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Based on the current World Health Organization classification criteria, five of 3895 consecutive cases of surgically resected primary lung carcinomas (0.13%) categorized as enteric-type were analyzed. Three cases completely comprised tumor cells that resemble colorectal adenocarcinoma, while the other two cases exhibited features of conventional adenocarcinomas admixed with enteric components. Immunohistochemically, all patients expressed at least three of the five intestinal markers: CDX2, CK20, HNF4α, MUC2, and SATB2. None of the patients expressed TTF-1 and NKX3.1. Three cases showed nuclear accumulation of β-catenin, indicating activation of the Wnt/β-catenin signaling pathway; APC mutations were detected in one of these cases. TP53 mutations were detected in three cases. Mutated EGFR or ALK fusions were not detected. Our study demonstrates that pulmonary enteric-type adenocarcinomas share immunohistochemical features and genetic alterations with colorectal adenocarcinomas, which are characterized by frequent activation of the Wnt/β-catenin signaling pathway and a lack of actionable mutations., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Gastric adenocarcinoma (GA) with enteroblastic differentiation (GAED) is an aggressive carcinoma histologically characterized by a glycogen-rich clear cytoplasm and fetal gut-like structures. GAED shows the expression of at least one of the following enteroblastic markers (EMs): glypican-3 (GPC3), spalt-like transcription factor 4 (SALL4), and α-fetoprotein (AFP). Despite the absence of clear cytoplasm, we often encounter GA with EMs expression (GA with EM); however, the clinicopathological characteristics of GA with EM remain unclear. Immunohistochemical (IHC) expression of three EMs (AFP, GPC3, and SALL4) was examined on tissue microarray. According to the status of the clear cytoplasm of tumor cells, GAs showing IHC expression of EMs were classified as either GAED or GA with EM, and this analysis categorized 688 GAs into 94 GAEDs (13.7%), 58 GAs with EM (8.4%), and 536 conventional GAs (CGAs). Both GAED and GA with EM showed frequent lymphovascular invasion, lymph node metastasis, and liver metastasis compared to CGA. However, a higher frequency of venous invasion, but not of lymphatic invasion, was noted for GAED in comparison to CGA. GAED and GA with EM showed similar overall survival. GAED had significantly poorer prognosis than CGA; however, not for GA with EM. Furthermore, GA showing EM expression had a worse prognosis than CGA. Interestingly, GA showing EM-positive group was more aggressive than CGA group as they had frequent venous invasion and liver metastasis despite its smaller tumor size. GAED and GA with EM can be clinically classified as aggressive tumors but pathologically they seem to be slightly different., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: A distinct subset of lung adenocarcinomas (LADs), arising from a series of peripheral lung cells defined as the terminal respiratory unit (TRU), is characterised by thyroid transcription factor 1 (TTF-1) expression. The clinical relevance of transcription factors (TFs) other than TTF-1 remains unknown in LAD and was explored in the present study., Methods and Results: Seventy-one LAD samples were subjected to high-throughput transcriptome screening of LAD using cap analysis gene expression (CAGE) sequencing data; CAGE provides genome-wide expression levels of the transcription start sites (TSSs). In total, 1083 invasive LAD samples were subjected to immunohistochemical examination for paired box 9 (PAX9) and TTF-1 expression levels. PAX9 is an endoderm development-associated TF that most strongly and inversely correlates with the expression of TTF-1 TSS subsets. Immunohistochemically, PAX9 expression was restricted to the nuclei of ciliated epithelial and basal cells in the bronchi and bronchioles and the nuclei of epithelial cells of the bronchial glands; moreover, PAX9 expression was observed in 304 LADs (28%). PAX9-positive LADs were significantly associated with heavy smoking, non-lepidic subtype, EGFR wild-type tumours and PD-L1 expression (all P < 0.0001). All these characteristics were opposite to those of TRU-type LADs with TTF-1 expression. PAX9 expression was an independent prognostic factor for decreased overall survival (P = 0.022)., Conclusions: Our results revealed that PAX9 expression defines an aggressive subset of LADs preferentially occurring in smokers that may arise from bronchial or bronchiolar cells., (© 2022 John Wiley & Sons Ltd.)

Introduction: This study aimed to clarify the diagnostic structural features in cytology specimens that are useful in subtyping non-small cell lung carcinoma (NSCLC) into adenocarcinoma (ADC) and squamous cell carcinoma (SQCC)., Methods: Cytology specimens (n = 233) of NSCLCs, which included ADCs (n = 149) and SQCCs (n = 84), were analyzed. The following cytological features were evaluated: isolated cell, flat sheet, three-dimensional cluster with irregular arrangement, papillary-like structure, micropapillary-like structure, acinar-like structure, palisading pattern, protrusion of nuclei at the periphery of the cluster, honeycomb pattern, streaming arrangement, three-dimensional sheets with regular arrangement, flattening at the periphery of the cluster, fuzzy pattern at the periphery of the cluster, and mutual inclusion., Results: ADCs exhibited significantly higher frequencies of flat sheet (p < 0.001), papillary-like structure (p < 0.001), micropapillary-like structure (p = 0.028), acinar-like structure (p < 0.001), and protrusion of nuclei at the periphery of the cluster (p < 0.001) than SQCCs. The latter exhibited significantly higher frequencies of streaming arrangement (p < 0.001), three-dimensional sheets with regular arrangement (p < 0.001), flattening at the periphery of the cluster (p < 0.001), fuzzy pattern at the periphery of the cluster (p < 0.001), and mutual inclusion (p < 0.001) than ADCs., Discussion: Cytological structural features, such as flat sheet, papillary-like structure, micropapillary-like structure, acinar-like structure, and protrusion of nuclei at the periphery of the cluster, indicated ADC, whereas streaming arrangement, three-dimensional sheets with regular arrangement, flattening at the periphery of the cluster, fuzzy pattern at the periphery of the cluster, and mutual inclusion indicated SQCC. Paying attention to these cytological structural features can enable the accurate subtyping of NSCLC into ADC and SQCC., (© 2023 S. Karger AG, Basel.)

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

This real-world study examined the prevalence of programmed death ligand-1 (PD-L1) expression and assessed the frequency of microsatellite instability-high (MSI-H) status and Epstein-Barr virus (EBV) positivity in Japanese patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. This multicenter (5 sites), retrospective, observational study (November 2018-March 2019) evaluated Japanese patients with advanced gastric and GEJ adenocarcinoma after surgical resection (Stage II/III at initial diagnosis) or unresectable advanced cancer (Stage IV). The primary objectives were prevalence of PD-L1 expression (combined positive score [CPS] ≥1), MSI status, and EBV positivity. Tumor specimens of 389/391 patients were analyzed (male, 67.1%; mean age, 67.6 ± 12.2 years); 241/389 (62%) were PD-L1 positive, 24/379 (6.3%) had MSI-H tumors, and 13/389 (3.3%) were EBV positive. PD-L1 expression was higher in tumor-infiltrating immune cells than in tumor cells for lower CPS cutoffs. Among patients with MSI-H tumors and EBV-positive tumors, 19/24 (79.2%) and 9/13 (69.2%), respectively, were PD-L1 positive. A greater proportion of patients with MSI-H tumors (83.3% [20/24]) were PD-L1 positive than those with MSI-low/stable tumors (60.8% [216/355]; p = .0297); similarly, an association was observed between history of H pylori infection and PD-L1 expression. A higher proportion of patients with MSI-H tumors demonstrated PD-L1 expression with a CPS ≥10 (66.7% [16/24]) vs those with MSI-low/stable tumors (24.8% [88/355]; p < .0001). The prevalence of PD-L1 positivity among Japanese patients was comparable to that in previous pembrolizumab clinical trials and studies in gastric cancer. Particularly, higher PD-L1 expression was observed in MSI-H tumors.

The prevalence of NTRK fusions in non-small cell carcinoma (NSCLC) is only approximately 0.2%, most of which harbor NTRK1 fusions. NSCLCs with NTRK3 fusions are extremely rare. Herein, we report a case of low-grade tracheal adenocarcinoma in a 64-year-old woman. Histologically, areas of complicated tubule-papillary or cribriform patterns constituted a major component of the tumor and comprised cuboidal to columnar epithelial tumor cells with pale eosinophilic cytoplasm and cytoplasmic mucin, similar to subsets of sinonasal low-grade non-intestinal-type adenocarcinomas. Immunohistochemically, the tumor was positive for MUC5AC and MUC4 and showed nuclear expression of the pan-Trk antibody. ETV6::NTRK3 was identified by reverse transcription-polymerase chain reaction using formalin-fixed paraffin-embedded tissues. To the best of our knowledge, this is the first case of low-grade tracheal adenocarcinoma with ETV6::NTRK3 fusion. Our case illustrates that low-grade adenocarcinomas with ETV6::NTRK3 fusion may exist throughout the respiratory tract., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Recently, Helicobacter pylori (HP)-uninfected gastric mucosal cancer has been reported; however, the clinicopathological and molecular features of HP-uninfected gastric cancer have not been elucidated., Methods: We evaluated the clinicopathological, immunohistochemical, and genetic alterations in HP-uninfected early gastric adenocarcinoma using next-generation sequencing (NGS)., Results: Among 968 primary early gastric carcinomas, 64 (6.6%) were HP-uninfected gastric adenocarcinoma and were pathologically classified as gastric adenocarcinoma of fundic-gland type (GA-FG, n = 39), differentiated gastric adenocarcinoma (DGA, n = 16), and signet-ring cell carcinoma (SRCC, n = 9). Based on the expression profile of the mucin core protein, DGAs were classified into a gastrointestinal phenotype showing either MUC5AC or MUC6 expression and MUC2 or CD10 expression simultaneously (n = 5), and a gastric phenotype (n = 11) showing either MUC5AC or MUC6 expression. All DGAs with a gastrointestinal phenotype shared similar endoscopic characteristics, such as reddish depressed lesions in the antrum. In contrast, DGAs with a gastric phenotype exhibited several distinct endoscopic features, including a raspberry-shaped appearance and whitish flat-elevated appearance; the former expressed only MUC5AC and the latter exhibited co-expression of MUC5AC and MUC6. Among 16 HP-uninfected DGAs, seven were subjected to NGS. APC was recurrently mutated in DGA (42.9%) and was enriched in DGAs with a gastrointestinal phenotype (75%)., Conclusions: Overall, HP-uninfected gastric adenocarcinomas showed distinct clinicopathologic and endoscopic characteristics. Furthermore, HP-uninfected DGAs, especially those with a gastrointestinal phenotype, may be characterized by recurrent APC mutations., (© 2022. Japanese Society of Gastroenterology.)

Although neoadjuvant therapy (Nac) is recommended for high-risk resectable pancreatic cancer (R-PDAC), evidence regarding specific regimes is scarce. This report aimed to investigate the efficacy of S-1 Nac for R-PDAC. In a multicenter phase II trial, we investigated the efficacy of Nac S-1 (an oral fluoropyrimidine agent containing tegafur, gimeracil, and oteracil potassium) in R-PDAC patients. The protocol involved two cycles of preoperative S-1 chemotherapy, followed by surgery, and four cycles of postoperative S-1 chemotherapy. Two-year progression-free survival (PFS) rates were the primary endpoint. Overall survival (OS) rates and median survival time (MST) were secondary endpoints. Forty-nine patients were eligible, and 31 patients underwent resection following Nac, as per protocol (31/49; 63.3%). Per-protocol analysis included data from 31 patients, yielding the 2-year PFS rate of 58.1%, and 2-, 3-, and 5-year OS rates of 96.8%, 54.8%, and 44.0%, respectively. MST was 49.2 months. Intention-to-treat analysis involved 49 patients, yielding the 2-year PFS rate of 40.8%, and the 2-, 3-, and 5-year OS rates of 87.8%, 46.9%, and 33.9%, respectively. MST was 35.5 months. S-1 single regimen might be an option for Nac in R-PDAC; however, the high drop-out rate (36.7%) was a limitation of this study., (© 2022. The Author(s).)

Objectives: Programmed death ligand 1 and 2 (PD-L1 and PD-L2) bind programmed death 1 (PD-1). PD-L1 is an established predictive biomarker of response to immunotherapies targeting PD-1 and PD-L1 in lung adenocarcinoma (LUAD). However, the clinical relevance of PD-L2 expression in patients with LUAD remains unclear; we aimed to examine this aspect using LUAD specimens., Materials and Methods: PD-L2 expression status was immunohistochemically evaluated in 980 surgically resected LUAD specimens. PD-L2 expression status was classified based on the tumor proportion score (TPS) as negative (<1%), weakly positive (1-49%), or strongly positive (≥50%). Correlations between PD-L2 and PD-L1 expression status, clinicopathological features, driver oncogene alterations (EGFR, KRAS, ALK, ROS1, and RET), and prognosis were also analyzed., Results: PD-L2 expression was negative in 720 (73%) of 980 LUADs, weakly positive in 190 (19%), and strongly positive in 70 (7%). The concordance rate between PD-L1 and PD-L2 expression was 60%. Male sex, smokers, tumors > 3 cm in size, high-grade tumors, tumors without EGFR mutation or ALK fusion, and tumors with KRAS mutation were more common in patients with PD-L2-positive tumors (TPS ≥ 1%) than in patients with PD-L2-negative tumors (TPS < 1%). PD-L2 expression was not associated with overall survival (OS) or relapse-free survival (RFS). However, positive PD-L2 expression tended to be associated with better OS/RFS in PD-L1-positive patients and worse OS/RFS in PD-L1-negative patients., Conclusions: PD-L2-positive LUADs showed biologically aggressive characteristics. PD-L2 expression status was not associated with survival outcomes, but tended to show contrasting prognostic impacts based on PD-L1 expression status., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Esophagogastric junctional cancer is classified into three categories according to the Siewert classification, which reflects the epidemiological and biological characteristics. Therapeutic strategies have been evaluated according to the three Siewert types. There is a consensus that types I and III should be treated as esophageal cancer and gastric cancer, respectively. On the other hand, type II is often described as true cardiac cancer, which has different clinicopathological features from the other types. Thus, there is no consensus on the surgical management of type II esophagogastric junctional cancer. The optimal surgical management should focus on the principles of cancer surgery, which take into consideration oncological curability, including an appropriate resection margin, adequate lymphadenectomy, and minimization of postoperative complications. In this review, we evaluate the current relevant literature and evidence, on the surgical treatment of esophagogastric junctional cancer, focusing on type II. Esophagectomy with a thoracic approach has the advantage of ensuring a sufficient proximal resection margin and adequate mediastinal lymphadenectomy. However, the oncological benefit is offset by a high incidence of postoperative complications. Minimally invasive esophagectomy could be a possible solution to reduce complications and improve long-term outcomes. Further development of surgical treatments for Siewert type II is required to improve the outcomes. Furthermore, the surgical team should have expertise in both gastric cancer and esophageal cancer treatment, or patients should be managed with close collaboration between thoracic surgeons and gastric cancer surgeons., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The mucin phenotypes of colorectal carcinoma (CRC) is related to the biological behavior and prognosis. But there has been no studies evaluating phenotypic characteristics in a large number of cases. Furthermore, colorectal adenocarcinoma with enteroblastic differentiation (CAED) is a rare subtype of CRC and having poor prognosis. The aims of this study were to clarify the correlation between mucin phenotypes and tumor development, including biological behavior in CRC, as well as to investigate characteristic of mucin phenotypes in CAED., Methods and Results: 974 CRC cases and 42 CAED cases of CRCs were classified five types (large-intestinal, small-intestinal, gastric, mixed, and unclassified) of mucin phenotypes by using immunohistochemistry (IHC). IHC was performed on tissue microarrays with antibodies against followings: MUC2, MUC5AC, MUC6, and CD10. In CRCs, large-intestine type has a relatively better prognosis, small-intestinal type frequently shows venous invasions, and liver metastases, gastric type has more high-histological grades and lymphatic invasions, mixed type shows originating from the right side of the colon, larger tumor size and mucinous type, but less venous invasions and liver metastasis, whereas the unclassified type showed poorer prognosis in overall survival with statistical significance. The majority of CAED were found to be small-intestinal type or unclassified type., Conclusions: The phenotypic classification is useful for predicting the prognosis of CRCs. Small-intestinal type and unclassified type showed dismal prognosis in CRCs. We speculate that CAED having aggressive behavior and poor prognosis might reflect characteristics of small-intestinal and unclassified types., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Purpose: Gastric cancer with para-aortic node (PAN) metastasis has a chance to be cured with multidisciplinary treatment of D2 and PAN dissection (PAND) following neoadjuvant chemotherapy (NAC), but its prognosis remains unsatisfactory. To establish a better multidisciplinary treatment, a better surrogate endpoint is needed. The present study focused on a pathological complete response at the PANs alone as a new surrogate endpoint and evaluated its prognostic value., Methods: The study examined patients who received radical gastrectomy with D2 and PAND after NAC for gastric cancer with PAN metastasis from 2004 to 2015. The study compared five methods of evaluating the response to NAC: RECIST, clinical disappearance of PANs (cPAN), histological response of the primary tumor defined by Japanese Classification of Gastric Carcinoma (JCGC histological criteria) and Becker's criteria, and pathological disappearance of PANs (pPAN). The efficacy of these methods was compared using the hazard ratio (HR) for death between responders and non-responders., Results: Thirty-two patients were analyzed. The respective HR and 5-year overall survival rates of responders and non-responders were 1.316 and 49.1% vs. 60.0% by RECIST, 1.106 and 52.9% vs. 52.5% by cPAN, 0.246 and 71.3% vs. 28.6% by JCGC histological criteria, 0.239 and 76.2% vs. 36.8% by Becker's criteria, and 0.074 and 81.0% vs. 0.0% by pPAN., Conclusions: A pathological complete response at the PANs had the lowest HR and clearly differentiated the survival, suggesting it might be a good surrogate endpoint for identifying future candidates for NAC in multidisciplinary treatment for gastric cancer with PAN metastasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: We evaluated the significance of lymph node dissection for gastric neuroendocrine carcinoma (NEC) by calculating the therapeutic value index for each station., Methods: This study included 2164 advanced gastric cancer patients (common-type [Common-GC], n = 2125; and gastric NEC [NEC-GC], n = 39). Clinicopathological data were collected, and survival, type of recurrence, and the index for each type of gastrectomy were determined., Results: NEC-GC was characterized by an older population (P = 0.009), upper tumor location (P = 0.021), frequent venous invasion (P < 0.001), and less neural invasion (P = 0.043). NEC-GC tended to be more frequent in men (P = 0.152), and to be associated with total gastrectomy (P = 0.177) and M1 cases (P = 0.167). The five-year overall survival rates of the Common-GC and NEC-GC groups were 73.8% (95% confidence interval: 71.8-75.6) and 54.7% (37.5-68.9), respectively (P = 0.016). Both groups showed similar index values in each station. Regarding the index of the peri-gastric nodal station (D1 station)/stations away from the stomach (D2 station), although the index of the D1 station was similar in the two groups (41.3 and 43.1), the index of the D2 station in the NEC-GC group was approximately half that of the Common-GC group (10.0 and 5.3). The total recurrence rates of the two groups were similar (P = 0.871). However, the rates of hematogenous and lymphatic recurrence tended to be higher in the NEC-GC group (P = 0.132 and P = 0.152)., Conclusions: The therapeutic efficacy of the D1 station was similar in Common-GC and NEC-GC but that of the D2 station was worse in NEC-GC. Gastrectomy with D2 dissection would be less effective for NEC-GC., Competing Interests: Declaration of competing interest Dr. Yamagata has nothing to disclose. Dr. Yoshikawa reports personal fees from ONO, personal fees from MSD, personal fees from Lilly, personal fees from TAIHO, personal fees from Chugai, personal fees from Nihon Kayaku, personal fees from BMS, personal fees from Daiichi Sankyo, personal fees from TERUMO, personal fees from Johnson and Johnson, personal fees from Pfizer, personal fees from Olympus, personal fees from Yakult, personal fees from Eizai, personal fees from Kyowa, personal fees from Covidien, outside the submitted work;. Dr. Ishizu has nothing to disclose. Dr. Kamiya has nothing to disclose. Dr. Wada has nothing to disclose. Dr. Hayashi has nothing to disclose. Dr. Otsuki has nothing to disclose. Dr. Katai has nothing to disclose., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

To date, several studies have described the mechanism of resistance to first- or second-generation anaplastic lymphoma kinase (ALK) inhibitors. Secondary ALK mutations, ALK gene amplification, and other bypass signal activations (i.e., KRAS mutation, EGFR mutation, amplification of KIT, and increased autophosphorylation of EGFR) are known as resistance mechanisms. However, little has been previously reported on acquired resistance mechanisms to lorlatinib. Here, we report a case of a patient with ALK-positive lung adenocarcinoma that acquired resistance to lorlatinib during treatment for brain metastasis and showed histological transformation to squamous cell carcinoma with MET amplification. We also review the previous literature on the resistance mechanism to ALK inhibitors., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

We report a rare case of cavitary lung metastasis of rectal cancer, diagnosed initially as septic pulmonary embolism. A 55- year-old woman underwent emergency Hartmann's operation for perforation of the rectal cancer with multiple liver metastases. A 2 cm-sized thin-walled cavitary lesion was seen in the left upperlobe of the lung by CT, and septic pulmonary embolism was suspected. She recoverd from sepsis after intensive care treatment. Pathological diagnosis is adenocarcinoma (tub2), T3N1M1, Stage Ⅳ, she underwent chemotherapy. Serum CEA level was high preoperatively but gradually decreased to normal 4 months after the operation. Multiple liver metastases showed calcification, and the lung lesions remained unchanged on CT. She continued chemotherapy while changing the anticancer drug due to side effects. One year and 5 months after operation, lung CT showed thickened wall and spicula around the cavitary lesion. Serum CEA level was normal, SLX and NSE slightly increased and serum aspergillus antigen was positive. Bronchial lavage cytology was Class Ⅰ and scrape cytology was Class Ⅲ in bronchoscopy. Lung metastasis, primary lung cancer or aspergilloma were suspected and we performed partial lung resection. The pathological diagnosis was rectal cancer lung metastasis.

Background: Colorectal adenocarcinoma with enteroblastic differentiation (CAED) is a rare subtype of colorectal malignancy with expression of enteroblastic markers (glypican 3, SALL4, AFP); however, the clinicopathological and epidemiological features are not fully elucidated., Aims: The aims of this study were to elucidate and establish the molecular and clinicopathological characteristics of CAED., Materials and Methods: In addition to three cases recently diagnosed as CAED, colorectal carcinoma (CRC) with expression of enteroblastic markers were selected by using immunohistochemistry (IHC) on tissue microarrays of 988 advanced CRC. We employed next-generation sequencing (NGS) and Sanger sequencing for the detection of genetic alterations. IHC for p53 and HER2, HER2-FISH and MSI status was also investigated. Survival analyses for clinicopathological parameters were performed using Kaplan-Meier methods., Results: Thirty-nine cases (4.0%) were positive for at least one enteroblastic marker. Histological evaluation of the total of 42 cases revealed that 10 contained tumour cells with clear cytoplasm. Enteroblastic marker-positive cases had aggressive behaviour and poor prognosis. NGS revealed TP53 as the most frequently mutated gene. The rate of HER2-positive cases and MSI-H cases was 9.5% (four of 42) and 12.2% (five of 41), respectively. Among these 42 cases, there were no molecular and clinicopathological differences according to the presence of tumour cells with clear cytoplasm., Conclusions: Enteroblastic marker-positive CRC could be grouped together as CAED regardless of clear cell cytoplasm. Using this definition, the frequency of CAED is 4.0% and has a poorer prognosis than that for conventional CRCs. HER2 targeted therapy would be a meaningful treatment for CAED, and CAEDs contain both MSI-H and MSI-stable CRCs, although the MSS phenotype is dominant., (© 2020 John Wiley & Sons Ltd.)

Background: The aim of this study was to evaluate the impact of postoperative infectious complications on long-term outcomes after curative resection of gastric cancer., Patients and Methods: Patients who underwent curative gastrectomy with lymphadenectomy for gastric cancer at Yokohama City University and Kanagawa Cancer Center from January 2000 to August 2015 were retrospectively selected from medical records. Clinicopathological factors between patients with and without infectious complications were compared. Prognostic factors of long-term survival were analyzed by univariate and multivariate Cox proportional hazards analyses., Results: A total of 2,254 patients were eligible for inclusion in the present study. Fifty-eight patients had postoperative infectious complications (IC group); 2,196 had no postoperative infectious complications (NC group). In the IC group, the median age (p=0.031), body mass index (p=0.004), American Society of Anesthesiologists physical status (p=0.006) and percentage of male patients (p<0.001) were higher in comparison to the NC group. The operation time was longer (p<0.001) and the incidence of intestinal-type histology was higher (p=0.017) in the IC group. The 5-year overall survival rates of the IC and NC groups were 59.8% and 83.2%, respectively (p<0.001). Univariate and multivariate analyses demonstrated that postoperative infectious complications were a significant risk factor for poorer overall survival (hazard ratio=2.38; 95% confidence interval=1.47-3.85, p<0.001)., Conclusion: Perioperative management is necessary to reduce the incidence of postoperative infectious complications and improve the survival of patients after curative resection of gastric cancer., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Cancer cells are often found postoperatively at surgical resection margins (RM) in patients with gastric cancer because of submucosal infiltration or hesitation to secure adequate RM. This study was designed to evaluate risk factors for microscopic positive RM and to clarify which patients should undergo intraoperative frozen section diagnosis (IFSD)., Methods: Patients who underwent R0/1 gastrectomy for gastric adenocarcinoma between 2000 and 2018 in a single cancer center in Japan were studied. We divided the patients into a positive RM group and negative RM group according to the results of definitive histopathological examinations. We performed multivariate analysis to analyze risk factors for positive RM by and used the identified risk factors to risk stratify the patients., Results: A total of 2757 patients were studied, including 49 (1.8%) in the positive RM group. The risk factors significantly associated with positive RM were remnant gastric cancer (odds ratio [OR] 4.7), esophageal invasion (OR 6.3), tumor size ≥80 mm (OR 3.9), and a histopathological diagnosis of undifferentiated type (OR 3.6), macroscopic type 4 (OR 3.7), or pT4 disease (OR 4.6). On risk stratification analysis, the incidence of positive RM was 0.1% without any risk factors, increasing to 0.4% with one risk factor, 3.1% with two risk factors, 5.3% with three risk factors, 21.3% with four risk factors, and 85.7% with five risk factors., Conclusions: The risk of macroscopically positive RM increased in patients who have risk factors. IFSD should be performed in patients who have four or more risk factors.

Purpose: There are no criteria for administering first- or second-generation anti-androgens (FGA and SGA, respectively) to patients with non-metastatic castration-resistant prostate cancer (nmCRPC). This study aimed to assess the efficacy of alternative FGA therapy in nmCRPC patients and the prognosis of these patients and to identify factors for predicting patients potentially responsive to FGA., Methods: Data from 63 men with nmCRPC who underwent alternative FGA therapy (bicalutamide, flutamide, or chlormadinone acetate) as first-line therapy after failure of primary androgen-deprivation therapy (PADT) between 2004 and 2017 at Hiroshima University Hospital and affiliated hospitals were retrospectively investigated. The associations of clinicopathological parameters with overall survival (OS) and prostate-specific antigen (PSA) progression-free survival (PFS) of alternative FGA-treated patients were analyzed., Results: Time to CRPC [p = 0.007, hazard ratio (HR) = 4.77], regional lymph node involvement at the diagnosis of CRPC (p = 0.022, HR = 2.42), and PSA-PFS of alternative FGA therapy ≤ 6 months (p = 0.020, HR = 2.39) were identified as prognostic factors using a multivariate analysis. Additionally, Cox proportional hazard models revealed that PSA nadir value > 1 ng/mL during PADT (p = 0.034, HR = 2.40) and time from starting PADT to PSA nadir ≤ 1 year (p = 0.047, HR = 1.85) were predictive factors for worse PSA-PFS in alternative FGA therapy., Conclusions: Shorter time to CRPC, regional lymph node involvement, PSA nadir during PADT > 1 ng/mL, and time from starting PADT to PSA nadir ≤ 1 year might suggest the potential benefit of immediate commencement of SGA, compared to FGA administration after nmCRPC diagnosis.

Purpose: Preoperative treatment is recommended for borderline resectable pancreatic ductal adenocarcinoma. However, the standard treatment has not yet been determined. We conducted a multicenter phase 2 study to investigate the efficacy of neoadjuvant treatment of sequential chemoradiation followed by chemotherapy., Methods and Materials: All enrolled patients were treated by preoperative chemoradiation (a total dose of 50.4 Gy in 28 fractions and orally administered S-1 at 80 mg/m 2 on the day of irradiation) followed by chemotherapy (administration of gemcitabine at 1000 mg/m 2 /dose on days 1, 8, and 15 in 3 cycles of 4 weeks) and attempted curative resection. The primary outcome was an R0 resection rate among patients who completed preoperative treatment and pancreatectomy. The threshold of the R0 resection rate was defined as 74% based on a previous study of up-front surgery., Results: Forty-five patients were included. Twenty-one patients could not undergo pancreatectomy because of progressive diseases (n = 14), adverse events (n = 5), or consent withdrawal (n = 2), and 4 patients underwent additional resection after dropping out. The resection rates were 53.3% and 62.2% in the per-protocol set (PPS) and full analysis set (FAS) populations, respectively. The R0 resection rates were 95.8% (95% confidence interval, 78.9%-99.9%) and 96.4% (81.7%-99.9%) in the PPS and FAS populations, respectively. The median overall survival and progression-free survival of all the included patients were 17.3 and 10.5 months, respectively. The median survival time of the patients with pancreatectomy was significantly longer than that of the patients without pancreatectomy in the PPS (27.9 vs 12.3 months; P = .001) and FAS populations (32.2 vs 11.8 months; P < .001)., Conclusions: This study revealed that a long duration of preoperative treatment of sequential chemoradiation followed by systemic chemotherapy provides a high rate of R0 resection and sufficient survival time in patients undergoing pancreatectomy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

miRNAs are key players in the integrated regulation of cellular processes and shape many of the functional properties that define the "cancer stem cell" (CSC) phenotype. Little is known, however, about miRNAs that regulate such properties in human colorectal carcinoma. In this study, we compared the expression levels of 754 miRNAs between paired samples of EpCAM + /CD44 + cancer cells (enriched in CSCs) and EpCAM + /CD44 neg cancer cells (with CSC depletion) sorted in parallel from human primary colorectal carcinomas and identified miR-221 as the miRNA that displayed the highest level of preferential expression in EpCAM + /CD44 + cancer cells. High levels of miR-221 expression were associated with Lgr5 + cells in mouse colon crypts and reduced survival in patients with colorectal carcinoma. Constitutive overexpression of miR-221 enhanced organoid-forming capacity of both conventional colorectal carcinoma cell lines and patient-derived xenografts (PDX) in vitro . Importantly, constitutive downregulation of miR-221 suppressed organoid-forming capacity in vitro and substantially reduced the tumorigenic capacity of CSC populations from PDX lines in vivo . Finally, the most abundant splicing isoform of the human Quaking ( QKI ) gene, QKI-5 , was identified as a functional target of miR-221; overexpression of miR-221-reduced QKI-5 protein levels in human colorectal carcinoma cells. As expected, overexpression of QKI-5 suppressed organoid-forming capacity in vitro and tumorigenic capacity of colorectal carcinoma PDX cells in vivo . Our study reveals a mechanistic link between miR-221 and QKI and highlights their key role in regulating CSC properties in human colorectal cancer. SIGNIFICANCE: These findings uncover molecular mechanisms underlying the maintenance of cancer stem cell properties in colon cancer. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5151/F1.large.jpg., (©2019 American Association for Cancer Research.)

Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare variant of gastric adenocarcinoma. Clinicopathologically, GAED is known to be aggressive and is characterized by frequent vascular invasion, lymphatic invasion, and liver metastasis even in early stages. SMAD4 was identified as a frequently deleted gene in GAED by copy number variation analysis in our previous next-generation sequencing study; therefore, we examined the clinicopathological impacts of SMAD4 in 51 cases of GAEDs (early: 17, advanced: 34). We performed Sanger sequencing for SMAD4 mutations and loss of heterozygosity (LOH) analysis of the SMAD4 locus, in addition to immunohistochemistry for SMAD4, to determine its clinicopathological correlations and impacts on survival. The frequency of LOH at the SMAD4 locus was 45.1%, and it was significantly higher in GAED compared to in conventional gastric adenocarcinoma. SMAD4 mutations were not found in any case. Reduced SMAD4 expression was found in 60.8% of cases; it was significantly correlated with advanced stages and lymph node metastasis and showed trends of larger tumor size and lymphatic invasion. Reduced SMAD4 expression in metastatic lymph nodes was found in 21 of 36 cases. Survival analysis revealed that reduced SMAD4 expression significantly affected the patient's overall survival (OS) and recurrence-free survival (RFS), although multivariate analysis showed that only liver metastasis and lymphatic infiltration (Ly+) were independent prognostic factors for OS and RFS. The SMAD4 locus is one of the susceptibility genes in this tumor, although SMAD4 mutation was not detected. Furthermore, the inactivation of SMAD4 appeared to contribute to the aggressiveness of GAED., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare variant of aggressive adenocarcinoma. We demonstrated previously that GAED is genetically characterized by frequent TP53 mutation. In this study, we aimed to further clarify the mechanism of inactivation of TP53 in GAED in the light of promoter methylation of TP53, and expression of methylation-associated proteins such as Ten-eleven translocation (TET) 1 and 5-hydroxymethylcytosine (5-hmc) in addition to ATM mutations. We analyzed 51 cases of GAED. The ATM mutation was detected in only one case. Promoter methylation of TP53 was detected in 18% and frequency of loss of heterozygosity (LOH) at TP53 locus was 37.2%. Reduced TET1 expression was found in 29 cases (56.9%) and was significantly associated with advanced stage (p = 0.01), lymph node metastasis (p = 0.04), and macroscopic type (p = 0.01). Reduced 5-hmc expression was found in 28 cases (54.9%) and was significantly associated with advanced stage (p = 0.01), gender (p = 0.01), tumor location (p = 0.03), tumor size (p = 0.01), and lymph node metastasis (p = 0.01). Among 9 cases with TP53 promoter methylation, reduced expression of TET1 was observed in 6 cases, and reduced expression of 5-hmc was observed in 5 cases. Reduced expression of both TET1 and 5-hmc was significantly associated with adverse clinical outcomes. In summary, promoter methylation of TP53 is partly involved in loss of p53 expression. Aberrant methylation by reduced TET1 and 5-hmc may be involved in the development of aggressive GAED.

Introduction: We evaluated differences in the clinicopathologic characteristics and prognosis based on the presence of ground glass opacity (GGO) components in small-sized lung adenocarcinoma., Methods: We retrospectively investigated 634 lung adenocarcinomas classed as c-stage IA in the eighth edition TNM classification. Staging was defined according to the solid component size measured by thin-section computed tomography. All tumors were grouped into either a GGO or solid group, based on the presence of a GGO component., Results: Of the cases, 215 (34%) were classed as c-stage IA1 (T1mi: 88, T1a-GGO: 102, T1a-solid: 25), 255 (40%) as c-stage IA2 (T1b-GGO: 122, T1b-solid: 133), and 164 (26%) as c-stage IA3 (T1c-GGO: 44, T1c-solid: 120). Among the 546 c-stage IA cases excluding the T1mi lesions, Cox regression analysis revealed that presence of GGO was an independently significant prognosticator (p = 0.024). The result was validated in 494 c-stage IA lung adenocarcinomas with a nonpredominant GGO component, showing the presence of GGO as a significant prognosticator (p = 0.048). When we evaluated the prognostic impact of GGO presence in each clinical stage, the 5-year overall survival (OS) was significantly different between the GGO and solid groups (IA1: 97.8% versus 86.6%, p = 0.026; IA2: 89.3% versus 75.2%, p = 0.007; IA3: 88.5% versus 62.3%, p = 0.003). Furthermore, the 5-year overall survival b was distinct in parallel similar pathologic findings when comparing a lepidic versus an invasive component (IA1: 97.9% versus 85.6%, p = 0.031; IA2: 86.1% versus 69.4%, p = 0.007; IA3: 77.5% versus 55.8%, p < 0.001)., Conclusions: Clinicopathologic and oncologic outcomes were disparate based on the presence of a GGO component in the eighth edition TNM classification of c-stage IA lung adenocarcinoma., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

An 81-year-old man with esophageal cancer had undergone subtotal thoracic esophagectomy and retrosternal reconstruction using a gastric tube. He developed anemia. Gastrointestinal endoscopy was performed, which revealed a tumor in the posterior wall of the lower part of the gastric tube. Biopsy revealed well-differentiated adenocarcinoma. There was no lymph node metastasis and no distal metastasis on CT. We performed partial resection of the stomach tube because of his age and physical condition. We identified the position of the tumor by upper gastrointestinal series CT and gastrointestinal endoscopy. The tumor was located on the posterior wall of the lower part of the gastric tube and the back of the sternum lower border. Marking was performed by gastrointestinal endoscopy before operation. We simulated the operation and decided to perform laparostomy without sternotomy incision. We cut the anterior wall of the gastric tube in front of the tumor using the endoscope. We could then confirm the diagnosis of cancer, and clipped and removed the tumor from the posterior wall. The resected site was sutured with 4-0 absorbable thread. The pathological diagnosis was T1a(M)N0M0, ly0, v0, PM0, DM0, pStage ⅠA.

Case 1: A 75-year-old man underwent distal gastrectomy with Billroth Ⅰ reconstruction and resection of the involved transverse mesocolon. Microscopic examination revealed adenocarcinoma(tub2, tub1), pT4b(SI)N3M0, pStageⅢc. Adjuvant chemotherapy with S-1 was performed for 6 months after the operation. One year later, CT revealed a localized dissemination in the transverse mesocolon; therefore, we performed transverse colectomy. Adjuvant chemotherapy with PTX was performed, and the patient remains free from recurrence 7 years after the initialoperation. Case 2: A 65-year-old man was diagnosed with gastric scirrhous carcinoma by esophagogastroduodenoscopy. CT and colonoscopy showed a tumorous lesion in the pelvis(Schnitzler's metastasis). Neo-adjuvant chemotherapy with S-1 plus CDDP was performed. After 6 courses, CT and endoscopy showed shrinkage of the tumors, and no other distant metastasis was detected by PET-CT. We performed totalgastrectomy(D2), splenectomy, and low anterior resection of the rectum simultaneously. Microscopic examination revealed adenocarcinoma(tub2, por2, sig), pT4a(SE)N0, and the histological response was Grade 1a. S-1 was administered, and the patient has had no recurrence in the 1 year 6 months after the operation. Dissemination of gastric cancer tends to be difficult to treat and has a poor prognosis. However, in some cases, the proper combination of chemotherapy and surgery might be beneficial for long survival.

A 60-year-old woman underwent colonoscopy, which revealed a red, 5-mm protruded lesion in the sigmoid colon, surrounded by white spots in white-light imaging. Indigo carmine spray indicated endoscopic morphological type Is + IIc. The vessel pattern was diagnosed as JNET-type 2B in magnifying narrow-band imaging, and magnified crystal violet-stained images revealed a VI low-grade pit pattern. We endoscopically diagnosed this lesion as an intramucosal or slightly invasive submucosal carcinoma with low confidence, and performed endoscopic mucosal resection to obtain a total biopsy. Hematoxylin and eosin staining of the resected specimen showed that the surface of the lesion was well-differentiated adenocarcinoma. The muscularis mucosae was identified by desmin immunostaining. There was no lymphovascular infiltration. Structural atypia was notable in the invasive front, indicating well-to-moderately differentiated adenocarcinoma, which invaded the lamina muscularis mucosae. In addition, desmoplastic reaction was recognized to be present. The lesion was, therefore, diagnosed as an intramucosal invasive (Tis) carcinoma, rather than high-grade dysplasia, according to the World Health Organization definition.

Here, we present a case of non-small cell lung carcinoma (NSCLC) with widespread and strong nuclear immunopositivity for both thyroid transcription factor-1 (TTF-1) and ΔNp63/p40 (p40). Double immunofluorescence for TTF-1 and p40 showed coexpression of both markers in the tumor cells. Furthermore, PTEN (pHis123Asp) and TP53 (pVal272Leu) mutations were identified as possible mitogenic driver mutations by next-generation sequencing. To the best of our knowledge, this is the first case of NSCLC harboring concurrent PTEN and TP53 mutations with widespread and strong coexpression of TTF-1 and p40, which has been confirmed in the resected specimen, and only the second documented case of NSCLC with TTF-1 and p40 diffuse coexpression in the carcinoma cells from the same individual. Our case illustrates the possibility that poorly differentiated NSCLCs with widespread and strong nuclear positivity for TTF-1 and p40 may be an underrecognized and new entity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Histologically tubulopapillary structures with glycogen-rich clear cytoplasm in gastric adenocarcinoma with enteroblastic differentiation (GAED) are well known, but a solid growth pattern can also be observed as a minor component. In contrast, hepatoid adenocarcinoma (HAC) of the stomach shows many overlapping features, including solid pattern and α-fetoprotein expression. In this study, we employed next-generation sequencing (NGS) to establish a molecular/clinicopathological concept of GAED and clarify whether these two tumors should be grouped together in one category. Among 2273 primary gastric cancers treated in our hospital between 2008 and 2017, we defined 51 cases as GAEDs showing tubulopapillary or solid patterns that express at least one of the following markers: α-fetoprotein, glypican-3, or spalt-like transcription factor 4. All cases previously diagnosed as HAC in our hospital had clear cytoplasm and were included as GAEDs by histological re-evaluation and immunohistochemical findings. We performed NGS for 24 histologically typical GAEDs and Sanger sequencing for the remaining cases. The most frequently mutated gene was TP53, and almost all cases with missense mutation showed p53 overexpression. An analysis of copy number variation revealed that ERBB2 amplification was the most frequent in GAED. Additionally, HER2 immunohistochemistry and fluorescence in situ hybridization confirmed that 22% of informative cases were HER2 positive. There was no correlation between molecular/clinicopathological parameters and α-fetoprotein expression or growth patterns in GAED. Our analysis showed that GAED frequently harbors TP53 mutations and ERBB2 amplification. As with conventional gastric adenocarcinoma, trastuzumab may be effective for GAED. Furthermore, HAC may be subcategorized as a solid-type GAED., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Body weight loss (BWL) is frequently observed in gastric cancer patients who undergo gastrectomy for gastric cancer. The risk factors for severe BWL after gastrectomy remain unclear., Methods: The present study retrospectively examined patients who underwent curative gastrectomy for gastric cancer between January 2012 and June 2014 at Kanagawa Cancer Center. All patients received perioperative care based on the enhanced recovery after surgery protocol. The %BWL value was calculated based on the percentage of body weight at 1 month after surgery in comparison to the preoperative body weight. Severe BWL was defined as %BWL > 10%. The risk factors for severe BWL were determined by both univariate and multivariate logistic regression analyses., Results: There were 278 patients examined. The median age of the patients was 68 years. The operative procedures included total gastrectomy [n=97; open (n=61) and laparoscopic {n=36)] and distal gastrectomy (n=181). Surgical complications of grade ≥ 2 (as defined by the Clavien-Dindo classification) were observed in 37 patients, these included: pancreatic fistula (n=9), anastomotic leakage (n=5), and abdominal abscess (n=3). There were no cases of surgery-associated mortality. Both univariate and multivariate logistic analyses demonstrated that surgical complications, and total gastrectomy were significant risk factors for severe BWL., Conclusions: Surgical complications and total gastrectomy were identified as being significant risk factors for severe BWL in the 1 st month after gastrectomy. To maintain body weight after gastrectomy, physicians should pay careful attention to patients who undergo total gastrectomy and those who develop surgical complications., (Copyright © 2017. Published by Elsevier Taiwan LLC.)

Background: The therapeutic efficacy of dissection of the splenic hilar lymph nodes (#10) has not been fully evaluated in locally advanced proximal gastric cancer (LAGC) invading the greater curvature of the stomach., Methods: Patients with LAGC invading the greater curvature who underwent D2 total gastrectomy with splenectomy between January 2000 and May 2015 were retrospectively examined. The therapeutic value index was calculated by multiplying the metastatic rate of a station and the 5-year survival of patients with metastasis to that station; the metastatic rate and the index of each lymph node station were then compared., Results: In total, 82 patients were eligible for the present study. The most frequent metastatic node was #3, followed by #1, #4d and #7, #2, #4sa and #10, and #4sb and #9. These lymph nodes had a metastatic rate of more than 10%. The node station with the highest index was #3, followed by #7, #4d, #1, #4sb, #4sa, #2, and #9. The index of #10 was lower, but exceeded those of #8a and #11p., Conclusions: The metastatic rate of #10 was relatively high at 13%, and the therapeutic value index was as high as those of other suprapancreatic nodes. D2 dissection for proximal cancer located in the greater curvature should include removal of node #10.

Background and Study Aims: Endocytoscopic images closely resemble histopathology. We assessed whether endocytoscopy could be used to determine T1 colorectal cancer histological grade., Patients and Methods: Endocytoscopic images of 161 lesions were divided into three types: tubular gland lumens, unclear gland lumens, and fused gland formations on endocytoscopy (FGFE). We retrospectively compared endocytoscopic findings with histological grade in the resected specimen superficial layer, and examined the incidence of risk factors for lymph node metastasis., Results: Of the 118 eligible lesions, the sensitivity, specificity, accuracy, negative predictive value, and positive likelihood ratio of tubular or unclear gland lumens to identify well-differentiated adenocarcinomas were 91.0 %, 93.1 %, 91.5 %, 77.1 %, and 13.20, respectively. To identify moderately differentiated adenocarcinomas for FGFE, these values were 93.1 %, 91.0 %, 91.5 %, 97.6 %, and 10.36, respectively. In the 35 lesions with FGFE, the rates of massive invasion, lymphovascular infiltration, and tumor budding were 97.1 %, 60.0 %, and 37.1 %, respectively., Conclusions: Endocytoscopy could be used to diagnose T1 colorectal cancer histological grade, and FGFE was a marker for recommending surgery., Competing Interests: Competing interests: None., (© Georg Thieme Verlag KG Stuttgart · New York.)

We have previously shown that galectin-4 expression is an independent predictor for lymph node metastasis and serves as an adverse prognostic indicator in patients with acinar adenocarcinoma of the lung. In contrast, thyroid transcription factor-1 (TTF-1) expression in non-small cell lung carcinoma has been shown to be associated with a favorable prognosis. In the present study, 208 cases of acinar adenocarcinoma of the lung and 36 cases with distant metastatic lesions of lung adenocarcinoma were immunohistochemically examined for expression of galectin-4 and TTF-1 to elucidate their correlation with clinicopathological factors. TTF-1 expression was observed in 145 cases (69.7%) and associated with smaller tumor size, infrequent pleural invasion, and lower TNM stage. Galectin-4 expression was observed in 86 cases (41.3%). Furthermore, galectin-4-positive carcinoma cells and TTF-1-positive carcinoma cells existed exclusively within the same lesion. Expressions of TTF-1 and galectin-4 were favorable and adverse prognostic factors, respectively. Approximately 40% (15/36 cases) of lung adenocarcinoma at the distant metastatic sites were immunohistochemically negative for TTF-1. Four out of five galectin-4-positive metastatic lesions were negative for TTF-1. We found an inverse correlation between galectin-4 and TTF-1 expressions in acinar adenocarcinoma, and this phenomenon was also found to be present in metastatic sites. These findings suggest that we should not exclude the possibility of metastatic adenocarcinoma of the lung, even if the tumor cells are immunohistochemically negative for TTF-1 in the primary unknown tumor, because aggressive lung adenocarcinomas often lack TTF-1 expression.

Objectives: DNA mismatch repair (MMR) deficiency has recently received increasing attention as a significant biomarker to predict the treatment effect of immune checkpoint inhibitors for various malignant neoplasms. To evaluate MMR status, we analyzed the microsatellite instability (MSI) of lung adenocarcinomas., Materials and Methods: Frozen tissues of lung adenocarcinoma and corresponding normal lung were obtained from 341 patients, including 141 with tumors harboring driver gene alterations (50 EGFR gene mutations, 50 KRAS gene mutations, 21 ALK fusions, 10 ROS1 fusions, and 10 RET fusions) and 200 with pan-negative tumors (100 never- or light-smokers and 100 heavy-smokers), who were surgically treated between 2007 and 2015. Genomic DNA extracted from tumors and corresponding normal lung tissues were used for MSI analysis using the Promega panel (5 mononucleotide markers: BAT-25, BAT-26, NR-21, NR-24, and MONO-27; and 2 pentanucleotide markers: Penta C and Penta D)., Results: MSI was identified in only 1 pan-negative tumor from a 64-year-old male heavy smoker. MSI was found in 4 mononucleotide markers. Although no clinical background of Lynch syndrome was evident, somatic MLH1 gene mutation was identified. MLH1 was expressed in tumor-infiltrating lymphocytes and was not expressed in cancer cells. PD-L1 was not expressed in cancer cells, and PD-1 was not expressed in tumor-infiltrating lymphocytes., Conclusion: MSI is a rare event in lung adenocarcinoma regardless of smoking status and mutation status of driver oncogenes. Accordingly, MMR deficiency status cannot be used as a biomarker for immune checkpoint inhibitor treatment for lung adenocarcinoma., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: White globe appearance (WGA) refers to a small white lesion of globular shape underneath cancerous gastric epithelium that can be clearly visualized by magnifying endoscopy with narrowband imaging (M-NBI). WGA has been reported to be a novel endoscopic marker that is highly specific in differentiating early gastric cancer (GC) from low-grade adenoma, and has a significantly higher prevalence in early GCs than in noncancerous lesions. However, interobserver agreement in detecting WGA and whether training intervention can improve diagnostic accuracy are unknown., Methods: Twenty sets of M-NBI images were examined by 16 endoscopists. The endoscopists attended a lecture about WGA, and examined the images again after the lecture. Interobserver agreement in detecting WGA in the second examination and increases in the proportion of correct diagnoses and the degree of confidence of diagnoses of cancerous lesions were evaluated., Results: The kappa value for interobserver agreement in detecting WGA in the second examination was 0.735. The proportion of correct diagnoses was significantly higher in the second examination compared with the first examination when WGA was present (95.5% vs 55.4%; P < 0.001), but not when WGA was absent (61.6% vs 52.7%; P = 0.190). The proportion of correct diagnoses with a high degree of confidence was significantly higher in the second examination, both with WGA (91.1% vs 29.5%; P < 0.001) and without WGA (36.6% vs 20.5%; P = 0.031)., Conclusions: The detection of WGA by endoscopists was highly reproducible. A brief educational lecture about WGA increased the proportion of correct diagnoses and the degree of confidence of diagnoses of GC with WGA.

Introduction: Subcentimeter NSCLC is not always an early-stage disease despite its small tumor size. We investigated the prognostic impact of such cancers on the basis of the findings of thin-section computed tomography (CT)., Methods: We evaluated the clinicopathological features and prognosis of 328 surgically resected clinical-N0 NSCLCs 1.0 cm or less in size. Consolidation-to-tumor ratio (CTR) was evaluated for all, and tumors were classified into three groups, namely, pure ground glass opacity (GGO) (CTR = 0 [n = 139]), part solid (0 < CTR < 1.0 [n = 123]), and pure solid (CTR = 1.0 [n = 66])., Results: Pathological nodal involvement was observed in seven patients, with all cases found exclusively in pure solid subcentimeter NSCLC (10.9%). Furthermore, a multivariate analysis revealed that the presence of GGO was an independently significant clinical factor in overall survival (OS) and recurrence-free survival (RFS) (OS: p = 0.0340; RFS: p = 0.0018). Histological examination revealed that 134 of the 139 cases of pure GGO (97%), 99 of the 123 cases of part solid tumor (81%), and 16 of the 66 cases of pure solid tumor (25%) were lepidic predominant lung adenocarcinoma. Evaluation of the oncological outcomes on the basis of CTR revealed that 5-year OS and RFS rates were significantly better in patients with nonsolid tumors (OS and RFS = 100%) or part solid tumors (OS = 97.5% and RFS=94.9%), whereas the OS and RFS rates of patients with pure solid subcentimeter NSCLC were 87.6% and 79.3%, respectively (OS: p = 0.0015; RFS: p < 0.0001)., Conclusions: The findings of thin-section CT are extremely important when considering the prognosis of subcentimeter NSCLC. Radiologically determined solid subcentimeter NSCLCs should be treated as invasive tumors regardless of their small size., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to clarify the diagnostic significance of cytoplasmic lipid accumulation (CLIA) in the cribriform variant of papillary thyroid carcinoma (CV-PTC)., Methods: We performed a histological, immunohistochemical, and cytological examination of 35 CV-PTC cases at the Kuma Hospital. CLIA was defined as bubble-like multivacuolation in cytoplasm with distinct cell border. We also examined 100 conventional PTC (con-PTC) cases as controls., Results: Histological analysis showed the presence of carcinoma cells with CLIA in 60.0% of CV-PTC and 5.0% of con-PTC cases. The vacuoles tended to distribute in the subnuclear portion of carcinoma cells showing papillary growth. They were positive for oil red O staining and adipophilin. The carcinoma cells without the vacuoles showed a subnuclear dot-like expression for adipophilin in CV-PTC cases, but not in the con-PTC cases. Cytological analysis showed CLIA in 17 (54.8%) of the 31 CV-PTC cases, but not in the con-PTC cases., Conclusion: This is the first study to report the presence of carcinoma cells with CLIA in CV-PTC. The subnuclear dot-like expression of adipophilin may be characteristic of CV-PTC. These findings might be related to degenerative changes occurring in CV-PTC., (© 2017 The Author(s) Published by S. Karger AG, Basel.)

Background: Complete surgical resection is essential for a cure for most gastric cancer. Recently it was reported that surgical Apgar score (SAS) can predict postoperative complication and that postoperative complication is associated with poor long-term survival. The aim of this study is to assess whether SAS can predict overall survival (OS) after surgery for gastric cancer., Methods: We retrospectively compared clinicopathological characteristics and survival between high and low SAS score groups in patients who underwent gastrectomy for gastric cancer., Results: Low-scored SAS group (group L) was significantly more common among ASA-PS 2, open approach, total gastrectomy, D2 lymph node dissection, postoperative complication grade 2-4, deep tumor invasion, lymph node metastases, and advanced pathological TNM stage than high-scored SAS group (group H). The 5-year OS of group H and group L were 81.6 and 55.9 %, respectively (p < .001); OS of group L tended to be poorer than that of group H in stage III patients (p = .060) and in stage IV patients (p < .001). In multivariate analysis, pathological stage and SAS were identified as independent predictors for OS., Conclusions: SAS is useful for predicting survival after surgery for gastric cancer.

Background: Although a few studies have reported the use of reduced-port laparoscopic gastrectomy (RPG) in gastric cancer patients, the feasibility of routinely using this technique remains unclear. It is therefore important to evaluate the surgical advantages of this technique in this patient group., Methods: Between August 2010 and July 2015, 165 patients underwent RPGs at our hospital, performed by a single surgeon. Of these patients, 88 underwent reduced-port laparoscopic distal gastrectomy (RPLDG) and 77 underwent reduced-port laparoscopic total gastrectomy (RPLTG). In addition to short-term surgical outcomes after RPG, survival times and the surgical learning curve were also evaluated., Results: Blood losses during lymph node dissection in the RPLDG and RPLTG groups were not significantly different (p = 0.160). Conversion to open surgery was necessary in only two patients. Postoperative morbidities were observed in 14.8 % of the RPLDG group and 14.3 % of the RPLTG group, but there were no deaths. Most patients expressed high cosmetic satisfaction in both groups. In the RPLDG group, operation time during reconstruction decreased over the first 50 cases and then plateaued, as the surgeon's experience of the technique increased. In contrast, in the RPLTG group, operation times dropped with surgical experience for both lymph node dissection, plateauing after 40 cases, and for reconstruction, plateauing after 30 cases. Only three patients died of gastric cancer in the follow-up period and three patients died of other diseases. Five-year overall survival and 5-year disease-specific survival were 95.6 and 98.0 %, respectively., Conclusions: We have shown that reduced-port gastrectomy (RPG) could be an acceptable and satisfactory procedure for treating gastric cancer for an experienced laparoscopic gastric surgeon who has sufficient previous experience of conventional laparoscopic gastrectomies.

A 75-year-old man admitted for left lateral abdominal pain was found to have advanced poorly differentiated gastric adenocarcinoma with abdominal para-aortic and Virchow's lymph node metastases, which was diagnosed to be clinical Stage IV (T3N3H0M1[LYM]). As curative surgery was not deemed possible, we started chemotherapy administration using S-1 (120mg/day)administered orally for 3 weeks and cisplatin(CDDP 100mg/body)administered intravenously on day 8. After 6 courses of chemotherapy, a CT scan showed that all lymph nodes metastases had disappeared, resulting in downstaging to clinical Stage II (T3[SE]N0H0P0M0). Thus, we performed total gastrectomy, lymph node dissection(D2), and splenectomy. Histological findings showed no residual tumor cells in any of the lymph nodes. However, cancer cells remained in the primary gastric lesion. The pathological response to chemotherapy was judged to be Grade 2. The patient has been recurrence-free for 5 years after surgery.

We encountered 4 cases of colorectal cancer with para-aortic lymph node(LN)metastases.Para -aortic LN dissection was performed after the diagnosis of solitary LN metastases.Case 1: A 69-year-old woman was diagnosed with ascending colon cancer.She underwent right hemicolectomy with D3 LN dissection.After 1 year and 3 months, tumor marker levels(CEA) were elevated, and para-aortic LN metastases were detected on CT.She was administered FOLFOX.After 1 year, para-aortic LN dissection was performed.She is doing well without any recurrence for 8 years and 9 months.Case 2: A 52-year-old man was diagnosed with rectal cancer.He underwent abdominoperineal resection with lateral pelvic LN dissection.After 5 months, his tumor marker levels(CEA)were elevated, and para-aortic LN metastases were detected on CT.He was administered various chemotherapies, but the LN were swollen.After 6 years and 2 months, para-aortic LN dissection was performed.He received systematic chemotherapy, and is alive with recurrent disease.Case 3: A 67-year-old man was diagnosed with obstructive sigmoid colon cancer.He underwent high-anterior resection with D3 LN and para-aortic LN dissection.He received systematic chemotherapy and is alive with recurrent disease.Case 4: A 61-year-old man was diagnosed with obstructive rectal cancer.He underwent low-anterior resection with D3 LN and para-aortic LN dissection.He is doing well without recurrences for 2 years and 1 month.Our results suggest that patients with localized para-aortic metastases of colorectal cancer may achieve good long-term survival after dissection of para-aortic LN.and surgical treatment is indicated in selected cases.

Neoadjuvant chemotherapy(NAC)is thought to be effective to improve the outcomes in patients with adenocarcinoma of the esophago-gastric junction(AEG). We encountered 3 patients who were confirmed as having a pathological complete response following gastrectomy after NAC. The first patient had Siewert type II and clinical Stage III AEG, the second patient had Siewert type I and clinical Stage III AEG, while the third had Siewert type II and clinical Stage II AEG. Two patients received NAC with 2 courses of S-1 plus cisplatin, while the third patient received 2 courses of docetaxel, S-1, and cisplatin. All of the patients were treated with D2 gastrectomy after the NAC, and remain alive at more than 40 months after initial chemotherapy treatment without recurrence. We report the details of these 3 cases and review the literature.

We report a case of advanced esophageal and gastric cancer that was successfully treated via multimodal therapy. A 65- year-old man with hoarseness was referred to our hospital. He was diagnosed with clinical T4aN2M0, Stage IV esophageal squamous cell carcinoma and clinical T3N1M0, Stage II B gastric adenocarcinoma. He was treated with 3 courses of chemotherapy, administered over 4weeks, with S-1(80mg/m / / 2: day 1-14), cisplatin(60mg/m2: day 1), and docetaxel(40mg/m2: day 1). Computed tomography(CT)revealed shrinkage of the primary esophageal tumor, gastric tumor, and lymph node metastases. Next, we selected definitive radiation chemotherapy(CRT), because lymph node metastases remained around the bilateral recurrent laryngeal nerves. After CRT with a total 60 Gy plus administration of 5-fluorouracil and cisplatin, CT showed that the primary esophageal tumor and lymph node metastases had disappeared. Then, distal gastrectomy was performed for the remaining gastric cancer, as part of the multimodal therapy. After gastrectomy, no systemic chemotherapy was performed. At a follow-up examination 5 years and 6 months after the start of chemotherapy, the patient is alive without recurrence.

Background: Sarcopenia is a decrease in both muscle mass and strength. It remains unclear whether sarcopenia is associated with morbidity after gastric cancer surgery. This study evaluated the impact of sarcopenia on the morbidity of gastric cancer surgery., Methods: A total of 293 gastric cancer patients who underwent curative surgery between May 2011 and June 2013 were retrospectively examined. Patients with performance status 3 or 4 were excluded. Preoperative lean body mass (LBM) was evaluated by bioelectrical impedance analysis and expressed as LBM index. Preoperative muscle function was measured by hand grip strength (HGS). The cutoff values were the gender-specific lowest 20 %. Grade 2 or higher morbidities, as retrospectively evaluated by the Clavien-Dindo classification, were obtained from the patient record. The risk factors for morbidity were examined by univariate and multivariate analyses., Results: Morbidity was observed in 39 patients (13.3 %), including 7 with pancreatic leakage, 12 with anastomotic leakage, and 4 with intraabdominal abscesses, but no mortality was observed. The univariate analysis showed that male gender, total gastrectomy, splenectomy, and a low HGS were significant risk factors for morbidity. A low LBM was not a significant risk factor. A low HGS, male gender, and total gastrectomy remained significant in the multivariate analysis., Conclusions: A low hand grip strength was a significant risk factor for morbidity after gastric cancer surgery. The importance of the hand grip strength as a risk factor should be examined in future prospective studies.

Background and Aim: Recent advances in endoscopic technology have allowed many T1 colorectal carcinomas to be resected endoscopically with negative margins. However, the criteria for curative endoscopic resection remain unclear. We aimed to identify risk factors for nodal metastasis in T1 carcinoma patients and hence establish the indication for additional surgery with lymph node dissection., Methods: Initial or additional surgery with nodal dissection was performed in 653 T1 carcinoma cases. Clinicopathological factors were retrospectively analyzed with respect to nodal metastasis. The status of the muscularis mucosae (MM grade) was defined as grade 1 (maintenance) or grade 2 (fragmentation or disappearance). The lesions were then stratified based on the risk of nodal metastasis., Results: Muscularis mucosae grade was associated with nodal metastasis (P = 0.026), and no patients with MM grade 1 lesions had nodal metastasis. Significant risk factors for nodal metastasis in patients with MM grade 2 lesions were attribution of women (P = 0.006), lymphovascular infiltration (P < 0.001), tumor budding (P = 0.045), and poorly differentiated adenocarcinoma or mucinous carcinoma (P = 0.007). Nodal metastasis occurred in 1.06% of lesions without any of these pathological factors, but in 10.3% and 20.1% of lesions with at least one factor in male and female patients, respectively. There was good inter-observer agreement for MM grade evaluation, with a kappa value of 0.67., Conclusions: Stratification using MM grade, pathological factors, and patient sex provided more appropriate indication for additional surgery with lymph node dissection after endoscopic treatment for T1 colorectal carcinomas., (© 2015 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Lean body mass loss after surgery, which decreases the compliance of adjuvant chemotherapy, is frequently observed in gastric cancer patients who undergo gastrectomy for gastric cancer. However, the risk factors for loss of lean body mass remain unclear., Methods: The current study retrospectively examined the patients who underwent curative gastrectomy for gastric cancer between June 2010 and March 2014 at Kanagawa Cancer Center. All the patients received perioperative care for enhanced recovery after surgery. The percentage of lean body mass loss was calculated by the percentile of lean body mass 1 month after surgery to preoperative lean body mass. Severe lean body mass loss was defined as a lean body mass loss greater than 5 %. Risk factors for severe lean body mass loss were determined by both uni- and multivariate logistic regression analyses., Results: This study examined 485 patients. The median loss of lean body mass was 4.7 %. A lean body mass loss of 5 % or more occurred for 225 patients (46.4 %). Both uni- and multivariate logistic analyses demonstrated that the significant independent risk factors for severe lean body mass loss were surgical complications with infection or fasting (odds ratio [OR] 3.576; p = 0.001), total gastrectomy (OR 2.522; p = 0.0001), and gender (OR 1.928; p = 0.001)., Conclusions: Nutritional intervention or control of surgical invasion should be tested in future clinical trials for gastric cancer patients with these risk factors to maintain lean body mass after gastrectomy.

Adipophilin, a lipid droplet-associated protein that regulates lipid droplet structure and formation, is expressed in a wide variety of tumors. The aims of this study were to evaluate the frequency and distribution pattern of adipophilin expression in gastric epithelial neoplasia and to correlate these variables with clinicopathological features and the mucin phenotype. We retrospectively examined 159 cases of gastric epithelial neoplasia, which were classified according to the Vienna classification system as 52 noninvasive low-grade adenoma (category 3), 65 noninvasive high-grade neoplasia (category 4), and 42 invasive neoplasia (category 5). Immunohistochemistry for adipophilin was performed, and phenotypic marker expression was determined by immunohistostaining with MUC2, MUC5AC, CD10, MUC6, and villin. Adipophilin was expressed in 41 of the 52 (79 %) category 3 cases, in 42 of the 65 (65 %) category 4 cases, and in 23 of the 42 (55 %) category 5 cases. Expression of adipophilin was only present in lesions with complete or incomplete intestinal phenotypes. Adipophilin was expressed more frequently in the surface epithelium in category 3, whereas there was a stepwise increase in cryptal staining of adipophilin from category 3 to category 5. In conclusion, adipophilin expression is closely related to the intestinal differentiation of the tumor. The pattern of immunostaining for adipophilin might be a useful new marker for discriminating adenomas from adenocarcinomas.

Background: It was unclear whether the transhiatal approach and D2 total gastrectomy after neoadjuvant chemotherapy (NAC) for adenocarcinoma of the esophago-gastric (AEG) junction are as feasible and safe as D2 gastrectomy following NAC., Patients and Methods: We clarified the short-term surgical results in AEG and non-AEG patients in a subset analysis of the COMPASS trial., Results: Eighty-three patients, 24 with AEG and 59 with non-AEG, were registered in the study. Among 24 patients with AEG, 5 were classified to have Siewert type I, 11 to have type II and 8 to have type III. The tumor progression, completion of NAC, and clinical and pathological responses were similar between the groups. Twenty-four AEG and 51 non-AEG patients proceeded to surgery. The extent of dissection (D1/D2) was 3/21 in the AEG and 3/48 in the non-AEG patients. The R0 resection rate was 69% in the non-AEG and 88% in the AEG patients. Neither grade 3b/4 morbidity nor surgical mortality was observed in either group., Conclusions: The transhiatal approach and D2 total gastrectomy after NAC seem to be as safe and feasible as D2 gastrectomy for non-AEG cancer., (© 2016 S. Karger AG, Basel.)

Background/aim: Previous reports stated that pedunculated T1 colorectal carcinomas with 'head invasion' showed almost no nodal metastasis, requiring endoscopic treatment alone. However, clinically, some lesions develop nodal metastasis. We aimed to validate the necessity of distinguishing between 'pedunculated' and 'non-pedunculated' lesions, and also between 'head' and 'stalk' invasions., Methods: Initial or additional surgery with lymph node dissection was performed in 76 pedunculated and 594 non-pedunculated cases. Among pedunculated lesions, the baseline was defined as the junction line between normal and neoplastic epithelium (Haggitt's level 2). The degree of invasion was classified as 'head invasion' (above the baseline) or 'stalk invasion' (beyond the baseline). Clinicopathological factors were analyzed with respect to nodal metastasis., Results: Nine of 76 (11.8%) pedunculated cases and 52/594 (8.8%) non-pedunculated cases developed nodal metastasis (p = 0.40). No significant differences were found in the rate of nodal metastasis between 'head invasion' (4/30, 13.3%) and 'stalk invasion' (5/46, 10.9%). All the 4 cases with 'head invasion' had at least one pathological factor., Conclusions: 'Head invasion' was not a metastasis-free condition. Even for pedunculated T1 cancers with 'head invasion', additional surgery with lymph node dissection should be considered if these have pathological risk factors., (© 2016 S. Karger AG, Basel.)