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Background Suppression of background parenchymal enhancement (BPE) is commonly observed after neoadjuvant chemotherapy (NAC) at contrast-enhanced breast MRI. It was hypothesized that nonsuppressed BPE may be associated with inferior response to NAC. Purpose To investigate the relationship between lack of BPE suppression and pathologic response. Materials and Methods A retrospective review was performed for women with menopausal status data who were treated for breast cancer by one of 10 drug arms (standard NAC with or without experimental agents) between May 2010 and November 2016 in the Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2, or I-SPY 2 TRIAL (NCT01042379). Patients underwent MRI at four points: before treatment (T0), early treatment (T1), interregimen (T2), and before surgery (T3). BPE was quantitatively measured by using automated fibroglandular tissue segmentation. To test the hypothesis effectively, a subset of examinations with BPE with high-quality segmentation was selected. BPE change from T0 was defined as suppressed or nonsuppressed for each point. The Fisher exact test and the Z tests of proportions with Yates continuity correction were used to examine the relationship between BPE suppression and pathologic complete response (pCR) in hormone receptor (HR)-positive and HR-negative cohorts. Results A total of 3528 MRI scans from 882 patients (mean age, 48 years ± 10 [standard deviation]) were reviewed and the subset of patients with high-quality BPE segmentation was determined (T1, 433 patients; T2, 396 patients; T3, 380 patients). In the HR-positive cohort, an association between lack of BPE suppression and lower pCR rate was detected at T2 (nonsuppressed vs suppressed, 11.8% [six of 51] vs 28.9% [50 of 173]; difference, 17.1% [95% CI: 4.7, 29.5]; P = .02) and T3 (nonsuppressed vs suppressed, 5.3% [two of 38] vs 27.4% [48 of 175]; difference, 22.2% [95% CI: 10.9, 33.5]; P = .003). In the HR-negative cohort, patients with nonsuppressed BPE had lower estimated pCR rate at all points, but the P values for the association were all greater than .05. Conclusions In hormone receptor-positive breast cancer, lack of background parenchymal enhancement suppression may indicate inferior treatment response. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Philpotts in this issue.

Postmortem computed tomography (CT) is currently a well-known procedure and helps in postmortem investigations. In this case report, we report a unique postmortem CT finding: delayed cerebral enhancement associated with the antemortem infusion of contrast medium. A 72-year-old female lost consciousness at a restaurant and was taken to a hospital in an ambulance. Despite resuscitation efforts, she died of hypoxic–ischemic encephalopathy caused by cardiac arrest. About 6 h before her death, she underwent enhanced antemortem CT of the head. No abnormal enhancement was observed in the cerebral parenchyma. Then, 11 h after her death, she underwent unenhanced postmortem CT, which showed bilateral hyperdense caudate nucleus and putamina, due to residual iodinated contrast medium, in addition to other characteristic findings of hypoxic–ischemic encephalopathy. The mechanism underlying this phenomenon could be the destruction of the blood–brain barrier, and/or selective vulnerability, due to hypoxic–ischemic changes in the gray matter. Enhancement of basal ganglia on postmortem CT due to antemortem infusion of iodinated contrast medium might suggest hypoxic–ischemic encephalopathy, which should be noted in postmortem CT interpretations.

Introduction Although hepatitis B virus infection is well-described, the additional risk posed by oral bleeding in individuals with chronic hepatitis B virus infection has not been determined. This study aimed to determine the quantity of hepatitis B virus in the saliva of carriers in Japan, as a means of understanding the potential risk for horizontal transmission. Methods Saliva samples from 48 confirmed hepatitis B virus carriers were included in the analysis. Hepatitis B virus concentrations and the presence of occult blood as periodontal disease were evaluated in each sample. Results Hepatitis B surface antigen was identified in 46 of the 48 samples (98%), with hepatitis B virus DNA identified in 19 of the 48 saliva samples (40%). Occult blood was detected in 32 (67%) samples with the prevalence increasing as a function of age (r = 0.413; P = 0.003). There was a significantly positive correlation between hepatitis B virus DNA levels in the serum and saliva specimens (r = 0.895; P Conclusions Occult blood in saliva was detected in most participants. The detection of hepatitis B virus DNA correlated positively with hepatitis B virus in the serum and occult blood in the saliva. Therefore, improved care of periodontal disease among older people is important for preventing horizontal transmission of hepatitis B virus.

Glisson invasion by CLM is associated with a risk of margin-positive resection, leading to poor long-term outcomes after hepatectomy. This study was performed to evaluate the efficacy of intraoperative ultrasonography (IOUS) for the diagnosis of Glisson’s capsule invasion by colorectal liver metastasis (CLM). This prospective study involved 50 consecutive patients undergoing hepatectomy for CLM. Preoperatively, all patients had undergone gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI). During hepatectomy, a contrast agent (perflubutane) was intravenously injected and Glisson invasion was estimated based on three characteristic findings: a tumor thrombus, peripheral dilatation, and border irregularity/caliber change. The diagnostic abilities of the preoperative and intraoperative imaging studies were evaluated based on pathological examinations of resected specimens. Among 187 CLMs resected, pathological examinations proved Glisson invasion in 24 tumors (13%). IOUS revealed a tumor thrombus in 3 tumors (1.6%), peripheral dilatation in 4 (2.1%), and border irregularity and/or caliber change in 24 (12.8%). The sensitivity and specificity of IOUS with any of the above three findings for diagnosis of Glisson invasion was 79% and 96%, respectively, while preoperative EOB-MRI detected Glisson invasion in only four tumors (sensitivity/specificity, 17%/100%). The cutoff value of caliber change for diagnosis of Glisson invasion was set at 140% by receiver operating characteristic analysis. The R0 resection rates were not significantly different between patients with (82%) and without (85%) Glisson invasion. Identification of characteristic findings (tumor thrombus, peripheral dilatation, and border irregularity/caliber change) by contrast-enhanced IOUS is useful for the prediction of Glisson invasion by CLM.

Basic and clinical research have shown that the expression of molecules involved in the hepatocellular carcinoma (HCC) cell signaling pathway is related to the sensitivity to molecular-targeted agents. We herein report a case of HCC that was effectively treated with lenvatinib after a poor response to sorafenib. The tumor showed a high expression of fibroblast growth factor receptor 4, which is reportedly related to the sensitivity to lenvatinib in vitro. The information obtained from this case and from our literature review highlights the importance of assessing the expression of the molecules involved in tumors for effective precision medicine.

Purpose Esophagectomy with extended lymph node (LN) dissection is a standard treatment for resectable esophageal cancer to prevent recurrence, but severe, potentially life-threatening postoperative complications are still important issues. Accurate diagnosis of LN metastases would enable the decision to dissect or leave the LNs in regions with high risk of complications. Advancements in intraoperative gamma probe and radioactivity detectors have made intraoperative navigation surgery possible using a radiotracer as a marker. F-FDG is one such candidate markers, and the diagnostic power of FDG through counting the radioactivity close to each LN should be elucidated. Materials and methods In 20 patients, 1073 LNs including 38 metastatic LNs were prospectively investigated. Preoperative FDG PET was performed on the same day before esophagectomy and visually surveyed in each LN station to identify abnormal uptake. The FDG radioactivity of each individual dissected LN was measured by a well-type counter, and the pathological diagnosis was compared with LN radioactivity on a one-by-one basis and with the preoperative FDG PET findings for each LN station. Results Lymph node station-based analysis showed a sensitivity and specificity of 28.6% and 96.7%, respectively. One-by-one LN-based analysis using a cutoff value obtained from the receiver operating characteristic curve showed a sensitivity and specificity of 94.7% and 78.7%, respectively, demonstrating higher accuracy compared with the use of LN weight or the shortest diameter. Conclusions The FDG uptake by each LN is a potentially useful marker for navigation surgery in esophageal cancer and has higher accuracy than LN weight or diameter.

OBJECTIVE. The purpose of this article was to evaluate the diagnostic performance of the kinetic parameters of ultrafast and standard dynamic contrast-enhanced MRI (DCE-MRI) compared with morphologic evaluation in differentiating benign from malignant nonmass enhancement (NME) breast lesions. MATERIALS AND METHODS. A total of 77 consecutive patients with 77 NMEs (23 benign and 54 malignant) underwent 3-T MRI, including one unenhanced and eight contrast-enhanced ultrafast DCE-MRI scans (7-second scans) and standard DCE-MRI scans. The two readers evaluated the lesions' likelihood of malignancy on a continuous scale from 0 to 100% as the morphologic score using standard DCE-MRI. The kinetic curves of ultrafast DCE-MRI were fitted using an empirical mathematical model, ΔS(t) = A × (1 - e-αt), where A is the upper limit of signal intensity, e is the Euler number, and alpha (s-1) is the rate of signal increase. The initial slope of the kinetic curve (A × α) and the initial AUC (AUC30, which is the integration of the kinetic curve from 0 to 30 seconds) were calculated. From standard DCE-MRI, initial enhancement rate and signal enhancement ratio (SER) were calculated. These parameters were compared between benign and malignant NMEs. RESULTS. The morphologic score of malignant NME was statistically significantly higher than that of benign NME (p < 0.0001). The upper limit of signal intensity, rate of signal increase, initial slope of the kinetic curve, and AUC30 of ultrafast DCE-MRI, initial enhancement rate, SER of standard DCE-MRI of malignant NMEs were statistically significantly higher than those of benign NMEs (p = 0.0011, 0.0045, < 0.0001, < 0.0001, 0.0017, and < 0.0001, respectively). AUC ROC analysis found no statistically significant difference between morphologic score, AUC30 of ultrafast DCE-MRI, or SER of standard DCE-MRI. CONCLUSION. The kinetic parameters of ultrafast and standard DCE-MRI were as effective as morphologic evaluation for differentiation between benign and malignant NMEs.

Immune checkpoint inhibitors (CPIs), including pembrolizumab, are becoming common oncological treatments. CPIs have been associated with a significant risk of developing immune-related adverse events (irAEs), such as nephritis and interstitial nephritis. However, the occurrence of glomerulonephritis has only rarely been reported. We herein present the case of a 75-year-old woman with non-small cell lung carcinoma (NSCLC) who developed proteinuria and microscopic hematuria during treatment with pembrolizumab. Renal biopsy revealed tubulointerstitial nephritis and IgA nephropathy. Considering that a urinalysis showed no abnormality before treatment, the condition might have been induced by pembrolizumab. In this report, we focus on the correct diagnosis and management of renal irAEs, which remain controversial.

Agents that block vascular endothelial growth factor (VEGF) and its downstream pathway have been reported to be associated with nephrotoxicity including hypertension, proteinuria, and renal dysfunction. Bevacizumab, a monoclonal antibody against VEGF, is known to cause thrombotic microangiopathy (TMA), while tyrosine kinase inhibitors (TKIs) that block VEGF downstream are mainly associated with minimal change disease or focal segmental glomerulosclerosis. The question regarding the source of the diverse phenotypes of nephrotoxicity associated with these agents remains enigmatic. Nintedanib, a multitargeted TKI, blocks fibroblast growth factor and platelet-derived growth factor receptor as well as VEGF receptor, and is indicated for the treatment of idiopathic pulmonary fibrosis. We describe a case of a 45-year-old male who presented with isolated proteinuria of 1.3 g/g Cr 3 years after beginning nintedanib treatment. The kidney biopsy revealed histological features consistent with renal TMA. He underwent single lung transplantation 6 months later, which enabled cessation of nintedanib, and, 1 month later, his proteinuria results were negative. Unlike other types of TKIs, the pathological findings of nintedanib-induced nephrotoxicities have been limitedly reported. This is the first case of isolated proteinuria likely caused by nintedanib-induced TMA.

Multiple myeloma (MM) belongs to hematological malignancy that derives pro-survival/proliferative signals from the bone marrow niche, and its incidence is increasing worldwide. Butyrate, a well-known epigenetic histone deacetylase inhibitor, reduces the viability of MM cells, induces MM cell apoptosis via transcriptional activation of p21. Inpresent review we discuss butyrate as a potential therapeutic drug for MM and case reports of MM, acute leukemia, malignant lymphoma and glioma patients.

The mechanism of how gut microbiota is involved in the host inflammatory processes that influence human immunodeficiency virus (HIV) replication and disease progression in HIV is elucidated in present review.

BACKGROUND Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare condition in patients with hepatocellular carcinoma (HCC); to date, few cases have been reported. While hepatic dysfunction has been focused on the later stages of HCC, the management of symptoms in PTTM is important for supportive care of the cases. For the better understanding of PTTM in HCC, the information of our recent case and reported cases have been summarized. CASE SUMMARY A patient with HCC exhibited acute and severe respiratory failure. Radiography and computed tomography of the chest revealed the multiple metastatic tumors and a frosted glass–like shadow with no evidence of infectious pneumonia. We diagnosed his condition as acute respiratory distress syndrome caused by the lung metastases and involvement of the pulmonary vessels by tumor thrombus. Administration of prednisolone to alleviate the diffuse alveolar damages including edematous changes of alveolar wall caused by the tumor cell infiltration and ischemia showed mild improvement in his symptoms and imaging findings. An autopsy showed the typical pattern of PTTM in the lung with multiple metastases. CONCLUSION PTTM is caused by tumor thrombi in the arteries and thickening of the pulmonary arterial endothelium leading to the symptoms of dyspnea in terminal staged patients. Therefore, supportive management of symptoms is necessary in the cases with PTTM and hence we believe that the information presented here is of great significance for the diagnosis and management of symptoms of PTTM with HCC.

Thirty years have passed since a possible association of Epstein-Barr virus (EBV) with gastric carcinoma was reported. We now know EBV-associated gastric carcinoma to be a specific subtype of gastric carcinoma. Global epigenetic methylation and counteraction of the antitumour microenvironment are two major characteristics of this subtype of gastric carcinoma. Recent development of therapeutic modalities for gastric carcinoma, such as endoscopic mucosal dissection and immune checkpoint inhibitor therapy, has made the presence of EBV infection a biomarker for the treatment of gastric carcinoma. This review presents a portrait of EBV-associated gastric carcinoma from initiation to maturity that we define as the 'gastritis-infection-cancer sequence', followed by its molecular abnormalities and interactions with immune checkpoint molecules and the microenvironment. EBV non-coding RNAs (microRNA and circular RNA) and exosomes derived from EBV-infected cells that were previously behind the scenes are now recognized for their roles in EBV-associated gastric carcinoma. The virus utilizes cellular machinery skilfully to control infected cells and their microenvironment. We should thus strive to understand virus-host interactions more fully in the following years to overcome this virus-driven subtype of gastric carcinoma.

Anaplastic large-cell lymphoma (ALCL) is characterized as extranodal lymphoma and usually chemosensitive disease with overall survival rate of 70%–90%. Prognosis is roughly distinguished by the existence of anaplastic lymphoma kinase (ALK) fusion in tumor cells with higher frequencies observed in the pediatric population, and the outcome of ALK fusion-positive ALCL is relatively good when appropriate treatment is completed. Here, we report a case of dermal-exposed ALK fusion-positive ALCL with intracranial invasion. The patient received straight chemotherapy (ALCL99 protocol) without any plastic or resection surgery. The dermal dehiscence was rapidly healed with controllable local infection, and the tumor was regressed without relapse. Therefore, straight chemotherapy has clinical relevance and is a useful treatment strategy for ALK fusion-positive ALCL with dermal dehiscence.

Diversion colitis (DC) is an inflammatory disorder caused by interruption of the fecal stream and subsequent nutrient deficiency from luminal bacteria. The utility of fecal microbiota transplantation (FMT) for DC was recently investigated; however, the precise pathogenesis of this condition remains unclear. This study aimed to evaluate the utility of autologous FMT in DC and to determine the related changes in the intestinal microbiota.Autologous FMT was performed to reestablish the intestinal microbiota in five patients (average age, 64.6 ± 8.3 years) with DC. They underwent double-ended colostomy. We assessed the diverted colon by endoscopy and evaluated the microbiota before and after FMT using the 16S rRNA gene sequencing method.All five patients had mild inflammation (ulcerative colitis endoscopic index of severity [UCEIS] 2-3) in the diverted colon based on the colonoscopic findings. Three patients presented with symptoms, such as tenesmus, mucoid stool, and bloody stool. With FMT treatment, all patients achieved endoscopic remission (UCEIS score of 0 or 1) and symptomatic improvement. We observed a significantly decreased α-diversity in DC patients compared to healthy controls. The frequency of aerobic bacteria, such asThis study was the first to show that the microbiota in the diverted colon was significantly affected by autologous FMT. Since interruption of the fecal stream is central to the development of DC, FMT can be considered a promising treatment.

Acute upper gastrointestinal bleeding (UGIB) is a common disorder and a gastroenterological emergency. With the development of new techniques and devices, the survivability after gastrointestinal bleeding is improving. However, at the same time, we are facing the difficulty of severely complicated cases with various diseases. For example, while endoscopic examination with a normal diameter endoscope is essential for the diagnosis and treatment of UGIB, there are several cases in which it cannot be used. In these cases, transnasal endoscopy (TNE) may be a viable treatment option. This report reviews current hemostatic devices for endoscopic treatment and the safety and efficiency of using TNE in complicated cases. The latter will be demonstrated in a case report where TNE was employed in a patient with severe esophageal stenosis. This review summarizes the advances made in the devices used and will provide further ideas for the physician in terms of combining these devices and TNE.

Esophageal neuroendocrine carcinoma (NEC) is a rare and aggressive subtype with a poor prognosis. Pembrolizumab was recommended for the treatment of PD-L1 positive tumors in esophageal cancer and the combined positive score (CPS) was reported to be a better predictor of efficacy compared to the tumor proportion score (TPS). We investigated the expression profile of potential therapeutic targets (PD-L1, HLA class I, Mismatch repair (MMR) proteins) and tumor infiltrating lymphocytes (TILs) in esophageal NEC. Methods 15 NECs of the esophagus including mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) with squamous cell carcinoma (SCC) component were investigated in the study. The expression of PD-L1 (quantitatively evaluated by CPS and TPS), HLA class I, and MMR protein expression were examined immunohistochemically. TIL abundance was examined semiquantitatively by observation of H&E slides. Results Nine (60%) showed a CPS ≥ 1, five (33%) showed a CPS ≥10, and five cases showed a TPS ≥1. Survival analysis showed a significantly longer overall survival in the CPS ≥1 group than in the CPS Conclusion In esophageal NEC, PD-L1 positivity and preserved HLA-Class I expression were frequently observed, and PD-L1 CPS ≥ 1 was significantly associated with the better prognosis of esophageal NEC. Therefore, the PD-1/PD-L1 pathway and HLA-class I are thought to be potential therapeutic targets in esophageal neuroendocrine carcinoma.

Background Schwannomas are neoplasms that typically arise from the myelin sheath of peripheral nerves and rarely originate within the brain parenchyma. Some case reports present schwannomas arising from the brainstem, but regrowth of the tumor and the efficacy of postoperative irradiation have not been examined. In addition, the genetic background of schwannomas arising from the brainstem has not been investigated. Case presentation A 21-year-old male presented with diplopia, dysphagia, and left-sided hemiparesis, dysesthesia, and ataxia. Intracranial imaging showed a heterogeneous mass with a cystic lesion in the pontomedullary junction. Since the tumor caused obstructive hydrocephalus, the patient underwent subtotal tumor resection. A histopathologic evaluation aided a diagnosis of brainstem intraparenchymal schwannoma. Gradual postoperative mass regrowth was recognized. Three-dimensional conformal radiotherapy was performed on the residual mass and surgical cavity. No tumor regrowth was observed 4 years after surgery. To investigate the genetic background of the tumor, target sequences for 36 genes, including NF2, SMARCB1, and LZTR1, and microsatellite analysis for loss of 22q did not show any somatic variants or 22q loss. Conclusions We suggest that brainstem schwannomas might differ from conventional schwannomas in their genetic background.

Background: The prevalence of Helicobacter pylori infection and chronic atrophic gastritis is decreasing in Japan, which has led to a decline in the incidence of gastric cancer. However, there are various subtypes of gastric cancer that arise from the background mucosa without H. pylori infection, and their histological characteristics are distinct from those of gastric cancer with chronic atrophic gastritis. Summary: In this review, after a brief overview of conventional gastric carcinoma with H. pylori infection, including its molecular classification, histological characteristics of gastric cancer after eradicating H. pylori are described. The clinicopathological characteristics of gastric cancer independent of H. pylori infection are then explained. Autoimmune gastritis (type A gastritis) increases the risk of gastric adenocarcinoma and neuroendocrine tumors. Gastric carcinoma without H. pylori infection has various histological subtypes, including fundic gland-type adenocarcinoma (oxyntic gland adenoma), foveolar-type adenocarcinoma/adenoma, signet ring cell carcinoma, and adenocarcinoma of the esophagogastric junction. In addition, some familial gastric cancer syndromes, including hereditary diffuse gastric cancer, familial adenomatous polyposis, and gastric adenocarcinoma and proximal polyposis of the stomach, are also discussed. Key Messages: Although the incidence of gastric cancer will decrease in the near future, the diversity of gastric cancer pathology will be enhanced because H. pylori-negative gastric cancer will have a significant impact on the clinical practice guidelines for gastric cancer. Gastroenterologists and pathologists should be aware of the morphological diversity of H. pylori-negative gastric cancer, and attention should be paid to the status of the background gastric mucosa while examining gastric cancer.

Overlap syndrome refers to a group of conditions that have clinical features of more than one well-characterised rheumatic disease and meet the respective classification criteria. There are no typical renal histological findings in overlap syndrome. When patients with overlap syndrome develop renal dysfunction, various potential causes, including lupus nephritis (LN), renal crisis by systemic sclerosis, interstitial nephritis, and so on, need to be distinguished. Here, we report a 44-year-old woman with overlap syndrome involving systemic lupus erythematosus (SLE), diffuse cutaneous systemic scleroderma, and Sjogren’s syndrome, who was also positive for anti-mitochondrial M2 antibody. She developed glomerular haematuria, proteinuria, and increase in creatinine appeared gradually. Suspecting LN, renal biopsy was performed. However, in the interstitium, mild infiltration of lymphocytes and plasma cells and very partial fibrosis were observed. Immunofluorescence microscopy revealed predominant mesangial immunoglobulin M, C3, and λ light chain staining. Overall, LN was not diagnosed based on these findings. Renal dysfunction was normalised by glucocorticoid treatment for 3 months. This case suggests the importance of a renal diagnosis based on renal pathological findings, especially in a case of overlap syndrome including SLE.

Background Two-dimensional (2D) specimen radiography (SR) and tomosynthesis (DBT) for breast cancer yield data that lack high-depth resolution. A volumetric specimen imager (VSI) was developed to provide full-3D and thin-slice cross-sectional visualization at a 360° view angle. The purpose of this prospective trial was to compare VSI, 2D SR, and DBT interpretation of lumpectomy margin status with the final pathologic margin status of breast lumpectomy specimens. Methods The study enrolled 200 cases from two institutions. After standard imaging and interpretation was performed, the main lumpectomy specimen was imaged with the VSI device. Image interpretation was performed by three radiologists after surgery based on VSI, 2D SR, and DBT. A receiver operating characteristic (ROC) curve was created for each method. The area under the curve (AUC) was computed to characterize the performance of the imaging method interpreted by each user. Results From 200 lesions, 1200 margins were interpreted. The AUC values of VSI for the three radiologists were respectively 0.91, 0.90, and 0.94, showing relative improvement over the AUCs of 2D SR by 54%, 13%, and 40% and DBT by 32% and 11%, respectively. The VSI has sensitivity ranging from 91 to 94%, specificity ranging from 81 to 85%, a positive predictive value ranging from 25 to 30%, and a negative predicative value of 99%. Conclusions The ROC curves of the VSI were higher than those of the other specimen imaging methods. Full-3D specimen imaging can improve the correlation between the main lumpectomy specimen margin status and surgical pathology. The findings from this study suggest that using the VSI device for intraoperative margin assessment could further reduce the re-excision rates for women with malignant disease.

The global incidence and mortality rates of colorectal cancer is rising, and has surpassed lung cancer as the highest incidence of all types of cancers in Japan [1]. Standard treatments include surgery and chemotherapy, however immunotherapy using Dendritic Cell (DC) vaccines is also recognized as an effective treatment for many cancers including colorectal cancer. DCs are the most potent antigen presenting cells, which activate CD 4+/CD8+ T cells and induce cytotoxic T lymphocytes (CTLs) to attack cancer cells. Tumor antigens used in DC vaccines are typically defined tumor-derived peptides, however, using autologous tumor lysates produces significantly higher response rates [2] . It is not always feasible to obtain fresh whole tumor to use as lysate, and particularly in the case of colorectal cancer, it is difficult to collect an aseptic specimen for use. We therefore explored the possibility of producing lysate from circulating tumor cells (CTCs) that can be collected aseptically from peripheral blood. We created a model of capturing live CTCs from a colorectal cancer cell line, culturing and expanding these cells, and creating lysate from these cultured CTCs.

Lifestyle-related chronic illnesses, such as metabolic syndrome, type 2 diabetes, cancer, and dementia are rising at an alarming, epidemic rate. In this modern world of increasing lifespan, we are actually decreasing our health span, placing an undue burden on healthcare costs to society. Modern medicine has largely gotten away from addressing key issues to prevent or even reverse some of these chronic conditions. Yet the evidence for successful interventions in four key areas – nutrition, sleep, physical activity and stress management – to manage and control our health are mounting. Lifestyle medicine as a part of personalized treatment and prevention of chronic illnesses is a necessary cornerstone of disease management as we look to the future. In this review, I discuss various key studies demonstrating the impact of lifestyle on epigenetic, endocrine, immunologic, and inflammatory changes which contribute to chronic disease and our overall health.

Background The aim of this study was to clarify whether a cancer stem cell marker could be an indicator of post-operative peritoneal recurrence of colon cancer. Methods Expression of four putative markers (CD133, CD44 variant 6, aldehyde dehydrogenase-1 and leucine-rich repeating G-protein-coupled receptor-5 (LGR5)) was evaluated immunohistochemically in primary tumour samples from 292 patients who underwent curative resection for non-metastasised pT4 colon cancer at the University of Tokyo Hospital between 1997 and 2015. Results Peritoneal recurrence was significantly higher in LGR5-negative cases (5-year cumulative incidence: 27.5% vs. 14.4%, p = 0.037). Multivariable analysis confirmed that negative LGR5 expression was an independent risk factor for peritoneal recurrence (hazard ratio (HR) 2.79, p = 0.005) in addition to poor differentiation, positive lymph node metastasis, preoperative carcinoembryonic antigen > 5 ng/mL and anastomotic leakage. The addition of LGR5 significantly improved the predictive value of the multivariable model (net reclassification improvement: 0.186, p = 0.028: integrated discrimination improvement: 0.047, p = 0.008). Conclusions Negative LGR5 expression was a significant predictor of peritoneal recurrence in patients with pT4 colon cancer. Therefore, LGR5 might be a promising biomarker to identify patients at high risk of post-operative peritoneal metastasis.

Purpose: To establish a cohort of high-risk women undergoing intensive surveillance for breast cancer. Experimental Design: We performed dynamic contrast-enhanced MRI every 6 months in conjunction with annual mammography (MG). Eligible participants had a cumulative lifetime breast cancer risk ≥20% and/or tested positive for a pathogenic mutation in a known breast cancer susceptibility gene. Results: Between 2004 and 2016, we prospectively enrolled 295 women, including 157 mutation carriers (75 BRCA1, 61 BRCA2); participants' mean age at entry was 43.3 years. Seventeen cancers were later diagnosed: 4 ductal carcinoma in situ (DCIS) and 13 early-stage invasive breast cancers. Fifteen cancers occurred in mutation carriers (11 BRCA1, 3 BRCA2, 1 CDH1). Median size of the invasive cancers was 0.61 cm. No patients had lymph node metastasis at time of diagnosis, and no interval invasive cancers occurred. The sensitivity of biannual MRI alone was 88.2% and annual MG plus biannual MRI was 94.1%. The cancer detection rate of biannual MRI alone was 0.7% per 100 screening episodes, which is similar to the cancer detection rate of 0.7% per 100 screening episodes for annual MG plus biannual MRI. The number of recalls and biopsies needed to detect one cancer by biannual MRI were 2.8 and 1.7 in BRCA1 carriers, 12.0 and 8.0 in BRCA2 carriers, and 11.7 and 5.0 in non-BRCA1/2 carriers, respectively. Conclusions: Biannual MRI performed well for early detection of invasive breast cancer in genomically stratified high-risk women. No benefit was associated with annual MG screening plus biannual MRI screening. See related commentary by Kuhl and Schrading, p. 1693

Gastric cancer (GC) is one of the most common and life-threatening malignancies. The course of disease and tumor aggressiveness vary among GCs, although how early fate is determined and by what factors remains elusive. To solve this question, we collected 43 gastric intramucosal neoplasias (GINs), comprising dysplasia/intraepithelial neoplasia (D/IEN; a premalignant lesion) and minute GC (miGC; ≤10 mm) of intestinal histotype and performed targeted deep DNA sequencing of 67 GC-related genes derived from large-scale data. Gastric D/IEN was classified into low or high grade (LG-D/IEN or HG-D/IEN). The most frequent mutations in D/IENs included APC (19/25; 76%), ARID2 (6/25; 24%) and MUC6 (5/25; 20%). All LG-D/IENs had APC mutation (12/12) and APC hotspot mutations affecting R1450 and E1554 were noted in both LG-D/IEN and HG-D/IEN. ARID2 mutation always co-occurred with APC mutation, whose tumor variant allele frequency (TVAF) was higher than that of ARID2 in D/IEN. APC and TP53 mutations were mutually exclusive in D/IEN (p = 0.031 [main cohort], p = 0.025 [expanding cohort]) and TP53-mutated D/IEN was exclusively HG-D/IEN (4/4). TP53 mutations were highly recurrent (11/14; 79%) in MLH1-positive miGCs and were detected even in two microscopic lesions measuring 1 and 3 mm, respectively. Furthermore, TVAF analyses suggested that TP53 mutation is the initial event in the TP53-mutated miGCs. In contrast, TP53 mutation was absent (0/4) in MLH1-negative small intramucosal carcinoma (8-24 mm). Advanced GC data suggested that early mutations (APC and TP53) may affect the potential of cancerous progression from D/IEN. This study revealed somatic mutational landscape and initial mutations of GINs, and we report for the first time that TP53 mutations precede other mutations in intestinal-type GC. Our results also indicate that molecular subtyping based on APC/TP53 mutations would be a high-priority approach for determining and predicting the malignant potential of GIN, including D/IEN. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Purpose To determine if the change in tumor apparent diffusion coefficient (ADC) at diffusion-weighted (DW) MRI is predictive of pathologic complete response (pCR) to neoadjuvant chemotherapy for breast cancer. Materials and Methods In this prospective multicenter study, 272 consecutive women with breast cancer were enrolled at 10 institutions (from August 2012 to January 2015) and were randomized to treatment with 12 weekly doses of paclitaxel (with or without an experimental agent), followed by 12 weeks of treatment with four cycles of anthracycline. Each woman underwent breast DW MRI before treatment, at early treatment (3 weeks), at midtreatment (12 weeks), and after treatment. Percentage change in tumor ADC from that before treatment (ΔADC) was measured at each time point. Performance for predicting pCR was assessed by using the area under the receiver operating characteristic curve (AUC) for the overall cohort and according to tumor hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) disease subtype. Results The final analysis included 242 patients with evaluable serial imaging data, with a mean age of 48 years ± 10 (standard deviation); 99 patients had HR-positive (hereafter, HR+)/HER2-negative (hereafter, HER2-) disease, 77 patients had HR-/HER2- disease, 42 patients had HR+/HER2+ disease, and 24 patients had HR-/HER2+ disease. Eighty (33%) of 242 patients experienced pCR. Overall, ΔADC was moderately predictive of pCR at midtreatment/12 weeks (AUC = 0.60; 95% confidence interval [CI]: 0.52, 0.68; P = .017) and after treatment (AUC = 0.61; 95% CI: 0.52, 0.69; P = .013). Across the four disease subtypes, midtreatment ΔADC was predictive only for HR+/HER2- tumors (AUC = 0.76; 95% CI: 0.62, 0.89; P < .001). In a test subset, a model combining tumor subtype and midtreatment ΔADC improved predictive performance (AUC = 0.72; 95% CI: 0.61, 0.83) over ΔADC alone (AUC = 0.57; 95% CI: 0.44, 0.70; P = .032.). Conclusion After 12 weeks of therapy, change in breast tumor apparent diffusion coefficient at MRI predicts complete pathologic response to neoadjuvant chemotherapy. © RSNA, 2018 Online supplemental material is available for this article.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) had clinical success in the treatment of non-small cell lung carcinoma (NSCLC). An effect of this drug on kidney has not been clarified and the occurrence of glomerulonephritis related to EGFR-TKI has rarely been reported. We present the case of a 71-year-old man with NSCLC who developed proteinuria and microscopic hematuria with the rise in a titer of MPO-ANCA, when 2 years and 3 months passed since the initiation of erlotinib, one of oral EGFR-TKI. Two serial biopsies support that ANCA-associated vasculitis may have been modified by the persistent use of erlotinib. We initiated intravenous pulse therapy with methylprednisolone followed by oral prednisone. The proteinuria has decreased and serum CRP was normalized. However, the serum creatinine level and hematuria did not change during the treatment period. While EGFR inhibition is implicated in protective control for glomerulonephritis, it may exacerbate vasculitis. Close monitoring of the kidney function and urinary findings is required during the use of EGFR inhibitors, such as erlotinib, because it may cause renal adverse events.

Prediction of tissue origin of esophagogastric junction (EGJ) adenocarcinomas can be important for therapeutic decision, but no molecular marker is available. Here, we aimed to develop such a marker taking advantage of tissue-specific profiles of DNA methylation. DNA methylation profiles of gastric adenocarcinomas (GACs) were obtained by an Infinium HumanMethylation450 BeadChip array, and those of esophageal adenocarcinoma (EACs) were obtained from the TCGA database. DNA from formalin-fixed paraffin-embedded (FFPE) samples was analyzed by bisulfite pyrosequencing. In the screening set, 51 of 145,841 CpG sites in CpG islands were methylated at significantly higher levels in 30 GACs compared to those in 30 EACs. Among them, SLC46A3 and cg09177106 were unmethylated in all the 30 EACs. Predictive powers of these two markers were successfully confirmed in an independent validation set (18 GACs and 18 EACs) (SLC46A3, sensitivity = 77.8%, specificity = 100%; cg09177106, sensitivity = 83.3%, specificity = 94.4%), and could be applied to FFPE samples (37 GACs and 18 EACs) (SLC46A3, P = 0.0001; cg09177106, P = 0.0028). On the other hand, EAC-specific markers informative in the FFPE samples could not be isolated. Using these GAC-specific markers, nine of 46 (19.6%) TCGA EGJ adenocarcinomas were predicted to be GACs. Two GAC-specific markers, SLC46A3 and cg09177106, had a high specificity for identifying the tissue origin of EGJ adenocarcinoma.

To work in a place where human access is restricted, using remotely controlled robots as alternative of human is one of the ideal solution, and it is particularly of significant value for harmful places. In Fukushima Daiichi Nuclear Power Station(FDNPS) of Tokyo Electric Power Company holdings(TEPCO), many remotely controlled robots are used for its decommissioning. However, remote operation using robots is not easy, and there were some problems in remote robot operations. Robot testing method considering the tasks of remote robot operation in FDNPS is important for development in robotics and training for operators. Then, we survey about these problems on remote robot operation at FDNPS, and develop robot testing methods to quantitatively evaluate robot capabilities for remote operation based on this survey. This paper introduces this survey and the robot testing methods.

Understanding repeatability of classification by classifier in the context of overall classification performance and operating points can contribute to improved design of computer-aided diagnosis (CADx). Breast lesions (243 benign, 853 malignant: 1,096 total) were segmented using a fuzzy c-means method from dynamic contrast-enhanced magnetic resonance images acquired over 2005-2015. Thirty-eight radiomic features were extracted. Overall classification performance, case-based classification repeatability, and attainment of ‘preferred’ target and ‘optimal’ sensitivity and specificity were investigated for three classifiers: linear discriminant analysis, support vector machine, and random forest using a 1000-iteration 0.632 bootstrap. The area under the receiver operating characteristic curve (AUC) for the task of classifying lesions as malignant or benign was determined using the 0.632+ bootstrap correction. AUC was compared between classifiers; statistical significance was indicated when the 98.33% confidence interval (CI) of the difference in AUC (corrected for multiple comparisons) excluded zero. Classifier repeatability was determined through 95% CI width of classifier output by case across classifier output range. Classifier output thresholds were determined from the training folds for target sensitivity (95%), target specificity (95%), and for a selected ‘optimal’ operating point determined by minimizing (1-sensitivity)2 + (1-specificity)2 and applied to the test folds. No difference in AUC was observed between the three classifiers. Classifier output, however, was more repeatable when the random forest classifier was used as indicated by a lower 95% CI width of classifier output overall. Moreover, limited differences by classifier in threshold to attain target and ‘optimal’ sensitivities and specificities along with attained sensitivities and specificities were observed. CADx design may benefit from these considerations when selecting which classifier is used.

Characterizing case-based repeatability of lesion classification in computer-aided diagnosis (CADx) can support clinical application of CADx in breast cancer imaging. A database of 516 full-field digital mammographic (FFDM) images, 268 unique breast lesions/cases (138 malignant, 130 benign) was retrospectively collected under HIPAA/IRB approval. Lesions were automatically segmented through a region-growing method. Twenty-nine radiomic features were extracted, characterizing lesion size, shape, margin, texture, and contrast. A 0.632 bootstrap/1000 iterations was used to divide cases into training and test folds for support vector machine classification as malignant or benign. Classifier output was averaged by case. The 0.632+ bootstrap-corrected area under the receiver operating characteristic (ROC) curve (AUC) in the task of classification of lesions as malignant or benign was determined. Classifier repeatability was determined as a function of median classifier output across all cases obtained in bootstraps sorted into 10 equal bins. 95% confidence intervals (CI) of sensitivity and specificity were examined as a function of classifier output, i.e., the decision variable in ROC analysis. Actual sensitivity and specificity in the test folds were determined for a target sensitivity (0.95), a target specificity (0.95), and an ‘optimal’ combination that minimized (1-sensitivity)2 + (1-specificity)2. The AUC [95% CI] was 0.82 [0.77, 0.86]. Classifier output was more repeatable at lower and upper ranges. Sensitivity and specificity at the targets were (median, [95% CI]) at 0.92 [0.83, 0.98] and 0.92 [0.82, 0.98] respectively. At an ‘optimal’ decision threshold, sensitivity was 0.73 [0.59, 0.85] and specificity 0.76 [0.62, 0.88]. These results characterize SVM classification repeatability for radiomic features extracted from FFDM images.

Dynamic contrast-enhanced (DCE) MRI provides both morphological and functional information regarding breast tumor response to neoadjuvant chemotherapy (NAC). The purpose of this retrospective study is to test if prediction models combining multiple MRI features outperform models with single features. Four features were quantitatively calculated in each MRI exam: functional tumor volume, longest diameter, sphericity, and contralateral background parenchymal enhancement. Logistic regression analysis was used to study the relationship between MRI variables and pathologic complete response (pCR). Predictive performance was estimated using the area under the receiver operating characteristic curve (AUC). The full cohort was stratified by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status (positive or negative). A total of 384 patients (median age: 49 y/o) were included. Results showed analysis with combined features achieved higher AUCs than analysis with any feature alone. AUCs estimated for the combined versus highest AUCs among single features were 0.81 (95% confidence interval [CI]: 0.76, 0.86) versus 0.79 (95% CI: 0.73, 0.85) in the full cohort, 0.83 (95% CI: 0.77, 0.92) versus 0.73 (95% CI: 0.61, 0.84) in HR-positive/HER2-negative, 0.88 (95% CI: 0.79, 0.97) versus 0.78 (95% CI: 0.63, 0.89) in HR-positive/HER2-positive, 0.83 (95% CI not available) versus 0.75 (95% CI: 0.46, 0.81) in HR-negative/HER2-positive, and 0.82 (95% CI: 0.74, 0.91) versus 0.75 (95% CI: 0.64, 0.83) in triple negatives. Multi-feature MRI analysis improved pCR prediction over analysis of any individual feature that we examined. Additionally, the improvements in prediction were more notable when analysis was conducted according to cancer subtype.

To investigate effective model composed of features from ultrafast dynamic contrast-enhanced magnetic resonance imaging (UF-MRI) for distinguishing low- from non-low-grade ductal carcinoma in situ (DCIS) lesions or DCIS lesions upgraded to invasive carcinoma (upgrade DCIS lesions) among lesions diagnosed as DCIS on pre-operative biopsy. Eighty-six consecutive women with 86 DCIS lesions diagnosed by biopsy underwent UF-MRI including pre- and 18 post-contrast ultrafast scans (temporal resolution of 3 s/phase). The last phase of UF-MRI was used to perform 3D segmentation. The time point at 6 s after the aorta started to enhance was used to obtain subtracted images. From the 3D segmentation and subtracted images, enhancement, shape, and texture features were calculated and compared between low- and non-low-grade or upgrade DCIS lesions using univariate analysis. Feature selection by least absolute shrinkage and selection operator (LASSO) algorithm and k-fold cross-validation were performed to evaluate the diagnostic performance. Surgical specimens revealed 16 low-grade DCIS lesions, 37 non-low-grade lesions and 33 upgrade DCIS lesions. In univariate analysis, five shape and seven texture features were significantly different between low- and non-low-grade lesions or upgrade DCIS lesions, whereas enhancement features were not. The six features including surface/volume ratio, irregularity, diff variance, uniformity, sum average, and variance were selected using LASSO algorism and the mean area under the receiver operating characteristic curve for training and validation folds were 0.88 and 0.88, respectively. The model with shape and texture features of UF-MRI could effectively distinguish low- from non-low-grade or upgrade DCIS lesions.

Background Gadoxetic acid (Gd-EOB-DTPA)-enhanced MRI is superior to CT in the detection of colorectal liver metastases (CRLMs) smaller than 10 mm. However, few studies have used MRI findings to predict patients' long-term prognosis. Purpose To investigate the relationship between Gd-EOB-DTPA-enhanced MRI findings in the liver parenchyma peripheral to CRLM and both pathologic vessel invasion and long-term prognosis. Materials and Methods This retrospective study included patients who underwent Gd-EOB-DTPA-enhanced MRI before curative surgery for CRLM, without neoadjuvant chemotherapy, between July 2008 and June 2015. Early enhancement, reduced Gd-EOB-DTPA uptake, and bile duct dilatation peripheral to the CRLM at MRI were evaluated by three abdominal radiologists. All tumor specimens were reevaluated for the presence or absence of portal vein, hepatic vein, and bile duct invasion. Predictors of recurrence-free survival (RFS) and overall survival (OS) after surgery were identified with Cox proportional hazard model with the Bayesian information criterion. Previously reported prognosticators were selected for multivariable analyses. The median follow-up period was 60 months (range, 9-127 months). Results Overall, 106 patients (mean age, 65 years ± 12 [standard deviation]; 68 men) with 148 CRLMs were evaluated. Bile duct dilatation peripheral to the tumor was associated with pathologic portal vein invasion (sensitivity, 12 of 50 [24%]; specificity, 89 of 98 [91%]; P = .02), bile duct invasion (sensitivity, eight of 19 [42%]; specificity, 116 of 129 [90%]; P = .001), poor RFS (P = .03; hazard ratio [HR] = 2.4 [95% confidence interval {CI}: 1.3, 4.2]), and poor OS (P = .01; HR = 2.4 [95% CI: 1.2, 4.9]). For RFS and OS, early enhancement and reduced Gd-EOB-DTPA uptake peripheral to the CRLM were eliminated by means of variable selection in the multivariable analysis, but the combination of these findings with bile duct dilatation provided a predictor of poor OS (P = .001; HR = 3.3 [95% CI: 1.6, 6.8]). Conclusion MRI signal intensity changes peripheral to the colorectal liver metastasis were predictors of long-term prognosis after curative surgery without neoadjuvant chemotherapy. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Bashir in this issue.

This study investigated the efficacy and safety of radiotherapy as part of multidisciplinary therapy for advanced hepatocellular carcinoma (HCC). Clinical data of 49 HCC patients treated with radiotherapy were assessed retrospectively. The efficacy of radiotherapy was assessed by progression-free survival, disease control rate, and overall survival. Safety was assessed by symptoms and hematological assay, and changes in hepatic reserve function were determined by Child&ndash, Pugh score and albumin&ndash, bilirubin (ALBI) score. Forty patients underwent curative radiotherapy, and nine patients with portal vein tumor thrombus (PVTT) underwent palliative radiotherapy as part of multidisciplinary therapy. Local disease control for curative therapy was 80.0% and stereotactic body radiotherapy was 86.7% which was greater than that of conventional radiotherapy (60.0%). Patients with PVTT had a median observation period of 651 days and 75% three-year survival when treated with multitherapy, including radiotherapy for palliative intent, transcatheter arterial chemoembolization, and administration of molecular targeted agents. No adverse events higher than grade 3 and no changes in the Child&ndash, Pugh score and ALBI score were seen. Radiotherapy is safe and effective for HCC treatment and can be a part of multidisciplinary therapy.

Streptococcal toxic shock syndrome (STSS) is a severe infection most commonly caused by group A streptococcus. It is clinically characterized by rapidly progressive multiple organ failure and septic shock. This report presents four fatal cases associated with STSS. In two cases (cases 2 and 3), the portals of entry may be ulcer and mucosa at the surgical site; the initial symptoms in these cases included fever. In the other cases, the portal of entry was unknown; the initial symptom was pain. In two cases (cases 1 and 3), malpractice was suspected before autopsy. At autopsy, blood culture was positive for group A streptococcus in all of the present cases. Although C-reactive protein levels were increased, procalcitonin levels were not markedly elevated. This is the first report of autopsy cases associated with STSS in which postmortem computed tomography was performed; the swelling of muscles and increased concentrations of peripheral subcutaneous tissue without gas may be characteristic findings. Histology revealed extensive bacterial colonies and necrosis with mild neutrophilic reaction in two cases (cases 3 and 4), and hemophagocytosis in two cases (cases 1 and 4). It is essential to perform appropriate examinations and make a proper diagnosis because STSS still has a high fatality rate and medical malpractice is often suspected. In addition, it is important to evaluate STSS again for the reduction of the fatal cases associated with STSS.

Biochemical response to treatment in patients with primary biliary cholangitis (PBC) reflects prognosis. However, the best predictive criteria to detect biochemical response remain undetermined. In addition, because these criteria need > 6 months until definition, parameters that can estimate its results before initiating treatment are needed. We conducted a single-center retrospective study on 196 patients with PBC, followed up for at least 12 months after initiating treatment. Kaplan–Meier analysis showed that Paris II (p = 0.002) and Rotterdam criteria (p = 0.001) could estimate the overall survival of PBC patients, whereas Paris II (p = 0.001), Rotterdam (p = 0.001), and Rochester criteria (p= 0.025) could estimate liver-related deaths. Cox hazard analysis revealed Paris II and Rotterdam criteria as significantly independent predictors of overall survival (hazard ratio (HR) 3.948, 95% CI 1.293–12.054, p = 0.016 and HR 6.040, 95% CI 1.969–18.527, p = 0.002, respectively) and liver-related deaths (HR 10.461, 95% CI 1.231–88.936, p = 0.032 and HR 10.824, 95% CI 1.252–93.572, p = 0.032, respectively). The results of Paris II criteria could be estimated by serum prothrombin time (Odds ratio (OR) 1.052, 95% CI 1.008–1.098, p = 0.021) and alanine transaminase level (OR 0.954, 95% CI 0.919–0.991, p = 0.014) whereas, those of Rotterdam criteria could be estimated by serum albumin level (OR 3.649, 95% CI 1.098–12.128, p = 0.035) at the time of diagnosis. This study highlights the best prediction criteria and pre-treatment parameters that facilitate the prognosis of PBC patients.

In alcoholic liver cirrhosis (LC) patients, obesity has become a problem that progresses into liver dysfunction. Herein, we investigated the relationship between the prognosis of steatohepatitis and body weight, along with fat accumulation in patients with alcoholic LC. We conducted a single-center retrospective study, enrolled 104 alcoholic LC patients without hepatocellular carcinoma (HCC) based on histological and clinical evidence, and investigated factors related to poor prognosis using multivariate Cox regression and cluster analyses. Cox regression analysis revealed three independent relevant factors: subcutaneous adipose tissue (SAT) index (median 34.8 cm2/m2, P = 0.009, hazard ratio [HR] 1.017, 95% confidence interval [CI] 1.004–1.030), total bilirubin level (median 1.7 mg/dL, P = 0.003, HR 1.129, 95% CI 1.042–1.223), and prothrombin time value (median 64%, P = 0.007, HR 0.967, 95% CI 0.943–0.991). In the cluster analysis, we categorized the patients into three groups: no adipose tissue accumulation (NAT group), SAT prior accumulation (SAT group), and visceral adipose tissue prior accumulation (VAT group). The results of the three groups revealed that the SAT group displayed a significantly poor prognosis of the Kaplan–Meier curve (67.1 vs 21.2 vs 65.3, P

AIMS Gastric neuroendocrine carcinoma (NEC) is a rare and aggressive subtype with a poor prognosis. We aim to investigate expression profiles of HER2 and programmed death ligand 1 (PD-L1) in gastric NEC to test the potential applicability of drugs targeting these molecules. METHODS AND RESULTS Expression levels of HER2 and PD-L1 were evaluated in 25 gastric NECs, including 10 pure NECs and 15 mixed adenocarcinoma-NECs, and a combined positive score (CPS) was used to evaluate PD-L1 expression. The correlations of expression levels with both clinicopathological features and the expression of p53, retinoblastoma protein (Rb) and mismatch repair proteins were also analysed. Eighteen of the 25 (72%) cases showed a PD-L1 CPS of ≥ 1, which was previously shown to be associated with response to pembrolizumab. Positive nodal metastasis and low tumour-infiltrating lymphocyte (TIL) levels at the invasive margin were significantly associated with a PD-L1 CPS of