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Oxidative stress serves an important role in carcinogenesis. The present study investigated the clinical significance of oxidative stress as a prognostic factor for diffuse large B-cell lymphoma (DLBCL). The participants comprised 55 consecutive patients with DLBCL. A commercially available derivatives of reactive oxygen metabolites (d-ROMs) test kit was used to assess oxidant levels. Similarly, a commercially available biological antioxidant potential (BAP) test was used to assess antioxidant levels. The antioxidative/oxidative stress ratio was calculated as d-ROMs/BAP. The median serum concentration of d-ROMs was 425 µM. The levels of d-ROMs were significantly higher in patients with DLBCL than in healthy volunteers (P<0.01). The complete remission (CR) rates in patients with d-ROMs <425 and ≥425 µM were 81.5 and 85.7%, respectively [not significant (NS)]. The 3-year overall survival (OS) rates for patients with d-ROMs <425 and ≥425 µM were 67.2 and 72.0%, respectively (NS). The median BAP was 2,002 µM. The CR rates of patients with BAP <2,002 and ≥2,002 µM were 77.8 and 88.9%, respectively (NS). The 3-year OS rates of patients with BAP <2,002 and ≥2,002 µM were 60.9 and 75.9%, respectively (NS). No significant difference in the d-ROMs/BAP ratio was observed between groups. Multivariate analysis revealed that d-ROMs were an independent prognostic factor for progression-free survival., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020, Spandidos Publications.)

The purpose of this study was to demonstrate the preparation of spherical submicron YAG:Ce particles with controllable particle outer diameters and crystallite sizes and their photoluminescence (PL) properties, which were produced using a flame-assisted spray-pyrolysis method followed by the annealing process. The correlation of particle outer diameter, crystallite size, and PL performance of the prepared particles was also investigated. Experimental results showed that the increases in the particle outer diameters have an impact on the obtainment of higher PL performance. Large particle outer diameters permitted the crystallites to grow more, whereas this is in contrast to the condition for small particle outer diameter having limitations in crystallite growth. This study also found that too large outer diameter (>557 nm) was not effective since crystallites cannot grow anymore and it permits possible scattering problems. This study provides significant information for optimizing synthesis parameters for controlling particle outer diameters and crystallite sizes, which could be relevant to other functional properties, especially for lens, solar cell, and LED applications., Competing Interests: We certify that all authors agree for publishing this work, and we have no conflict of interest to declare. We warrant that the article is the authors' original work., (This journal is © The Royal Society of Chemistry.)

Background: Chemotherapeutics, one of the standard treatment options for cancer worldwide, have various adverse effects, including erectile dysfunction (ED)., Aim: To investigate erectile function in an animal model after administration of the anticancer agent oxaliplatin (L-OHP)., Methods: Male Wistar/ST rats were divided into 2 groups: L-OHP rats (n = 21), which were intravenously administered L-OHP (4 mg/kg; twice a week for 4 weeks), and Control rats (n = 21), which were injected with the same volume of 5% glucose solution, using the same dosing schedule. At the end of the study period, erectile function was evaluated by measuring intracavernous pressure (ICP) and mean arterial pressure (MAP) after cavernous nerve stimulation (n = 9-10). Endothelial function was evaluated with an isometric tension study using corpus cavernosum strips (n = 11). Western blot analysis was used to assess neuronal nitric oxide (nNOS) and endothelial NO synthase (eNOS) protein levels (n = 7). Real-time quantitative polymerase chain reaction (qRT-PCR) was used to assess the expression of inflammation- and oxidative stress-related markers (nicotinamide adenine dinucleotide phosphate oxidase-1, p22 phox , interleukin [IL]-6, and nuclear factor-kappa B) (n = 6). Statistical significance was determined using the Student's t-test., Outcomes: The L-OHP group had a significantly lower ICP:MAP ratio than the control group (P < .05). Compared to the Control group, the L-OHP group exhibited significantly lower responses to ACh and eNOS protein levels and significantly higher inflammatory biomarker levels., Clinical Translation: The results based on this animal model indicate that use of the anticancer agent L-OHP should be considered as a risk factor for ED occurring via reduction of NO bioavailability in humans; our results provide possible treatment strategies for maintaining the erectile function of cancer survivors., Strengths and Limitations: Our study showed that the anticancer agent L-OHP has the propensity to cause ED in rats. A major limitation of this study is the lack of an established cure for ED associated with L-OHP and the lack of clinical evidence., Conclusions: L-OHP causes ED in rats via reduction of NO bioavailability caused by endothelial dysfunction. Kataoka T, Mori T, Suzuki J, et al. Oxaliplatin, an Anticancer Agent, Causes Erectile Dysfunction in Rats due to Endothelial Dysfunction. J Sex Med 2021;18:1337-1345., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Cancer-associated antigens are not only a good marker for monitoring cancer progression but are also useful for molecular target therapy. In this study, we aimed to generate a monoclonal antibody that preferentially reacts with colorectal cancer cells relative to noncancerous gland cells. We prepared antigens composed of HT-29 colorectal cancer cell lysates that were adsorbed by antibodies to sodium butyrate-induced enterocytically differentiated HT-29 cells. Subsequently, we generated a monoclonal antibody, designated 12G5A, which reacted with HT-29 colon cancer cells, but not with sodium butyrate-induced differentiated HT-29 cells. Immunohistochemical staining revealed 12G5A immunoreactivity in all 73 colon cancer tissue specimens examined at various degrees, but little or no immunoreactivity in noncancerous gland cells. Notably, high 12G5A immunoreactivity, which was determined as more than 50% of colon cancer cells intensively stained with 12G5A antibody, exhibited significantly higher association with a poor overall survival rate of patients with colorectal cancer (P = 0.0196) and unfavorable progression-free survival rate of patients with colorectal cancer (P = 0.0418). Matrix-assisted laser desorption ionization time-of-flight mass spectrometry, si-RNA silencing analysis, enzymatic deglycosylation, and tunicamycin treatment revealed that 12G5A recognized the glycosylated epitope on annexin A2 protein. Our findings indicate that 12G5A identified a cancer-associated glycosylation epitope on annexin A2, whose expression was related to unfavorable colorectal cancer behavior. KEY MESSAGE: • 12G5A monoclonal antibody recognized a colorectal cancer-associated epitope. • 12G5A antibody recognized the N-linked glycosylation epitope on annexin A2. • 12G5A immunoreactivity was related to unfavorable colorectal cancer behavior., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Although ribosome-profiling and translation initiation sequencing (TI-seq) analyses have identified many noncanonical initiation codons, the precise detection of translation initiation sites (TISs) remains a challenge, mainly because of experimental artifacts of such analyses. Here, we describe a new method, TISCA (TIS detection by translation Complex Analysis), for the accurate identification of TISs. TISCA proved to be more reliable for TIS detection compared with existing tools, and it identified a substantial number of near-cognate codons in Kozak-like sequence contexts. Analysis of proteomics data revealed the presence of methionine at the NH2-terminus of most proteins derived from near-cognate initiation codons. Although eukaryotic initiation factor 2 (eIF2), eIF2A and eIF2D have previously been shown to contribute to translation initiation at near-cognate codons, we found that most noncanonical initiation events are most probably dependent on eIF2, consistent with the initial amino acid being methionine. Comprehensive identification of TISs by TISCA should facilitate characterization of the mechanism of noncanonical initiation., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Rationale: Anti-PD-1 antibody is the standard therapy for treatment-resistant gastric cancer, but only a limited number of patients respond. Additionally, cases of hyper-progressive disease (HPD) in which tumor growth accelerates after anti-PD-1 antibody administration have been reported; however, the biological mechanism has not been elucidated., Patient Concerns: In the present case, metastatic gastric cancer was treated with the anti-PD-1 antibody, nivolumab, as third-line treatment., Diagnosis: After the initiation of nivolumab therapy, a rapidly enlarging para-aortic lymph nodes were observed leading to the diagnosis of HPD., Interventions: Multiplex immunohistochemistry was used to examine immune cells infiltrating in the primary tumor and in liver metastasis which were obtained before nivolumab treatment, and in lymph node metastasis which presented with HPD after nivolumab therapy., Outcomes: In the primary tumor, helper T (Th) cells, cytotoxic T lymphocytes (CTLs), regulatory T (Treg) cells, and PD-L1-negative macrophages were observed. On the other hand, in metastatic lymph nodes presenting with HPD, PD-L1-positive macrophages prominently increased, while Treg cells, CTLs, and Th cells decreased. PD-L1 expression was not observed in gastric cancer cells among the three specimens., Lessons: The findings suggest the possibility that PD-L1-positive M2 macrophage might contribute to acceleration of tumor growth with anti-PD-1 therapy in the present case., Competing Interests: The remaining authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

LDLR-related protein 1B (LRP1B) is believed to internalize ligands through receptor-mediated endocytosis. Previous epigenetic and genetic studies have indicated that impaired LRP1B mRNA expression might be related to gastric carcinogenesis. However, expression and prognostic significance of LRP1B protein remain to be elucidated. This study aimed to unravel the clinicopathological characteristics of LRP1B protein expression in gastric cancer. Immunohistochemical staining with antibodies specific to LRP1B peptide, which has an EXXXLL motif-containing region in the C-terminal flexible loop for intracellular sorting, was performed with 100 gastric cancer tissue specimens. Out of 100 tissue specimens, 45 exhibited cytoplasmic localization of LRP1B immunoreactivity. This cytoplasmic localization of LRP1B was significantly higher (P = 0.044) in intestinal-type gastric cancer (25 of 44) than in diffuse-type gastric cancer (20 of 56). Notably, cytoplasmic LRP1B immunoreactivity was significantly associated with low clinicopathological stage and favorable prognosis of patients with diffuse-type gastric cancer (P = 0.014), but nor with intestinal-type gastric cancer (P = 0.994). Multivalent analysis revealed that cytoplasmic LRP1B immunoreactivity had an independent favorable prognostic value in diffuse-type gastric cancer (P = 0.046; hazard ratio 3.058, 95% confidence interval 1.022-9.149). In contrast, no significant relation of cytoplasmic LRP1B immunoreactivity to patients' prognosis was found in intestinal-type gastric cancer. Double immunocytochemical staining demonstrated that cytoplasmic LRP1B was co-localized with RAB11FIP1, which constituted the endocytic recycling compartments in diffuse-type gastric cancer cells. The findings of this study indicated that impaired endocytosis of the cytoplasmic domain of LRP1B, resulting in insufficient ligand internalization, is related to poor prognosis of patients with diffuse-type gastric cancer.

Overexpression of Cleft Lip and Palate Transmembrane 1-Like (Clptm1L) confers cancer cell survival through the endoplasmic reticulum (ER) stress survival signaling pathway, while TMEM207 impairs the tumor suppressor function of WW domain containing oxidoreductase (WWOX), which sensitizes cancer cells to ER stress-induced apoptosis. In the present study, we examined whether these two ER stress-related proteins, Clptm1L and TMEM207, could be prognostic markers in oral squamous cell carcinoma (OSCC). Immunohistochemical staining using specific antibodies to Clptm1L or TMEM207 revealed that 31 of 89 tissue specimens exhibited concomitant expression of Clptm1L and TMEM207 at the cancer invasion front. A Kaplan-Meier plot of the patient survival curve followed by a log-rank test revealed that the coexpression of Clptm1L and TMEM207 was significantly associated with poor outcome in patients with OSCC ( P = 0.00252). Coexpression of Clptm1L and TMEM207 was closely related to lymph node metastasis ( P =0.000574). Both univariate and multivariate analyses demonstrated that coexpression of Clptm1L and TMEM207 predicted the poor prognosis of the patients with OSCC. The present study indicated that the double positive Clptm1L and TMEM207 immunoreactivity was closely related to lymph node metastasis with prognostic value in patients with OSCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hano, Hatano, Saigo, Kito, Shibata and Takeuchi.)

This study was designed to unravel the pathobiological role of impaired ARID1A expression in gastric carcinogenesis. We examined ARID1A expression immunohistochemically in 98 gastric cancer tissue specimens with regard to the clinicopathological features. Based on the proportion and intensity of ARID1A immunoreactivity at the cancer invasion front, we subdivided the specimens into low- and high-expression ARID1A groups. Notably, low ARID1A expression was significantly correlated with overall survival of the patients. Subsequently, we determined the molecular signature that distinguished ARID1A low/poor prognosis from ARID1A high/good prognosis gastric cancers. A comprehensive gene profiling analysis followed by immunoblotting revealed that a mitochondrial apoptosis mediator, Harakiri, was less expressed in ARID1A low/poor prognosis than ARID1A high/good prognosis gastric cancers. siRNA-mediated ARID1A downregulation significantly reduced expression of the Harakiri molecule in cultured gastric cancer cells. Interestingly, downregulation of ARID1A conferred resistance to apoptosis induced by the mitochondrial metabolism inhibitor, devimistat. In contrast, enforced Harakiri expression restored sensitivity to devimistat-induced apoptosis in ARID1A downregulated gastric cancer cells. The present findings indicate that impaired ARID1A expression might lead to gastric carcinogenesis, putatively through gaining resistance to the Harakiri-mediated apoptosis pathway.

Lenvatinib is a standard molecular targeted agent for the first-line treatment of unresectable hepatocellular carcinoma. Here, we report a case of colitis induced by Lenvatinib treatment in a patient with hepatocellular carcinoma. A 78-year-old man previously treated with Lenvatinib for unresectable hepatocellular carcinoma was admitted to our hospital complaining of right lateral abdominal pain without diarrhea. Our endoscopic findings showed multiple ulcers and erosions on his ascending colon, and he was diagnosed with colitis induced by Lenvatinib treatment. After the discontinuation of Lenvatinib, his colitis improved, and he resumed Lenvatinib at a lower dose. Colitis is a rare adverse event of Lenvatinib, and this is the first detailed report of colitis induced by Lenvatinib with endoscopic findings.

S-1 plus docetaxel is the standard postoperative adjuvant chemotherapy regimen for patients with stage III gastric cancer in Japan, which has increased the use of docetaxel. One of the most common adverse events of docetaxel, which is widely used to treat several malignancies, is fluid retention. Conversely, the most worrisome cause of ascites in patients who receive adjuvant chemotherapy is recurrence. Sometimes, the differential diagnosis of ascites is difficult if ascitic cytology is negative. In this study, we presented the case of a patient with massive ascites that appeared during adjuvant chemotherapy with S-1 plus docetaxel.

Background: Primary central nervous system lymphoma is a rare extra-nodal lymphoma of the central nervous system. Primary central nervous system lymphoma lesions usually appear in the vicinity of the ventricle, and there are few reports of primary central nervous system lymphoma with hypothalamic-pituitary lesions., Case Presentation: We treated a 56-year-old male with primary central nervous system lymphoma with the primary lesion in the hypothalamus, which was found by magnetic resonance imaging after sudden onset of endocrinological abnormalities. Initially, he was hospitalized to our department for hyponatremia. Endocrinological examination in conjunction with head magnetic resonance imaging and endoscopic biopsy revealed hypothalamic hypopituitarism and tertiary hypoadrenocorticism caused by a rapidly growing, diffuse large B-cell lymphoma in the hypothalamus. Remission of the tumor was achieved by high-dose methotrexate with whole brain radiotherapy, and some of the hormone responses were normalized., Conclusions: While primary central nervous system lymphoma is rare, it is important to note that hypopituitarism can result and that the endocrinological abnormalities can be partially restored by its remission.

Objectives: To determine the usefulness of the pneumococcal urinary antigen test (PUT) and to describe the characteristics of pneumococcal pneumonia., Methods: In this retrospective study, we examined the effects of prior antibiotic treatment, pneumonia onset period, and sputum quality on the results of PUT. Clinical information was collected via medical records from all adult patients who were hospitalized at the Fujita Health University Bantane Hospital with "pneumonia" as a new diagnosis from April 2015 to March 2018., Results: A total of 482 patients with pneumonia were included, of whom 103 had pneumococcal pneumonia. The frequency of PUT positivity did not differ significantly in patients with a pneumonia onset period of ≥3 days compared with those with a period of ≤2 days ( P =0.514). Patients with a history of prior antimicrobial therapy had a significantly lower rate of positive sputum culture vs those with no such history ( P =0.005); however, PUT positivity in the two groups did not differ significantly ( P =0.367)., Conclusions: Our results showed that urinary antigen testing for pneumococcal pneumonia is useful for diagnosis regardless of prior antibiotic treatment and time since symptom onset., Competing Interests: The authors declare no conflicts of interest associated with this manuscript.

Clear cell sarcoma (CCS) affects the deep soft tissues in young adults and is known to have high rates of metastasis, including lymphatic metastasis. In our previous study an xenoplant model of CCS was established, which exhibited local tumor growth, lymphatic metastasis, and distant metastasis in SCID-Beige mice. In the current study, the role of NK cells during metastasis in the same xenoplant murine model was investigated. Injection of murine or human NK cells significantly suppressed the metastasis of HS-MM CCS cells in SCID-Beige mice. Notably, reverse transcription-quantitative PCR analysis demonstrated that injection of NK cells did not alter the mRNA expression levels of ERSR1-ATF1 , which is specifically transcribed in CCS, in the buffy coat of circulating blood cells of HS-MM-xenoplanted SCID-Beige mice. BALB/c nude mice xenoplanted with HS-MM cells exhibited local growth without evident metastasis, whereas inoculation with the anti-asialo-GM1 antibody, which has previously been found to abolish NK-cell activity, resulted in metastasis of HS-MM cells in BALB/c nude mice. The injection of the anti-CD96 antibody, which increases the cytotoxicity of NK cells, significantly suppressed the metastasis of HS-MM cells in SCID-Beige mice. These results indicated that NK cells impaired the metastatic tumor microenvironments in the present mice xenoplant model., (Copyright: © Hanamatsu et al.)

Background and study aims  We aimed to evaluate the diagnostic performance of magnifying endoscopy with narrow-band imaging (M-NBI) in superficial non-ampullary duodenal epithelial tumors (SNADETs) regarding the absence or presence of biopsy before M-NBI diagnosis. Patients and methods  Clinicopathological data were retrospectively reviewed for 99 SNADETs from 99 patients who underwent endoscopic resection. The 99 tumors were divided into the non-biopsy group (32 lesions not undergoing biopsy before M-NBI examination) and the biopsy group (67 lesions undergoing biopsy before M-NBI examination). We investigated the correlation between the M-NBI diagnosis and the histopathological diagnosis of the SNADETs in both groups. Results  According to the modified revised Vienna classification, 31 tumors were classified as category 3 (C3) (low-grade adenoma) and 68 as category 4/5 (C4/5) (high-grade adenoma/cancer). The accuracy, sensitivity, and specificity of preoperative M-NBI diagnoses in the non-biopsy group vs the biopsy group were 88 % (95 % confidence interval: 71.0 - 96.5) vs 66 % (51.5 - 75.5), P  = 0.02; 95 % (77.2 - 99.9) vs 89 % (76.4 - 96.4), P  = 0.39; and 70 % (34.8 - 93.3) vs 14 % (3.0 - 36.3), P  < 0.01, respectively. Notably, in the biopsy group, the specificity of M-NBI in SNADETs was low at only 14 % because we over-diagnosed most C3 lesions as C4/5. M-NBI findings might have been compromised by the previous biopsy procedure itself. Conclusions  In the non-biopsy group, the accuracy of M-NBI in SNADETs was excellent in distinguishing C4/5 lesions from C3. The M-NBI findings in SNADETs should be evaluated while carefully considering the influence of a previous biopsy., Competing Interests: Competing interests The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Patients with advanced gastric cancer, especially diffuse-type gastric cancer, which is often accompanied by stromal fibrosis, commonly exhibit a poor prognosis. This study was designed to unravel the potential roles of C1q/TNF-related protein 6 (CTRP6) in the fibrotic cancer microenvironment of diffuse-type gastric adenocarcinoma. A total of 49 diffuse-type gastric cancer samples were evaluated in this study, and 23 of these samples exhibited focal CTRP6 immunoreactivity. CTRP6 immunoreactivity was found to be correlated with favorable survival outcomes, in terms of both overall and relapse-free survival rates, but this trend did not reach significance ( P = 0.15). By contrast, CTRP6 immunoreactivity was significantly correlated with relapse-free survival rates in patients with diffuse-type gastric cancer at a distal site ( P = 0.028). Notably, most gastric cancer cells at the cancer invasive front were CTRP6 negative, especially in areas of robust fibrosis. Double immunohistochemical staining demonstrated an inverse expression profile for CTRP6 and the activated fibroblast marker alpha smooth muscle actin (α-sma) in stromal and gastric cancer cells at the cancer invasion front. The addition of recombinant CTRP6 protein attenuated the TGF-β-induced α-sma expression in cultured human fibroblasts but did not alter the proliferation rate or Matrigel-invasion activity of the cultured gastric cancer cells. In addition, CTRP6 did not affect the viability of normal human gastric epithelial cells. This study suggests that CTRP6 may have potential application in combating stromal fibrosis in diffuse-type gastric cancers., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

A 38-year-old man visited our hospital with a complaint of diarrhea and abdominal pain. Contrast-enhanced computed tomography showed that the ileocecal site was intussuscepted to the transverse colon without ischemia. After we reduced intussusception with an enema using a water-soluble contrast agent, his abdominal pain disappeared. Colonoscopy was performed immediately after reduction and showed erosion and edema at the ileocecal site without tumor. The stool culture at admission revealed verotoxin 1 producing Escherichia coli O-26;therefore, we established a diagnosis of intussusception associated with Escherichia coli enterocolitis. Bacterial enteritis should be considered as a potential cause in adult patients with intussusception.

Colonic diverticular bleeding often recurs and requires hospital readmission. This study aimed to examine the relationship between the rate of readmission and the number of hospitalizations due to colonic diverticular bleeding. We retrospectively studied 98 patients first admitted between January 2008 and July 2017 for the treatment of colonic diverticular bleeding. We investigated the subsequent number of hospitalizations due to colonic diverticular bleeding and classified the patients into 3 groups:those admitted for the first time (first group), those admitted for the second time (second group), and those admitted for the third time or later (third group). Generally, the readmission rate increased as the number of hospitalizations increased (P<0.01). The 1-year readmission rates were 11.6%, 23.2%, and 34.2% in the first, second, and third groups, respectively. The 2-year readmission rates were 15.1%, 50.1%, and 62.4% in the first, second, and third groups, respectively. The 3-year readmission rates were 21.7%, 50.1%, and 74.9% in the first, second, and third groups, respectively. Thus, the number of hospitalizations due to colonic diverticular bleeding could be a predictive factor for readmission. We also classified the patients into 2 additional groups:those who had been readmitted (readmission group) and those who had not (no readmission group). Furthermore, we examined background and therapeutic factors, and found hypovolemic shock on admission to be an independent risk factor (odds ratio 14.1). Preventive treatments for such high-risk patients should be considered.

Background: White globe appearance (WGA) is a small white lesion with a globular shape identified during magnifying endoscopy with narrow-band imaging. However, the association between WGA and synchronous multiple gastric cancer (SMGC) remains unclear., Methods: Consecutive patients who underwent endoscopic submucosal dissection for gastric cancer (GC) between July 2013 and April 2015 at our institution were eligible for this study. We excluded patients with a history of gastric tumor or gastrectomy. Patients who had more than 2 GCs in their postoperative pathological evaluation were classified as SMGC-positive, and patients who had at least 1 WGA-positive GC were classified as WGA-positive patients. The primary outcome was a comparison of the prevalence of WGA in patients classified as SMGC-positive and SMGC-negative. Univariate and multivariate analyses were performed using the following variables: WGA, age, sex, atrophy, and Helicobacter pylori ( H. pylori ) status., Results: There were 26 and 181 patients classified as SMGC-positive and SMGC-negative, respectively. Univariate analysis revealed that WGA-positive classification (50% vs. 23%, P=0.008) and male sex (88% vs. 66%, P=0.02) were significant factors associated with SMGC classification, while age ≥65 years (81% vs. 81%, P>0.99), severe atrophy (46% vs. 46%, P>0.99), and H. pylori positivity (69% vs. 65%, P=0.8) were not. In the multivariate analysis, only WGA-positive classification (odds ratio 2.78, 95% confidence interval 1.16-6.67; P=0.02) was a significant independent risk factor for SMGC., Conclusions: Our exploratory study showed the possibility of WGA as a predictive factor for SMGC. In cases of WGA-positive gastric cancer, careful examination might be needed to diagnose SMGC., Competing Interests: Conflict of Interest: None, (Copyright: © 2021 Hellenic Society of Gastroenterology.)

CXCL12, also known as stromal cell-derived factor-1, is a chemokine classified into CXC families, which exerts its function by binding to specific receptors called CXCR4 and CXCR7. Human platelets express CXCR4 and CXCR7 on the plasma membrane. It has been reported that CXCL12 potentiates to induce platelet aggregation in cooperation with agonists including collagen. However, the precise roles and mechanisms of CXCL12 in human platelet activation are not fully elucidated. In the present study, we investigated the effect of simultaneous stimulation with low doses of collagen and CXCL12 on the activation of human platelets. The simultaneous stimulation with collagen and CXCL12 induced the secretion of platelet-derived growth factor (PDGF)-AB and the release of soluble CD40 ligand (sCD40L) from human platelets in addition to their aggregation, despite the fact that the simultaneous stimulation with thrombin receptor-activating peptide (TRAP) or adenosine diphosphate (ADP), and CXCL12 had little effects on the platelet aggregation. The agonist of Glycoprotein (GP) Ⅵ convulxin and CXCL12 also induced platelet aggregation synergistically. The monoclonal antibody against CXCR4 but not CXCR7 suppressed the platelet aggregation induced by simultaneous stimulation with collagen and CXCL12. The phosphorylation of p38 mitogen-activated protein kinase (MAPK), but not p44/p42 MAPK, was induced by the simultaneous stimulation. In addition, the simultaneous stimulation with collagen and CXCL12 induced the phosphorylation of HSP27 and the subsequent release of phosphorylated-HSP27 from human platelets. SB203580, a specific inhibitor of p38 MAPK, attenuated the platelet aggregation, the phosphorylation of p38 MAPK and HSP27, the PDGF-AB secretion, the sCD40L release and the phosphorylated-HSP27 release induced by the simultaneous stimulation with collagen and CXCL12. These results strongly suggest that collagen and CXCL12 in low doses synergistically act to induce PDGF-AB secretion, sCD40L release and phosphorylated-HSP27 release from activated human platelets via p38 MAPK activation., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Ramucirumab, an anti-vascular endothelial growth factor (VEGF) receptor2 monoclonal antibody, inhibits VEGF-A, VEGF-C, and VEGF-D binding and endothelial cell proliferation. We conducted a phase Ib study to determine the recommended phase II dose (RP2D) of fluorouracil, l-leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus ramucirumab., Methods: This phase Ib study investigated three dose levels of FOLFOXIRI plus ramucirumab (three dose levels of irinotecan and fluorouracil with fixed dose of oxaliplatin 85 mg/m 2 and ramucirumab 8 mg/kg on day 1, repeated every 2 weeks) in chemotherapy-naïve patients with metastatic colorectal cancer (mCRC). Dose-limiting toxicity (DLT) was assessed during the first cycle., Results: A total of ten patients were enrolled. The first four patients received the treatment at dose level 0 (irinotecan 150 mg/m 2 and fluorouracil 2400 mg/m 2 ), and subsequent six patients were treated at dose level 1 (irinotecan 165 mg/m 2 and fluorouracil 3200 mg/m 2 ). No DLT was observed in the nine DLT-evaluable patients, which indicated that the RP2D was dose level 1. Grade 3 or worse adverse events included neutropenia (70%), hypertension (20%), and febrile neutropenia (10%). No treatment-related death was observed in any cycle. The overall response rate was 70%., Conclusion: The RP2D of FOLFOXIRI plus ramucirumab was determined to be 8 mg/kg of ramucirumab, 165 mg/m 2 of irinotecan, 85 mg/m 2 of oxaliplatin, 200 mg/m 2 of l-leucovorin, and 3200 mg/m 2 of fluorouracil., Trial Registration Number: UMIN000023277.

Objective Cigarette smoking is a risk factor for arteriopathy, including acute coronary syndrome, stroke and peripheral vascular disease. Thus, cessation is strongly recommended in order to reduce these risks. We recently demonstrated that smoking cessation causes temporary hyper-aggregability of human platelets. We previously showed that heat shock protein 27 (HSP27) is released from human platelets stimulated by collagen, accompanied by its phosphorylation. Accumulating evidence indicates potent roles of extracellular HSP27 as a modulator of inflammation. In the present study, using the stored samples obtained in the previous study, we investigated the effect of cigarette smoking cessation on the release of phosphorylated-HSP27 from collagen-activated human platelets (n=15 patients). Methods We enrolled patients who visited smoking cessation outpatient services between January 2012 and November 2014. Platelet-rich plasma, chronologically obtained before and after the cessation, was stimulated by collagen using a PA-200 aggregometer in the previous study. The levels of phosphorylated-HSP27 released from platelets were determined by an enzyme-linked immunosorbent assay. The phosphorylation of HSP27 in platelets was evaluated by a Western blot analysis. Results Cessation of cigarette smoking significantly upregulated the levels of collagen-stimulated release of phosphorylated-HSP27 at four and eight weeks after quitting smoking compared to before cessation. However, there was no significant difference between the levels before cessation and those at 12 weeks after cessation. The levels of phosphorylated-HSP27 stimulated by collagen in the platelets at four weeks after smoking cessation were remarkably enhanced compared to before cessation. Conclusion Cigarette smoking cessation temporarily enhances the collagen-stimulated release of phosphorylated-HSP27 from human platelets in the short term.

Prosthetic hands are developed to replace lost hands. However, it has been hard to ensure the same level grasping and manipulating objects as human hands and the cosmetic appearance is also important. In a previous work, Rehand II: an electric and cosmetic prosthetic hand was developed. Its function is limited to simple object grasping, but it has the cosmetic appearance and is relatively light. This paper aimed to improve Rehand II by introducing tactile sense. Tactile sense is available to detect physical contact, recognize physical attributes of objects such as their softness and texture, and ensure delicate operation while handling the objects. Additionally, tactile sense is relevant to build the body recognition. We focused on vibrotactile sense from the aspects of a wide receptive field, contribution to contact detection and various frequency information involved. A simple electric and cosmetic prosthetic hand with vibrotactile sense was developed by improving Rehand II with polyvinylidene difluoride film sensors for detecting skin-propagated vibrations and soft vibrators for the feedback. The sensors were embedded at the thumb, index finger, and back of the hand of the prosthetic hand. First, recognition tests involving tapped part were conducted. Then, recognition and realistic rating tests involving operations were conducted. Results showed high recognition of tapped parts and operations and the good realistic.

An integrative understanding of nuclear events including transcription in normal and cancer cells requires comprehensive and quantitative measurement of protein dynamics that underlie such events. However, the low abundance of most nuclear proteins hampers their detailed functional characterization. We have now comprehensively quantified the abundance of nuclear proteins with the use of proteomics approaches in both normal and transformed human diploid fibroblasts. We found that subunits of the 26S proteasome complex were markedly down-regulated in the nuclear fraction of the transformed cells compared with that of the wild-type cells. The intranuclear proteasome abundance appeared to be inversely related to the rate of cell cycle progression, with restraint of the cell cycle being associated with an increase in the amount of proteasome subunits in the nucleus, suggesting that the nuclear proteasome content is dependent on the cell cycle. Furthermore, chromatin enrichment for proteomics (ChEP) analysis revealed enrichment of the proteasome in the chromatin fraction of quiescent cells and its apparent dissociation from chromatin in transformed cells. Our results thus suggest that translocation of the nuclear proteasome to chromatin may play an important role in control of the cell cycle and oncogenesis through regulation of chromatin-associated transcription factors.

Transcriptome data revealed α1 adrenoceptors (ARs) expression in platelet-derived growth factor receptor α + cells (PDGFRα + cells) in murine colonic musculature. The role of PDGFRα + cells in sympathetic neural regulation of murine colonic motility was investigated. Norepinephrine (NE), via α1A ARs, activated a small conductance Ca 2+ -activated K + (SK) conductance, evoked outward currents and hyperpolarized PDGFRα + cells (the α1A AR-SK channel signal pathway). α1 AR agonists increased intracellular Ca 2+ transients in PDGFRα + cells and inhibited spontaneous phasic contractions (SPCs) of colonic muscle through activation of a SK conductance. Sympathetic nerve stimulation inhibited both contractions of distal colon and propulsive contractions represented by the colonic migrating motor complexes (CMMCs) via the α1A AR-SK channel signal pathway. Postsynaptic signaling through α1A ARs in PDGFRα + cells is a novel mechanism that conveys part of stress responses in the colon. PDGFRα + cells appear to be a primary effector of sympathetic neural regulation of murine colonic motility., (© 2020 Federation of American Societies for Experimental Biology.)

Objectives: JAG2 is one of Notch ligands, which recently appear to exert various carcinogenesis. In the present study, we aimed to unveil the relation of JAG2 expression and clinicopathological features in oral squamous cell carcinoma (OSCC)., Materials and Methods: We examined JAG2 expression in OSCC plus adjacent nontumorous epithelia in eight patients. Ninety-one OSCC tissue specimens were immunohistochemically stained with specific antibodies to JAG2. The immunoreactivities of JAG2 were correlated with clinicopathological factors, including the prognosis of patients. Chi-square test, Kaplan-Meier survival, and Cox proportional hazard analysis were used to determine the statistical value of JAG2 expression in OSCC., Results: JAG2 mRNA expression was much expressed in OSCC tissues compared with adjacent tissue specimens in five of eight patients. JAG2 immunoreactivity was found at invasion front in 31 of 91 OSCC. JAG2 immunoreactivity was significantly associated with age, less than 50 years old of patients (P = .048). Kaplan-Meier analysis demonstrated that the patients with JAG2 immunoreactvty have a short overall survival. With the Cox proportional hazard regression mode, the independent factors predictive of poor overall survival included JAG2 immunoreactivity (P < .05)., Conclusions: The present findings suggest that JAG2 overexpression, especially at the cancer invasion front, has potential prognostic value., (© 2019 The Authors. Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.)

Purpose: To clarify the clinical usefulness of breath-hold compressed sensing three-dimensional magnetic resonance cholangiopancreatography (BH-MRCP) added to conventional respiratory-gating MRCP (RG-MRCP), we prospectively evaluated the image quality of BH-MRCP and compared it with that of RG-MRCP. We also evaluated to what extent the overall image quality was improved by adding BH-MRCP to RG-MRCP., Materials and Methods: A total of 113 patients who underwent RG-MRCP and BH-MRCP at a 3-T MR unit were enrolled. We set a scan time of approximately 180 s for RG-MRCP and 20 s for BH-MRCP before examination, and measured actual scan time and assessed image quality using a 5-point scale (5, good; 1, poor). Image quality scores of 1, 2 and 3 were considered clinically inadequate. Image quality scores of RG-MRCP and BH-MRCP were compared. In addition, we compared "RG-MRCP alone" and "hybrid MRCP" (the best-scoring image was picked from RG-MRCP and BH-MRCP when the RG-MRCP score was clinically inadequate)., Results: The mean actual scan time of RG-MRCP/BH-MRCP was 191/20 s. The mean scores of RG-MRCP, BH-MRCP and hybrid MRCP were 3.67, 3.35 and 3.92, respectively. The score of hybrid MRCP was significantly better than that of RG-MRCP (P <  0.05). The image quality of RG-MRCP was clinically inadequate in 43/113 (38 %) cases and the inadequate image quality was improved to be clinically adequate in 13/43 (30 %) cases by adding BH-MRCP., Conclusion: BH-MRCP brings added value to RG-MRCP because an additional examination of BH-MRCP could compensate for the image deterioration of RG-MRCP caused by motion artifacts., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background & Aims: Colonic musculature contain smooth muscle cells (SMC), interstitial cells of Cajal (ICC), and platelet-derived growth factor receptor α + cells (PDGFRα + cells), which are electrically coupled and operate together as the SIP syncytium. PDGFRα + cells have enriched expression of small conductance Ca 2+ -activated K + (SK) channels. Purinergic enteric neural input activates SK channels in PDGFRα + cells, hyperpolarizes SMC, and inhibits colonic contractions. Recently we discovered that PDGFRα + cells in mouse colon have enriched expression of α1A adrenoceptors (ARs), which coupled to activation of SK channels and inhibited colonic motility, and α1A ARs were principal targets for sympathetic regulation of colonic motility. Here we investigated whether PDGFRα + cells in human colon express α1A ARs and share the roles as targets for sympathetic regulation of colonic motility., Methods: Isometric tension recording, intracellular recording, and Ca 2+ imaging were performed on muscles of the human colon. Responses to α1 ARs agonists or electric field stimulation with AR antagonists and neuroleptic reagents were studied., Results: Exogenous or endogenous norepinephrine released from nerve fibers inhibited colonic contractions through binding to α1A ARs or enhanced colonic contractions by acting on α1D ARs. Inhibitory responses were blocked by apamin, an antagonist of SK channels. Phenylephrine, α1 AR agonists, or norepinephrine increased intracellular [Ca 2+ ] in PDGFRα + cells, but not in ICC, and hyperpolarized SMCs by binding to α1 ARs expressed by PDGFRα + cells., Conclusions: Human colonic contractions are inhibited by α1A ARs expressed in PDGFRα + cells and activated by α1D ARs expressed in SMC., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a diagnosis of exclusion, being the most common entity in mature T-cell neoplasms, and its molecular pathogenesis remains significantly understudied. Here, combining whole-exome and targeted-capture sequencing, gene-expression profiling, and immunohistochemical analysis of tumor samples from 133 cases, we have delineated the entire landscape of somatic alterations, and discovered frequently affected driver pathways in PTCL, NOS, with and without a T-follicular helper (TFH) cell phenotype. In addition to previously reported mutational targets, we identified a number of novel recurrently altered genes, such as KMT2C, SETD1B, YTHDF2, and PDCD1. We integrated these genetic drivers using hierarchical clustering and identified a previously undescribed molecular subtype characterized by TP53 and/or CDKN2A mutations and deletions in non-TFH PTCL, NOS. This subtype exhibited different prognosis and unique genetic features associated with extensive chromosomal instability, which preferentially affected molecules involved in immune escape and transcriptional regulation, such as HLA-A/B and IKZF2. Taken together, our findings provide novel insights into the molecular pathogenesis of PTCL, NOS by highlighting their genetic heterogeneity. These results should help to devise a novel molecular classification of PTCLs and to exploit a new therapeutic strategy for this group of aggressive malignancies.

Transmembrane protein 207 (TMEM207) is an important molecule involved in invasiveness of gastric signet ring cell carcinoma. To understand the pathobiological effects of TMEM207, we generated thirteen transgenic mouse lines, designated C57BL/6-Tg (ITF-TMEM207), where mouse TMEM207 is expressed heterotrophically, regulated by the proximal promoter of the murine intestinal trefoil factor ( ITF ) gene (also known as Tff3 ). A C57BL/6-Tg (ITF-TMEM207) mouse line unexpectedly exhibited a high incidence of a spontaneous condition resembling myeloproliferative disease-like phenotype. Increased numbers of CD117+ cells and appearance of dysplastic myeloid cells in bone marrow were observed. These histopathological features suggested human myeloproliferative disease or its precursor manifestations, and were found in almost all mice within 1 year. TMEM207 immunoreactivity was identified in megakaryocytes and erythroblasts of the transgenic mice. The ITF-TMEM207 construct was inserted into Atg4b on murine chromosome 1. Myeloproliferative disease was not observed in other C57BL/6-Tg (ITF-TMEM207) transgenic mouse lines. However, although several other genetically manipulated animal models of myeloproliferative disease and Atg4b knockout mice exist, this mouse line harboring a mutated Atg4b gene, and with overexpression of TMEM207 protein, has not been reported as a model of myeloproliferative disease to date. The present study demonstrated that the C57BL/6-Tg (ITF-TMEM207) mouse may be a valuable model for improved understanding of human myeloproliferative disease., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

It is firmly established that smoking is a risk factor of cardiovascular disease, stroke and peripheral vascular disease. Although smoking alters the hemostatic process, the influence of smoking on human platelet activation remains controversial. For patients undergoing surgery, cessation of smoking prior to the procedure is recommended as it increases the risk of postoperative morbidity or mortality. The presented study investigated the effects of smoking cessation on human platelet activation induced via collagen (n=19 patients). Blood samples were taken on four occasions: Before smoking cessation, and at 4, 8 and 12 weeks after smoking cessation. Platelet aggregation using citrated platelet-rich plasma (PRP) was monitored using a PA-200 aggregometer, which determined the size of platelet aggregates using laser scattering methods. A low dose of collagen (1 µg/ml) accelerated platelet aggregation at 4 or 8 weeks after smoking cessation when compared with results before cessation. After 12 weeks, levels of platelet aggregation induced by collagen were almost equal to those recorded prior to smoking cessation. The secretion levels of collagen-induced platelet-derived growth factor (PDGF)-AB at 4 or 8 weeks after smoking cessation were significantly higher than those before smoking was stopped. Furthermore, smoking cessation markedly strengthened the collagen-induced phosphorylation of p38 mitogen-activated protein (MAP) kinase after 4 weeks. The results of the current study indicated that smoking cessation causes temporary short-term human platelet hyper-activation. The further suggest that the incidence of complications due to human platelet hyper-reactivity may be lowered by considering the period of smoking abstinence., (Copyright: © Kito et al.)

C1q/tumor necrosis factor-related protein-6 (CTRP6), also known as CTRP6 is identified adiponectin paralog. Although recent studies have revealed that adiponectin has an inhibitory role in carcinogenesis, the role of CTRP6 in carcinogenesis remains unclear. In this study, we found that eukaryotic recombinant CTRP6 protein bound to the cell surface membrane of cultured oral squamous cell carcinoma cells by immunofluorescence staining. Screening of CTRP6 binding protein in expression library followed by co-immunoprecipitation assay revealed that CTRP6 bound to the precursor of laminin receptor. CTRP6 disturbed the binding of laminin to the laminin receptor. Interestingly, the eukaryotic recombinant CTRP6 protein significantly suppressed the proliferation and Matrigel invasion activity of oral squamous cell carcinoma SAS cells in a dose-dependent manner. Moreover, administration of CTRP6 significantly attenuated the growth of SAS cells in xenoplant mice model. Laminin and laminin receptor are known to be overexpressed and promote the tumor growth in OSCC. Combined together, the present findings suggest that CTRP6 could repress progression of oral squamous cell carcinoma cells, putatively through disrupting the laminin-laminin receptor axis.

A 48-year-old woman with advanced gastric cancer with peritoneal dissemination was treated with weekly paclitaxel from October 2015 and was then administered the CapeOX regimen. Although she had no adverse event during the 2-hour administration of the first oxaliplatin(L-OHP), sudden wheezing, subsequent decrease in blood pressure, and vomiting occurred after completing the administration. After intravenous injection of epinephrine(1mg)and drip infusion of methylprednisolone( 500mg), she received continuous administration of norepinephrine for 5 days. Hypersensitivity reaction to LOHP typically occurs after several cycles and within 30 minutes of starting the administration. However, we have to recognize that the hypersensitivity can also occur after the first cycle and at a later onset.

Cluster of differentiation 151 (CD151) is a potent therapeutic target for regulating tumor metastasis. In the present study, the role of CD151 in clear cell sarcoma of soft tissue was examined using a xenoplanted tumor model, which had high rates of metastasis. A clear cell sarcoma cell line, HS-MM, which was transplanted to the aponeuroses of the thighs, the most affected sites of human clear cell sarcoma, exhibited robust lymphatic invasion and nodal metastasis in SCID-beige mice. Serial in vivo passaging of peritoneally disseminated tumor cells accelerated the metastatic activity, which was accompanied by increased CD151 expression, and were designated as HS-MM high . Notably, inoculation of anti-CD151 antibody significantly suppressed the lymphatic invasion, peritoneal dissemination and distant metastasis of the present clear cell sarcoma model without affecting local tumor growth at the transplantation site. Small interfering RNA (siRNA)-mediated downregulation of CD151 did not alter cell proliferation, but significantly inhibited Matrigel invasion activity of HS-MM high cells. Downregulation of CD151 impaired matrix metalloproteinase-9 activity and phosphorylation of SMAD3 protein in HS-MM high cells. The present results suggest that CD151 may contribute to invasion and metastasis of clear cell sarcoma of soft tissue. Therefore, CD151 may serve as a potent target to regulate metastasis of clear cell sarcoma.

In total hip arthroplasty (THA), it is generally accepted that the bones of the acetabular cup and femur of hip joint must be accurately cut and components (artificial joint parts) be implanted in exact positions at exact angles to achieve improvement of daily living (ADL) and quality of life (QOL). However, with the conventional surgical method, it is difficult to grasp and measure the acetabular cup and femoral stem precisely during surgery, making some kind of reliable guide necessary. Although it was reported that an accurate angle was achieved in acetabular cup implantation by support instruments for surgical planning, an effective support instrument is now being developed for stem implantation on the out-of-reach femur side. This is the first clinical study to assess the efficacy and safety of anterolateral approach THA using an extracorporeal patient-specific femoral guide (PSG) for stem implantation with three-dimensional (3D) surgical support software in patients with hip joint disease.

Purpose: Cleft palate transmembrane protein 1 (Clptm1) and its paralog protein, Cisplatin resistance-related protein 9 (CRR9) constitute a highly conserved protein family, from Caenorhabditis elegans to Homo sapiens. In the present study, we examined the clinicopathological and biological significance of Clptm1 and CRR9 expression in oral squamous cell carcinoma (OSCC)., Methods: Ninety-eight OSCC tissue specimens were immunohistochemically stained with specific antibodies to Clptm1 and CRR9. The immunoreactivity of Clptm1 and CRR9 was then correlated with clinicopathological factors, including the prognosis of patients. siRNA-mediated gene silencing of CRR9 followed by cell proliferation, Matrigel invasion, anoikis assay, and gelatin zymography were performed using cultured OSCC cells. Subsequently, immunohistochemical examination including double staining was performed to determine the correlation between CRR9 and Bcl-xL expression in OSCC cells., Results: Non-tumorous oral squamous cells exhibited vague, weak, or little cytoplasmic staining with anti-Clptm1 and CRR9 antibodies. By contrast, robust Clptm1 and CRR9 immunoreactivity was found at the cancer invasion front in 55 and 54 of the 98 OSCC tissue specimens, respectively. Notably, CRR9 immunoreactivity was associated with more than 5 mm of depth of invasion, poor prognosis of the patients, and smoking habits (P < 0.05). siRNA-mediated gene silencing of CRR9 did not alter the cell proliferation but decreased Matrigel invasion and impaired anoikis resistance in cultured Ca9-22 and SAS cells. CRR9 and anti-apoptotic Bcl-xL expression levels were correlated in pT1 OSCC tissue specimens., Conclusions: Clptm1 and CRR9 were overexpressed in many OSCC tissues. In particular, CRR9 expression may promote tumor development and have a significant poor prognostic value in OSCC, possibly through conferring invasion ability and resistance to apoptotic stimuli possibly related to Bcl-xL expression. CRR9 could be a novel molecular target for patients with OSCC.

LRP1B intracellular domain is released and transported to the nucleus; however, pathological consequences of this nuclear transport are largely unclear. We aimed to unravel the pathobiological significance of nuclear localization of LRP1B intracellular domain in mammary gland carcinogenesis. Immunohistochemical staining using antibodies for LRP1B intracellular domain was performed to determine LRP1B expression in 92 invasive ductal breast carcinomas. LRP1B immunoreactivity was detected in the surface membrane and cytoplasm of 60 of 92 invasive ductal carcinomas and in the nucleus of 15 of 92 carcinomas. Nuclear LRP1B was significantly associated with poor patient prognosis, particularly luminal A type breast cancer, where it was significantly related to nodal metastasis. Doxycycline-dependent nuclear expression of LRP1B intracellular domain was established in cultured breast cancer cells. Enforced nuclear expression significantly increased Matrigel invasion activity in MCF-7 and T47D luminal A breast cancer cells. Moreover, enforced nuclear expression of LRP1B intracellular domain facilitated MCF-7 cells growth in mammary fat pad of nude mice, which was supplemented with estrogen. Comprehensive microarray-based analysis demonstrated that nuclear expression of LRP1B intracellular domain significantly increased long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) expression, which facilitates breast cancer invasion with poor prognosis. Nuclear-localized LRP1B intracellular domain promoted breast cancer progression with poor prognosis, possibly through the NEAT1 pathway. Nuclear transport of LRP1B intracellular domain could be a therapeutic target for breast cancer patients. KEY MESSAGES: Nuclear LRP1B was significantly associated with poor patient prognosis. Nuclear LRP1B increased Matrigel invasion activity of breast cancer cells. Nuclear expression of LRP1B intracellular domain increased NEAT1 expression.

We report the case of a 73-year-old woman with repeated recurrent small intestinal gastrointestinal stromal tumor(GIST) who was referred to our hospital for best supportive care. She underwent surgical resection 4 times and developed recurrent tumors that were resistant to imatinib. She complained of right lower abdominal pain caused by the recurrent tumor. We performed surgical resection of the tumor and the disseminated tumors synchronously. Histopathological findings of the resected specimen revealed a high-risk GIST. After the operation, she was administered sunitinib(50mg/day)as adjuvant therapy according to a 4-week-on/2-week-off schedule. Due to the resulting adverse effects, the schedule was changed to 1-week-on/1-week-off therapy. She showed no sign of recurrence 38months after the last surgery. Thus, surgical resection and adjuvant molecular targeted therapy may be an effective treatment strategy for recurrent GIST.

Purpose: Although oxaliplatin 130 mg/m 2 every 3 weeks was approved for advanced gastric cancer in Japan, data regarding S-1 plus oxaliplatin 130 mg/m 2 (SOX130) are limited in Japanese patients with advanced gastric cancer. We investigated the feasibility and safety of SOX130 in Japanese patients with advanced gastric cancer., Methods: Patients with unresectable or recurrent gastric adenocarcinoma, no previous chemotherapy, and Eastern Cooperative Oncology Group Performance Status of 0-1 were treated with SOX130. The primary endpoint was the 3-cycle completion rate, defined as the proportion of patients who completed the first three cycles with ≥ 80% relative dose intensity of oxaliplatin., Results: Twenty-five patients were enrolled from April 2015 to 2016. The 3-cycle completion rate was 72.0% (90% confidence interval: 53.8-86.1), which was higher than the predetermined threshold rate of 50%. With the median number of cycles being 6 (range, 1-19+), grade 3 or 4 adverse events occurred in 10 patients (40%). Major grade 3 adverse events were anorexia (24%), thrombocytopenia (16%), and neutropenia (12%). No febrile neutropenia or treatment-related deaths occurred. Among 12 patients with measurable lesions, the overall response rate was 58.3%. Median progression-free and overall survival were 5.7 months (95% confidence interval 2.9-8.5) and 13.1 months (95% confidence interval 7.4-19.0), respectively., Conclusion: Results indicated that SOX130 was feasible in Japanese patients with advanced gastric cancer.

Pirarubicin (tetrahydropyranyl adriamycin [THP]) is an anthracyclin with less cardiotoxicity than doxorubicin (DOX). We previously reported the efficacy and safety of R-THP-COP consisting of rituximab (R), THP, cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL) for diffuse large B cell lymphoma (DLBCL) in phase 2 studies. Here, we prospectively compared the efficacy and safety of the R-THP-COP and standard R-CHOP regimen (consisting of R, CPA, DOX, VCR, and PSL) in a noninferiority phase 3 trial. This prospective, randomized phase 3 study included patients younger than 70 years of age with previously untreated DLBCL. The regimen consisted of R (day 1), DOX, or THP (day 3), CPA (day 3), VCR (day 3), and PSL for 5 days every 3 weeks for 6 to 8 cycles. Between July 5, 2006 and June 11, 2013, 81 patients were randomly assigned to the treatment groups (R-CHOP group, 40 patients; R-THP-COP group, 41 patients). R-THP-COP was noninferior to R-CHOP, as assessed by the primary endpoint of complete response rate (85% vs 85% respectively). With a median follow-up of 75.2 months, the 5-year overall survival was 87% in the R-CHOP group and 82% in the R-THP-COP group (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.31-2.49; P = .82). The 5-year progression-free survival was 74% in the R-CHOP group and 79% in the R-THP-COP group (HR: 1.37, 95% CI: 0.56-3.55; P = .49). No grade 3 cardiac side effects were observed in either group. No serious late adverse reactions were observed in either group, with the exception of therapy-related acute myeloid leukemia in the R-THP-COP group. These data indicate that R-THP-COP is noninferior to R-CHOP with regard to clinical response, and has an acceptable safety profile. Thus, this regimen may be an alternative therapy to R-CHOP., (Copyright © 2018 John Wiley & Sons, Ltd.)

Recent findings indicate that the WW domain-containing oxidoreductase (WWOX) is a tumor suppressor protein that contains two N-terminal WW domains and a central short-chain dehydrogenase/reductase domain. WWOX protein mediates multiple signaling networks that suppress carcinogenesis through binding of its first WW domain to various cancer-associated proteins, i.e., p73, AP-2γ, and others. Although the tumor suppressor property of WWOX is inarguable, WWOX is not inactivated in the manner characteristic of the canonical Knudson hypothesis. Impairment of both alleles of WWOX is thought to be a rare event, only occurring in a few cancer cell lines. How is the tumor suppressor function of WWOX impaired in cancer cells? Recent advances highlight that a small transmembrane protein possessing a PPxY motif, called TMEM207, and its relatives are aberrantly expressed in various cancer cells and hinder the tumor suppressor function of WWOX through inhibiting its WW domain. Here, we review the recent findings related to the pathobiological properties of TMEM207 and its relatives based on clinicopathological and experimental pathological studies.

Clear cell sarcoma (CCS) is an aggressive type of soft tissue tumor that is associated with high rates of metastasis. In the present study, we found that CPI-613, which targets tumorous mitochondrial energy metabolism, induced autophagosome formation followed by lysosome fusion in HS-MM CCS cells in vitro. Interestingly, CPI-613 along with chloroquine, which inhibits the fusion of autophagosomes with lysosomes, significantly induced necrosis of HS-MM CCS cell growth in vitro. Subsequently, we established a murine orthotropic metastatic model of CCS and evaluated the putative suppressive effect of a combination of CPI-613 and chloroquine on CCS progression. Injection of HS-MM into the aponeuroses of the thigh, the most frequently affected site in CCS, resulted in massive metastasis in SCID-beige mice. By contrast, intraperitoneal administration of CPI-613 (25 mg/kg) and chloroquine (50 mg/kg), two days a week for two weeks, significantly decreased tumor growth at the injection site and abolished metastasis. The present results imply the inhibitory effects of a combination of CPI-613 and chloroquine on the progression of CCS., Competing Interests: The authors have declared that no competing interests exist.

Background: Standard treatment for unresectable esophageal squamous cell carcinoma (ESCC) without distant metastasis is definitive chemoradiotherapy (dCRT), in which the incidence of esophageal fistula (EF) is reported to be 10-12%. An ad hoc analysis of JCOG0303, a phase II/III trial of dCRT for patients with unresectable ESCC (including non-T4b), suggested that esophageal stenosis is a risk factor for EF. However, risk factors for EF in patients limited to T4b ESCC treated with dCRT have yet to be clarified. The aim of this study was to investigate risk factors for EF in T4b thoracic ESCC treated with dCRT., Methods: We retrospectively analyzed the data of consecutive T4b thoracic ESCC patients who were treated with dCRT (cisplatin and fluorouracil) at Shizuoka Cancer Center between April 2004 and September 2015., Results: Excluding 8 patients with esophageal fistula clearly attributable to other iatrogenic interventions, the data of 116 patients who met the inclusion criteria were analyzed. Esophageal fistula was observed in 28 patients (24%). Although the fistula was closed in 5 patients, overall survival was significantly shorter in patients who experienced esophageal fistula (8.0 vs. 26.8 months; p < 0.0001). Among four potential variables extracted in univariate analysis, namely, total circumferential lesion, elevated CRP level, elevated white blood cell count, and anemia, the first two were revealed as risk factors for esophageal fistula in multivariate analysis., Conclusions: This study demonstrated that total circumferential lesion and CRP ≥1.00 mg/dL are risk factors for esophageal fistula in T4b thoracic ESCC treated with dCRT., Trial Registration: This study was retrospectively registered.

Background: Several studies have demonstrated the benefit of hepatectomy for treating gastric cancer (GC) with liver-limited metastases (LLM). The survival benefit of hepatectomy compared with that of systemic chemotherapy is unknown, particularly in patients with multiple LLM. This study investigated the survival benefit of hepatectomy compared with that of systemic chemotherapy administered to patients with GC with multiple LLM., Methods: We retrospectively reviewed the data of consecutive patients with GC with two or three LLM who underwent hepatectomy or received systemic chemotherapy as initial treatment at the Shizuoka Cancer Center between December 2004 and December 2015., Results: Nine of 24 patients who met the inclusion criteria underwent hepatectomy, and 15 received chemotherapy. In the hepatectomy group, all patients achieved R0 resection and none died during hospitalization. Three patients received adjuvant chemotherapy. Disease recurred in eight patients (88.9%). In the chemotherapy group, three patients underwent hepatectomy following initial chemotherapy and did not experience recurrence or death during follow-up. Median follow-up was 47.9 months and median overall survival (OS) was 38.1 and 24.8 months in the chemotherapy and hepatectomy groups, respectively. Multivariate analysis of OS, including initial treatment, revealed that unilobar liver metastasis was the only independent favorable prognostic factor., Conclusions: Although hepatectomy for patients with GC with multiple LLM is not recommended as the initial therapy, it prolonged the survival of patients with tumors controlled using systemic chemotherapy.