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Importance: Biomarker testing for driver mutations is essential for selecting appropriate non-small cell lung cancer (NSCLC) treatment but is insufficient., Objective: To investigate the status of biomarker testing and drug therapy for NSCLC in Japan for identifying problems in treatment., Design, Setting, and Participants: The REVEAL cohort study included retrospective data collection and prospective follow-up from 29 institutions across Japan. Of 1500 patients diagnosed with advanced or recurrent NSCLC between January 1 and March 18, 2021, 1479 were eligible. Cases recognized at the wrong clinical stage (n = 12), diagnosed outside the study period (n = 6), not treated according to eligibility criteria before recurrence (n = 2), and with deficient consent acquisition procedure (n = 1) were excluded., Main Outcomes and Measures: The primary end point was the biomarker testing status. Treatment-related factors were examined., Results: Among the 1479 patients included in the analysis, the median age was 72 (range, 30-95) years; 1013 (68.5%) were men; 1161 (78.5%) had an Eastern Cooperative Oncology Group performance status 0 or 1; 1097 (74.2%) were current or past smokers; and 947 (64.0%) had adenocarcinoma. Biomarker status was confirmed in 1273 patients (86.1%). Multigene testing was performed in 705 cases (47.7%); single-gene testing, in 847 (57.3%); and both, in 279 (18.9%). Biomarker testing was performed for EGFR in 1245 cases (84.2%); ALK, in 1165 (78.8%); ROS1, in 1077 (72.8%); BRAF, in 803 (54.3%); and MET, in 805 (54.4%). Positivity rates among 898 adenocarcinoma cases included 305 (34.0%) for EGFR, 29 (3.2%) for ALK, 19 (2.1%) for ROS1, 11 (1.2%) for BRAF, and 14 (1.6%) for MET. Positivity rates among 375 nonadenocarcinoma cases were 14 (3.7%) for EGFR, 6 (1.6%) for ALK, 1 (0.3%) for ROS1, 3 (0.8%) for BRAF, and 8 (2.1%) for MET. Poor physical status, squamous cell carcinoma, and other comorbidities were associated with hampered multigene testing. Targeted therapy was received as first-line treatment by 263 of 278 cases (94.6%) positive for EGFR, 25 of 32 (78.1%) positive for ALK, 15 of 24 (62.5%) positive for ROS1, 9 of 12 (75.0%) positive for BRAF, and 12 of 19 (63.2%) positive for MET. Median overall survival of patients with positive findings for driver gene alteration and who received targeted therapy was 24.3 (95% CI, not reported) months; with positive findings for driver gene alteration and who did not receive targeted therapy, 15.2 (95% CI, 7.7 to not reported) months; and with negative findings for driver gene alteration, 11.0 (95% CI, 10.0-12.5) months. Multigene testing for nonadenocarcinomas and adenocarcinomas accounted for 705 (47.7%) of all NSCLC cases., Conclusions and Relevance: These findings suggest that multigene testing has not been sufficiently implemented in Japan and should be considered prospectively, even in nonadenocarcinomas, to avoid missing rare driver gene alterations.

Main Problems: In non-small-cell lung cancer, ground-glass opacity on computed tomography imaging reflects pathological noninvasiveness and is a favorable prognostic factor. However, the significance of pathological noninvasive areas (NIAs) has not been fully revealed. In this study, we aimed to elucidate the prognostic impact of NIAs on lung adenocarcinoma., Methods: We analyzed 402 patients with pathological stage (p-Stage) IA lung adenocarcinoma who underwent surgery in 2013-2016 at two institutions and examined the association of the presence of NIAs with clinicopathological factors and prognosis. Furthermore, after using propensity-score matching to adjust for clinicopathological factors, such as age, sex, smoking history, pathological invasive area size, pathological T factor (p-T), p-Stage, and histological subtype (lepidic predominant adenocarcinoma [LPA] or non-LPA), the prognostic impact of NIAs was evaluated., Results: Patients were divided into NIA-present (N = 231) and NIA-absent (N = 171) groups. Multivariable analysis showed that NIA-present was strongly associated with earlier p-T, earlier p-Stage, LPA, and epidermal growth factor receptor mutation. Kaplan-Meier survival analysis showed that the NIA-present group displayed a better prognosis than the NIA-absent group in disease-free survival (DFS) and overall survival (OS) (5-year DFS 94.6% vs. 87.2%, 5-year OS 97.2% vs. 91.1%). However, after adjusting for clinicopathological factors by propensity score matching, no significant differences in prognosis were identified between the NIA-present and NIA-absent groups (5-year DFS 92.4% vs 89.6%, 5-year OS 95.6% vs 94.3%)., Conclusions: Our current study suggests that the prognostic impact of the presence of NIAs on lung adenocarcinoma is due to differences in clinicopathological factors., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Colorectal cancer (CRC) is a heterogenous disease, and patients have differences in therapeutic response. However, the mechanisms underlying interpatient heterogeneity in the response to chemotherapeutic agents remain to be elucidated, and molecular tumor characteristics are required to select patients for specific therapies. Patient-derived organoids (PDOs) established from CRCs recapitulate various biological characteristics of tumor tissues, including cellular heterogeneity and the response to chemotherapy. Patient-derived organoids established from CRCs show various morphologies, but there are no criteria for defining these morphologies, which hampers the analysis of their biological significance. Here, we developed an artificial intelligence (AI)-based classifier to categorize PDOs based on microscopic images according to their similarity in appearance and classified tubular adenocarcinoma-derived PDOs into six types. Transcriptome analysis identified differential expression of genes related to cell adhesion in some of the morphological types. Genes involved in ribosome biogenesis were also differentially expressed and were most highly expressed in morphological types showing CRC stem cell properties. We identified an RNA polymerase I inhibitor, CX-5641, to be an upstream regulator of these type-specific gene sets. Notably, PDO types with increased expression of genes involved in ribosome biogenesis were resistant to CX-5461 treatment. Taken together, these results uncover the biological significance of the morphology of PDOs and provide novel indicators by which to categorize CRCs. Therefore, the AI-based classifier is a useful tool to support PDO-based cancer research., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background/aim: This study evaluated the efficacy of adjuvant chemotherapy (AC) for intraductal papillary mucinous carcinoma (IPMC)., Patients and Methods: We retrospectively analyzed patients who underwent pancreatectomy for invasive IPMC from January 2007 to June 2020. We evaluated outcomes of AC in the entire cohort and in patients with known prognostic factors., Results: A total of 51 patients with invasive IPMC underwent surgery, of which 35 received AC. In the entire cohort, there was no significant difference in median overall survival (OS) between the AC and surgery alone (SA) group [hazard ratio (HR)=0.54; p=0.232]. For patients with poorly differentiated adenocarcinoma, median OS was significantly longer in the AC group (HR=0.27; p=0.022). For patients with lymph node metastasis, median OS was significantly higher in the AC group (HR=0.07; p<0.001)., Conclusion: AC may be effective for selected invasive IPMC patients., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Pancreatic cancer is the fourth leading cause of cancer-related death in Japan. Pancreatic cancer is categorized as resectable, borderline resectable, or unresectable based on the degree of adjacent vascular invasion and the presence of distant metastases. Neoadjuvant chemotherapy with gemcitabine and S-1 (NAC-GS) has recently become a standard option for resectable pancreatic cancer in Japanese patients. According to previous reports, GS is considered to be relatively safe and feasible treatment for Japanese patients, including the elderly. However, NAC-GS is occasionally associated with severe adverse events which may ultimately render the patient unfit for surgery. A 60-year-old man with resectable pancreatic cancer suffered from severe necrotic enteritis during NAC-GS, which required surgical resection. Considering the time course and histological findings of the resected bowel, S-1 was believed to be the causative agent. The low urinary dihydrouracil to uracil ratio also suggested possible dihydropyrimidine dehydrogenase deficiency, which may have hindered the metabolism of S-1 and contributed to the development of necrotic enteritis. Life-threatening enteritis occurs in approximately 0.3% of all patients who receive S-1. As initial symptoms are non-specific, patients should be instructed to lower the hurdle for contacting the hospital during NAC-GS., (© 2021. Japanese Society of Gastroenterology.)

Genetic alterations underlying the development of lung cancer in individuals with idiopathic pulmonary fibrosis (IPF) have remained unclear. To explore whether genetic alterations in IPF tissue contribute to the development of IPF-associated lung cancer, we here evaluated tumor mutation burden (TMB) and somatic variants in 14 paired IPF and tumor samples from patients with IPF-associated lung adenocarcinoma. We also determined TMB for 22 samples of lung adenocarcinoma from patients without IPF. TMB for IPF-associated lung adenocarcinoma was significantly higher than that for matched IPF tissue (median of 2.94 vs. 1.26 mutations/Mb, P = 0.002). Three and 102 somatic variants were detected in IPF and matched lung adenocarcinoma samples, respectively, with only one pair of specimens sharing one somatic variant. TMB for IPF-associated lung adenocarcinoma was similar to that for lung adenocarcinoma samples with driver mutations (median of 2.94 vs. 2.51 mutations/Mb) and lower than that for lung adenocarcinoma samples without known driver mutations (median of 2.94 vs. 5.03 mutations/Mb, P = 0.130) from patients without IPF. Our findings suggest that not only the accumulation of somatic mutations but other factors such as inflammation and oxidative stress might contribute to the development and progression of lung cancer in patients with IPF.

An 80-year-old woman who visited our hospital with chief complaints of decreased appetite and diarrhea. Lower gastrointestinal endoscopy showed a type 2 tumor in the rectal Ra, and biopsy revealed a well-differentiated adenocarcinoma. The patient had locally advanced rectal cancer with widespread contact with the sacrum, and preoperative radiochemotherapy (S-1 100 mg/day plus radiotherapy 50 Gy/25 Fr)was performed. After the treatment was completed, the tumor was remarkably reduced, but the surgery was strongly rejected, and therefore chemotherapy became the policy. XELOX plus bevacizumab therapy was started, but in the second course was performed, obstructive symptoms appeared, so a semi-urgent lower anterior resection and ileostomy were performed. Postoperative pathological findings showed only a small amount of tumor cells in the mucosa, suggesting that preoperative treatment was effective.

Carcinoma ex pleomorphic adenoma is a rare type of cancer of the salivary gland that involves the malignant transformation of a primary or recurrent pleomorphic adenoma, which often metastasises to the lungs or bones, or both. To the best of our knowledge, however, nobody has reported a distant metastasis of this lesion to the brain without such previous metastasis. We report a case in a 64-year-old man., (Copyright © 2019 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: CD44 isoforms serve as a marker for cancer stem cells. CD44 variant 9 (CD44v9) contributes to the defense against reactive oxygen species, resulting in resistance to chemoradiotherapy. However, the significance of CD44v9 in patients with lung adenocarcinoma is unknown., Methods: We used immunohistochemical analysis to retrospectively analyze CD44v9 expression in 268 surgically resected lung adenocarcinomas and investigated the association between CD44v9 expression and patients' clinicopathological features., Results: The expression of CD44v9 in 193 of 268 (72.0%) patients was significantly associated with early-stage cancer, low-grade tumors, absence of vessel and pleural invasion, and a mutated epidermal growth factor receptor (EGFR) gene. Multivariate logistic analysis revealed that CD44v9 expression was significantly associated with early-stage disease [odds ratio (OR) 0.29, 95% confidence interval (CI) 0.14-0.59; p < 0.001] and mutant EGFR (OR 2.53, 95% CI 1.06-6.04; p = 0.036). The percentage of CD44v9-positive tumors was higher in the earlier stages of disease; however, there was no significant difference in the survival of patients in each stage of disease who had positive or negative CD44v9 expression., Conclusion: CD44v9 was highly expressed in EGFR-mutant tumors, particularly in early-stage lung adenocarcinoma, suggesting that CD44v9 expression may play an important role in EGFR-mutant tumors.

Background: Although intratumoral heterogeneity is commonly observed in several cancers, few studies have shown its presence in EGFR-mutated lung cancer. We performed immunohistochemistry to analyze the intratumoral heterogeneity in EGFR-mutated (L858R) lung cancer and performed targeted sequencing in specific cases. We discuss the effects of intratumoral heterogeneity and acquired resistance to EGFR-TKI., Methods: Twenty resected primary lung cancers known to harbor EGFR L858R were analyzed. IHC was performed using an L858R mutant-specific rabbit monoclonal antibody and the samples were scored by staining intensity (0-3) and proportion. For cases with heterogeneous L858R protein expression, the nucleic acids were extracted from each differently stained lesion, and targeted sequencing was performed. Single nucleotide variations (SNVs) and copy number variations (CNVs) were then analyzed. The cell proliferation and apoptosis were also evaluated by the ki-67 labeling index and TUNEL staining., Results: Among 20 cases, 3 showed heterogeneous staining. Genetic analyses for cases with heterogeneous staining revealed an increase in the copy number of EGFR in the IHC-positive part compared to the negative part, and an increase in the copy number of CCNE1 was observed in the IHC-positive part compared to the negative part in one case (case 1). In another case (case 2), an increase in the copy number of EGFR was observed in the IHC-positive part compared to the negative part, and an increase in the copy number of MDM2 was observed in the IHC-positive part compared to the negative part. In three cases, no SNV changes were observed. An increase in the ki-67 labeling index in the L858R-positive part in case 1 and increased apoptosis in the L858R-positive part in case 2 were observed, suggesting the functional significance of CNV changes., Conclusion: These cases exhibiting L858R IHC intratumoral heterogeneity suggest a heterogeneous effect on the cell activity due to CNV heterogeneity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive effector, and its expression is associated with prognosis in several cancer types. Here, we investigated the relationship between IDO1 expression in lung adenocarcinoma and patient prognosis and clinicopathological features, including programmed cell death-ligand 1 (PD-L1) expression., Materials and Methods: In this study, surgically resected primary lung adenocarcinoma specimens from 427 patients were evaluated for IDO1 and PD-L1 expression by immunohistochemistry, and lung adenocarcinoma cell lines were evaluated for IDO1 and PD-L1 protein expression by enzyme-linked immunosorbent assay and flow cytometry and for messenger RNA levels by real-time reverse-transcriptase polymerase chain reaction analysis., Results: IDO1 was expressed in 260 patients (60.9%) at 1% cut-off and 63 patients (14.8%) at 50% cut-off. Tissues from 145 patients (34.0%) were positive for PD-L1 using the cut-off of 1%. Multivariate analysis showed that ≥1% IDO1 positivity was significantly associated with higher tumour grade, vascular invasion and PD-L1 expression. IDO1 and PD-L1 proteins were co-expressed in 123 patients (28.8%), and co-expressing tumours exhibited significantly more malignant traits than those positive for one or neither protein. In multivariate analysis, co-expression of IDO1 and PD-L1 was significantly associated with shorter disease-free survival and overall survival. Both proteins were upregulated in lung adenocarcinoma cell lines by treatment with interferon-γ and transforming growth factor-β., Conclusion: These results suggest that IDO1 and PD-L1 co-expression may define an aggressive form of lung adenocarcinoma., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have been approved as a standard therapy for metastatic non-small cell lung cancer (NSCLC). Although PD-L1 expression serves as a predictive biomarker for the efficacy of immunotherapy, there are no established biomarkers to predict the expression of PD-L1. The inflammatory markers C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) were recently shown to predict the efficacy of nivolumab for NSCLC patients. Therefore, here we investigated the potential association of PD-L1 expression with systemic inflammatory markers, including CRP, NLR, lymphocyte-monocyte ratio and platelet-lymphocyte ratio., Methods: We retrospectively examined tumor PD-L1 expression in 508 surgically resected primary NSCLC cases by immunohistochemical analysis (cut-off value: 1%). The association of PD-L1 expression with preoperative systemic inflammatory markers was assessed by univariate and multivariate analyses. We generated a PD-L1 association score (A-score) from serum CRP level (cut-off value: 0.3 mg/dl) and smoking status to predict PD-L1 expression., Results: Among the total 508 patients, 188 (37.0%) patients were positive for PD-L1 expression at the 1% cut-off value and 90 (17.5%) had elevated serum CRP level. Multivariate logistic regression revealed that PD-L1 positivity was significantly associated with advanced stage, the presence of vascular invasion and high serum CRP level (P = .0336, .0106 and 0.0018, respectively). Though not significant, smoking history tended to be associated with PD-L1 protein expression (P = .0717). There was no correlation with other inflammatory markers. Smoking history with elevated CRP level (A-score: 2) was strongly associated with PD-L1 protein expression (odds ratio: 5.18, P < .0001), while it was inversely associated with EGFR mutation (odds ratio: 0.11, P < .0001)., Conclusions: Our results indicate that among all systemic inflammatory markers examined, serum CRP seems to predict PD-L1 expression in patients with NSCLC however the clinical applicability is limited given the obtained area under the receiver operating characteristic curve values., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Next-generation sequencing (NGS) has enabled comprehensive detection of genomic alterations in lung cancer. Ethnic differences may play a critical role in the efficacy of targeted therapies. The aim of this study was to identify and compare genomic alterations of lung adenocarcinoma between Japanese patients and the Cancer Genome Atlas (TCGA), which majority of patients are from the US. We also aimed to examine prognostic impact of additional genomic alterations in patients harboring EGFR mutations. Genomic alterations were determined in Japanese patients with lung adenocarcinoma (N = 100) using NGS-based sequencing of 415 known cancer genes, and correlated with clinical outcome. EGFR active mutations, i.e., those involving exon 19 deletion or an L858R point mutation, were seen in 43% of patients. Some differences in driver gene mutation prevalence were observed between the Japanese cohort described in the present study and the TCGA. Japanese cohort had significantly more genomic alterations in cell cycle pathway, i.e., CDKN2B and RB1 than TCGA. Concurrent mutations, in genes such as CDKN2B or RB1, were associated with worse clinical outcome in patients with EGFR active mutations. Our data support the utility of comprehensive sequencing to detect concurrent genomic variations that may affect clinical outcomes in this disease.

Background: Surgical outcomes of early-stage non-small cell lung cancer (NSCLC) are poor. The Geriatric Nutritional Risk Index (GNRI) is a useful parameter for evaluating nutritional status. We aimed to investigate if preoperative GNRI could be a predictive factor for pathological stage I NSCLC patients., Patients and Methods: We retrospectively selected 141 consecutive pathological stage I NSCLC patients treated from August 2005 to August 2010. We analyzed their preoperative GNRI in univariate and multivariate Cox regression analyses for postoperative recurrence-free survival (RFS)., Results: A preoperative abnormal GNRI was significantly associated with postoperative recurrence (P = 0.0107). Univariate analyses showed that serum carcinoembryonic antigen (CEA) levels (P = 0.0013), preoperative serum albumin level (P < 0.0001), preoperative GNRI (P = 0.0009), pleural invasion (P < 0.0001) and blood vessel invasion (P = 0.0137) significantly affected RFS. In multivariate analysis, preoperative GNRI (P = 0.0084), CEA level (P = 0.0031), preoperative serum albumin level (P = 0.0041) and pleural invasion (P = 0.0018) were independent prognostic factors. In Kaplan-Meier analysis of RFS, cancer-specific survival (CS), and overall survival (OS) by preoperative GNRI, the abnormal GNRI group had significantly shorter RFS, CS, and OS (5-year RFS, CS, and OS: 52.81% vs. 89.15%; P < 0.0001, 81.73% vs. 94.73%; P = 0.0014 and 50.84% vs. 89.57%; P < 0.0001, log-rank test, respectively)., Conclusions: Preoperative GNRI is a novel prognostic factor for pathological stage I NSCLC patients, which can identify high-risk patients for postoperative recurrence and cancer-related death., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: The development of immune checkpoint inhibitors against programmed death 1 has paved the way for a new era of treatment of lung cancer. Programmed death-ligand 1 (PD-L1) is expected to predict the response of immune checkpoint inhibitors in lung cancer. Predicting PD-L1 expression using a noninvasive method before immunotherapy would, therefore, help identify patients for whom immunotherapy can be successful., Patients and Methods: A total of 394 patients with resected lung adenocarcinoma who had undergone preoperative thin-section computed tomography (CT) were analyzed for PD-L1 expression by immunohistochemistry and evaluated to determine the association between PD-L1 expression and CT characteristics, including convergence, surrounding ground glass opacity (GGO), air bronchogram, notching, pleural indentation, spiculation, and cavitation., Results: Of the 394 patients, 78 (19.8%) were positive and 316 (80.2%) were negative for PD-L1 expression. Univariate analysis demonstrated that PD-L1 + adenocarcinoma was significantly associated with the presence of convergence (P < .01), notching (P < .01), spiculation (P < .01), and cavitation (P < .01) and the absence of surrounding GGO (P < .01) compared with PD-L1 - cases. On multivariate analysis, the presence of convergence (P < .01) and cavitation (P < .01) and the absence of surrounding GGO (P = .02) and air bronchogram (P = .03) were significantly associated with PD-L1 expression., Conclusion: PD-L1 + adenocarcinoma cases showed convergence and cavitation more frequently than did PD-L1 - cases. In contrast, surrounding GGO and air bronchogram were observed less frequently in PD-L1 + cases than in PD-L1 - cases. These results will prove helpful in identifying PD-L1-expressing adenocarcinoma by CT before immunotherapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background/aim: Women with breast cancer are at increased risk of subsequent primary malignancies, specifically lung cancer. The aim of this study was to report the frequency of lung cancer in patients with breast cancer, and patients' characteristics and surgical outcomes., Patients and Methods: We investigated 1,066 consecutive female patients undergoing surgical resection for breast cancer and 666 undergoing surgical resection for lung cancer., Results: Lung cancer with breast cancer was observed in 14 patients (1.3% of breast cancer and 2.1% of lung cancer cases; mean age=65 years), and 3/14 (21.4%) patients were smokers. Sixteen lung cancer lesions in 14 patients were adenocarcinomas and one was squamous cell carcinoma. All 14 patients were alive at the time of this report; 4/14 (28.6%) patients had recurrent breast cancer and 1/14 (7.1%) had recurrent lung cancer. In synchronous cases, 5/6 (83.3%) patients received concomitant surgery for both breast cancer and lung cancer. Patients' postoperative courses were uneventful. In metachronous cases, eight patients had lung cancer a mean of 33 months after breast cancer surgery. All eight patients received adjuvant therapies and 4/8 (50%) patients received adjuvant therapies for recurrent breast cancer, including chemotherapy, radiotherapy, hormonal therapy, and anti-HER2 therapy. All patients had early-stage lung adenocarcinoma and underwent surgical resection., Conclusion: Concomitant surgery for synchronous lung and breast cancer was feasible and safe. In metachronous cases, lung cancers tended to be detected within 3 years after surgery for breast cancer. Careful follow-up for postoperative breast cancer may contribute to the detection of early-stage lung cancer., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The acidic tumor microenvironment is associated with progression of cancers. The purpose of this study was to investigate the association between an alkaline diet and the effect of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) patients., Patients and Methods: Eleven advanced or recurrent NSCLC patients with EGFR mutations treated with EGFR-TKI after being instructed to follow an alkaline diet were retrospectively evaluated., Results: The median progression-free survival (PFS) and overall survival (OS) were 19.5 (range=3.1-33.8) and 28.5 (range=15.4-46.6) months. The average dosage of EGFR-TKI was 56±22% of the standard dosage. Urine pH was significantly increased after the alkaline diet (6.00±0.38 vs. 6.95±0.55; p<0.05)., Conclusion: An alkaline diet may enhance the effect of EGFR-TKI treatment in NSCLC patients with EGFR mutations., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: Emphysematous bullae (EB) are known to be associated with a high incidence of lung cancer; however, the reason for this has yet to be elucidated. The objective of the present study was to clarify the prevalence of programmed death-ligand-1 (PD-L1) expression in EB-associated lung adenocarcinomas., Patients and Methods: A total of 369 patients with resected lung adenocarcinoma whose preoperative computed tomography findings were available for the examination of EB were analyzed for PD-L1 expression by immunohistochemistry and evaluated to determine the association between PD-L1 expression and EB-related adenocarcinomas., Results: Among 369 patients, EB and cancer adjoining EB (Ca-ADJ) were identified in 81 (22.0%) and 50 (13.6%) patients, respectively. EB and Ca-ADJ were significantly associated with male gender, a smoking habit, a decreased forced expiratory volume in 1 second, a relatively higher tumor grade, advanced T status and stage, the presence of pleural and vessel invasion, invasive pathologic subtypes, and wild-type epidermal growth factor receptor. Seventy patients (19.0%) were positive for PD-L1 expression, whereas the remaining 299 patients (81.0%) were negative. Thirty-six (44.4%) and 29 (58.0%) of 81 and 50 patients with EB and Ca-ADJ, respectively, were positive for PD-L1 expression, which was shown to be significant by the Fisher exact test (P < .001 and P < .001, respectively). Among the 81 lung adenocarcinomas with EB, Ca-ADJ was significantly associated with PD-L1 expression (P = .021). In a multivariate analysis, the presence of Ca-ADJ was found to be an independent predictor of PD-L1 expression., Conclusions: EB-associated lung adenocarcinomas express PD-L1 protein more frequently than those without EB., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Interleukin (IL)-38, a novel member of the IL-1 cytokine family, is homologous to IL-1 receptor antagonist (IL-1Ra) and IL-36Ra, and has been reported to act as an antagonist. IL-38 expression is found in tonsil, placenta, and spleen, and recent studies suggest an association between IL-38 and autoimmune diseases. However, whether IL-38 plays a role in carcinogenesis or cancer growth is unclear. In the present study, we identified increases in IL-38 expression by immunohistochemistry in multiple types of cancer cells. In the examination of 417 surgically resected primary lung adenocarcinomas, Fisher's exact tests showed significant associations between high IL-38 expression and high tumor grades, an advanced T status, advanced N status, advanced stage, and the presence of pleural and vessel invasions. Survival analyses by the Kaplan-Meier method showed that patients with high expression of IL-38 had significantly shorter disease-free survival and shorter overall survival after surgery than patients with low expression of IL-38 (log-rank test: P = 0.0021 and P = 0.0035, respectively). Moreover, programmed cell death-ligand 1 (PD-L1)-positive cases showed higher expression of IL-38 than PD-L1-negative cases (Wilcoxon rank-sum test: P < 0.0001). In conclusion, IL-38 was expressed in tumor cells of various cancers, and IL-38 expression was associated with poor survival of lung adenocarcinoma patients. IL-38 may affect host immunity or the tumor microenvironment, and contribute to the progression of lung adenocarcinoma.

Background: Programmed death ligand 1 (PD-L1) was reported to predict the response of immunotherapy; however, the association between PD-L1 expression and radiologic and pathologic features has yet to be elucidated., Methods: In all, 292 patients with resected pathologic stage I adenocarcinoma were analyzed for PD-L1 expression by immunohistochemistry and evaluated to determine the association between PD-L1 expression and the radiologic/pathologic invasiveness. Specifically, the radiologic invasiveness and noninvasiveness were determined based on the consolidation/tumor ratio, with a cutoff value of 0.25 by thin-section computed tomography., Results: Among 292 patients, 47 (16.1%) were positive for PD-L1 expression; the remaining 245 patients (83.9%) were negative for PD-L1 expression. Fisher's exact test demonstrated that PD-L1 expression was significantly associated with a higher consolidation/tumor ratio (p = 0.029) and higher maximum standardized uptake value (p = 0.004). The mean values of consolidation/tumor ratio and maximum standardized uptake in patients with and without PD-L1 expression were 0.845 ± 0.052 and 7.241 ± 0.795, and 0.607 ± 0.023 and 3.60 ± 0.364, respectively (p < 0.001 and p < 0.001, respectively). Among 47 adenocarcinomas harboring PD-L1 expression, the frequencies of PD-L1 expression for consolidation/tumor ratios of 0, 0.1 to 0.25, 0.26 to 0.5, and 0.51 or more were 6.4%, 2.1%, 4.3%, and 87.2%, respectively (p = 0.007). Pathologically, PD-L1 was identified exclusively only in more invasive subtypes, not in less invasive ones, such as atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant ones (p < 0.001)., Conclusions: Expression of PD-L1 was significantly associated with radiologic/pathologic invasive adenocarcinomas. This study provides the first evidence of the radiologic and pathologic invasiveness in resected pathologic stage I adenocarcinoma with PD-L1 expression., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The usefulness of the controlling nutritional status (CONUT) score for preoperative nutritional assessment has been reported in resected colorectal and esophageal cancer, but not in lung cancer with obstructive lung disease., Patients and Methods: We retrospectively reviewed 109 patients with adenocarcinoma with obstructive pulmonary disease. We set 1 as the cut-off value for the CONUT score and classified patients into high (≥1) and low (0) CONUT groups., Results: Among 109 patients, 35 (32.1%) had low CONUT scores, and 74 (67.8%) had high CONUT scores. The high-CONUT group was significantly associated with a lower body mass index (p=0.025) and wild-type epidermal growth factor receptor mutation status (p=0.011). A multivariate analysis showed that the CONUT score was independently associated with disease-free and overall survival., Conclusion: The results of this study suggest that the CONUT score was an independent prognostic factor for disease-free and overall survival in patients with lung adenocarcinoma with obstructive lung disease., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction Radiotherapy is not commonly used for the treatment of gastric cancer in Japan, where surgery is the standard local treatment. We report the results of chemoradiotherapy in patients with advanced or recurrent gastric cancer which was deemed difficult to treat surgically. Methods Twenty-one patients with gastric cancer (including sixteen with advanced/recurrent gastric cancer and five with poor general condition) underwent chemo-radiotherapy, for whom the therapeutic efficacy, toxicity and survival period were analysed. Results The tumour response to chemoradiotherapy was categorised as complete, partial, stable or progressive in 5, 9, 3, and 4 patients, respectively, with an overall response rate of 67%. No serious complications such as gastrointestinal perforation or bleeding occurred, and no cardiac, hepatic or renal dysfunction developed during the follow-up period. The mean survival time was 19.8 months (range, 3-51 months). One patient died of another disease, 18 died of primary cancer and the cause of death was unknown in 2 patients. Conclusions Chemoradiotherapy appears to be an effective treatment for localised gastric cancer without distant metastases, but further studies are needed to determine the indications for chemoradiotherapy and late adverse effects, as well as the chemotherapy regimens to be used.

Aim: The purpose of this study was to investigate the biological role of DNA damage-response genes and chromosomal instability in primary lung adenocarcinoma., Materials and Methods: We investigated 60 surgically-resected lung adenocarcinomas. Levels of checkpoint kinase 2 gene (CHEK2) and breast cancer type 1 susceptibility protein gene (BRCA1) mRNA expression were evaluated by polymerase chain reaction (PCR). Epidermal growth factor receptor (EGFR) mutations (exon 19 deletion and exon 21 mutation) were detected by the PCR clamp method. Mutations in Kirsten rat sarcoma viral oncogene homolog gene (KRAS) and TP53 were examined by direct sequencing. Expression levels of p27 and p16 proteins were assessed by immunohistochemistry. Chromosomal aberrations (CA) were examined in 20 samples with single-nucleotide polymorphism-comparative genomic hybridization., Results: CHEK2 mRNA levels were significantly increased in tumor tissues compared to normal tissues (p=0.0123, paired t-test), whereas BRCA mRNA levels were not increased. TP53 mutation positivity and BRCA1 mRNA expression were positively associated with CHEK2 mRNA expression status (p=0.022 and p=0.0008). High CHEK2 mRNA expression was associated with poor recurrence-free survival (p=0.028). CHEK2 mRNA levels were higher in samples with a high CA frequency than in those with a low CA frequency (averages: 0.326 vs. 0.185; p=0.0129)., Conclusion: The CHEK2 mRNA expression level was found elevated in lung adenocarcinoma and was related to a poor prognostic outcome. The CHEK2 pathway may be important for the proliferation of lung adenocarcinoma, especially in tumors with chromosomal instability., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that is deeply involved in the pathogenesis of lung cancer. We evaluated the metabolic characteristics of non-small cell lung cancer (NSCLC) in patients with and without expression of EZH2 using 18 F-fluorodeoxyglucose positron-emission tomography/ computed tomography ( 18 F-FDG PET/CT)., Materials and Methods: The EZH2 protein expression of 268 patients with resected NSCLC, whose preoperative 18 F-FDG PET/CT information was available, was evaluated by immunohistochemistry with clone 6A10 antibody; cases with Allred score ≥3 were considered positive., Results: Maximized standard uptake values in cases of EZH2-positive NSCLC and adenocarcinoma were significantly higher in comparison to EZH2-negative cases (p<0.001, and p<0.001, respectively). The expression of EZH2 in NSCLC and adenocarcinoma was associated with significantly poorer survival., Conclusion: In patients with NSCLC and adenocarcinoma, EZH2 positivity was associated with a high uptake of FDG, suggesting that EZH2 might define metabolically malignant lung cancer., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A 49-year-old man complaining of fever, chest pain, and hemosputum was examined at a local hospital. A chest computed tomography (CT) scan revealed a 35 mm mass shadow with cavity in the right upper lobe, but a transbronchial lung biopsy could not establish a complete diagnosis. After 1 month follow-up, the patient was referred to our hospital because the mass shadow wall remained thick despite the cavity shrinking. The mass shadow cavity disappeared 2 months after the 1st CT at our hospital. Video-assisted thoracic surgery was performed for both making diagnosis and treatment. The patient was diagnosed with non-small cell lung cancer with pulmonary aspergillosis during surgery, and a right upper lobectomy with systematic lymph node dissection was performed. Pathological examinations revealed that the tumor was a T3N0M0 stage II B adenocarcinoma with pulmonary aspergillosis. The patient was treated with adjuvant chemotherapy 4 months after surgery and is under follow-up.

Background/aim: Surgical resection can be applied in cases of early-stage small-cell lung cancer (SCLC). Predicting the histology of SCLC and discriminating SCLC from other histologies would be useful for determining the optimal treatment strategies for small pulmonary nodules that have not been preoperatively diagnosed., Materials and Methods: The study population included 17 patients with resected SCLC and 296 patients with adenocarcinoma (ADC) whose preoperative CT were available. The tumors of all patients were smaller than 3.0 cm., Results: Univariate and multivariate analyses demonstrated that SCLC was significantly associated with the presence of notching and the absence of surrounding ground glass opacity, air bronchogram, pleural indentation, and spiculation in comparison to ADC., Conclusion: The CT scans of patients with SCLC of less than 3.0 cm in size showed notching more frequently than those of patients with ADC, whereas surrounding GGO, air bronchogram, pleural indentation and spiculation were observed less frequently compared to ADC., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: The clinicopathological features of carcinomas expressing programmed death ligand 1 (PD-L1) and their associations with common driver mutations, such as mutations in the EGFR gene, in lung adenocarcinoma are not clearly understood. Here, we examined PD-L1 protein expression in surgically resected primary lung adenocarcinoma and the association of PD-L1 protein expression with clinicopathological features, EGFR mutation status, and patient outcomes., Methods: The expression of PD-L1 protein in 417 surgically resected primary lung adenocarcinomas was evaluated by immunohistochemical analysis. The cutoff value for defining PD-L1 positivity was determined according to the histogram of proportions of PD-L1-positive cancer cells., Results: Samples from 85 patients (20.4%) and 144 patients (34.5%) were positive for PD-L1 protein expression according to 5% and 1% PD-L1 cutoff values, respectively. Fisher's exact tests showed that PD-L1 positivity was significantly associated with male sex, smoking, higher tumor grade, advanced T status, advanced N status, advanced stage, the presence of pleural and vessel invasions, micropapillary or solid predominant histological subtypes, and wild-type EGFR. Univariate and multivariate survival analyses revealed that patients with PD-L1 positivity had poorer prognoses than those without PD-L1 protein expression at the 1% cutoff value (disease-free survival p < 0.0001, overall survival p < 0.0001)., Conclusions: PD-L1 protein expression was significantly higher in smoking-associated adenocarcinoma and in EGFR mutation-negative adenocarcinoma. PD-L1 protein expression was associated with poor survival in patients with lung adenocarcinoma. The PD-L1/programmed cell death 1 pathway may contribute to the progression of smoking-associated tumors in lung adenocarcinoma., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

We report the case of a patient who had synchronous primary lung cancers in the left upper lobe (S(1+2)a, S(1+2)c), and underwent S(1+2) segmentectomy. The lesion in S(1+2)c was non-palpable, and the location was confirmed using intraoperative computed tomography (CT) scan. After A(1+2) and B(1+2) had been cut, the intersegmental border was marked with clips and intraoperative CT was performed. After confirming the correct anatomical intersegmental border and the resection margin was sufficient, we cut the intersegmental border. The two lesions were both adenocarcinomas. Intraoperative CT was useful for confirming the locations of non-palpable lesions and anatomical intersegmental borders.

Differentiated thyroid carcinoma (DTC) is generally indolent in nature and, even though it metastasizes to distant organs, the prognosis is normally excellent. In contrast, the overall survival (OS) of patients with radioactive iodine (RAI)-refractory and progressive metastases is dire, because no effective therapies have been available to control the metastatic lesions. However, recently, administration of tyrosine-kinase inhibitors (TKIs) has become a new line of therapy for RAI-refractory and progressive metastases. Previous studies have reported significant improvement regarding the progression-free survival rates of patients with metastatic lesions. However, TKIs cause various severe adverse events (AEs) that damage patients' quality of life and can even be life-threatening. Additionally, metastatic lesions may progress significantly after stopping TKI therapy. Therefore, it is difficult to determine who is a candidate for TKI therapy, as well as how and when physicians start and stop the therapy. The present review, created by Committee of pharmacological therapy for thyroid cancer of the Japanese Society of Thyroid Surgery (JSTS) and the Japan Association of Endocrine Surgeons (JAES) describes how to appropriately use TKIs by describing what we do and do not know about treatment using TKIs.

Aim: The purpose of this study was to investigate the prognostic significance of epidermal growth factor receptor (EGFR) sensitizing mutations in patients with lung adenocarcinoma who underwent complete surgical resection., Patients and Methods: We retrospectively reviewed the clinical records of 164 patients with lung adenocarcinoma who underwent surgery from 2003 to 2010. Seventy-four patients harbored EGFR mutations; two with exon 18 mutations, 27 with exon 19 mutations, and 45 with exon 21 mutations., Results: There were more female patients and more never-/light smokers among patients with EGFR mutations than among patients without EGFR mutations. Patients with EGFR mutations had a trend for better disease-free survival and overall survival compared to patients without EGFR mutations (p=0.068 and p=0.049, respectively). Patients with exon 21 mutations had significantly better disease-free survival than patients with exon 19 mutations (p=0.027)., Conclusion: Adenocarcinomas harboring EGFR exon 21 mutation were less malignant than adenocarcinomas harboring exon 19 mutation., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Six years after primary surgical treatment for gastric cancer, fluoro-deoxy-glucose positron emission tomography/computed tomography was performed in a 72-year-old man, and demonstrated an increased fluoro-deoxy-glucose uptake in the apex of the left ventricle. Magnetic resonance imaging also revealed a solitary small myocardial tumor. Under cardiopulmonary bypass, tumorectomy was performed with a macroscopically sufficient margin. Histopathologic examination showed adenocarcinoma with poor differentiation developed in the myocardium and pericardial fat; these findings were compatible with the previously resected gastric cancer. The postoperative course was uneventful; the patient has been alive for 29 months without any evidence of local recurrence or cardiac events., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

A 60s male was admitted to our hospital because of appetite loss and nausea. After examination, he was diagnosed with type 3 advanced gastric cancer in the antrum. Abdominal computed tomography showed gastric cancer invasion to the left liver lobe. We initiated neoadjuvant chemotherapy using S-1 plus CDDP after laparoscopic gastrojejunostomy. S-1 was orally administered for 3 weeks followed by a 2-week drug-free period. CDDP was administered intravenously on day 8 of each course. After 5 courses of chemotherapy, the gastric cancer was reduced in size. We therefore performed total gastrectomy with D2-affiliated left liver resection. S-1 plus CDDP is expected to improve outcomes in unresectable or locally advanced gastric cancer.

Purpose: Lung adenocarcinomas among never-smokers are more common in females than in males. This implies that gender-dependent hormones promote smoking unrelated lung adenocarcinoma. We therefore investigated mRNA expression of aromatase, an intrinsic estrogen synthetase, in lung adenocarcinoma and assessed its correlation to clinicopathologic factors, including EGFR mutations and postsurgical prognosis., Experimental Design: Aromatase mRNA expression in primary tumor samples from 110 patients with lung adenocarcinoma was evaluated with qRT-PCR. Inhibitory effects of the aromatase inhibitor exemestane were assessed in lung adenocarcinoma cell lines (11-18 and HCC4006), which have EGFR mutations, separately and combined with EGFR tyrosine kinase inhibitor erlotinib., Results: Aromatase gene expression was not correlated with patients' clinicopathologic factors, including EGFR mutation status. High aromatase expression was associated with poor prognosis for both recurrence-free survival (P = 0.004) and overall survival (P = 0.003). In addition, the prognostic significance of aromatase expression was limited to females, never-smokers, and patients with EGFR mutations, but not in their counterparts. HCC4006, which has a low aromatase mRNA expression level, was not sensitive to exemestane, either alone or combined with erlotinib. In contrast, growth of 11-18 cells, which have high aromatase expression, was significantly inhibited by exemestane, both alone and combined with erlotinib., Conclusions: Aromatase is a candidate prognostic factor in patients with lung adenocarcinoma, especially in those with EGFR mutations, and may also be a beneficial therapeutic target in those patients., (©2014 American Association for Cancer Research.)

Background/aims: Aim of this study is to find subgroup of early gastric cancer with lymph node metastasis for which successive further surgical operation is needed after endoscopic resection., Methodology: A total of 559 lesions of early gastric cancer, which had undergone curative gastrectomy, were enrolled in this study. We retrospectively investigated 10 clinicopathological factors predictive of lymph node metastasis by univariate and multivariate analysis. We showed the frequency of lymph node metastasis of subgroups in combination of independent factors selected by multivariate analysis., Results: Lymph node metastases were detected in 57 lesions (10.2%). Univariate analysis revealed that lesion size > 30 mm, undifferentiated components, sm massive invasion, lymphatic invasion and venous invasion were factors significantly correlated with lymph node metastasis. By multivariate analysis, risk factors for lymph node metastasis were lesion size > 30 mm, undifferentiated components, sm massive invasion, and lymphatic invasion, with odds ratios of 2.17, 2.30, 5.88 and 8.24, respectively. In lesions with undifferentiated components, LNM were found in all subgroups., Conclusions: When we treat early gastric cancers contained undifferentiated components, even if they are predominantly differentiated-type intramucosal lesions, an additional surgical procedure should be considered or careful follow-up is required.

Background: The clinical significance of Brachyury expression and its relationship to epithelial-mesenchymal transition in primary lung carcinoma is unclear., Methods: Expression of Brachyury mRNA was investigated in 104 surgically resected primary lung carcinoma tissues. Immunohistochemical analysis of Brachyury transcription factor, Slug, E-cadherin, IL-8, N-cadherin, and Ki67 was performed in 67 of 104 cases, and their expression was correlated to prognoses and clinicopathological factors., Results: Brachyury mRNA expression in primary lung carcinoma tissues was a significant predictor of poor prognosis for 5-year disease-free survival and overall survival rates and was significantly correlated to vascular invasion, lymphatic permeation, histological grade, pathologic T stage, and pathologic N stage (P < 0.05). Brachyury mRNA expression was significantly inversely correlated to E-cadherin expression (P = 0.0252) and positively correlated to IL-8 protein (P = 0.0241) and to Slug protein (P = 0.0243) in adenocarcinoma tissues., Conclusions: A positive association between Brachyury and Slug and IL-8, and a negative association with E-cadherin may lead to invasiveness and metastasis in primary lung carcinoma. Brachyury mRNA expression is a significant predictor of poor prognosis in primary lung carcinoma.

A 65-year-old male underwent a chest CT scan, which revealed an 8 mm nodule on the wall of a bulla in the left lower lobe of the lung, and was thus suspected to be lung cancer. Pulmonary wedge resection of the left lower lobe by means of video-assisted thoracoscopic surgery was thus performed. A specimen of the lung revealed the presence of intrapulmonary lymph node on the wall of a bulla. The histopathological findings of the resected lung specimen showed non-caseating granulomas in the lymph node, and adenocarcinoma in situ. We concluded that the sarcoid-like reaction observed in the intrapulmonary lymph node was therefore related to the adenocarcinoma in situ.

A 83-year-old woman was referred to our hospital due to an abnormal shadow in the right lower lung field and pleural effusion on chest X-ray. Cytology of the pleural fluid showed adenocarcinoma. EGFR sequencing showed exon19 and T790M mutations. Gefitinib was prescribed as first-line treatment for stage IV(pulmonary metastasis)lung adenocarcinoma from March 2011. The response to the treatment was improved pleural effusion and shrunken tumors. She showed recurrence 13 months after administration of gefitinib. Erlotinib was given as second-line treatment from May 2012. She showed good response with shrinkage of the pulmonary metastases, and was alive with no sign of recurrence for 3 months after administration of erlotinib.

Although postoperative liver metastasis for pancreatic adenocarcinoma is a major problem that directly influences patient outcome, there is no useful predictor reported to date. We reviewed 174 surgically resected pancreatic tubular adenocarcinomas for their clinicopathological data and time for the appearance of postoperative liver metastasis to occur, using the Cox proportional hazards model. Multivariate analysis revealed three independent risk factors for postoperative liver metastasis: G3 histological grading, venous system invasion, and increased preoperative carbohydrate antigen 19-9. Furthermore, the additive effect of these three variables for predicting postoperative liver metastasis was evaluated. Two-year disease-free survival rate for the liver in patients without any factor was 82%, which was significantly higher than that of those with one, two, or three factors (35%, 33%, or 0%, respectively). Our data suggest that these three conventional clinicopathological variables are useful to predict postoperative liver metastasis in patients with pancreatic cancer.

Background: Histological findings of metastatic lymph nodes are important prognosticators in patients with gastric cancer. The aim of this study was to clarify the clinical significance of various pathological characteristics of the early phase of lymph node metastasis in patients with gastric cancer, by selecting patients with tumors that had single lymph node metastases, no serosal invasion, and no metastases to the peritoneum, liver, or distant organs., Methods: Seventy-eight patients were eligible and were entered in this study. These patients were subdivided according to the following histological characteristics of the one metastatic lymph node: size of the metastasis (i.e., amount of tumor cells [AT]), proliferating pattern (PP), intranodal location (IL), and the presence or absence of extracapsular invasion (ECI) and/or fibrotic focus (FF). Associations between clinicopathological factors, survival, and the nodal findings were examined., Results: There were no correlations between AT or PP and any clinicopathological factors. IL was significantly correlated with venous invasion and the pathological characteristics of the primary tumor. ECI and FF were observed significantly more frequently in pT2 than in pT1 cancer. Overall survival (OS) differed significantly according to depth of invasion, venous invasion, and the presence or absence of ECI or FF, although OS was not affected by AT, PP, or IL. The 10-year overall survival rates of patients with and without ECI were 50% and 80%, respectively, while these rates for patients with and without FF were 50% and 79%, respectively. Multivariate analysis revealed that ECI and FF were significant prognosticators of survival., Conclusion: These results strongly suggested that the presence of ECI or FF could affect the survival of patients with gastric cancer.

Pulmonary metastases (PM) to different lobes are classified as M1 disease in non-small cell lung cancer. We report on three patients with lung adenocarcinoma who had undergone complete resection as the initial treatment and thereafter had recurrence of multiple PMs but only in a different ipsilateral lobe 19, 9, and 6 months after surgery. Two patients underwent completion pneumonectomy for the ipsilateral recurrent PM and are doing well without recurrence at 7 and 1 year after the second operations. The other patient received three regimens of chemotherapy over 2.5 years and is alive with PM but without any other metastases. Our findings suggest that some patients with recurrent multiple PM limited to a different ipsilateral lobe have a good prognosis with aggressive treatment, including surgery, and suggest that the PM in such patients occurs through a local route within the ipsilateral thorax.

Background Purpose: Although carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) are the most studied serum tumor markers that have been evaluated for diagnosis and prognosis in patients with pancreatic cancer, little is known of the value of these markers for the prediction of curability and resectability., Methods: We retrospectively reviewed preoperative serum levels of CEA and CA 19-9 in 244 consecutive patients with pancreatic operations., Results: Although 159 pancreatic operations seemed "resectable", 93 of them were judged curative (R0) and the other 66 turned out to be noncurative (R1/2). The remaining 85 failed resection because of unexpected metastasis or locally advanced disease (LD), which was unresectable compared with levels in those patients without liver metastasis or LD. CEA levels were significantly higher in patients with liver metastasis and LD, while CA 19-9 levels were correlated with liver and peritoneal metastases. When both markers were negative, curative (R0) and respectable (R0 + R1/2) operation were performed in 70% and 85% of patients, respectively. Logistic regression analysis indicated that under conditions where both CEA and CA 19-9 were negative, the odds ratios for curative and respectable operations were 4.43 and 3.58, respectively., Conclusions: Our data suggest that combined preoperative CEA and CA 19-9 levels are suitable for assessing expected curability and resectability in patients with pancreatic cancer.

Oxaliplatin (L-OHP) is a new third-generation platinum which is efficacious in treating advanced unresectable recurrent colorectal cancer as a first-line regimen. The marketing authorization was given in Japan in March, 2005. Its increased use has resulted in rare serious adverse effects, including anaphylactic shock. We experienced a case that developed anaphylactic shock by L-OHP. We report a 69-year-old man who was treated for recurrent colorectal cancer who underwent systemic chemotherapy with FOLFOX 4. After eight cycles he developed severe L-OHP associated neuropathy and lung metastases was a progressive tendency. The FOLFOX 4 regimen was discontinued and another modality, FOLFIRI regimen, was used. After eight cycles of FOLFIRI regimen, lung and liver metastases showed progressive disease for response assessment by RECIST criteria. Although a patient was stopped L-OHP for neurotoxicity, neuropathy was disappeared after 4 months interval. Therefore, we reintroduced L-OHP, FOLFOX 4 regimen. Anaphylactic shock occurred in the second cycle of reintroduction of the FOLFOX 4 regimen (total 10 cycles), 30 minutes after infusion of L-OHP. L-OHP infusion was immediately withdrawn and he was treated with intravenous hydroxyzine hydrochloride and methylprednisolone. The anaphylaxis symptoms resolved in 30 minutes. Chemotherapy based on L-OHP for unresectable recurrence colorectal cancer causes anaphylactic shock as a rare severe complication. The prediction factor is not proved. We should take steps for early detection of anaphylactic reaction and perform the appropriate treatment.

A 67-year-old man was admitted to our hospital, complaining of productive cough and chest pain. Chest radiograph and computed tomography revealed a huge mass invading the mediastinum, enlargement of right hilar and cardiophrenic lymph nodes and nodules in right lower lobe and left upper lobe. Multiple space occupying regions in the liver were also observed. Cytology for exfoliated sputum revealed adenocarcinoma, so he was diagnosed with advanced lung cancer (clinical stage T 4 N 2 M 1, stage IV). He was enrolled in a clinical phase II study, and received combination chemotherapy with TS-1 and cisplatin. TS-1 was administered on days 1-21. Cisplatin was administered on day 8. Every cycle was repeated every 5 weeks. The patient then received 6 cycles of chemotherapy,and yielded a partial response (87% decrease in size determined by RECIST criteria version 2. 0). Grade 2 leukopenia and neutropenia were observed, and non-hematologic toxicities were also mild. The disease progressed after the end of chemotherapy, and he was given 5 regimens of chemotherapy, including gefitinib. He died of brain metastases. Time to progression of his disease for combination chemotherapy using TS-1 and cisplatin chemotherapy was 240 days. Survival time was 709 days. This combination chemotherapy was effective in the present case, and might prolong survival. We think it is valuable to confirm the efficacy of TS-1 and cisplatin combination chemotherapy.

Background: With the development of endoscopic submucosal dissection, an expansion of the criteria for local treatment was suggested for lesions with ulcerous changes or undifferentiated-type adenocarcinoma., Aim of the Study: To determine the efficacy of endoscopic ultrasonography for such lesions, we retrospectively analyzed factors that influenced accurate diagnosis by endoscopic ultrasonography of the depth of tumor invasion., Methods: We investigated 267 gastric adenocarcinomas for which histopathological results were obtained by endoscopic mucosal resection or gastrectomy. The lesions were divided into four groups by histological type and the presence of ulcerous changes. Five clinicopathological factors were assessed for their possible associations with incorrect diagnosis., Results: The positive predictive value (PPV) for cancer limited within the mucosa (endoscopic ultrasonography, EUS-M) and cancer invaded into the submucosal layer (EUS-SM) were 88.0% (125 of 142 lesions) and 60.0% (30 of 50 lesions), respectively. The lesions diagnosed as EUS-M/SM borderline (37 lesions) included 19 lesions (51.4%) of M cancer and 17 lesions (45.9%) of SM cancer. In logistic analysis, ulcerous changes (p < 0.0001) and macroscopic classification (p = 0.0284) were factors that caused incorrect diagnosis by endoscopic ultrasonography. In the group having differentiated-type adenocarcinoma with ulcerous changes, the PPV of EUS-SM was 25% (3 of 12), and there was a significant difference (p < 0.05) between the EUS-SM of this group and that of the differentiated-type adenocarcinoma without ulcerous changes., Conclusion: The accuracy of endoscopic ultrasonography tumor staging was not sufficient for the lesions with ulcerous changes in our study. Therefore, we should be careful to perform endoscopic submucosal dissection for lesions with ulcerous changes.

We encountered a 69-year-old man with lung adenocarcinoma and pulmonary sequestration. The cancer lesion was located in the left upper lobe, with sequestration of the left lower lobe. Left upper lobectomy was performed after induction chemoradiotherapy, but the sequestered lung lobe was preserved because the preoperative respiratory function was poor. Preservation of the sequestered lung during surgery for lung cancer should be considered in patients who have poor respiratory function and no signs of respiratory infection.

Background/aims: When a benign-malignant borderline lesion is diagnosed by the usual small gastric biopsy, there is sometimes difficulty in making a clinical decision. To clarify potentially useful findings to predict the existence of gastric cancer in borderline lesions diagnosed by forceps biopsy, we retrospectively analyzed endoscopic features., Methodology: We diagnosed 68 consecutive gastric benign-malignant borderline lesions (57 cases) by forceps biopsy and endoscopically resected them. The final diagnosis for 24 lesions (35.3%) was adenocarcinoma (adenocarcinoma group), and for 40 lesions (58.8%) was adenoma (adenoma group). Comparison with endoscopic findings for the groups was carried out using digitally filed endoscopic photos., Results: We found six endoscopic findings (distal location, reddish surface color, lack of smoothness, lack of glossiness, focal roughness, and focal redness) having statistically significant relationships with adenocarcinoma at the final pathological diagnosis. In multivariate analysis, focal redness (p<0.01) and lack of glossiness (p<0.05) were found to have a significant relationship to gastric cancer., Conclusions: Endoscopic findings such as focal redness and lack of glossiness were potentially predictive of gastric cancer in borderline lesions diagnosed by forceps biopsy.

Objective: The postoperative development or exacerbation of interstitial pneumonia (IP) in lung cancer patients often affects prognoses. We analyzed the patients who suffered from IP after surgery, to determine treatment and prevention of IP., Methods: One hundred and one consecutive patients who underwent resection were enrolled in the study. Clinical background and post-, perioperative course were compared between patients who developed IP and those who did not., Results: If IP developed or was exacerbated, steroid pulse (SP) therapy, immunosuppressant (IS) therapy or nitric oxide (NO) inhalation therapy was employed. Of 101 patients, 20 had suffered from IP before surgery. In four of these 20 (20%), postoperative exacerbation was observed. SP therapy was given to all patients. To one patient, IS and NO therapy were added. Three of the four patients died. 81 patients did not have IP; three of them (3.7%) developed IP after the operation and were treated with SP therapy. To one patient, IS and NO therapy were added. Two of the three patients died. IP development or exacerbation after surgery was observed in seven of 101 patients, and five of them died. It was significantly more frequent in patients with poorly differentiated squamous cell carcinoma, restrictive change in pulmonary function tests, and a low percentage diffusion capacity for carbon monoxide. Postoperative development or exacerbation was observed in patients who had undergone lobectomy or pneumonectomy., Conclusions: Postoperative IP is a serious complication. Further studies are needed to determine definitive therapeutic options. For the patients with the aforementioned risk factors, limited surgery must be considered.

Pulmonary embolism after lung resection (PEALR) has a high mortality rate, and it is one of the most severe complications after lung resection. Early diagnosis and treatment are essential for PEALR. Here we present 3 cases of severe PEALR. In these cases, transthoracic Doppler echocardiography was useful for confirming the diagnosis of PEALR. Thrombolysis with recombinant tissue plasminogen activator (r-tPA) was used to treat the embolism, and these patients were subsequently discharged. Thus echocardiography may become a primary procedure to confirm the diagnosis of severe PEALR, and thrombolysis with second-generation r-tPA may be the preferred choice for treatment.