancer patients, with severe adhesion of lung parenchyma to grafts of the internal thoracic artery. We avoided dissection of the lung from the grafts and divided the lung parenchyma. No intrathoracic infection or local recurrence was found 5 years after surgery in either patient. The present 'non-dissection technique' is a feasible and safe optional procedure during a lobectomy after coronary artery bypass grafting using internal thoracic artery grafts.

NR0B1, an orphan nuclear receptor, is expressed in side population cells and its knockdown reduces tumorigenic and anti-apoptotic potential in lung adenocarcinoma. Peroxisome proliferator-activated receptor γ (PPARγ) is another member of the nuclear receptor family which induces apoptosis in lung cancer. The interaction of NR0B1 with PPARγ was examined. The transactivation ability of PPARγ was inhibited by NR0B1 in lung adenocarcinoma, and the N-terminal region of NR0B1 containing LxxLL motifs mediated its inhibition. Co-immunoprecipitation experiments revealed that this N-terminal region of NR0B1 was essential for the physical interaction with PPARγ. Aldehyde dehydrogenase (ALDH) activity and ALDH3A1 expression, which are correlated with tumorigenic potential of lung adenocarcinoma, increased when NR0B1 expression was induced, but its increase was inhibited by PPARγ overexpression. ALDH activity increased by treatment with PPARγ inhibitor, and the increase was further enhanced when the expression of NR0B1 was induced. Furthermore, the high NR0B1 and low PPARγ expression was a negative prognostic factor in Pathological-Stage IA clinical cases. These results indicate the reciprocal relationship between NR0B1 and PPARγ on the malignant grade of lung adenocarcinoma.

Background: The evidence for a role of tobacco smoking, alcohol drinking, and body mass index (BMI) in the etiology of small intestine cancer is based mainly on case-control studies from Europe and United States., Subjects and Methods: We harmonized the data across 12 cohort studies from mainland China, Japan, Korea, Singapore, and Taiwan, comprising over 500,000 subjects followed for an average of 10.6 years. We calculated hazard ratios (HRs) for BMI and (only among men) tobacco smoking and alcohol drinking., Results: A total of 134 incident cases were observed (49 adenocarcinoma, 11 carcinoid, 46 other histologic types, and 28 of unknown histology). There was a statistically non-significant trend toward increased HR in subjects with high BMI [HR for BMI>27.5 kg/m2, compared with 22.6-25.0, 1.50; 95% confidence interval (CI) 0.76-2.96]. No association was suggested for tobacco smoking; men drinking>400 g of ethanol per week had an HR of 1.57 (95% CI 0.66-3.70), compared with abstainers., Conclusions: Our study supports the hypothesis that elevated BMI may be a risk factor for small intestine cancer. An etiologic role of alcohol drinking was suggested. Our results reinforce the existing evidence that the epidemiology of small intestine cancer resembles that of colorectal cancer.

Background: The enzyme dihydropyrimidine dehydrogenase (DPD) is involved in the metabolism of 5-fluorouracil (5-FU). The aim of this study was to clarify the correlation between the expression of DPD and the efficacy of 5-FU therapy in patients with lung adenocarcinoma (AD)., Patients and Methods: We examined surgically resected specimens from 90 stage I to IIIA patients with lung ADs to determine the level of intra-tumoral DPD mRNA., Results: Administration of 5-FU improved the prognosis of patients with low DPD-expressing tumors, whereas it did not do so for patients with high DPD expressing tumors. Patients with low DPD-expressing tumors administered with 5-FU had a significantly better prognosis than those who underwent surgery alone. A Cox proportional hazards regression model revealed that administration of 5-FU was an independent variable to predict prognosis in patients with low DPD-expressing tumors., Conclusion: Quantification of DPD mRNA levels is useful for determining the subgroup of lung AD patients who would benefit most from 5-FU after surgery.

We report two cases of needle-tract seeding after percutaneous cryoablation for lung metastases of colorectal cancer. The targeted lung tumor was solitary in both cases. In patient 1, cryoablation was performed with a single cryoprobe, which was removed without freezing the cryoprobe tract. In patient 2, cryoablation was performed with two cryoprobes, both of which were removed after freezing of the cryoprobe tract. The seeding nodule appeared 5 and 7 months after cryoablation on the follow-up computed tomographic scan, respectively. In both cases, the seeding nodules were solitary and existed primarily in the subcutaneous to chest muscle layer, and could be completely resected under local anesthesia. Both lesions were pathologically confirmed as metastases from colorectal cancer. Local control was maintained in patient 1 for 4 years, until death due to progressive lung metastases. Patient 2 is alive without recurrences 8 months after resection., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

In Western countries, the standard treatment for locally advanced rectal cancer is preoperative chemoradiotherapy followed by total mesorectal excision. On the other hand, in Japan, treatment results without radiotherapy are by no means inferior; therefore, extrapolation of results of preoperative treatment in Western countries to Japan is controversial. We consider that survival may be improved by preoperative treatment with new anticancer agents as they are expected not only to decrease the local recurrence rate but also to prevent distant metastases. We are conducting a multicentre Phase II study to evaluate the safety and efficacy of neoadjuvant chemotherapy using XELOX plus bevacizumab without radiotherapy in patients with locally advanced rectal cancer. The primary endpoint of the study is treatment compliance. Secondary endpoints are overall survival, disease-free survival, local recurrence-free survival, objective response rate, R0 resection rate and adverse events. Thirty patients are required for this study.

Purpose: To evaluate a custom-developed software for analyzing malignant degrees of small peripheral adenocarcinomas on volumetric CT data compared to pathological prognostic factors., Materials and Methods: Forty-six adenocarcinomas with a diameter of 2cm or less from 46 patients were included. The custom-developed software can calculate the volumetric rates of solid parts to whole nodules even though solid parts show a punctate distribution, and automatically classify nodules into the following six types according to the volumetric rates of solid parts: type 1, pure ground-glass opacity (GGO); type 2, semiconsolidation; type 3, small solid part with a GGO halo; type 4, mixed type with an area that consisted of GGO and solid parts which have air-bronchogram or show a punctate distribution; type 5, large solid part with a GGO halo; and type 6, pure solid type. The boundary between solid portion and GGO on CT was decided using two threshold selection methods for segmenting gray-scale images. A radiologist also examined two-dimensional rates of solid parts to total opacity (2D%solid) which was already confirmed with previous reports., Results: There were good agreements between the classification determined by the software and radiologists (weighted kappa=0.778-0.804). Multivariate logistic regression analyses showed that both 2D%solid and computer-automated classification were significantly useful in estimating lymphatic invasion (p=0.0007, 0.0027), vascular invasion (p=0.003, 0.012), and pleural invasion (p=0.021, 0.025)., Conclusion: Using our custom-developed software, it is feasible to predict the pathological prognostic factors of small peripheral adenocarcinomas., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: The benefits of adjuvant chemotherapy for completely resected non-small cell lung cancer (NSCLC) have been demonstrated using mainly cisplatin (CDDP)-based chemotherapeutic regimens. However, treatment-related deaths sometimes occur. Therefore, the development of a safer regimen is necessary., Patients and Methods: The patients were randomized to either carboplatin (CBDCA) area under the curve (AUC) 3 and paclitaxel (PTX) 90 mg/m(2) (PCb arm) or CBDCA (AUC3) plus gemcitabine (GEM) (1000 mg/m(2)) (GCb arm) every 2 weeks for 8 cycles after surgery. The primary endpoint was the compliance with the regimen, while the secondary endpoints were safety and toxicity., Results: A total of 75 patients were enrolled in a multi-institutional study. Twenty-one out of 39 patients (54%) in the PCb arm and 25 of 36 patients (69%) in the GCb arm completed 8 cycles, and 59% in the PCb arm and 81% in the GCb arm completed ≥6 cycles. The predominant toxicity was neutropenia. Non-hematological adverse effects were infrequent and no treatment-related death was registered. The estimated disease-free survival and overall survival at 2 years were 70.8% and 66.3% in the PCb and 91.4% and 79.1% in the GCb arm, respectively., Conclusion: This adjuvant bi-weekly scheduled chemotherapy resulted in good compliance in both arms, and the regimen was feasible, with acceptable levels of toxicity in completely resected Japanese NSCLC patients. Therefore, these regimens represent a new treatment option suitable for outpatients with completely resected NSCLC.

Purpose: To report a case of bilateral regression of choroidal metastasis with adenocarcinoma of the lung treated with gefitinib., Methods: Retrospective case review of a 68-year-old woman with pulmonary adenocarcinoma with choroidal metastasis who presented with visual loss in the left eye as the initial manifestation. Her visual acuity was 6/6 in the right eye and 6/60 in the left eye before the start of gefitinib administration. Best-corrected visual acuity and spectral-domain optical coherence tomography were compared between baseline and 3 months after treatment., Results: Best-corrected visual acuity in the left eye had improved to 6/30 3 months after oral gefitinib. The elevated lesions of the right eye disappeared, with decrease of subretinal fluid and retinal pigment epithelial atrophy. Spectral-domain optical coherence tomography showed that subretinal fluid of the left eye was also reduced., Conclusions: Oral gefitinib could be effective for regression of choroidal metastasis in patients with adenocarcinoma of the lung and provides a potential treatment option.

We report a case of pathologically complete response of multiple liver metastases from rectal cancer after neoadjuvant chemotherapy. The patient was a 74-year-old woman who had advanced rectal cancer with synchronous liver metastases (T4N1M1). Following resection of the primary tumor, she received biweekly mFOLFOX6 plus bevacizumab neoadjuvant chemotherapy. After 5 courses, the liver tumors were markedly reduced in size. Three weeks after the final treatment, she underwent partial hepatectomies. Histologically, no cancer cells were detected in any resected specimens. The postoperative course was uneventful, and she has been well without recurrence for one year at the time of writing. Regimens containing bevacizumab may result in good tumor response. Surgical resection is crucial for proof of pathologically complete response.

Cancer stem cells are a limited population of tumor cells that are thought to reconstitute whole tumors. The Hoechst dye exclusion assay revealed that tumors are composed of both a main population and a side population of cells, which are rich in cancer stem cells. NR0B1 is an orphan nuclear receptor that is expressed to a greater extent in the side population, as compared with the main population, of a lung adenocarcinoma cell line. In this study, we investigated the role of NR0B1 in lung adenocarcinoma cells. Reduction of NR0B1 expression levels in lung adenocarcinoma cell lines resulted in vulnerability to anti-cancer drugs and decreased abilities for invasion, in vitro colony formation, and tumorigenicity in non-obese diabetic/severe compromised immunodeficient mice. When 193 cases of lung adenocarcinoma were immunohistochemically examined, higher levels of NR0B1 expression correlated with higher rates of lymph node metastasis and recurrence. Multivariate analysis revealed high NR0B1 expression levels, stage of the disease, and size of tumor to be independent unfavorable prognostic factors for overall and disease-free survival rates. In clinical samples, NR0B1 expression levels inversely correlated to the proportion of methylated CpG sequences around the transcription initiation site of the NR0B1 gene, suggesting the epigenetic control of NR0B1 transcription in lung adenocarcinoma. In conclusion, NR0B1 might play a role in the malignant potential of lung adenocarcinoma.

CUB domain containing protein (CDCP1), a transmembrane protein with intracellular tyrosine residues which are phosphorylated upon activation, is supposed to be engaged in proliferative activities and resistance to apoptosis of cancer cells. Expression level of CDCP1 was examined in lung adenocarcinoma, and its clinical implications were evaluated. CDCP1 expression was immunohistochemically examined in lung adenocarcinoma from 200 patients. Staining intensity of cancer cells was categorized as low and high in cases with tumor cells showing no or weak and strong membrane staining, respectively. MIB-1 labeling index was also examined. There were 113 males and 87 females with median age of 63 years. Stage of disease was stage I in 144 cases (72.0%), II in 19 (9.5%), and III in 37 (18.5%). Sixty of 200 cases (30.0%) were categorized as CDCP1-high, and the remaining as CDCP1-low. Significant positive correlation was observed between CDCP1-high expression and relapse rate (P < 0.0001), poor prognosis (P < 0.0001), MIB-1 labeling index (P < 0.0001), and occurrence of lymph node metastasis (P = 0.0086). There was a statistically significant difference in disease-free survival (DFS) (P < 0.0001) and overall survival (OS) rates (P < 0.0001) between patients with CDCP1-high and CDCP1-low tumors. Univariate analysis showed that lymph node status, tumor stage, and CDCP1 expression were significant factors for both OS and DFS. Multivariate analysis revealed that only CDCP1 expression was an independent prognostic factor for both OS and DFS. CDCP1 expression level is a useful marker for prediction of patients with lung adenocarcinoma

CD22 [Siglec-2 (sialic acid-binding, immunoglobulin-like lectin-2)], a negative regulator of B-cell signalling, binds to alpha2,6- sialic acid-linked glycoconjugates, including a sialyl-Tn antigen that is one of the typical tumour-associated carbohydrate antigens expressed on various mucins. Many epithelial tumours secrete mucins into tissues and/or the bloodstream. Mouse mammary adenocarcinoma cells, TA3-Ha, produce a mucin named epiglycanin, but a subline of them, TA3-St, does not. Epiglycanin binds to CD22 and inhibits B-cell signalling in vitro. The in vivo effect of mucins in the tumour-bearing state was investigated using these cell lines. It should be noted that splenic MZ (marginal zone) B-cells were dramatically reduced in the mice bearing TA3-Ha cells but not in those bearing TA3-St cells, this being consistent with the finding that the thymus-independent response was reduced in these mice. When the mucins were administered to normal mice, a portion of them was detected in the splenic MZ associated with the MZ B-cells. Furthermore, administration of mucins to normal mice clearly reduced the splenic MZ B-cells, similar to tumour-bearing mice. These results indicate that mucins in the bloodstream interacted with CD22, which led to impairment of the splenic MZ B-cells in the tumour-bearing state.

The prognosis of patients with carcinomatous meningitis from non-small-cell lung cancer (NSCLC) remains poor, and the available treatment options for the lung cancer do not relieve the severe symptoms of this sequela. We report the successful treatment of two cases of carcinomatous meningitis caused by NSCLC, using gefitinib and a ventriculo-peritoneal (V-P) shunt. The first patient was a 43-year-old woman with pT1N0M0 adenocarcinoma. Multiple brain and vertebral metastases were found 13 months after surgery. She had undergone gamma-knife radiosurgery for the brain metastases, radiotherapy for the vertebral metastases, and two regimens of systemic chemotherapy, before carcinomatous meningitis was diagnosed. She was given gefitinib, and then a V-P shunt was placed. She continued to take gefitinib and was free of subjected symptoms for 5 months until she died. The second patient was a 64-year-old woman with cT4N0M0 adenocarcinoma. After local chemotherapy using cisplatin and OK-432 for carcinomatosis pleuritis and two regimens of systemic chemotherapy, carcinomatous meningitis was detected. A V-P shunt was placed, and she was sequentially given gefitinib. At her 15-month follow-up, she was free of symptoms of carcinomatous meningitis. No adverse effects or shunt problems were detected in either patient. This therapeutic modality may liberate carcinomatous meningitis patients with severe symptoms from hospitalization and improve their quality of life.

Background: Although endoscopic submucosal dissection (ESD) is expected to reduce the local recurrence of gastric cancers, we still experience cases of recurrence after an ESD., Objective: To characterize clinical and pathologic features of cases with local recurrence of early gastric cancer after an ESD., Design: A prospective cohort study., Setting and Patients: A total of 306 patients with gastric cancers removed by ESD at Okayama University Hospital and Tsuyama Central Hospital between March 2001 and December 2005 were enrolled., Intervention: ESD., Main Outcome Measurement: Local recurrence., Results: The incidence of a complete en bloc resection was 80.4% when pathologically evaluated. Within a median follow-up period of 26 months (12-64 months), a local recurrence was found in 7 cases, all of which had been declared incomplete resections. One patient underwent a second ESD, and the remaining 6 underwent a surgical resection. All removed lesions were mucosal cancers. No lymph-node metastases were found in patients with a surgical resection. There was a significant correlation between the incidence of an incomplete resection and that of a local recurrence (P < .0001). Among the clinical characteristics, tumor size (>30 mm vs <20 mm; odds ratio [OR] 16 mm [95% CI, 2.0-130 mm]) and tumor location (upper vs middle or lower; OR 7.6 [95% CI, 1.3-45]) were identified as factors that were significantly associated with the incidence of a local recurrence., Limitation: Short follow-up duration., Conclusions: The incidence of a local recurrence was strongly associated with that of an incomplete resection. The frequency of a local recurrence also showed significant correlations with the tumor size and location within the stomach.

Objective: Recent technologic developments in computed tomography have increased the incidence of surgical intervention for small-sized lung cancer. Although indications of a sublobar resection for early disease have been discussed, we occasionally encounter locally advanced small-sized lung cancer with node metastasis. The present study aimed to clarify the histopathologic factors influencing nodal involvement and prognosis of such patients., Methods: We studied 97 patients who underwent complete resection for an adenocarcinoma of 2 cm or less in diameter. Lymph node metastasis and necrosis were microscopically evaluated, whereas immunohistochemical studies were also performed with Ki-67 and D2-40 for proliferation activity and lymphatic invasion, respectively. In addition, carcinoembryonic antigen expression in the tumor and its level in serum were investigated. Survival analysis was then conducted by using these clinicopathologic factors., Results: The 5-year disease-free survival rate was 90%. Nodal involvement was significantly frequent in patients with tumors showing microscopic necrosis, a Ki-67 labeling index of greater than 5%, and an increased serum carcinoembryonic antigen level. Furthermore, 5-year disease-free survival was worse in patients with lesions showing microscopic necrosis (68%), a Ki-67 labeling index of greater than 5% (76%), and lymphatic invasion detected with D2-40 staining (77%). Multivariate analysis identified lymphatic invasion detected with D2-40 to be an independent predictor for postoperative recurrence., Conclusions: These results indicate that microscopic necrosis, Ki-67 labeling index, and serum carcinoembryonic antigen level are predictors of nodal involvement. Careful postoperative follow-up examinations for recurrence are required for patients with tumors that show microscopic necrosis, high Ki-67 labeling index, and lymphatic invasion, even in those with stage IA disease.

Although smoking is a major cause of lung cancer, the proportion of lung cancer cases among Japanese women who never smoked is high. As the prevalence of smoking in Japan is relatively high in men but low in women, the development of lung cancer in non-smoking Japanese women may be significantly impacted by passive smoking. We conducted a population-based prospective study established in 1990 for Cohort I and in 1993 for Cohort II. The study population was defined as all residents aged 40-69 years at the baseline survey. 28,414 lifelong non-smoking women provided baseline information on exposure to tobacco smoke from their husband, at the workplace and during childhood. Over 13 years of follow-up, 109 women were newly diagnosed with lung cancer, of whom 82 developed adenocarcinoma. Compared with women married to never smokers, hazard ratio (HR) [95% confidence interval (CI)] for all lung cancer incidence in women who lived with a smoking husband was 1.34 (95% CI 0.81-2.21). An association was clearly identified for adenocarcinoma (HR 2.03, 95% CI 1.07-3.86), for which dose-response relationships were seen for both the intensity (p for trend = 0.02) and amount (p for trend = 0.03) of the husband's smoking. Passive smoking at the workplace also increased the risk of lung cancer (HR 1.32, 95% CI 0.85-2.04). Moreover, a higher risk of adenocarcinoma was seen for combined husband and workplace exposure (HR 1.93, 95% CI 0.88-4.23). These findings confirm that passive smoking is a risk factor for lung cancer, especially for adenocarcinoma among Japanese women., ((c) 2007 Wiley-Liss, Inc.)

Background: The secretion of biologically active estrogen through the conversion of circulating precursor androgens has been suggested to play important roles in the pathophysiology of estrogen-dependent carcinomas. In the present study, we examined aromatase expression in gastric carcinoma., Methods: Nineteen specimens of gastric carcinoma were obtained from Japanese patients at the Department of Surgery, Tottori University Hospital, Japan. Nontumoral tissues adjacent to the carcinoma were also available for analysis. The histological features of the gastric carcinomas were as follows: 8 intestinal-type and 11 diffuse-type adenocarcinomas. Tissue specimens removed at surgery were used for the preparation of RNA or for immunohistochemical analysis. Six cell lines derived from human gastric cancers were also used as a model system. Using conventional and real-time reverse transcription-polymerase chain reactions, aromatase mRNA expression and promoter usage were assayed. Immunohistochemical analysis was performed using an anti-aromatase antibody., Results: We demonstrated the molecular basis of aromatase mRNA expression, which depended on three proximal promoters in tumoral and nontumoral tissues, for the first time. The tumoral tissues exhibited positive staining for anti-aromatase antibody. At the same time, positive staining was also observed in nontumoral mucosa, predominantly in the parietal cells., Conclusion: We provide evidence suggesting a mechanism for the secretion of estrogen through the conversion of a precursor androgen in tumoral and nontumoral tissues in the stomach.