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In Japan, accessible Helicobacter pylori (Hp) eradication therapy is associated with an increase in the prevalence of gastric cancers (GCs) in Hp uninfected stomachs. Signet ring cell carcinoma (SRCC) is the most common of these GCs. Intramucosal SRCC with poorly differentiated adenocarcinoma (PDA) occurring in Hp uninfected gastric mucosa is rare; furthermore, many Hp uninfected pure SRCCs exhibit discoloration and flat or slightly depressed lesions, and morphological elevation is relatively rare. We report a case of intramucosal SRCC with PDA with an elevated, verrucous gastritis-like lesion in a 57-year-old male patient. In the present case, the PDA area showed dense tumor cell growth and coexisting desmoplastic and fibrotic reactions. Histopathology and immunohistochemical staining identified extensive fibromuscular obliteration with smooth muscle bundles extending from the muscularis mucosa into the lamina propria. The patient underwent curative endoscopic submucosal dissection. The reporting and analysis of such rare cases may lead to a better understanding of the characteristics of advanced Hp uninfected GCs., (© 2024. The Author(s).)

Background: The clinicopathological features and prognosis of primary small bowel adenocarcinoma (PSBA), excluding duodenal cancer, remain undetermined due to its rarity in Japan., Methods: We analyzed 354 patients with 358 PSBAs, between January 2008 and December 2017, at 44 institutions affiliated with the Japanese Society for Cancer of the Colon and Rectum., Results: The median age was 67 years (218 males, 61.6%). The average tumor size was 49.9 (7-100) mm. PSBA sites consisted of jejunum (66.2%) and ileum (30.4%). A total of 219 patients (61.9%) underwent diagnostic small bowel endoscopy, including single-balloon endoscopy, double-balloon endoscopy, and capsule endoscopy before treatment. Nineteen patients (5.4%) had Lynch syndrome, and 272 patients (76.8%) had symptoms at the initial diagnosis. The rates for stages 0, I, II, III, and IV were 5.4%, 2.5%, 27.1%, 26.0%, and 35.6%, respectively. The 5-year overall survival rates at each stage were 92.3%, 60.0%, 75.9%, 61.4%, and 25.5%, respectively, and the 5-year disease-specific survival (DSS) rates were 100%, 75.0%, 84.1%, 59.3%, and 25.6%, respectively. Patients with the PSBA located in the jejunum, with symptoms at the initial diagnosis or advanced clinical stage had a worse prognosis. However, multivariate analysis using Cox-hazard model revealed that clinical stage was the only significant predictor of DSS for patients with PSBA., Conclusions: Of the patients with PSBA, 76.8% had symptoms at the initial diagnosis, which were often detected at an advanced stage. Detection during the early stages of PSBA is important to ensure a good prognosis., (© 2024. The Author(s).)

Purpose: Limited information is available regarding the characteristics and outcomes of stage IV small bowel adenocarcinoma (SBA) in Japan. This study examined the clinical and pathological characteristics and outcomes according to the treatment strategies in patients with stage IV SBA., Methods: This retrospective observational study used the data of patients with jejunal or ileal adenocarcinoma collected by the Small Bowel Malignant Tumor Project of the Japanese Society for Cancer of the Colon and Rectum. Descriptive statistics were expressed as the mean (standard deviation) or median (range). Survival analysis was performed using Kaplan-Meier curves and pairwise log-rank tests., Results: Data from 128 patients were analyzed. The treatment strategies were chemotherapy alone (26 of 128, 20.3%), surgery alone (including palliative surgery; 21 of 128, 16.4%), surgery + chemotherapy (74 of 128, 57.8%), and best supportive care (7 of 128, 5.5%). The median (range) overall survival was 16 (0-125) months overall, and 11 (1-38) months, 8 (0-80) months, 18 (0-125) months, and 0 (0-1) months for the chemotherapy, surgery, surgery + chemotherapy, and best supportive care groups, respectively. Three main categories of chemotherapeutic regimen were used: a combination of fluoropyrimidine and oxaliplatin (F + Ox), fluoropyrimidine and irinotecan (F + Iri), and single-agent fluoropyrimidine. Among patients treated with chemotherapy, the median (range) OS was 16 (1-106) months overall, and 17 (1-87) months, 29 (7-39) months, and 16 (1-106) months in patients treated with fluoropyrimidine, F + Iri, and F + Ox, respectively., Conclusion: Patients treated with surgery, chemotherapy, or both had a better prognosis than those who received best supportive care. Among patients who received chemotherapy, survival did not differ according to the chemotherapeutic regimen.

We present a rare case that showed the coexistence of gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma in Helicobacter pylori-naive stomach. A 72-year-old man was followed up after surgery for epithelial carcinoma of the glottis at the Department of Otolaryngology. He underwent an upper gastrointestinal endoscopy for an abnormal PET-CT accumulation, which revealed gastric adenocarcinoma of fundic gland type in the gastric fundus and MALT lymphoma in the upper gastric body. Hence, we performed an endoscopic submucosal dissection for gastric cancer and diagnosed gastric adenocarcinoma of fundic gland type derived from a hamartomatous-inverted polyp. Subsequently, Gastric MALT lymphoma was treated with radiation therapy because the API2-MALT1 gene was positive and the Helicobacter pylori infection was negative. A complete response was observed. Even in Hp-naive stomachs, cases such as the present case are complicated by special types of gastric cancer and MALT lymphoma, and endoscopic examination should be performed with these diseases in mind., (© 2023. Japanese Society of Gastroenterology.)

Background: When a lesion does not meet the curative criteria of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC), referred to as non-curative resection or curability C-2 in the guidelines, an additional surgery is the standard therapy because of the risk of lymph node metastasis (LNM)., Objective: This study aimed to identify high-risk patients for recurrence after additional surgery for curability C-2 ESD of EGC., Methods: This multicenter retrospective cohort study enrolled 1064 patients who underwent additional surgery after curability C-2 ESD for EGC. We evaluated the recurrence rate and the risk factors for recurrence after additional surgery in these patients., Results: The 5-year recurrence rate after additional surgery was 1.3%. Multivariate Cox analysis revealed that the independent risk factors for recurrence after additional surgery were LNM (hazard ratio [HR] 32.47; p < 0.001) and vascular invasion (HR 4.75; p = 0.014). Moreover, patients with both LNM and vascular invasion had a high rate of recurrence after additional surgery (24.6% in 5 years), with a high HR (119.32) compared with those with neither LNM nor vascular invasion. Among patients with no vascular invasion, a high rate of recurrence was observed in those with N2/N3 disease according to the American Joint Committee on Cancer TNM staging system (27.3% in 5 years), in contrast with no recurrence in those with N1 disease., Conclusions: Patients with both LNM (N1-N3) and vascular invasion, as well as those with N2/N3 disease but no vascular invasion, would be candidates for adjuvant chemotherapy after additional surgery for curability C-2 ESD of EGC.

Background and Aims: Cancer recurrence is observed in some patients without additional radical surgery after endoscopic submucosal dissection (ESD) that does not fulfill the curability criteria for early gastric cancer (EGC), categorized as "noncurative resection" or "curability C-2" in the guidelines. However, time to cancer recurrence is different in such patients. Thus, we aimed to identify the risk factors of early and late cancer recurrences in these patients., Methods: Between 2000 and 2011, this multicenter study analyzed 905 patients who were followed up without additional radical surgery after ESD for EGC categorized as curability C-2. We evaluated the risk factors for early and late cancer recurrences, separately, after ESD. The cut-off value was defined at 2 years., Results: Time to cancer recurrence in the enrolled patients showed a bimodal pattern, and the 5-year cancer recurrence rate was 3.2%. Multivariate Cox analyses revealed that lymphatic invasion (hazard ratio [HR], 8.56; P = .003) was the sole independent risk factor for early cancer recurrence. Regarding late cancer recurrence, vascular invasion (HR, 4.50; P = .039) was an independent risk factor, and lymphatic invasion tended to be a risk factor (HR, 3.63; P = .069)., Conclusions: This multicenter study with a large cohort demonstrated that lymphatic invasion is mainly associated with early cancer recurrence; however, vascular invasion was a risk factor only for late recurrence in patients without additional treatment after ESD for EGC categorized as curability C-2. This finding may contribute to decision making for treatment strategies after ESD, especially for patients with a relatively short life expectancy., (Copyright © 2019 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Serrated adenocarcinoma (SAC) is considered the end stage of the serrated neoplasia pathway. Although SAC prognosis is not widely recognized, the serrated pathway-associated subtype consistently exhibits unfavorable prognosis in genetic studies. Herein, we classified molecularly distinct subtypes of serrated adenocarcinomas and clarified their associated clinicopathological characteristics and genetic changes. We examined 38 early-stage colorectal SACs. Of these, 24 were classified into three molecularly distinct groups by colon cancer subtyping (CCS). The clinicopathological characteristics, Ki 67 labeling index (LI), and SAC epithelial serration were assessed. The DNA from carcinomas and normal tissue/adenoma was extracted by laser microdissection and sequenced by next-generation sequencing, and mutation numbers and patterns of a 15-oncogene panel were determined. The CCS groups included CCS1 (CDX2+, HTR2B-, FRMD6-, ZEB1-, and microsatellite instable-low [MSI-L]/microsatellite stable [MSS]; 14 cases), CCS2 (microsatellite instable-high [MSI-H], 5 cases), and CCS3 (CDX2-, HTR2B+, FRMD6+, ZEB1+, and MSI-L/MSS; 5 cases). Invasive cancer was significantly more frequent in CCS3 than in CCS1 (5/5 versus 3/14, respectively). Ki67 LI and epithelial serration were higher in CCS3 than in CCS1 (83.0 ± 5.8 versus 65.4 ± 4.0 and 5/5 versus 3/14, respectively; p = 0.031 and 0.0048). CCS2 showed the highest mutation number, whereas KRAS and BRAF mutation numbers were higher in CCS3 than in CCS1. Early-stage SACs were classified into three molecularly distinct subtypes with different clinicopathological and genetic characteristics., Competing Interests: We used one testing TruSight Tumor 15 kit received from Illumina; however, we did not receive other financial support from Illumina. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Serrated adenocarcinoma (SAC) is a distinct colorectal carcinoma variant that accounts for approximately 7.5% of all advanced colorectal carcinomas. While its prognosis is worse than conventional carcinoma, its early-stage clinicopathologic features are unclear. We therefore aimed to clarify the clinicopathologic and endoscopic characteristics of early-stage SACs., Methods: Forty consecutive early-stage SAC patients at Hiroshima University Hospital were enrolled; SACs were classified into epithelial serration (Group A, n = 17) and non-epithelial serration (Group B, n = 23) groups. Additionally, we classified serrated adenoma into 4 types: sessile serrated adenoma (SSA), traditional serrated adenoma (TSA), unclassified, and non-serrated adenoma type., Results: There were significant differences between Groups A and B in terms of tumor size (27.6 vs. 43.1 mm), incidences of T1 carcinoma (71% vs. 13%), and having the same color as normal mucosa (47% vs. 17%), respectively (p <0.01). In SACs >20 mm, the incidence of T1 carcinoma in Group A (70%) was significantly greater than that in Group B (13%) (p <0.05). There were significant differences in 'Japan NBI Expert Team' type 3 and type V pit pattern classifications between the 2 groups. The average TSA-type tumor size (42.6 mm) was significantly larger than that of the SSA (17.2 mm) and non-serrated component types (18.3 mm). The incidences of submucosal invasion in SSA- (80%), unclassified- (100%), and non-serrated-type (100%) tumors were significantly higher than that in the TSA type (11%)., Conclusions: Epithelial serration in the cancerous area and a non-TSA background indicated aggressive behavior in early-stage SACs.

Background and Aims: Endoscopic submucosal dissection (ESD) is an effective procedure for en bloc resection of superficial colorectal tumors regardless of tumor size or location. However, there are few reports on long-term outcomes for patients with superficial colorectal tumors after ESD. We therefore aimed to evaluate the long-term outcomes after ESD for superficial colorectal tumors., Methods: ESD was performed on 257 colorectal tumors in 255 consecutive patients at Hiroshima University Hospital between June 2003 and July 2010. We investigated the following variables: patient characteristics, the American Society of Anesthesiologists score, tumor location, tumor size, growth type, histology, en bloc resection rate, achievement of curative resection, procedure time, and adverse events. The 5-year overall survival (OS), 5-year disease-specific survival (DSS), local recurrence, and metachronous tumor occurrence were also analyzed., Results: We identified 224 tumors in 222 patients who were confirmed dead or had follow-up data for more than 5 years. After a median follow-up of 79 months, 5-year OS and DSS rates were 94.6% and 100%, respectively. The local recurrence rate (1.5%) was significantly higher in patients undergoing piecemeal resection (9.1%) compared with en bloc resection (0.6%), in cases of histologic incomplete resection compared with complete resection, and in cases of non-R0 resection compared with R0 resection. The rates of total number of tumors (≥6 mm) and carcinoma metachronous tumors after ESD without additional surgical resection were 18.9% (38/201) and 4.0% (8/201), respectively., Conclusions: Long-term outcomes after ESD for superficial colorectal tumors are favorable. Patients should be surveyed for both local recurrence and metachronous tumors after ESD., (Copyright © 2017 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: No previous study has confirmed the safety of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in the super-elderly patient population. The current study aimed to evaluate the validity of ESD for EGC in super-elderly patients aged ≥85 years with comorbidities., Methods: Our study group included 85 super-elderly patients (102 EGCs) who were diagnosed at Hiroshima University Hospital between April 2002 and October 2014. We evaluated the en bloc resection rates, R0 resection rates, complication rates, and prognosis in relation to the degree of comorbidities (group A-H, patients with high-risk comorbidities; group A-L, patients with low-risk comorbidities; group B, patients without comorbidities; and group C, patients followed without ESD)., Results: The en bloc resection rates were 100, 96, and 100 % in groups A-H, A-L, and B, respectively. R0 resection rates were 94, 96, and 94 % in groups A-H, A-L, and B, respectively. There were no severe complications related to ESD. During the follow-up period, there was a significantly higher frequency of death in group A than in group B (p < 0.01), and there were no significant differences between groups A-H and A-L. However, there were no cases of death related to gastric cancer., Conclusions: ESD was performed safely, and death related to gastric cancer was prevented in super-elderly patients with comorbidities, regardless of the degree of the disease. However, patients with comorbidities are at a high risk of poor prognosis.

BACKGROUND Circulating tumor cells (CTCs) are tumor cells that are shed from primary tumors and circulate in the peripheral blood. CTCs, as a surrogate of micro-metastasis, can be a useful clinical marker, but their clinical significance remains unclear in lung cancer. We now report a case of lung cancer in which the count of CTCs was useful in monitoring postoperative recurrence. CASE REPORT A 50-year-old man had undergone right upper lobectomy for lung cancer (pT1bN2M0, stage IIIA adenocarcinoma), followed by cisplatin-based adjuvant chemotherapy. After the patient's operation, we initiated monitoring of CTCs using CellSearch, and documented the change in the CTC count along with the development of cancer recurrence and response or progression to chemotherapy given for recurrent disease. CONCLUSIONS The CTC count may be useful in monitoring blood of patients with lung cancer.

We present a rare case of colorectal T1 carcinoma with metastasis of previous lung carcinoma found at the deepest invasive portion. A 61-year-old man presented with cervical lymphadenopathy 18 years after undergoing surgery for right lung carcinoma [poorly differentiated adenocarcinoma stage IIb (T3N0M0)]. Contrast-enhanced computed tomography showed enlarged lymph nodes (LNs) in the neck and mediastinal regions. Combined hybrid-F-fluorodeoxyglucose positron emission-computerized tomography showed increased radionuclide uptake in multiple cervical LNs and mediastinal LNs. LN biopsy revealed a poorly differentiated adenocarcinoma, suspected to be a metastatic tumor of the lung. Subsequent colonoscopy revealed a pedunculated-type lesion with a depressed area in the ascending colon. We performed polypectomy as total excisional biopsy; this tumor was composed mainly of moderately differentiated adenocarcinoma, partially mixed with mucinous adenocarcinoma. The pathological findings of the invasive front of the colorectal carcinoma showed poorly differentiated adenocarcinoma with a morphological pattern similar to that of the previous lung carcinoma. Furthermore, immunohistochemical results for the histological type of the deepest invasive portion of the tissue specimen were positive for thyroid transcription factor-1 but negative for Caudal-type homeobox 2. From these morphological and immunohistochemical findings, the final diagnosis was moderately differentiated lung carcinoma, pTX N3 M1b (LN, colon) Stage IV.

Background: The risk for lymph node metastasis and the prognostic significance of pedunculated-type T1 colorectal carcinomas (CRCs) require further study. We aimed to assess the validity of the 2014 Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines based on long-term outcomes of pedunculated-type T1 CRCs., Methods: In this multicenter retrospective cohort study, we examined 176 patients who underwent resection endoscopically or surgically at 14 institutions between January 1990 and December 2010. Patients meeting the JSCCR curative criteria were defined as "endoscopically curable (e-curable)" and those who did not were "non-e-curable". We evaluated the prognosis of 116 patients (58 e-curable, 58 non-e-curable) who were observed for >5 years after treatment., Results: Overall incidence of lymph node metastasis was 5 % (4/81; 95 % confidence interval 1.4-12 %: three cases of submucosal invasion depth ≥1000 μm [stalk invasion] and lymphatic invasion, one case of head invasion and budding grade 2/3). There was no local or metastatic recurrence in the e-curable patients, but six of them died of another cause (observation period, 80 months). There was no local recurrence in the non-e-curable patients; however, distant metastasis was observed in one patient. Death due to the primary disease was not observed in non-e-curable patients, but six of them died of another cause (observation period, 72 months)., Conclusions: Our data support the validity of the JSCCR curative criteria for pedunculated-type T1 CRCs. Endoscopic resection cannot be considered curative for pedunculated-type T1 CRC with head invasion alone.

Background and Aim: Colorectal laterally spreading tumor granular type (LST-G) is generally divided into two subtypes based on morphology. Here, we retrospectively investigated the clinical significance of a concrete, objective LST-G subclassification., Methods: This study examined 636 consecutive cases that were resected endoscopically or surgically. LST-G was subclassified as follows: Type 1, a lesion with homogenous uniform granules with uniform (<5 mm) nodules; Type 2, a lesion with granules and small nodules (≥5 mm, <10 mm); or Type 3, a lesion accompanied by large nodules (≥10 mm). For the validation study, 194 images were compiled from 97 cases investigated using conventional colonoscopy and chromoendoscopy with indigo carmine dye spraying. Images were distributed in a randomized order to students without prior endoscopy experience, less-experienced endoscopists (LEE group), and highly experienced endoscopists (HEE group). Diagnostic accuracy and interobserver agreement were then evaluated., Results: There was no submucosal invasion in Type 1 lesions. The incidence of deep submucosal invasive carcinoma was higher for Type 3 lesions than for Type 2 lesions. Interobserver agreement was good in each group. Diagnostic accuracy was higher in the HEE group than in the student and LEE groups. Chromoendoscopy had a higher accuracy rate than conventional colonoscopy in the LEE and HEE groups (LEE, 0.74 vs 0.69, P < 0.05; HEE, 0.84 vs 0.78, P < 0.05)., Conclusions: This subclassification of LST-G according to the diameters of granules and nodules was both useful for choosing therapeutic strategies in the clinical setting and universally applicable., (© 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

A 73-year-old Japanese man visited a local hospital due to palpitations and dyspnea. He was diagnosed as having lung cancer (adenocarcinoma, cT1aN2M1b (BRA), stage Ⅳ), but he did not want to receive any anticancer medications, and was simply being observed. Several months later, he was referred to our hospital due to exacerbation of the dyspnea. His chest computed tomography revealed massive pericardial effusion, therefore he was diagnosed as having cardiac tamponade due to carcinomatous pericarditis and was immediately hospitalized. Upon admission, pericardial fenestration was firstly applied in order to drain pericardial effusion, and intraoperative cardiac findings showed suspicion of myocardial and pericardial metastasis. Immediately after the pericardiotomy, he suffered from cardiac arrest caused by shock. In lung cancer patients with pericardial effusion, even though it is rare, myocardial metastasis in addition to carcinomatous pericarditis and pericardial metastasis should be kept in mind.

Background: Advances in diagnostic techniques have allowed early stage detection of superficial Barrett's adenocarcinoma (SBA) as well as resection by endoscopic submucosal dissection (ESD). Few reports exist, however, on the safety and efficacy of ESD for SBA., Objective: To analyze outcomes of ESD for SBA in relation to clinicopathological features of the lesions., Design: Retrospective study., Setting: University hospital., Patients: Twenty-three patients (21 men, 2 women; mean age, 63 years) with 26 SBAs., Intervention Esd Main Outcome Measurements: We examined outcomes of ESD in relation to the clinicopathological features of SBAs. The main outcomes assessed were en bloc resection rate, operation time, adverse event rates, additional resection rate, and time between ESD and any recurrence., Results: Twenty lesions (87%) derived from short-segment Barrett's esophagus, and 3 lesions (13%) derived from long-segment Barrett's esophagus. The majority of SBAs (54%) were located in the 0 to 3 o'clock circumferential quadrant. Median tumor size was 15 mm (range 5-60 mm). Macroscopic types were flat elevated (n = 13, 50%), depressed (n = 12, 46%), and protruded (n = 1, 4%). The SBAs appeared red (n = 23, 88%) or normally pale (n = 3, 12%). Under magnifying narrow-band imaging, all SBAs showed an irregular mucosal pattern and an irregular vascular pattern. The endoscopic en bloc resection rate was 100% (26/26), and the pathological en bloc resection rate was 85% (22/26). The median procedure time was 95 minutes (range, 30-210 minutes). Delayed bleeding occurred in 1 case, but there was no perforation. The SBAs were of the differentiated type (n = 25, 96%) or poorly differentiated type (n = 1, 4%). The tumor had invaded the superficial muscularis mucosa (n = 3, 12%), lamina propria mucosa (n = 5, 19%, deep muscularis mucosa (n = 9, 34%), SM1 (n = 3, 12%), and SM2 (n = 6, 23%). Additional surgical resection after ESD was performed in 9 cases, and there were no residual tumors, but 1 lymph node metastasis was found. There were no recurrent tumors; however, 1 metachronous adenocarcinoma was diagnosed 42 months after ESD., Limitations: Single-center, retrospective study., Conclusions: ESD appears to be a safe and effective treatment strategy for early stage SBA., (Copyright © 2014 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Patients with inflammatory bowel diseases (IBD) have a high risk of colitis-associated dysplasia and cancer. It is important that careful surveillance with colonoscopy is performed for all patients with IBD and, more frequently, for those considered to be at high risk. Traditionally, flat dysplasia in ulcerative colitis has been considered to be detectable only by using random biopsy specimens of mucosa that appeared unremarkable during endoscopy. However, recent studies have shown that most of them are visible; thus, their detection as nonpolypoid colorectal neoplasms is an integral component in the prevention of colitic cancer., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The overexpression of Arf6 and GEP100 is responsible for the invasive activity that is crucial for the activation of the epidermal growth factor receptor (EGFR) signaling pathways in human cancer. However, whether or not the expression of the EGFR-GEP100-Arf6 axis can be used as a biomarker for the prognosis of lung cancer has yet to be fully determined. Tumor specimens were collected from 182 patients who underwent a complete resection for lung adenocarcinoma. We analyzed phospho-EGFR (p-EGFR), GEP100, and Arf6 expression levels in the primary tumor by immunohistochemical analysis. The expression of p-EGFR, GEP100, and Arf6 was observed in 65 (35.7%), 95 (52.2%), and 20 (11.0%) patients, respectively. Significant associations between p-EGFR and GEP100 expression and vessel invasion were identified. The expression of these individual molecules was not associated with any statistically significant differences in survival. However, triple positive expression of p-EGFR, GEP100, and Arf6 was significantly associated with an increased risk of death based on the multivariate analysis. The EGFR-GEP100-Arf6 axis affected the prognosis of patients with primary lung adenocarcinoma. The combination of p-EGFR, GEP100, and Arf6 staining can predict the prognosis of patients after surgery., (© 2014 S. Karger AG, Basel.)

Aim: The purpose of this study was to investigate the clinical significance of expression of cancer/testis (CT) antigen and down-regulation of HLA class-I in patients with stage I non-small cell lung cancer (NSCLC), which underwent complete surgical resection., Patients and Methods: The expression of HLA class-I molecules was evaluated in 136 resected NSCLC specimens by immunohistochemistry. The results were scored as the percentage of stained tumor cells and categorized into two groups: 0-79%, reduced expression; and >80%, normal expression. The expression of CT antigen was performed by reverse transcription-polymerase chain reaction (RT-PCR)., Results: The expression of HLA class-I was normal in 49 tumors (36%), and there was reduced expression in 87 tumors (64%). The expression of Melanoma antigen (MAGE)-A3, MAGE-A4, and Kita-Kyushu lung cancer antigen-1 (KK-LC-1) was positive in 34 (25.0%), 22 (16.2%), and 42 (30.9%) patients, respectively. There was no significant difference in the proportion of HLA class-I expression associated with the expression of any of the CT antigens. Among the patients with positive expression of at least one of the CT antigens, the 5-year survival rate of the patients with the normal expression of HLA class-I was 87.5%; however, it was 63.4% in patients with the reduced expression of HLA class-I (p=0.0477)., Conclusion: Reduced expression of HLA class-I was an unfavorable prognostic factor in patients with positive expression of CT antigen, and represents an important hurdle to antigen-based cancer immunotherapy.

We evaluated the tumour shape as a potential prognostic indicator in lung adenocarcinoma patients. Among 994 patients who underwent curative surgery, 78 cases of adenocarcinoma (N0M0) with tumours ≥ 31 mm in diameter were reviewed. The patients were divided into two groups based on the ratio between the longest and the smallest axis length. The patients who had tumours whose ratios were > 0.5 were defined as the globular shape group (GL) and the others, whose ratio was 0.5 or less, were defined as the ellipse shape group (EL). The 78 patients were divided into two subgroups (57 in the GL and 21 in the EL). The tumour shape was related to the prognosis, and the 5-year overall survival (OS) rate in the GL was 51.5%, and that in the EL was 85.5% (P = 0.018). The 5-year disease-free survival rate of the GL was 46.6% and that of the EL patients was 85.0% (P = 0.04). The multivariate analysis showed that the shape of the tumour and the presence of pleural invasion were the independent and significant factors predicting the OS (P = 0.04 and P < 0.01, respectively). In adenocarcinoma patients, the shape of the tumour is related to the postoperative survival.

Background and Aim: In guidelines 2010 for the treatment of colorectal cancer from the Japanese Society for Cancer of the Colon and Rectum (JSCCR), the criteria for identifying curable T1 colorectal carcinoma after endoscopic resection were well/moderately differentiated or papillary histologic grade, no vascular invasion, submucosal invasion depth less than 1000 µm and budding grade 1 (low grade). We aimed to expand these criteria., Methods: A total of 499 T1 colorectal carcinomas, resected endoscopically or surgically, were analyzed. Relationships between clinicopathologic findings and lymph node metastasis were evaluated., Results: Lymph node metastasis was found in 41 (8.22%) of the 499 cases. The incidence of lymph node metastasis was significantly higher in lesions featuring poorly differentiated/mucinous adenocarcinoma, submucosal invasion ≥ 1800 µm, vascular invasion, and high-grade tumor budding than in other lesions. Multivariate logistic regression analysis showed all of these variables to be independent risk factors for lymph node metastasis. When cases that met three of the JSCCR 2010 criteria (i.e. all but invasion < 1000 µm) were considered together, the incidence of lymph node metastasis was only 1.2% (3/249, 95% confidence interval: 0.25-3.48%), and there were no cases of lymph node metastasis without submucosal invasion to a depth of ≥ 1800 µm., Conclusions: Even in cases of colorectal carcinoma with deep submucosal invasion, the risk of lymph node metastasis is minimal under certain conditions. Thus, even for such cases, endoscopic incisional biopsy can be suitable if complete en bloc resection is achieved., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Background and Aims: Colorectal laterally spreading tumors (LST) > 20 mm are usually treated by endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR). Endoscopic piecemeal mucosal resection (EPMR) is sometimes required. The aim of our study was to compare the outcomes of ESD and EMR, including EPMR, for such LST., Methods: A total of 269 consecutive patients with a colorectal LST > 20 mm were treated endoscopically at our hospital from April 2006 to December 2009. We retrospectively evaluated the complications and local recurrence rates associated with ESD, hybrid ESD (ESD with EMR), EMR, and EPMR., Results: ESD and EMR were performed successfully for 89 and 178 LST, respectively: 61 by ESD; 28 by hybrid ESD; 70 by EMR; and 108 by EPMR. Between-group differences in perforation rates were not significant. Local recurrence rates in cases with curative resection were as follows: 0% (0/56) in ESD; 0% (0/27) in hybrid ESD; 1.4% (1/69) in EMR; and 12.1% (13/107) in EPMR; that is, significantly higher in EPMR. No metastasis was seen at follow up. The recurrence rate for EPMR yielding ≥ three pieces was significantly high (P < 0.001). All 14 local recurrent lesions were adenomas that were cured endoscopically., Conclusions: As for safety, ESD/hybrid ESD is equivalent to EMR/EPMR. ESD/hybrid ESD is a feasible technique for en bloc resection and showed no local recurrence. Although local recurrences associated with EMR/EPMR were seen, which were conducted based on our indication criteria, all local recurrences could obtain complete cure by additional endoscopic treatment., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Background: The purpose of the current study was to clarify the clinical role of insulin-like growth factor receptor-1 (IGF1R) in NSCLC., Patients and Methods: Tumor specimens were collected from 285 patients who underwent complete resection for adenocarcinoma (AD, n = 182), squamous cell carcinoma (SCC, n = 77), and other histologic types of cancer (n = 26) of the lung. The expression of IGF1R and Ki-67 was evaluated by immunohistochemical (IHC) analysis., Results: Positive expression of IGF1R was detected in 87 (30.5%) of 285 cases, of which 43 (23.6%) of 182 cases were AD, 36 (46.8%) of 77 cases were SCC, and 8 (30.8%) of 26 cases were other histologic types (SCC vs. AD, p < .001; SCC vs. non-SCC, p < .001). Positive IGF1R expression was also identified in 20 (44.4%) and 67 (27.9%) of the patients with and without recurrence, respectively (p = .027). Multivariate logistic regression models indicated that positive staining for IGF1R expression was an independent factor in AD associated with tumor recurrence (p = .040) but not in NSCLC, SCC, and other types of cancer. A positive IGF1R expression tended to demonstrate a poor disease-free survival (DFS) in NSCLC according to the Kaplan-Meier DFS curves (p = .053). The tumors showing a positive expression of IGF1R were observed more frequently in tumors with a positive expression of Ki-67 than in the tumors with a negative expression of Ki-67 (p = .010)., Conclusion: IGF1R expression was associated with reduced DFS correlating with postoperative recurrence. In addition, a significant relationship was also observed between IGF1R and Ki-67 expression in NSCLC. However, in subgroup analysis, a significant correlation was not observed. IGF1R expression predicts postoperative recurrence in patients with AD, but not in those with non-AD of NSCLC., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: The epithelial-mesenchymal transition (EMT) is also involved in cancer progression and metastasis. The expression of mesenchymal marker genes might be associated with a more aggressive form of the disease. CD146 is a marker of mesenchymal cells, a potentially metastasis-promoting cell adhesion molecule, and its expression has been described in various types of solid tumors. We, herein, evaluated the expression of CD146 in patients with adenocarcinoma of the lung by using immunohistochemistry to clarify its clinical significance., Materials and Methods: Tumor specimens were collected from 183 consecutive patients who underwent complete resection for lung adenocarcinoma from 2003 to 2007 in our Department. We analyzed the CD146 expression levels in the primary lung adenocarcinoma by immunohistochemistry., Results: Positive expression of CD146 was identified in 16 (8.7%) patients. A significant association was only observed between the CD146 expression level and male patient gender (p=0.03); other factors were not associated with CD146 expression. The 5-year overall survival (OS) rate in patients with tumors that were negative and positive for CD146 expression was 84.4% and 50.0%, respectively (p<0.01). A positive CD146 expression was found to be associated with the OS based on a univariate survival analysis (p=0.013)., Conclusion: CD146 expression was more frequently detected in males than in females. The positive expression of CD146 was associated with a poorer OS according to the survival analysis. CD146 may be a useful marker for predicting poor prognosis in patients with NSCLC following complete resection.

Aim: The human epidermal growth factor receptor HER-2/neu (HER2) gene is a proto-oncogene involved in the signal transduction pathways leading to cell growth and differentiation. The present study focused on the clinical significance of the expression of HER2 in non-small cell lung cancer (NSCLC)., Patients and Methods: Consecutive specimens of 159 adenocarcinomas and 77 squamous cell carcinomas, from patients who had been treated by complete resection of NSCLC in our department between 2003 and 2005, were studied. The HER2 expression was evaluated by immunohistochemical staining with score of membranous staining being 0=none, 1=weak, 2=10-30% cells, 3≥30% cells stained., Results: The staining scores in adenocarcinoma were 0 in 121 patients (76.1%), 1 in 16 (10.0%), 2 in 17 (10.7%), and 3 in 5 patients (3.1%). The HER2 expression scores in squamous cell carcinoma were 0 in 74 patients (96.1%), 1 in 1 (1.2%), 2 in 1 (1.2%), and 3 in 1 patient (1.2%). The postoperative 5-year survival rate of patients with adenocarcinoma according to the expression of HER2 scores 0, 1, 2 and 3 was 75.3%, 77.8%, 76.5% and 20.0%, respectively. Patients with adenocarcinoma with score 3 staining had a significantly unfavorable prognosis compared to those with staining scores of 0-2 (p=0.0216)., Conclusion: HER2 overexpression (score 3) in adenocaricinoma was a significantly unfavorable prognostic factor. Since the number of NSCLC patients with HER2 overexpression was small, further investigations will be necessary to clarify the efficacy of molecular targeted therapy for this subgroup.

Background: Ki-67 expression has been established as a predictive marker for recurrence in breast cancer, and proliferating cell nuclear antigen (PCNA) which is also a proliferation marker, is also herein discussed regarding its role in the prognosis of various types of cancer. However, no useful data are presently available regarding the biological significance of both molecules in lung cancer., Patients and Methods: Tumor specimens were collected from 183 consecutive patients who underwent a complete resection for lung adenocarcinoma from 2003 to 2007 in our Department. We analyzed the Ki-67 and PCNA expression levels in primary lung adenocarcinoma by immunohistochemistry., Results: Positive expression of Ki-67 and PCNA was identified in 41 (22.4%) and 149 (81.4%) patients, respectively. The positive expression of Ki-67 was identified in 14 (50.0%) out of 28 patients and 27 (18.1%) out of 155 patients with and without recurrence, respectively (p<0.001). PCNA expression was not correlated with recurrence. Positive expression of Ki-67 was associated with a poorer disease-free survival according to the survival analysis. A multivariate analysis also demonstrated that Ki-67 expression was independently associated with an increased risk of poor disease-free survival., Conclusion: Ki-67 may be a useful marker for predicting postoperative recurrence in patients with non-small cell lung cancer following complete resection.

We carried out a retrospective questionnaire survey of 792 submucosal colorectal carcinoma (CRC) cases from 15 institutions affiliated with the Colorectal Endoscopic Resection Standardization Implementation Working Group in Japanese Society for Cancer of the Colon and Rectum. In these cases, endoscopic resection (ER) and surveillance was carried out without additional surgical resection. Local recurrence or metastasis was observed in 18 cases. Local submucosal recurrence was observed in 11 cases, and metastatic recurrence was observed in 13 cases. Among the 15 cases in which the depth of submucosal invasion was measured, two cases showed depth less than 1000 µm, which has other risk factors for metastasis. Metastatic recurrence was observed in the lung, liver, lymph node, bone, adrenal glands, and the brain; in some cases, metastatic recurrence was observed in multiple organs. Death due to primary disease was observed in six cases. The average interval between ER and recurrence was 19.7 ± 9.2 months. In 16 cases, recurrence was observed within 3 years after ER. Thus, validity of ER without additional surgical resection for cases with the conditions that the depth of submucosal invasion is less than 1000 µm and the histological grade is well or moderately differentiated adenocarcinoma with no lymphatic and venous involvement was proven., (© 2011 The Authors. Digestive Endoscopy © 2011 Japan Gastroenterological Endoscopy Society.)

Introduction: We evaluated the feasibility and safety of the video-assisted thoracic surgery (VATS) lobectomy for non-small cell lung cancer (NSCLC) in patients with comorbidity., Methods: Between April 2000 and December 2006, a prospective database of 58 consecutive patients undergoing a VATS lobectomy for NSCLC, who had a Charlson comorbidity index score of 2 or more, was retrospectively analyzed. The demographic, perioperative, histopathologic, and outcome variables, including the recurrence and survival, were assessed., Results: The VATS lobectomy was successfully performed in 57 patients (16 women and 41 men; median age, 70 years). Twenty-three patients (40.4%) were aged 75 years or older. The total score of the Charlson comorbidity index was as follows: 2 in 26 patients, 3 in 13 patients, 4 in 12 patients, 5 in five patients, and 6 in one patient. None of the patients required a blood transfusion during surgery or during the postoperative course. We observed no intraoperative or in-hospital deaths, and no complications occurred in the 45 patients (78.9%). At a median follow-up of 34 months, a recurrence was observed in five patients who had advanced stages: a local recurrence in one and a distant recurrence in four. The overall 5-year survival rates for postoperative stage IA (n = 25) and IB (n = 16) were 100% and 94%, respectively., Conclusions: We believe that a VATS lobectomy is a feasible and safe procedure for NSCLC in patients with comorbidity because this modality demonstrates an acceptable morbidity and a favorable oncologic outcome.

Introduction: Endoscopic ultrasonography (EUS) is a useful method for visualizing features of gastric cancer. However, a previously reported classification system tended to result in overstaging. We investigated the usefulness of EUS for evaluation of the depth of gastric cancer invasion and indications for endoscopic treatment., Methods: Accuracy of EUS for determining the depth of invasion and incidences of a positive basal margin were assessed in 235 patients who underwent endoscopic treatment or surgery for gastric cancer. The EUS-determined depth of invasion was classified as follows: EUS-M (lesion confined to sonographic layers 1 and 2); EUS-M/SM border (lesion with changes in sonographic layer 3 but no deeper than 1 mm); EUS-SM (lesion with changes in sonographic layer 3 deeper than 1 mm); or EUS-AD (lesion with changes in sonographic layer 4 or 5)., Results: Accuracy of EUS for determining the depth of invasion was as follows: EUS-M, 99% were M and SM1 lesions; EUS-M/SM border, 87% were M and SM1 lesions; EUS-SM, 91% were SM2 lesions; EUS-AD, 100% were muscularis propria or deeper lesions. There was no EUS-M or EUS-M/SM border lesion for which endoscopic treatment resulted in a positive basal margin., Conclusions: EUS is useful for accurately determining the depth of invasion of gastric cancer. When there are no endoscopically determined ulcerous changes, endoscopic treatment should be considered for EUS-M and EUS-M/SM border lesions, and EUS-SM lesions should be treated surgically.

Background: Endoscopic submucosal dissection (ESD) has been positively applied to and gradually standardized for early stomach cancer, particularly in Japan. However, because it is technically difficult to perform ESD of the colon, ESD is not a commonly used technique., Objective: The aim of this study was to evaluate the possibility of standardizing colorectal ESD., Setting: ESD was performed at the Department of Endoscopy, Hiroshima University Hospital., Design: Time required for ESD, rate of complete en bloc resection, complication, and postoperative local persistence and recurrence were investigated retrospectively in 70 cases of colorectal neoplasia, wherein the lesion was more than 20 mm in diameter., Interventions: All lesions were resected by ESD., Results: The average (+/-SD) time required for ESD was 70.5+/-45.9 minutes (range, 15-180 minutes), and the histologic rate of complete en bloc resection was 80.0% (56/70). With regard to complication, 1.4% of cases of postoperative hemorrhage (1/70) and 10.0% of cases of perforation (7/70) were observed in total. The rate of perforation was investigated with respect to the type of knife used for ESD and the period after the induction of ESD. The rate of perforation markedly decreased with the practice of the technique. Moreover, the rate of perforation was high when an insulated-tip diathermic knife was used; practicing this technique was insufficient to reduce the rate of perforation. The average duration of follow-up was 614+/-289.5 days, and no case of local persistence and recurrence or metastasis was observed., Limitations: The ESD technique depends on the level of each skill of each colonoscopist., Conclusions: With regard to ESD of the colon, complication, eg, perforation, could be decreased by sufficient practice and selection of an appropriate knife. It is suggested that, in the near future, ESD will be standardized for the colon.

Background: Laser-scanning confocal microscopy (LCM) is a new, noninvasive method of optical imaging that may be able to provide an instant microscopic image of untreated tissue under endoscopy., Objective: The aim of this study was to compare LCM images and histologic images of GI lesions to clarify the usefulness of LCM in diagnosing neoplastic lesions., Design: This study was a feasibility study., Setting: The Department of Endoscopy, Hiroshima University Hospital., Patients and Main Outcome Measurements: The study materials were GI lesions resected endoscopically at our institute. Twenty-two areas of 15 untreated specimens from the esophagus (normal mucosa, n=1; dysplasia, n=1), stomach (normal mucosa, n=3; cancer, n=5), and colon (normal mucosa, n=3; adenoma, n=8; cancer, n=1) were examined. LCM images and images of hematoxylin and eosin-stained sections were compared. A prototype probe LCM system that is equipped with a semiconductor laser that oscillates at 685 nm and that analyzes reflected light was used., Results: Smooth nuclei of cells were visualized by LCM in the normal esophageal-mucosa specimen. Irregular nuclei were visualized in 3 of 5 gastric-cancer specimens and in cells around the crypt of the colonic-cancer specimen. Nuclei were visualized in 5 of 8 colonic-adenoma specimens. Nuclei were not visualized in 2 of 3 normal gastric-mucosa specimens or in normal colonic-mucosa specimens., Conclusions: LCM provides instant microscopic images, and, with further technical improvement, in the future this novel method will aid in immediate diagnosis under endoscopy without the need for tissue biopsy.

Background: It is controversial as to whether the development of gastric cancer is influenced by Helicobacter pylori eradication. If eradication itself influences the tumour morphology, this may affect the tumour discovery rate., Aim: To investigate the morphological changes in the gastric neoplasm after H. pylori eradication., Methods: We studied 37 patients with eradication therapy. After a 1-month follow-up, endoscopic re-evaluation was performed and the appearance was compared with first image. All lesions were resected endoscopically, and were subjected to histological assessment and to immunohistochemistry. Serum gastrin levels were determined before and after eradication., Results: Twenty-nine of 37 patients underwent successful eradication. The appearance of 11 lesions (33% of 33 lesions) became indistinct after successful eradication. All lesions were of the superficial-elevated type and the height of the lesions decreased. We detected normal columnar epithelium over the neoplasm in eight of the lesions. Higher expression of single-stranded deoxyribonucleic acid in the deep area was characteristic in tumours with an indistinct appearance. These changes did not correlate with the serum gastrin levels., Conclusions: The morphology of the gastric neoplasm change after eradication in the short-term. This may contribute to the decreased tumour discovery rate.

The aim of this study was to investigate whether angiogenic factors influence the occurrence of spontaneous apoptosis in advanced gastric cancer. The apoptotic indices (AIs) of 97 tumors from 97 patients with advanced gastric cancer (pT3, pN0, pM0, Stage II) were analyzed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL) method. Intratumoral microvessel densities (IMVDs) of tumors stained with anti-CD34 monoclonal antibody were quantified under x 200 magnification using computer-assisted image analysis. The expressions of angiogenic factors, such as vascular endothelial growth factor (VEGF), thymidine phosphorylase (dThdPase), transforming growth factor-alpha (TGF-alpha), and p53 were analyzed immunohistochemically and compared with IMVDs and AIs. The mean IMVD of the 97 tumors was 365/mm2 (range 147-990/mm2). The mean AI of tumors was 2.1% (range 0-11.3%). A significant inverse correlation between the AIs and the IMVDs was shown (p = -0.278, P = 0.0064). The mean IMVDs of tumors with high expressions of dThdPase, TGF-alpha, or p53 were significantly higher than those of tumors with low expressions of these factors. The mean AI of tumors with high expressions of dThdPase was significantly lower than that of tumors with low expressions of dThdPase (P = 0.023). However, no significant correlations were detected between AIs and the expression levels of VEGF, TGF-alpha, or p53. In gastric cancer, dThdPase may play an important role in tumor progression by increasing microvessels and by suppressing apoptosis of cancer cells.

Objective: An estrogen-regulated lysosomal protease, cathepsin D, has been detected in a variety of tissues. This proteinase has been described as closely associated with tumor progression and metastasis in malignant tumors. The purpose of this study was to determine the clinicopathological and prognostic significance of cathepsin D expression in gastric adenocarcinoma., Methods: In a consecutive series of 478 patients with gastric carcinoma (median follow-up period: 93 months, range: 1-285 months), cathepsin D expression in tumors was quantitatively analyzed with immunohistochemistry using a monoclonal antibody against cathepsin D (clone: 1C11). The percentage of cathepsin-D-positive cancer cells (the CD index) was calculated. In addition, the amount of cathepsin-D-positive stromal cells was evaluated; three grades (high, intermediate, and low) were used for the classification., Results: The mean CD index of 478 tumors was 12.8% (range: 0-100%, median: 8%). The mean CD index of diffuse-type gastric carcinomas (14.9%) was significantly higher than that of intestinal-type carcinomas (10.1%, p < 0.0001). Cathepsin D expression of cancer cells was significantly associated with the depth of tumor invasion in both types. The percentage of tumors with high cathepsin D expression in stromal cells was significantly higher in well-differentiated tumors (25.5%) than in moderately differentiated (12.8%) or in poorly differentiated tumors (19.1%). Cathepsin D expression of stromal cells was significantly associated with the depth of tumor invasion in the intestinal type, in contrast to the diffuse type. Highly expressed cathepsin D in cancer cells was associated with a poor prognosis in both types of carcinoma, but in stromal cells highly expressed cathepsin D was associated to a poor prognosis in the intestinal type only., Conclusion: These results indicate that cathepsin D expression in cancer cells may play an important role in tumor progression in diffuse-type gastric carcinoma, whereas in the intestinal type of carcinoma, cathepsin D expression in stromal cells may play an important role in tumor progression., (Copyright 2001 S. Karger AG, Basel)

Background/aims: The clinicopathological characteristics of gastric cancer (GC) with a positive family history of site-specific GC have not been well discussed. The aim of this study was to estimate the risk of familial aggregation of GC in a hospital-based case-control study and to analyze the clinicopathological characteristics of GC with familial aggregation of GC., Methods: Our series was comprised of 926 histologically confirmed patients with GC (588 males and 338 females) and 2,052 non-cancer outpatients between 1985 and 1996. The odds ratios (ORs), as estimators of relative risks, together with the corresponding 95% confidence intervals (CIs) for a family history of GC and for a family history of other cancers were calculated. Moreover, the clinicopathological findings of patients with GC who had a GC family history were compared with those of patients with GC who had no GC family history., Results: A positive family history of GC was associated with a statistically significant increase in the risk of GC (OR = 2.15; 95% CI = 1.77-2.63), while no association was observed between the risk of GC and a family history of other cancers (OR = 1.11; 95% CI = 0.91-1.36). The incidence of a multifocal occurrence of GCs was higher in patients with a family history of GC (19.4%) than in patients without a family history of GC (12%, p = 0.005). The risk (OR) of occurrence of multiple cancers in the stomach in patients who had a family history of GC was 1.77 (95% CI = 1.19-2.64)., Conclusions: Our results suggest that a family history of GC seemed to be a risk factor for the development of GC. Further, a family history of GC was found to be associated with a multifocal occurrence of GC., (Copyright 2001 S. Karger AG, Basel)

Background/aims: Although many studies have attempted to clarify the prognostic indicators for gastric carcinoma, there have been few studies regarding the factors that correlate with the survival period of patients with postoperative recurrence., Methodology: Among 504 advanced gastric adenocarcinoma patients who had undergone curative gastrectomy, 188 patients who had died of recurrence were used in this study., Results: Univariate analysis indicated that age, the presence of lymph node metastasis and blood vessel invasion, the number of positive lymph nodes, and gastrectomy significantly correlated with the survival period. Multivariate analysis indicated that the length of the survival period was independently influenced by the number of positive lymph nodes and blood vessel invasion. The survival time of patients with less than 3 positive lymph nodes and no accompanying blood vessel invasion was significantly longer than that of other patients., Conclusions: The number of positive lymph nodes and the presence of blood vessel invasion are the most important factors predicting the survival period of patients with postoperative recurrence after curative resection for advanced gastric carcinoma.

Nuclear profiles have been reported as useful prognostic predictors in various cancers. Data from computerized morphometry are objective and can be quickly derived using conventional microscopic analysis, but image analysis of nuclear features has only rarely been applied to investigations of gastric cancer. The aim of this study was to evaluate the correlation between one of these morphological nuclear features and the clinicopathological parameters in patients with gastric cancer. The morphometric nuclear feature (nuclear area) was analysed in 400 patients with gastric cancer. In each case, 300 cancer nuclei on routine haematoxylin and eosin-stained slides were analysed through the use of a computer-assisted image analysis system which traced the nuclear profiles (magnificationx400) on a computer monitor. The morphometric data were compared with the patients' clinicopathological status and survival rate. The mean nuclear area (NA) of cancer cells from 400 cases of gastric cancer was 47.2 microm(2). The NAs of cancer cells from tumours with microvessel invasion (lymphatic or venous invasion), lymph node metastasis or hepatic metastasis at the time of operation were significantly larger than those of cancer cells from tumours without such invasion or metastases. Cytokeratin (CK) immunostaining was performed on 2577 lymph nodes from 91 patients with advanced gastric cancer (pT3, pN0, pM0, stage II) to detect micrometastases. CK-positive lymph nodes were detected in 350 of 2577 lymph nodes (13. 6%) and in 62 of 91 patients (68.1%). The mean NA of cancer cells from 62 tumours with micrometastases (44 microm(2)) was larger than that of cancer cells from 29 tumours without micrometastases (38.8 microm(2), p=0.043), and a significant positive correlation was detected between the NAs of cancer cells from 91 tumours and the number of micrometastatic lymph nodes of 91 patients (rho=0.278, p=0. 008). Cancer cells with large NA correlated strongly with haematogenous and lymph node recurrence or relapse after gastrectomy and the NA of cancer cells was identified as an independent prognostic factor in gastric cancer. Nuclear morphometry is an objective, reproducible, and technically uncomplicated procedure. The NA of cancer cells correlates closely with the metastatic potential of gastric cancer. Nuclear morphometry may therefore be useful for the selection of patients who are at risk of haematogenous or lymph node metastatic recurrence after surgery., (Copyright 2000 John Wiley & Sons, Ltd.)

Background: Transforming growth factors beta (TGFs beta) are involved in a variety of important cellular functions, including cell growth and differentiation, adhesion, migration, extracellular matrix formation, and immune function. Moreover, it has been reported that TGFs beta are correlated with angiogenesis. However, the role of TGF-beta as an angiogenic factor in gastric carcinoma is still unclear., Methods: TGF-beta1 expression was determined in 101 patients with gastric carcinoma by immunohistochemical procedures, and this expression was compared in the current study with both the expression of vascular endothelial growth factor (VEGF), which is thought to be the most potent angiogenic factor, and microvessel density, to evaluate the effect of TGF-beta1 on the angiogenesis of gastric carcinoma tissues., Results: TGF-beta1 expression was detected in 23 tumors (22.8%). TGF-beta1 expression was more frequent in differentiated than in undifferentiated gastric carcinoma. Furthermore, TGF-beta1 expression was significantly correlated with the depth of invasion and the stage of disease. There was a close correlation between TGF-beta1 expression and VEGF expression. There was no correlation between TGF-beta1 expression and microvessel density, whereas VEGF expression was significantly correlated with microvessel density. With regard to prognosis, the 5-year survival rate was 55.9% for patients with TGF-beta1 positive tumors and 67.0% in patients with TGF-beta1 negative tumors. Accordingly, the prognosis for patients with TGF-beta1 negative tumors was significantly better than that for patients with TGF-beta1 positive tumors. Multivariate analysis indicated that lymph node metastasis, tumor size, and TGF-beta1 expression were independent prognostic factors., Conclusions: These results suggest that TGF-beta1 might be associated with tumor progression by indirectly stimulating angiogenesis through the up-regulation of VEGF expression in gastric carcinoma., (Copyright 1999 American Cancer Society.)

The expression of thymidine phosphorylase (TP) and the density of microvessel in advanced gastric carcinoma were examined by immunohistochemistry to evaluate the significance of TP. The expression of TP was negative in 72 cases, positive in 54. The microvessel density correlated with the expression of TP. In total cases, patients with TP-positive tumours survived longer than those with TP-negative tumours. In patients treated with fluorouracil derivatives (FUs), the expression of TP significantly correlated with favourable prognosis and with unfavourable prognosis in those not treated with FUs. The patients with TP-positive tumours, the prognosis of patients treated with FUs was significantly better than that of those not treated with FUs. In patients with TP-positive tumours, treatment with FUs and lymph node metastasis were independent prognostic factors according to the Cox proportional hazards model. Depth of invasion and lymph node metastasis were independent prognostic factors in patients with TP-negative tumours. The determination of the expression of TP might be useful for predicting the efficacy of post-operative chemotherapy using FUs to prevent recurrence in advanced gastric carcinoma patients who undergo curative gastrectomy.

Background: It has been recently reported that thymidine phosphorylase (dThdPase) is identical to platelet-derived endothelial cell growth factor (PD-ECGF). dThdPase is known to be one of the angiogenic factors. Expression of dThdPase has been detected both in cancer cells and in stroma cells. However, the role of dThdPase, in cancer cells and in stroma cells regarding, neovascularization in gastric adenocarcinoma is still unclear. In this study, we analyzed the correlation between dThdPase activity and neovascularization in gastric cancer., Materials and Methods: We obtained fresh samples (tumors and adjacent normal mucosas) from 67 patients with gastric cancer who underwent gastrectomy between 1993 and 1994. The dThdPase activity was analyzed by the ELISA (enzyme-linked immunosorbent assay) method and by the immunohistochemical staining. Microvessel density (MVD) and vascular endothelial growth factor expression of tumors were analyzed by immunohistochemical staining., Results: The dThdPase activity of tumors (117 +/- 98 U/mg protein) was significantly higher than that of normal mucosas (46 +/- 36 U/mg protein, P < 0.0001). The expression of dThdPase was detected by immunostaining in stroma cells but not in mucosal cells in normal tissues. Based on the immunostaining results, 16 tumors expressed dThdPase both in cancer cells and stroma cells. The mean dThdPase activity and the mean MVD of these 16 tumors were significantly higher than those of 15 tumors with expression of dThdPase only in the stroma cells, and than those of 36 tumors with expression of dThdPase in neither the cancer cells or the stroma cells. The MVD of tumors strongly correlated with the dThdPase activity of tumors detected by the ELISA method (P < 0.0001)., Conclusions: The total amount of dThdPase produced by cancer cells and stroma cells may influence tumor angiogenesis in gastric cancer.

Objective: To evaluate the correlation between the morphologic nuclear features and clinicopathologic parameters in patients with advanced gastric cancer., Summary Background Data: Nuclear profiles have been reported as useful prognostic predictors in various cancers. Data from computerized morphometries are objective and quickly derived using conventional microscopic analysis. However, this image analysis of nuclear features has rarely been applied to investigations of gastric adenocarcinoma. Moreover, it remains to be shown what types of biologic factors influence the nuclear features., Methods: Morphometric nuclear features (nuclear area, perimeter, and shape) were analyzed in 202 patients with serosal-invaded gastric cancer (stage II and III) who underwent curative gastrectomy. In each case, 300 cancer nuclei were analyzed on routine hematoxylin and eosin-stained slides through the use of a computer-assisted image analysis system by tracing the nuclear profiles (magnification x400) on a computer monitor. The morphometric data were compared with patient survival, clinicopathologic status, DNA ploidy pattern of tumors, expression of p53 protein, and proliferative activity of cancer cells., Results: Lymph node metastasis, lymphatic invasion, and venous invasion were more frequently detected in patients with large nuclear areas. Significant correlations were detected between the size of the nuclear area of cancer cells and the biologic factors of tumors, such as expression of p53, Ki-67 labeling index, and DNA ploidy pattern. The 5-year survival rate of the 100 patients in the large-nuclear group (nuclear area >45.3 microm2) was 47.6% and was significantly lower than the 74.4% rate of the 98 patients in the small-nuclear group (nuclear area < or =45.3 microm2). Moreover, the nuclear area was found to be an independent prognostic factor in the multivariate analysis., Conclusions: Gastric cancer cells with a large nuclear area express mutated p53 protein and have high proliferative activity. Moreover, such cancer cells have high potential for invasion to the microvessels in the gastric wall. Thus, nuclear morphometry is a new and useful morphologic predictor for metastatic potential in advanced gastric cancer.

Esterases in normal hamster pancreas and pancreatic tubular adenocarcinoma of ductal origin induced by N-nitrosobis(2-oxopropyl)amine were stained in cryostat sections with mixtures of a diazonium salt (fast blue RR) and with each of the enantiomers of alpha-naphthyl N-methoxycarbonylalaninate, N-methoxycarbonylvalinate, and N-acetylprolinate. Azo coupling of alpha-naphthol formed by enzymatic hydrolysis with the diazonium salt gives an azo dye that indicates the presence and amount of the enzyme activity in situ. Comparison between the color intensities obtained with each of the enantiomers of a chiral alpha-naphthyl ester shows the stereoselectivity, or enantiomeric preference, of the enzyme. Esterases in acinar cells of the normal pancreas showed slight stereoselectivity for N-methoxycarbonylalaninate, while esterases in fat cells scattered throughout the exocrine pancreas showed high stereoselectivity for (R)-N-acetylprolinate. These esterase activities were not found in the tumor, but another prominent esterase activity with high stereoselectivity for (S)-N-methoxycarbonylvalinate was found. Similar results were obtained by staining after polyacrylamide gel electrophoresis showing that the bands of esterases in the adenocarcinoma stained only with the S enantiomer of the N-methoxycarbonylvalinate. The present method is a valuable tool for designing anticancer prodrugs that are activated by tumor-specific esterases.

A case of perianal invasive Paget's disease associated with a sigmoid colon carcinoma is presented. The chief complaint was perianal irritation for a year. Histologic examination yielded a correct diagnosis and abdominosacral resection with wide excision of the cutaneous component was performed. Histology of the resected specimen revealed the Paget's disease to be invasive of the dermis, the sigmoid colon carcinoma to be in Dukes' A stage and the two lesions to be different. The patient has been disease-free for more than 5 years after the operation.

BX-1, an adenocarcinoma spontaneously arising from nude mouse bearing Br-10, a human breast carcinoma strain was characterized. And the purification of a hormone independent murine carcinoma strain, BX-1 was found in August 1986 in three institutes where a hormone dependent transplantable human breast carcinoma cell line Br-10 has been serially passaged. The histological features of BX-1 were different from any other strains which were maintained in these three institutes. Estrogen receptor of BX-1 was negative and no estrogen dependency was observed while Br-10 was the receptor positive and the growth of Br-10 was dependent on estrogen. Although the graft of BX-1 into the thymus intact littermates was rejected, the chromosomal analysis revealed only murine chromosomes for BX-1, while both of human and murine chromosomes were detected in Br-10 tumor. By incubating Br-10 tumor in untreated female nude mice for 2 months and stimulating the growth of the tumor by exogenous estradiol, the purification of Br-10 from BX-1 could be achieved. Whereas the stability of human tumor xenografts in nude mice is confirmed, the spontaneously arising murine tumor from nude mice bearing human tumor xenografts should be considered for the experiments.