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Objectives To evaluate the long-term efficacy and safety of zonisamide, an antiepileptic agent, in dementia with Lewy bodies (DLB). Design Phase three clinical trial with 12 week, randomized, placebo-controlled, double-blind, and subsequent 40 week, open-label, extension periods. Setting A total of 109 centers in Japan between April 2015 and November 2017. Participants Outpatients diagnosed with probable DLB. Intervention Outpatients were randomly assigned to receive placebo (P) or zonisamide 25 or 50 mg/day for 12 weeks. In the subsequent open-label 40 week period, all patients initially received zonisamide 25 mg/day for at least 2 weeks followed by optional flexible dosing with zonisamide 25 or 50 mg/day for the remaining period. Measurements The primary outcome was efficacy on motor symptoms, assessed using the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score, over the total 52 week trial period. Effects on behavioral and psychological symptoms of dementia and cognitive function, and safety were also evaluated. Results In total, 335 patients were included in the long-term analysis: 106, 117, and 112 in the P-, 25mg-, and 50mg-Flex groups, respectively. UPDRS-III score continued to improve for an additional 12 to 16 weeks in the open-label period (mean [standard deviation] change from baseline at Week 28: −5.1 [7.3] and −6.3 [8.2] in the 25mg- and 50mg-Flex groups) and remained almost constant thereafter. No unexpected neurological or psychiatric adverse events occurred, and no adverse events increased in incidence in the open-label period. Conclusions Long-term treatment with zonisamide was well tolerated and yielded sustained improvement in motor symptoms. Trial registration JapicCTI-152839 (Registered on 9 March 2015) https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-152839

Aim Matrix metalloproteinases (MMPs) play critical roles in acute myocardial infarction (AMI). This trial was conducted to determine the potential effects of higher-dose rosuvastatin on circulating MMP levels in patients with AMI. Methods This was a multicenter, open-label, 1:1 randomized, parallel-group study. Patients with AMI were randomly assigned to the appropriate-dose group (10 mg rosuvastatin once daily) or the low-dose group (2.5 mg rosuvastatin once daily) within 24 hours after percutaneous coronary intervention. MMP-2 and MMP-9 levels were measured on day 1 and at week 4, 12, and 24 after enrollment. The primary endpoint was the change in MMP levels at 24 weeks after enrollment. The secondary endpoints were change in MMP levels at day 1 and weeks 4 and 12 after enrollment. Results Between August 2017 and October 2018, 120 patients with AMI from 19 institutions were randomly assigned to either the appropriate-dose or the low-dose group. There were 109 patients who completed the 24-week follow-up. The primary endpoint for both MMP-2 and MMP-9 was not significantly different between the two groups. The change in the active/total ratio of MMP-9 at week 12 after baseline was significantly lower in the appropriate-dose group compared with the low-dose group (0.81 [-52.8-60.1]% vs. 70.1 [-14.5-214.2]%, P=0.004), while the changes in MMP-2 were not significantly different between the two groups during the study period. Conclusions This study could not demonstrate the superiority of appropriate-dose of rosuvastatin in inhibiting serum MMPs levels in patients with AMI.

Background and Aims Sequential therapy with molecular‐targeted agents (MTAs) is considered effective for unresectable hepatocellular carcinoma (HCC) patients. This study purposed to evaluate the efficacy of sequential therapy with sorafenib (SORA) as a first‐line therapy and to investigate the therapeutic impact of SORA in nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steato hepatitis (NASH)‐related HCC. Methods We evaluated 504 HCC patients treated with SORA (Study‐1). The times of administration for sorafenib from 2009 to 2015, 2016 to 2017, and 2018 and later were defined as the early‐, mid‐, and late‐term periods, respectively. Among them, 180 HCC patients treated with SORA in addition to MTAs in the mid‐ and late‐term periods were divided into groups based on disease etiology (NAFLD or NASH [n = 37] and viral or alcohol [n = 143]), and outcomes were compared after inverse probability weighting (IPW) (Study‐2). Results Overall survival (OS) of HCC patients who received sequential MTA therapy after first‐line SORA was significantly longer. The median survival times (MST) were 12.6 versus 17.6 versus 17.4 months in the early‐term group, mid‐term group, and the later‐time group (early vs. mid, p = 0.014, early vs. later. p = 0.045), respectively. (Study‐1). In Study‐2, there was no significant differences in OS between the Virus/alcohol group and the NAFLD/NASH group in patients who received sequential therapy (MST was 23.4 and 27.0 months p = 0.173, respectively). The NAFLD or NASH, female sex, albumin‐bilirubin (ALBI) grade 2b, and major Vp (Vp3/Vp4) were significant factors for OS treated with SORA. Conclusions Sequential therapy with SORA as the first‐line treatment improved the prognosis of unresectable HCC patients and was effective regardless of HCC etiology., Sequential therapy with SORA as the first‐line treatment prolonged the prognosis of unresectable HCC patients and was effective regardless of HCC etiology.

BACKGROUND AND AIM Direct-acting antivirals (DAAs) have contributed to the improvement of outcomes for all patients with chronic hepatitis C. The aim of this study was to evaluate the long-term hepatic benefits of hepatitis C virus (HCV) cure by DAAs in patients with compensated cirrhosis. METHODS This multicenter cohort study consisted of consecutive patients with compensated cirrhosis who initiated interferon-free DAA treatment before September 2016. The impact of treatment on long-term hepatic function was followed for at least 4 years after the end of treatment, and the progression to decompensation was evaluated. RESULTS The data of 394 patients were available for study. The median age was 70, and 41% had modified albumin-bilirubin (ALBI) grade 2b. During a short-term follow-up 1 year after the end of treatment, FIB-4 index and ALBI score significantly improved. The achievement rates of FIB-4

Dai Aoki,1,2 Nobuyuki Kajiwara,3,4 Keiko Irishio,5 Yasuhiro Kato,6 Shinya Suezaki,1 Misaki Kageyama,1 Masahiro Misago,1 Daisuke Tamai,7 Shinichiro Nakao,1 Takato Ueoka,1 Mototoshi Ito,1 Shinichiro Murakami1,4 1Department of Emergency and General Medicine, Ikeda City Hospital, Ikeda, Osaka, Japan; 2Fukuchiyama City Hospital Ooe-Branch, Fukuchiyama, Kyoto, Japan; 3Department of Nephrology, Ikeda City Hospital, Ikeda, Osaka, Japan; 4Toyono Town National Health Insurance Clinic, Toyono, Osaka, Japan; 5Department of Clinical Research, Ikeda City Hospital, Ikeda, Osaka, Japan; 6Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; 7Tamai Medical Clinic, Hannan, Osaka, JapanCorrespondence: Dai AokiDepartment of Emergency and General Medicine, Ikeda City Hospital, 3-1-18 Johnan, Ikeda, Osaka, 563-8510, JapanTel +81-72-751-2881Fax +81-72-754-6380Email 1000.0.d511@gmail.comObjective: A total of 105 patients (64 women) who were started on glucocorticoid (GC) treatment for polymyalgia rheumatica (PMR) and/or remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome at Ikeda City Hospital from July 2004 to December 2019 were reviewed (PMR: 81, overlap: 20, pure RS3PE syndrome: 4). Then, 32 cases that had stopped GC and 17 cases that had continued GC for 7.5 years or longer were evaluated (women:men, stopped GC 12:20, continued GC 13:4, respectively) (PMR:overlap:pure RS3PE syndrome, stopped GC 26:6:0, continued GC 14:2:1, respectively).Methods: The GC continuation rate in all patients was examined using the Kaplan–Meier method. The following were compared between the two groups: age at starting GC; sex; erythrocyte sedimentation rate, C-reactive protein, hemoglobin, ferritin, aspartate aminotransferase, and alanine aminotransferase before starting GC; days from the onset of symptoms to GC initiation; GC maximum dose; GC dose half a year after its start; presence of relapse; and existence of concomitant malignant disease.Results: The GC continuation rate 7.5 years after GC initiation was 52.5%, higher in women (69.2%), than in men (27.1%). The rates then remained unchanged for 15 years. Hemoglobin was high, and relapse was uncommon in the group that stopped GC. There were no differences in other items.Conclusion: It is difficult to stop GC therapy for PMR in women in Japan, especially in cases with severe anemia.Keywords: discontinuation of therapy, glucocorticoid, polymyalgia rheumatica, remitting seronegative symmetrical synovitis with pitting edema syndrome, sex difference

Adipocyte-rich omentum offers "good soil" for disseminating ovarian cancer (OvCa), contributing to therapeutic difficulty. However, little is understood about the association between adipocytes and tumor growth at peritoneal dissemination site. Herein, we report the induction of adipocyte dedifferentiation by OvCa cells and pro-tumorigenic effects of resulted adipocyte-derived fibroblasts. We confirmed that malignant ascites promoted the dedifferentiation of the primary human adipocytes obtained from surgical omental specimen into omental adipocyte-derived fibroblast (O-ADF) that possess both mesenchymal stem cell and myofibroblast-like features. This promotion of dedifferentiation by malignant ascites was blocked by addition of Wnt signaling inhibitor. The effects of dedifferentiated adipocytes in proliferation and migration of OvCa cells were analyzed with in vitro co-culturing experimental models and in vivo mice model, and we demonstrated that OvCa cell lines showed enhanced proliferative characteristics, as well as increased migratory abilities upon co-culturing with O-ADF. Additionally, exogenous transforming growth factor-β1 augmented desmoplastic morphological change of O-ADF, leading to higher proliferative ability. Our results suggest that OvCa cells promote dedifferentiation of peritoneal adipocytes by activating Wnt/β-catenin signaling, and generated O-ADFs exhibit pro-tumoral hallmarks. This article is protected by copyright. All rights reserved.

Purpose Hematopoietic cell transplantation (HCT) is a curative therapy for patients with severe combined immunodeficiency (SCID). Here, we conducted a nationwide study to assess the outcome of SCID patients after HCT in Japan. Methods A cohort of 181 SCID patients undergoing their first allogeneic HCT in 1974–2016 was studied by using the Japanese national database (Transplant Registry Unified Management Program, TRUMP). Results The 10-year overall survival (OS) of the patients who received HCT in 2006–2016 was 67%. Umbilical cord blood (UCB) transplantation was performed in 81 patients (45%). The outcomes of HCT from HLA-matched UCB (n = 21) and matched sibling donors (n = 22) were comparable, including 10-year OS (91% vs. 91%), neutrophil recovery (cumulative incidence at 30 days, 89% vs. 100%), and platelet recovery (cumulative incidence at 60 days, 89% vs. 100%). Multivariate analysis of the patients who received HCT in 2006–2016 demonstrated that the following factors were associated with poor OS: bacterial or fungal infection at HCT (hazard ratio (HR): 3.8, P = 0.006), cytomegalovirus infection prior to HCT (HR: 9.4, P = 0.03), ≥ 4 months of age at HCT (HR: 25.5, P = 0.009), and mismatched UCB (HR: 19.8, P = 0.01). Conclusion We showed the potential of HLA-matched UCB as a donor source with higher priority for SCID patients. We also demonstrated that early age at HCT without active infection is critical for a better prognosis, highlighting the importance of newborn screening for SCID. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-021-01112-5.

Objective Brachial artery transposition (BAT) is not a well known method for obtaining vascular access (VA) for maintenance haemodialysis. This study evaluated the outcomes of BAT. Methods This multicentre retrospective cohort study included 233 consecutive patients who underwent BAT between January 2012 and December 2013. The indications were inadequate vessels for obtaining VA, severe heart failure, hand ischaemia, central vein stenosis/occlusion, or a history of catheter/graft infection. The transposed brachial artery was used only for arterial inflow and other routes were used for outflow. Results BAT was successful in 227 patients, and adequate blood flow was achieved during dialysis sessions. The first successful cannulation was after a median of 18 days. BAT was performed using superficial veins as the return route in 127 patients and arteriovenous fistula (AVF) creation in 63 patients to prevent maturation failure. In 41 patients with central venous catheterisation, the transposed brachial artery was used for arterial inflow. The complications of BAT were impaired wound healing in 14 patients, including skin necrosis in two; large aneurysms in six, including a mycotic pseudo-aneurysm in one; arterial thrombosis in five; hand ischaemia in five; lymphorrhoea in four; and haematoma/bleeding in three. The transposed brachial artery was abandoned in four, three, three, and one case of arterial thrombosis/stenosis, haematoma/bleeding, skin necrosis, and large aneurysm, respectively. Access to the return routes failed in 48 cases because of vein damage caused by cannulation in 22, AVF thrombosis/stenosis in 14, catheter infection in six, and catheter occlusion in six. At two years, the primary patency rates of the transposed brachial artery and access circuit were 88% and 54%, respectively. Conclusion BAT is a safe and effective technique. The patency was high for the transposed brachial artery but adequate for the access circuit. BAT can be considered for patients with an unobtainable standard arteriovenous access.

The mitogen-activated protein kinase (MAPK) pathway plays an important role in the colorectal cancer (CRC) progression, being supposed to be activated by the gene mutations, such as BRAF or KRAS. Although the inhibitors of extracellular signal-regulated kinase (ERK) have demonstrated efficacy in the cells with the BRAF or KRAS mutations, a clinical response is not always associated with the molecular signature. The patient-derived organoids (PDO) have emerged as a powerful in vitro model system to study cancer, and it has been widely applied for the drug screening. The present study aims to analyze the association between the molecular characteristics which analyzed by next-generation sequencing (NGS) and sensitivity to the ERK inhibitor (i.e., SCH772984) in PDO derived from CRC specimens. A drug sensitivity test for the SCH772984 was conducted using 14 CRC cell lines, and the results demonstrated that the sensitivity was in agreement with the BRAF mutation, but was not completely consistent with the KRAS status. In the drug sensitivity test for PDO, 6 out of 7 cases with either BRAF or KRAS mutations showed sensitivity to the SCH772984, while 5 out of 6 cases of both BRAF and KRAS wild-types were resistant. The results of this study suggested that the molecular status of the clinical specimens are likely to represent the sensitivity in the PDOs but is not necessarily absolutely overlapping. PDO might be able to complement the limitations of the gene panel and have the potential to provide a novel precision medicine.

This study aimed to examine the beneficial effects of a novel prophylactic barbiturate therapy, step-down infusion of barbiturates, using thiamylal with normothermia (NOR+sdB), on the poor outcome in the patients with severe traumatic brain injuries (sTBI), in comparison with mild hypothermia (MD-HYPO). From January 2000 to March 2019, 4133 patients with TBI were admitted to our hospital. The inclusion criteria were: a Glasgow coma scale (GCS) score of ≤8 on admission, age between 20 and 80 years, intracranial hematoma requiring surgical evacuation of the hematoma with craniotomy and/or external decompression, and patients who underwent management of body temperature and assessed their outcome at 6-12 months. Finally, 43 patients were included in the MD-HYPO (n = 29) and NOR+sdB (n = 14) groups. sdB was initiated intraoperatively or immediately after the surgical treatment. There were no significant differences in patient characteristics, including age, sex, past medical history, GCS on admission, type of intracranial hematoma, and length of hospitalization between the two groups. Although NOR+sdB could not improve the patient's poor outcome either at discharge from the intensive care unit (ICU) or at 6-12 months after admission, the treatment inhibited composite death at discharge from the ICU. The mean value of the maximum intracranial pressure (ICP) in the NOR+sdB group was

Programmed cell death is a central process in the control of tissue development, organismal physiology, and disease. Ferroptosis is a recently identified form of programmed cell death that is uniquely defined by redox-active iron-dependent hydroxy-peroxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids and a loss of lipid peroxidation repair capacity. This distinctive form of lipotoxic cell death has been recently implicated in multiple human diseases, spanning ischemia-reperfusion heart injury, brain damage, acute kidney injury, cancer, and asthma. Intriguingly, settings that have been associated with ferroptosis are linked to placental physiology and trophoblast injury. Such circumstances include hypoxia-reperfusion during placental development, physiological uterine contractions or pathological changes in placental bed perfusion, the abundance of trophoblastic iron, evidence for lipotoxicity during the pathophysiology of major placental disorders such as preeclampsia, fetal growth restriction, and preterm birth, and reduced glutathione peroxidation capacity and lipid peroxidation repair during placental injury. We recently interrogated placental ferroptosis in placental dysfunction in human and mouse pregnancy, dissected its relevance to placental injury, and validated the role of glutathione peroxidase-4 in guarding placental trophoblasts against ferroptotic injury. We also uncovered a role for the phospholipase PLA2G6 (PNPLA9) in attenuating trophoblast ferroptosis. Here, we summarize current data on trophoblast ferroptosis, and the role of several proteins and microRNAs as regulators of this process. Our text offers insights into new opportunities for regulating ferroptosis as a means for protecting placental trophoblasts against lipotoxic injury.

Emergent scientific evidence indicates the central role of cancer-associated fibroblasts in determining whether the microenvironment of cancer works as friend or foe of the host; however, there is no unified histological evaluation framework of fibrotic stroma in colorectal cancers. Myxoid stroma and keloid-like collagen are site-specific histopathological features generated by cancer-associated fibroblasts, which appear exclusively in the tumor front during desmoplastic reaction. On the basis of these two stromal components, desmoplastic reaction is categorized into three patterns—immature, intermediate and mature—using hematoxylin and eosin staining. In January 2020, a prospective randomized clinical trial, JCOG1805, to elucidate the value of adjuvant chemotherapy in stage II colorectal cancer patients with pathological risk factors of recurrence was launched in Japan, in which intermediate/immature desmoplastic reaction is one of the four risk factors selected as inclusion criteria. This paper covers the diagnostic criteria for the desmoplastic reaction classification being used in the JCOG1805 study., The present article illustrates the diagnostic criteria of desmoplastic reaction classification, a novel prognostic factor in colorectal cancer, used in the JCOG1805 trial conducted by the Japan Clinical Oncology Group.

Background and aim The Mayo Endoscopic Subscore (MES) and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) are used to assess endoscopic mucosal healing in patients suffering from ulcerative colitis. Although mucosal healing is defined by MES 0, relapse of ulcerative colitis is often observed. Over a 48-month period, this study investigated the efficacy of linked color imaging (LCI) in predicting the long-term prognosis of ulcerative colitis patients diagnosed with MES 0. Methods Overall, 26 patients in ulcerative colitis remission, diagnosed with MES 0, were enrolled. Using a LASEREO endoscopic system (Fujifilm Co., Tokyo, Japan), endoscopic colonic images were assessed with linked color imaging and the colitis endoscopic index of severity. Endoscopic LCI images were separated into three subgroups (A, no redness; B, redness with visible vessels; and C, redness without visible vessels). The Geboes score was used to evaluate histology; active mucosa was defined as GS > 2B.1. Results Linked color imaging classification subdivided colonic mucosa, which had been diagnosed with MES 0, into two classes. The LCI-A group did not relapse, and the non-relapse rate was significantly higher (P = 0.018) than that in the LCI-B group. No difference in relapse rates was observed between patients with a colitis endoscopic index of severity of 0 and 1 (P = 0.655). There was no statistical difference between the composition of LCI-A group and the relapse rate between active and inactive mucosa diagnosed by Geboes score. Conclusions This methodology can be used to evaluate mucosal healing and predict long-term outcomes in ulcerative colitis patients.

BACKGROUND Appropriate surgical treatment of epithelial ovarian tumors is reliant on intraoperative diagnosis. A retrospective study to compare the diagnostic accuracies of imprint cytology (IC) with frozen section histology (FSH) in these tumors was performed. METHODS About 78 cases of IC-based and FSH-based diagnoses against the final histopathologic diagnoses in terms of both histologic subtype (serous, mucinous, endometrioid, or clear cell tumor) and behavioral type (benign, borderline, or malignant) were compared. The cytomorphologic features of the tumor cells (nuclear atypia, papillary clusters, adenoma cells, and necrosis) in relation to behavioral types were also evaluated. RESULTS While the diagnostic accuracy of IC and FSH were similar with respect to behavioral type (87% and 88%, respectively), the diagnostic accuracy of IC was superior to that of FSH with respect to histologic subtype (83% and 74%, respectively). Among histopathologically confirmed malignant tumors, the diagnostic accuracy of IC (62/64; 97%) was superior to that of FSH (58/64; 91%). The presence of necrosis and absence of adenoma cells were significantly more prevalent among malignant group than among borderline and benign groups (P

Background The role of IL-12/23 in the pathogenesis of ulcerative colitis (UC) is unclear. We analyzed mucosal IL-12/23 expression and its relationship with endoscopic severity, histological activity, and UC relapse. Methods Rectal biopsies were collected from 70 UC patients with clinical remission. IL-12, IL-23, IFN-γ, IL-17A, and IL-17F mRNA expression was measured by real-time PCR. Endoscopic severity and histological activity were evaluated using the Mayo endoscopic subscore (MES) and the Geboes score, respectively. Results The longest follow-up period was 51 months. Thirty-four patients relapsed during the study period. Samples from these subsequently relapsed patients formed the “relapse” group, while those from patients that did not relapse formed the “remission” group. IL-12 (P = 0.0003) and IL-23 (P = 0.014) mRNA expression was significantly higher in the relapse than the remission group. Expression of IL-23 (P = 0.015) but not IL-12 (P = 0.374) was correlated with MES. However, in patients with an MES of 0 and 1, IL-12 expression was statistically higher in the relapse than the remission group (P = 0.0015, P = 0.0342). IL-12 and IL-23 expression did not vary significantly between histologically active and inactive mucosa; both were higher in histologically inactive patients in the remission group (IL-12: P = 0.0002, IL-23: P = 0.046). Conclusions Rectal IL-12 and IL-23 expression was elevated in the relapse group, but IL-12 was more strongly associated with UC relapse, irrespective of endoscopic severity and histological activity. Mucosal IL-12 was elevated in patients with deep mucosal healing. Our results suggest an important role of IL-12 in UC pathogenesis and the molecular mechanism of UC relapse.

This study aimed to investigate the side effects of silicone gel sheet (Lady Care®) and evaluate its prophylactic efficacy in preventing abnormal scarring. Sixty women who underwent caesarean section were recruited from September 2016 to September 2017 in this prospective study. Lady Care® was applied from the 2nd to the 6th postoperative months. Side effects of Lady Care® were evaluated through medical examinations and questionnaires. A plastic surgeon diagnosed abnormal scarring. Pruritus was diagnosed in 25 (47.2%) patients; folliculitis, four (7.5%); dry skin, four (7.5%); contact dermatitis, three (5.7%); wound infection, two (3.8%); and epidermolysis, one (1.9%), albeit with mild severity. Following Lady Care® application, no abnormal scarring and mild hypertrophic scarring was observed in 32 (64.0%) and 18 (36.0%) patients respectively. Of seven patients with pre-existing hypertrophic scars, only two showed hypertrophic scarring after Lady Care® application. Our findings support the safety and prophylactic efficacy of Lady Care®.Impact StatementWhat is already known on this subject? The incidence of abnormal scarring, i.e. keloid or hypertrophic scar formation after caesarean section (CS) is reported to be ∼41%. Abnormal or excessive scar formation can lead to functional limitations, pruritus, pain and cosmetic issues. Studies have also shown a prophylactic effect of the application of silicone materials against the development of hypertrophic and keloid scars, though prohibitive cost and lack of adhesiveness of such gel sheets are known factors limiting their usage.What the results of this study add? The new silicone gel sheet 'Lady Care®' has strong adhesive properties and is consequently not easily peeled off. Furthermore, it is easy to use and economically efficient.What the implications are of these findings for clinical practice and/or further research? This is the first clinical trial on the application of Lady Care® silicone gel sheet for the prevention of CS scarring. Our findings support the safety and prophylactic efficacy of Lady Care®.

We investigated the susceptibility of type I and type II skeletal myofibres to atrophy in hens with hepatic fibrosis induced by bile duct ligation (BDL). Seven hens, approximately 2 years old, were randomly assigned to BDL (n = 4) and sham surgery (SHAM) (n = 3) groups. Mean body weight and mean liver weight as a percentage of mean body weight were significantly lower in the BDL group than in the SHAM group at 4 weeks post surgery (P = 0.002, P = 0.005, respectively). Mean plasma aspartate aminotransferase activity was slightly higher, while total cholesterol (P 0.001), total bilirubin (P = 0.022) and NH

Sialadenoma papilliferum (SP) is a rare benign tumor of the salivary glands, and only three unequivocal cases of SP arising in the bronchus have been reported. We herein describe the histomorphologic and molecular features of four bronchial SP cases and discuss the differential diagnosis of this entity and the relationship with its clinicopathological mimics, in particular, glandular papilloma and mixed squamous cell and glandular papilloma (GP/MP). We encountered 2 male and 2 female patients with bronchial SP (mean 66.8 years old). All four tumors arose in the central bronchus and were characterized by a combination of surface exophytic endobronchial papillary proliferation and a submucosal multicystic component with complex architecture. The neoplastic epithelium consisted predominantly of non-ciliated stratified columnar cells with ciliated, squamous, and mucinous cells present focally. While 2 tumors (50%) harbored a BRAF V600E mutation by molecular and immunohistochemical analysis, similar to GP/MP, no KRAS, HRAS, AKT1 or PIK3CA mutations were detected in any of the cases. Two patients were treated with limited resection, while two patients underwent lobectomy based on the diagnosis of adenocarcinoma or possible squamous cell carcinoma in situ in the preoperative biopsy. All survived without recurrence or metastasis for 23 to 122 months after treatment. SP can develop in the central bronchus as the bronchial counterpart of the salivary gland tumor and should be considered in the differential diagnosis of endobronchial tumors. In addition, some histological resemblance and frequent BRAF V600E mutation raise the possibility of SP and GP/MP being on the same disease spectrum.

We report a rare case of amebiasis associated with an intraabdominal abscess without colitis, an intestinal perforation, or other extraintestinal amebiasis. A patient was admitted with cirrhosis and a history of spontaneous bacterial peritonitis (SBP) and was found to have a high C-reactive protein (CRP) level. Dynamic CT and ultrasound echo findings showed an intraabdominal abscess. No intestinal lesions or extraintestinal lesions other than the intraabdominal abscess were observed. Blood cultures and puncture fluid cultures were negative for bacteria. However, microscopic examination of the puncture fluid showed a cystic form of amoeba, leading to a diagnosis of an amoeba abscess. The abscess disappeared after 10 days of oral treatment with metronidazole. When an abdominal abscess is seen in an immunocompromised patient such as a cirrhotic patient, amoeba infection should be considered as a possible diagnosis.

We report on a 69-year-old man with locally-advanced left maxillary sinus cancer who underwent treatment with intra-arterial chemoradiotherapy. Angiography showed that the main feeding arteries were the left maxillary artery and the ophthalmic artery, arising from the internal carotid artery. Due to acute branching of the ophthalmic artery, conventional microcatheters could not be inserted. Using a steerable microcatheter, we were able to repeatedly administer chemoradiotherapy via the ophthalmic artery. The tumor has mostly disappeared after intra-arterial chemoradiotherapy, and the patient is still alive two years after treatment. A steerable microcatheter is very useful for acute-angled vascular branches.

Background & Aims: Intermediate hepatocellular carcinoma (HCC) treatment has become complicated due to the development of various molecular-targeted agents (MTAs). We aimed to determine whether the administration of MTAs in patients with intermediate-stage HCC contributed to the prevention of progression to an advanced stage. Methods: We enrolled and retrospectively examined 289 patients with Child-Pugh class A who had been diagnosed with intermediate-stage HCC and underwent initial trans-arterial chemoembolization (TACE). Patients were classified into 2 groups: a group in which MTAs were administered to patients whose condition was refractory to TACE (n = 65) and a group in which MTAs were not administered (n = 65) at intermediate-stage HCC after propensity score matching (PSM). Time to stage progression (TTSP) and overall survival (OS) were calculated using the Kaplan-Meier method and analyzed using a log-rank test after PSM. Results: TTSP and OS of the group with MTA administration were significantly longer than those of the group without MTA administration (TTSP: 36.4 vs. 17.9 months, p < 0.001; median survival time [MST]: 44.6 vs. 26.6 months, p = 0.001). Within the up-to-seven criteria and administration of MTAs at the intermediate-stage HCC were identified as independent factors for TTSP and OS in the multivariate analysis. TTSP and OS in the era of the multi-MTA group were significantly longer than those in the era of the mono-MTA group (TTSP: 44.8 vs. 27.4 months, p = 0.01; MST: 53.4 vs. 33.3 months, p = 0.01). Conclusion: The administration of MTAs in patients with intermediate-stage HCC contributes to the prevention of stage progression and prolongs OS.

Background Amoebiasis caused by the protozoan species Entamoeba histolytica rarely develops into fulminant amoebic colitis (FAC), but when it does, it shows an aggressive clinical course including colonic perforation, necrotizing colitis, and high mortality. Surgical treatment for FAC patients should be carried out urgently. However, even after surgery, the mortality rate can be 40–50%. Although FAC is one of the most unfavorable surgical diseases with a poor prognosis, there are a few reports on the perioperative diagnosis and management of FAC based on autopsy findings. We herein report the surgical case of a 64-year-old man who developed multiple colon necrosis and perforation due to FAC. A detailed autopsy revealed FAC as the cause of death. Additionally, we reviewed the existing literature on FAC patients who underwent surgery and followed their perioperative diagnosis and management. Case presentation A 64-year-old man presented with anorexia, diarrhea, and altered consciousness on arrival to our hospital. Computed tomography revealed a large mass in the upper right lobe of his lung, and the patient was admitted for close investigation. Bloody diarrhea, lower abdominal pain, and hypotension were observed soon after admission. Urgent abdominal contrast-enhanced computed tomography scan revealed extensive intestinal ischemia, intestinal pneumatosis, and free intra-abdominal gas. The preoperative diagnosis was bowel necrosis and perforation with intussusception of the small intestinal tumor. Emergency subtotal colectomy and enterectomy were performed soon after the contrast-enhanced computed tomography. He was taken to an intensive care unit after surgery. However, he could not recover from sepsis and died with disseminated intravascular coagulation and multiple organ failure on the 10th-day post-surgery. A histopathological examination of the resected colon showed transmural necrosis and massive amoebae invasion. He was diagnosed with FAC. An autopsy revealed that he had developed pulmonary large cell carcinoma with small intestinal metastasis. The death was caused by intestinal ischemia, necrosis and the perforation of the residual bowel caused by amoebae invasion. Conclusions Since FAC is a lethal disease with a high mortality rate and antibiotic therapies except metronidazole are ineffective, preoperative serological testing and perioperative metronidazole therapy in FAC patients can dramatically improve their survival rates.

Categorizing desmoplastic reaction (DR) based on the histological findings of cancer-associated fibroblasts is shown to be a promising novel method to predict prognosis of patients with colorectal cancer (CRC). Periostin (POSTN) in cancer-associated stroma is reportedly associated with poor clinical outcomes. Immunohistochemical staining with an anti-POSTN antibody was performed in 73 patients with pStage III CRC (cohort 1). In addition, to evaluate mRNA and protein expression levels of POSTN, we analyzed paired normal and invasive cancer frozen specimens by quantitative real-time polymerase chain reaction and western blot analysis in 41 patients (cohort 2). In cohort 1, according to the DR categorization, 18, 22, and 33 patients were classified as immature, intermediate, and mature, respectively. High immunoreactivity of POSTN was observed 100%, 68.2%, and 27.3%, respectively (p

Background: The sensitivity of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in hepatocellular carcinoma (HCC) is low; however, clinical evidence demonstrating its prognostic value in patients with HCC has recently been reported. This study aimed to assess the value of 18F-FDG-PET/CT as a tool for evaluating the response of HCC to lenvatinib treatment. Methods: We evaluated 11 consecutive patients with HCC diagnosed by dynamic CT or magnetic resonance imaging combined with 18F-FDG-PET/CT from April 2018 to December 2019. The tumor-to-normal liver ratio (TLR) of the target tumor was measured before and during the course of lenvatinib treatment with 18F-FDG-PET/CT (pre and post analysis, respectively), with a TLR ≥2 classified as PET-positive HCC. At the time of each evaluation, we also used the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the modified RECIST (mRECIST), and the tumor marker alfa-fetoprotein (AFP). Results: Of 11 patients, 3 (27%) and 8 (73%) had an objective response to lenvatinib treatment at the time of post-analysis by RECIST 1.1 and mRECIST, respectively. There were 3 (27%) and 7 (64%) patients with PET-positive HCC at the time of pre- and post-analysis, respectively. There was a significant correlation between the rates of change in AFP and TLR during lenvatinib treatment (r = 0.69, p = 0.019). Based on these results, we were able to perform liver resection on 4 patients with PET-positive HCC as conversion therapy. Three samples from these patients showed poorly differentiated tumors. Conclusion: 18F-FDG-PET/CT has potential as an evaluation tool for describing biological tumor behavior and reflecting disease progression, location, and treatment response. This modality may provide useful information for considering prognosis and subsequent therapy.

We report a 71-year-old man with non-B non-C chronic liver damage who had been regularly visiting our hospital since he was 38 years of age. He underwent three partial hepatectomies for hepatocellular carcinoma (HCC) diagnosed at 65, 67, and 71 years of age, respectively. A histopathological examination showed moderately-differentiated HCC, and chronic hepatitis with mild fibrosis stage in non-tumor areas. alpha-fetoprotein (AFP) and PIVKAII were not useful for the early prediction of HCC, but TERT promotor mutation (C228T) in serum cell-free DNA was useful. This is the first report on the importance of long-term follow-up in non-B non-C chronic liver damage, regardless of the fibrosis stage.

Background: The aims of this study were to evaluate the efficacy of additional treatment, especially lenvatinib-transarterial chemoembolization (TACE) sequential therapy, for unresectable hepatocellular carcinoma (HCC). Methods: Consecutive 56 patients who underwent lenvatinib treatment were reviewed. Oncological aggressiveness of tumor was estimated using a dynamic CT enhancement pattern classification, and clinical impact of subsequent treatment was investigated through analysis of progression-free survival (PFS), post-progression survival (PPS), and multivariate analysis of potential confounders for survival after progression during lenvatinib therapy. Results: Heterogeneous enhancement patterns (Type-3 and -4), which are reportedly associated with higher oncological aggressiveness of HCC, were associated with better objective response to lenvatinib compared to homogeneous enhancement pattern (Type-2) (86 and 85% vs. 53% in modified Response Evaluation Criteria in Solid Tumors), resulting in similar PFS (p = 0.313). Because of significantly worse PPS, overall survival of Type-4 tumor was poor compared to Type-2 or -3 tumors (p = 0.009). However, subgroup of patients who achieved subsequent treatment showed significantly better PPS, regardless of CT enhancement pattern. Multivariate analysis confirmed that use of lenvatinib-TACE sequential treatment after progression during lenvatinib therapy was associated with better PPS (hazard ratio [HR], 0.08; 95% CI, 0.01–0.71; p = 0.023), while Type-4 enhancement pattern was correlated with worse PPS (HR, 2.92; 95% CI, 1.06–8.05; p = 0.039). Conclusion: Oncological aggressiveness of HCC estimated by CT enhancement pattern was predictive of PPS after progression during lenvatinib. Successful subsequent treatment with lenvatinib-TACE sequential therapy may offer survival benefit regardless of CT enhancement pattern of HCC.

Mesothelin (MSLN) is a cell surface glycoprotein that is normally expressed in the mesothelial cells but highly expressed in several malignant tumors, where the high expression is generally associated with poor prognosis. In this work, 512 patients with stage III colorectal cancer (CRC) were examined to ascertain the prognostic value of MSLN expression in preoperative endoscopic biopsy specimens. MSLN expression was evaluated by immunohistochemical staining. The tumor cells were MSLN-positive in 61 of the 512 patients (11.9%). MSLN expression was associated with a shorter disease-specific survival (DSS) period (5-year DSS = 68.7%, P = 0.0008). Besides, by multivariate analysis, MSLN expression was identified to be a marker of poor prognosis by multivariate analysis (P = 0.0033, hazard ratio (HR) = 2.31) as well as macroscopic type (P = 0.047, HR = 1.82) among the factors that can be evaluated preoperatively. MSLN-positive patients had a significantly poorer prognosis regardless of adjuvant chemotherapy administration (P = 0.0081 and P = 0.0018 for surgery alone and chemotherapy, respectively). MSLN-positive patients in the adjuvant chemotherapy group exhibited a significantly lower risk of recurrence when compared with those in the surgery alone group (P = 0.0090). In conclusion, high MSLN expression observed in preoperative endoscopic biopsy specimens of stage III CRC was an independent poor prognostic factor. Preoperative evaluation of MSLN by immunohistochemical staining might be applied to select individuals for intensive preoperative chemotherapy among the stage III CRC patients.

OBJECTIVES To assess the change in rates of recurrence-free survival (RFS) and progression-free survival (PFS) based on the duration of survival without recurrence or progression among patients with intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC), and to examine the predictive factors for recurrence at different time points by assessing conditional RFS and PFS. PARTICIPANTS AND METHODS A cohort of 602 patients treated with transurethral resection of bladder tumour and histopathologically diagnosed with IR NMIBC was included in this retrospective study. RESULTS The conditional RFS rate at 1, 2, 3, 4 and 5 years improved with increased duration of RFS; however, the conditional PFS rate did not improve over time. Multivariable analyses showed that recurrent tumour, multiple tumours, tumour size (>3 cm), immediate postoperative instillation of chemotherapy, and administration of BCG were independent predictive factors for recurrence at baseline. The predictive ability of these factors disappeared with increasing recurrence-free survivorship. Subclassification of these patients with IR NMIBC into three groups using clinicopathological factors (recurrent tumour, multiple tumours, tumour size) demonstrated that the high IR group (two factors) had significantly worse RFS than the intermediate (one factor, P < 0.001) and low IR groups (no factor, P = 0.005) at baseline. This subclassification stratified conditional risk of RFS also at 1, 3 and 5 years, which provides the basis for distinct surveillance protocols among patients with IR NMIBC. CONCLUSION Conditional survival analyses of patients with IR NMIBC demonstrate that RFS changes over time, while PFS does not change. These data support distinct surveillance protocols based on the subclassification of IR NMIBC.

Reports on the prognosis for 5-year survivors with lung adenocarcinoma after resection are sparse. This study aimed to identify factors associated with overall survival (OS) and cancer-specific survival (CSS) for 5-year survivors with completely resected lung adenocarcinoma, and to determine whether preoperative imaging factors, including the presence of ground-glass opacity (GGO) components, affect late recurrence in long-term survivors. Complete resection of lung adenocarcinoma was performed for 1681 patients between January 2000 and December 2013. Of these patients, 936 who survived 5 years or longer after surgery were identified, and factors associated with OS and CSS were determined using the Cox proportional hazard model. Multivariable analysis demonstrated that lymph node metastasis (p

Thermal ablative techniques are used increasingly to treat renal cell carcinoma (RCC). Percutaneous cryoablation of tumors at the upper pole of the kidney may result in pulmonary damage due to the intervening lung parenchyma. We treated two patients with RCC in the upper pole of the kidney by inducing pneumothorax with a pneumoperitoneum needle before proceeding to percutaneous cryoablation. The procedures, performed under computed tomography (CT) fluoroscopy guidance, resulted in complete tumor necrosis. There was no pulmonary damage.

Background To provide normal knee function, a total knee arthroplasty (TKA) implant with an anatomic surface shape and an adequate sagittal position has been developed. However, it is unclear how this modern implant influences knee joint kinetics and muscle activation during a gait. Therefore, we evaluated this modern TKA prosthesis and compared it with a conventional TKA prosthesis for gait analysis in terms of kinetics and muscle activation. Methods Subjects were patients (>60 years of age) with knee osteoarthritis who had undergone unilateral TKA. Twelve patients received the modern TKA prosthesis (group modern), and the other 12 patients received a conventional TKA prosthesis (group conventional). The subjects underwent motion capture analyses with a force plate, and kinematic and kinetic data were acquired from a 10-m gait test. Electromyography data of 6 lower limb muscles were simultaneously collected during the gait test. The 2 groups were compared using unpaired t-tests. Results In group modern, gait speed was faster, step length was longer, and the knee flexion angle during the initial stance phase was larger. Furthermore, in group modern, the maximum knee extension moment was higher; however, the quadriceps muscle activity tended to be lower than that in group conventional. Conclusions Gait characteristics of group modern were more like a normal gait, and knee joint extension moments were greater. This finding indicates that the quadriceps muscles can be more effectively activated, and the anterior stability function of the anterior cruciate ligament may be reproduced with the shape of the modern implant.

Background Tumour budding is an important prognostic feature in early‐stage colorectal cancer, but its prognostic significance in metastatic disease has not been fully investigated. Methods Patients with stage IV disease who had primary colorectal tumour resection without previous chemotherapy or radiotherapy from January 2000 to December 2018 were reviewed retrospectively. Budding was evaluated at the primary site and graded according to the criteria of the International Tumor Budding Consensus Conference (ITBCC) (BD1, low; BD2, intermediate; BD3, high). Patients were categorized by metastatic (M1a, M1b) and resectional (R0/R1, R2/unresected) status. Subgroups were compared for overall (OS) and recurrence‐free (RFS) survival in R0/R1 subgroups; R2/unresected patients were evaluated for the rate of tumour progression, based on change in tumour size from baseline. Results Of 371 patients observed during the study, 362 were analysed. Patients with BD3 had a lower 5‐year OS rate than those with BD1 + BD2 (18·4 versus 40·5 per cent; P, In stage IV colorectal cancer, tumour budding graded by International Tumor Budding Consensus Conference criteria is an important morphological marker that can predict prognosis and, possibly, tumour chemoresistance. The clinical relevance was maintained consistently in both resection subgroups (R0/R1 and R2/unresected). Tumor budding and colorectal metastasis

Background/aim Bladder cancer with histological variant (HV) has different morphological features from usual urothelial carcinoma (UC). The aim of this study was to evaluate the oncological outcomes of HV in patients with bladder cancer. Patients and methods We retrospectively evaluated data from 102 patients with UC of the bladder treated with radical cystectomy between 1998 and 2017. Pathological findings including HV were assigned by one dedicated pathologist. Recurrence-free survival (RFS) and cancer-specific survival (CSS) and overall survival (OS) were estimated by Cox regression models. Results In total, 26 patients (25.5%) had HV, and the most common variant was squamous differentiation, followed by glandular differentiation and a mixed variant consisted of squamous and glandular differentiation. The presence of HV was associated with RFS and CSS (p=0.018, p=0.036, respectively). Conclusion HV has more aggressive tumor biological features compared to those with pure UC. The presence of HV was associated with poor survival.

Hallux valgus (HV) is a foot deformity with deviation of the greater toe and the first metatarsal. There is little evidence on training the abductor hallucis muscle (AbdH) to treat HV because of the difficulty in implementing the necessary interventions. Although neuromuscular electrical stimulation (NMES) has been used to induce voluntary exercise, there is currently no study on NMES for AbdH. We aimed to verify the immediate effect of NMES on the AbdH muscle function. For the NMES group (n = 15), electrical stimulation was applied for 20 min. In the sham group (n = 15), the stimulating device was set but not turned on. Electromyogram, HV angle (HVA) at rest and during abduction of the big toe, and strength of the AbdH were evaluated. Analysis of covariance was used to investigate differences within groups using the baseline as the covariate. NMES significantly improved the maximal voluntary isometric contractions (%MVIC), HVA at exercise, and muscle strength (%MVIC

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis. Patients with inoperative PDAC require effective chemotherapy and pain control to increase their quality of life. We investigated whether duloxetine, a serotonin-noradrenaline reuptake inhibitor, improves quality of life in a KPPC (LSL-Kras;Trp53;Pdx1-cre) mouse model of PDAC. Six-week-old KPPC mice were orally administered 4 mg/kg/d duloxetine (n = 12); 4 mg/kg/d duloxetine with 0.15 mg/kg/d atipamezole, a synthetic α2 adrenergic receptor antagonist (n = 9); or vehicle water (n = 11). Body weight and food intake were measured daily, and cancer pain was evaluated by the hunching score and mouse grimace scale. At the endpoint, the tumor status, angiogenesis, and immunoinflammatory condition were analyzed. The pain level using the hunching and mouse grimace scale scores improved by duloxetine in KPPC mice (P < 0.01), whereas the scores that had been reduced by duloxetine were elevated by administration of atipamezole. Kaplan-Meier analysis demonstrated that duloxetine-treated mice had significantly prolonged survival (P < 0.05) with delayed appetite loss, cachexia, and body weight loss. Duloxetine inhibited the proliferation of PDAC cells and cancer-associated fibroblasts in vivo with a shift into an antitumor immunoinflammatory condition and the corresponding plasma cytokine levels. The migrative/invasive potentials of PDAC were inhibited by duloxetine in vitro. Meanwhile, atipamezole did not inhibit the antitumor effects of duloxetine in vitro and in vivo. Therefore, our results indicate that duloxetine mainly improves cancer-associated pain by enhancement of the noradrenergic pathway rather than the serotonergic pathway, whereas duloxetine modulates antitumor effects on PDAC without involvement of the noradrenergic pathway.

Penicillium marneffei is a thermally dimorphic fungus that causes penicilliosis, and become the third-most-common opportunistic fungal infection in immunocompromised patients in Southeast Asia. Azoles and amphotericin B have been introduced for the treatment, however, it is important to investigate possible mechanisms of azole resistance for future treatment failure. We identified 177 putative MFS transporters and classified into 17 subfamilies. Among those, members of the Drug:H+ antiporter 1 subfamily are known to confer resistance to antifungals. Out of 39 paralogs, three (encoded by PmMDR1, PmMDR2, and PmMDR3) were heterologously overexpressed in S. cerevisiae AD∆ conferred resistance to various drugs and compounds including azoles, albeit to different degrees. PmMDR1-expressing strain showed resistance to the broadest range of drugs, followed by the PmMDR3, and PmMDR2 conferred weak resistance to a limited range of drugs. We conclude that PmMDR1 and PmMDR3, may be able to serve as multidrug efflux pumps.

IL-17 plays a critical role in the immunological control of various infectious diseases; its function has been investigated in the removal of both extracellular and intracellular bacteria. Our group previously revealed the importance of IL-17 in neutrophil migration following Legionella infection by using IL-17AF knockout mice; however, aside from neutrophil infiltration, alternative causes for the reduced survival of these mice have not been characterized. In this study, we found that γδ T cells in IL-17AF knockout mice were markedly increased and produced the cytotoxic substances granzyme B and perforin. Moreover, the elimination of γδ T cells from these mice, via an anti-TCRδ Ab, caused a substantial reduction in the level of lactate dehydrogenase in bronchoalveolar lavage fluid, indicating that γδ T cells contribute to lung tissue damage. Moreover, although cells lysed by cytotoxic substances are typically eliminated by phagocytic cells, in IL-17AF knockout mice, lung homeostasis was not maintained because of a decrease in phagocytic cells that impaired the clearance of dead cells. Our results indicate that increased γδ T cells in IL-17AF knockout mice help eliminate Legionella by releasing cytotoxic substances and lysing infected cells; however, this results in tissue damage due to insufficient removal of dead cells by phagocytic cells. This study enhances our understanding of the protective response against Legionella and provides insights into γδ T cell–mediated protective immunity against various infectious diseases.

Background Direct-acting antiviral (DAA) treatment has revolutionized hepatitis C virus (HCV) care. We aimed to evaluate the risk for the development of hepatocellular carcinoma (HCC) in patients aged 75–84 years with chronic hepatitis C after HCV elimination. Methods This multicenter cohort study included 2405 consecutive patients with chronic hepatitis C without a history of HCC who achieved HCV elimination by DAAs. Patients in whom HCC developed within 1 year of DAA initiation were excluded. Propensity score matching analysis was used to evaluate differences in HCC risk between patients aged 75–84 versus 60–74 years. Results The median observational period was 3.5 years. Among patients aged 75–84 years with a high Fibrosis-4 (FIB-4) index (≥3.25 at baseline), there was no significant difference in the annual incidence of HCCs between groups with an FIB-4 index ≥3.25 (2.75 per 100 person-years [PY]) versus Conclusions Older patients aged 75–84 years remained at high risk for the development of HCC, even after HCV elimination and the improvement of the FIB-4 index to

Rationale: Aspirin-exacerbated respiratory disease is characterized by severe asthma, nonsteroidal antiinflammatory drug hypersensitivity, nasal polyposis, and leukotriene overproduction. Systemic ...

It was recently identified that the vasohibin family may regulate angiogenesis through suppression by the vasohibin-1 gene and promotion by the vasohibin-2 gene. We assessed vasohibin expression in gastric cancer patients and its effect on their prognosis. We evaluated vasohibin immunohistochemical expression in 210 patients with gastric cancer, who underwent radical surgery. The patients were divided first into a vasohibin-1-positive group and a vasohibin-1-negative group, and then into groups with high or low vasohibin-2 expression, to allow us to investigate the clinicopathological factors of prognosis retrospectively. There were 139 patients in the vasohibin-1-positive group and 71 patients in the vasohibin-1-negative group, among which there were and 108 with high vasohibin-2 expression and 102 with low vasohibin-2 expression. Vasohibin-1 was associated with Ly (P = 0.003) and pT (P = 0.037), whereas vasohibin-2 was associated with Ly (P

Many patients undergoing hepatectomy for colorectal liver metastases (CRLM) experience recurrence. However, no criteria for screening candidates to undergo repeat hepatectomy (RH) for CRLM have been established. Budding, one form by which colorectal carcinoma malignancies are expressed, is a new pathologic index. This study aimed to analyze prognostic factors, including budding, and to provide criteria for screening candidates to undergo RH for recurrent CRLM. Data of 186 consecutive patients who underwent hepatectomy for CRLM between April 2008 and December 2015 were collected. Survival was calculated using the Kaplan–Meier method. Uni- and multivariate analyses were performed to determine factors significantly affecting mortality. Of 186 patients, 131 experienced recurrence after hepatectomy, with 83 of the 131 patients showing recurrence in the liver, and 52 of these 83 patients undergoing primary surgery at the authors’ institution and having information on budding grade. In the univariate analysis, preoperative chemotherapy, budding grade, extrahepatic metastases, and number of liver metastases at the time of recurrence were associated with overall survival (OS) for the 52 patients. In the multivariate analysis, budding grade and number of liver metastases at the time of recurrence were associated with OS. The study examined simple prognostic factors that could help to screen patients better for RH. Repeat hepatectomy improved the prognosis for patients with recurrent CRLM. The independent prognostic factors for OS were number of liver metastases at recurrence as a conventional factor and budding grade as a new pathologic factor. With budding used as an index, patients who could benefit from hepatectomy can be screened more precisely.

Gorlin syndrome is a rare autosomal dominant hereditary disease with high incidence of tumors such as basal cell carcinoma and medulloblastoma. Disease-specific induced pluripotent stem cells (iPSCs) have now been used as a model to analyze disease pathogenesis as well as an animal model. In this study, we generated iPSCs derived from fibroblasts of four patients with Gorlin syndrome (Gln-iPSCs) with a heterozygous mutation of the PTCH1 gene. Gln-iPSCs from the four patients developed medulloblastoma in 100% (four out of four), a manifestation of Gorlin syndrome, in the teratomas after implantation into immunodeficient mice, but none (0/584) of the other iPSC-teratomas. One of the medulloblastomas had loss of heterozygosity in the PTCH1 gene while benign teratoma, i.e. non-medulloblastoma part, did not, indicating a close clinical correlation between tumorigenesis in Gorlin syndrome patients and Gln-iPSCs.

Primary central nervous system lymphoma (PCNSL) is a brain malignant non-Hodgkin’s B-cell lymphoma. The standard treatments are high-dose methotrexate (MTX)-based chemotherapies and deferred whole brain radiotherapy. However, MTX resistance-dependent global expression and signaling pathway changes and their relationship with prognoses have not yet been elucidated. Here, we conducted a global expression analysis with next-generation sequencing and gene set enrichment analysis (GSEA) in MTX-resistant PCNSL cell lines (HKBML-MTX and TK-MTX) and PCNSL tissues. In rank scores, genes listed in HKBML-MTX and TK-MTX were enriched in PCNSL with poor prognoses. In fold changes, a part of differentially-expressed genes in PCNSL tissues were also detected in HKBML-MTX and TK-MTX cells; FOXD2-AS1 and MMP19 were commonly expressed in both HKBML-MTX and TK-MTX, FABP5 and CD70 were HKBML-MTX-specifically expressed, and CLCN2, HOXB9, INE1, and LRP5L were TK-MTX-specifically expressed, which may provide a combination of prognostic markers on MTX-sensitivities in PCNSL. Additionally, PCNSL subgroups, divided with hierarchical clustering and Kaplan-Meier methods, included twenty commonly expressed genes in both HKBML-MTX and TK-MTX, ten HKBML-MTX-specifically expressed genes, and two TK-MTX-specifically expressed genes. These results suggest that the GSEA-assisted gene signatures can provide a combination for prognostic markers in recurrent PCNSL with MTX resistances.

BACKGROUND AND AIMS Tenofovir alafenamide (TAF) has been newly approved for the treatment of chronic hepatitis B (CHB). We aimed to assess the effectiveness and renal safety of switching from entecavir (ETV) or nucleos(t)ide analogue (NA) combination therapy to TAF. METHODS This multicentre, retrospective, cohort study included 313 consecutive CHB patients who switched to TAF monotherapy after treatment with ETV or a nucleos(t)ide analogue (NA) combination for over 2 years. Virological/laboratory responses were evaluated for 48 weeks after switchover. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR)

Dupilumab is a fully human monoclonal antibody directed against the interleukin (IL)‐4 receptor α subunit (IL‐4Rα) of IL‐4 heterodimeric type I and type II receptors that mediate IL‐4/IL‐13 signaling through this pathway. Blockade of these receptors broadly suppresses type 2 inflammation associated with atopic/allergic diseases, including atopic dermatitis and asthma. Six phase 1 studies investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of dupilumab in healthy subjects. Two randomized, double‐blind, placebo‐controlled, sequential studies assessed safety and tolerability of single escalating dupilumab doses administered intravenously or subcutaneously (one included various racial groups, and one included exclusively Japanese subjects); 3 randomized, parallel‐group, single‐dose studies compared the pharmacokinetic profiles of different dupilumab products and formulations after single subcutaneous doses; and one study assessed dupilumab administered as fast versus slow subcutaneous injections. Dupilumab concentrations in serum were measured in all studies, and total immunoglobulin E (IgE) and thymus‐ and activation‐regulated chemokine (TARC) concentrations were measured in 2 studies as pharmacodynamic markers. Across the phase 1 studies, dupilumab exhibited target‐mediated pharmacokinetics consisting of parallel linear and nonlinear elimination, with the target‐mediated phase highly dominated by nonlinearity at lower drug concentrations. Systemic exposure and tolerability of dupilumab were consistent irrespective of differences in product, formulation, or racial background. Dupilumab reduced circulating concentrations of total IgE and TARC, indicating blockade of IL‐4Rα–mediated signaling. Dupilumab had a favorable safety profile across the wide range of doses administered. Together, these findings support the continued development and use of dupilumab in treatment of type 2 diseases.

Tumor budding, a microscopic finding of dedifferentiation at the invasive margin, has been reported as a definite prognostic marker in colon cancer (CC). Herein, we aimed to generate a molecular budding signature (MBS) based on DNA microarray data and to examine its prognostic significance. Frozen tissue samples from 85 patients with stage II/III CC were used for DNA microarray analyses. First, we selected candidate genes that were differentially expressed (twofold change) between the invasive frontal regions and corresponding tumor centers of three extremely high-grade budding tumors. Subsequently, using microarray data from whole-tissue sections of the 85 patients, we selected MBS-constituent genes from the candidates based on correlation to the pathological budding grade. The MBS score was calculated using the sum of the logarithm of the expression of each gene. We selected seven MBS-constituent genes: MSLN, SLC4A11, WNT11, SCEL, RUNX2, MGAT3, FOXC1. A comparison of relapse-free survival (RFS) rates revealed a significant impact of the MBS score [5-year RFS, 77.4% (score-high) vs. 95.1% (score-low); P = 0.044]. Analyses of public databases revealed that low MBS score patients exhibited better prognosis than those with high-score cancers (GSE14333: 5-year RFS, 83.1% vs. 66.6%, P = 0.028; GSE39582: 5-year disease-free survival, 72.2% vs. 58.1%, P = 0.0005). Multivariate analysis revealed that the MBS score is an independent prognostic indicator in GSE39582 (hazard ratio, 1.611; P = 0.013). We developed a new gene classification method, i.e., MBS, and demonstrated its clinical relevance as an indicator of high recurrence risk of CC.

Introduction Patients with residual disease usually have a poor prognosis after neoadjuvant chemotherapy for breast cancer. The aim of this study was to explore therapeutic targets and potential additional adjuvant treatments for patients with residual disease after standard neoadjuvant chemotherapy. Patients and Methods We retrieved publicly available complementary DNA microarray data from 399 human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer samples from patients who underwent standard neoadjuvant chemotherapy. We analyzed the messenger RNA (mRNA) expression levels of key breast cancer markers and therapeutic target genes according to residual cancer burden (RCB) classification: RCB-0/I, RCB-II, and RCB-III. Results Among hormone receptor–positive samples, there were more luminal A tumors by PAM50 (Prediction Analysis of Microarray 50 [Prosigna], aka Prosigna Breast Cancer Prognostic Gene Signature Assay) in RCB-III than in RCB-0/I and RCB-II (P < .01). The mRNA expressions of ESR1 and PGR were significantly higher, and that of MKI67 was lower in RCB-II and RCB-III than in RCB-0/I. The mRNA expression of cyclin D1 was up-regulated in RCB-III and that of CDKN2A was down-regulated in RCB-III (P = .027 and < .01). Among triple-negative (TN) samples, RCB-III had higher clinical stage and more lymph node–positive samples than RCB-0/1 and RCB-II (P < .01). In both subtypes, VEGF-C expression was significantly higher in RCB-III than in RCB-0/I and RCB-II. Conclusion In hormone receptor–positive breast cancer, biological features such as luminal A were associated with RCB; this trend was not observed in TN breast cancer. Further, some targeted therapies should be tested as new strategies after standard neoadjuvant chemotherapy in future clinical trials.

Purpose: To evaluate the effectiveness of the transarterial infusion of iodized oil and gelatin particles for marking before CT-guided percutaneous cryoablation (PCA) in patients with renal cell carcinoma (RCC).Material and methods: This study included ten patients (seven men, three women; mean age 53 years) with 13 RCCs between July 2016 and September 2017. The transarterial infusion of iodized oil and gelatin particles was considered successful when iodized oil accumulated in the target area on CT. CT value of the tumor before and after marking was measured and two diagnostic radiologists evaluated the visualization scores by using a five-point scale (5 = excellent to 1 = invisible).Results: Preoperative marking was successful in all 13 tumors; the median visualization score was 5 post-lipiodol marking and 4 at the time of PCA. The mean CT density was 597 ± 371 Hounsfield units (HU) just after marking and 437 ± 234 HU at the time of PCA. All 13 CT-guided PCA procedures were successful. There were no significant complications. During follow-up (median 11.5 ± 7.0 months) there were no local recurrences.Conclusion: As the transarterial infusion of iodized oil and gelatin particles improved RCC visualization on CT, its delivery before CT-guided PCA may improve its safety and success rate in patients with RCC.

In this study, we aimed to identify prognostic determinants and to comparably analyze clinical features of patients with both resected and unresected superior sulcus tumors (SSTs). The data of 56 patients who underwent any treatment for an SST from 2004 through 2016 in our hospital were reviewed. Overall survival (OS) rates were estimated using the Kaplan–Meier method. Univariate and multivariate analyses were performed to determine independent prognostic factors for patients with resected and unresected SST separately. The number of patients with resected and unresected SSTs was 24 (43%) and 32 (57%), respectively. Of the 24 patients who underwent surgery, 20 received induction therapy, with 32% achieving pathological complete response. Complete resection (R0) was performed in 22 patients (92%). On multivariate survival analysis, preoperative serum carcinoembryonic antigen (CEA) level (median 8.3 ng/ml, p = 0.021) was identified as the independent determinant of OS in surgical patients; whereas, initial treatment response (complete response or partial response, p = 0.032) was the independent OS indicator in non-surgical patients. The 5-year OS of the patient with resected and unresected SST was 68.8% and 29.1% (p = 0.008), respectively. Significant prognostic factors differ among patients stratified by the presence of surgical resection for SSTs. Preoperative CEA level in surgical candidates and initial treatment response in non-surgical patients were the independent factors associated with OS. Surgical candidates are expected to have more favorable survival than patients with unresectable SSTs.