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Primary pancreatic lymphoma is a rare pancreatic malignancy, reportedly accounting for only 0.2-0.7% of all primary pancreatic tumors. Primary pancreatic lymphoma is often difficult to distinguish from other diseases, such as acute pancreatitis. We herein report the autopsy of a patient with primary pancreatic lymphoma with imaging findings resembling those of severe acute pancreatitis, with a focus on the gross and histological features.

Background Special subtypes of pancreatic cancer, such as acinar cell carcinoma (ACC), adenosquamous carcinoma (ASC), and anaplastic carcinoma of the pancreas (ACP), are rare, and so data on them are limited. Using the C-CAT database, we analyzed clinical and genomic characteristics of patients with these and evaluated differences on comparison with pancreatic ductal adenocarcinoma (PDAC) patients. Methods We retrospectively reviewed data on 2691 patients with unresectable pancreatic cancer: ACC, ASC, ACP, and PDAC, entered into C-CAT from June 2019 to December 2021. The clinical features, MSI/TMB status, genomic alterations, overall response rate (ORR), disease control rate (DCR), and time to treatment failure (TTF) on receiving FOLFIRINOX (FFX) or GEM + nab-PTX (GnP) therapy as first-line treatment were evaluated. Results Numbers of patients with ACC, ASC, ACP, and PDAC were 44 (1.6%), 54 (2.0%), 25 (0.9%), and 2,568 (95.4%), respectively. KRAS and TP53 mutations were prevalent in ASC, ACP, and PDAC (90.7/85.2, 76.0/68.0, and 85.1/69.1%, respectively), while their rates were both significantly lower in ACC (13.6/15.9%, respectively). Conversely, the rate of homologous recombination-related (HRR) genes, including ATM and BRCA1/2, was significantly higher in ACC (11.4/15.9%) than PDAC (2.5/3.7%). In ASC and ACP, no significant differences in ORR, DCR, or TTF between FFX and GnP were noted, while ACC patients showed a trend toward higher ORR with FFX than GnP (61.5 vs. 23.5%, p = 0.06) and significantly more favorable TTF (median 42.3 vs. 21.0 weeks, respectively, p = 0.004). Conclusions ACC clearly harbors different genomics compared with PDAC, possibly accounting for differences in treatment efficacy.

Several studies have assessed the effect of cool temperature on colonic peristalsis. Transient receptor potential melastatin 8 (TRPM8) is a temperature-sensitive ion channel activated by mild cooling expressed in the colon. We examined the antispasmodic effect of cool temperature on colonic peristalsis in a prospective, randomized, single-blind trial and based on the video imaging and intraluminal pressure of the proximal colon in rats and TRPM8-deficient mice.In the clinical trial, we randomly assigned a total of 94 patients scheduled to undergo colonoscopy to 2 groups: the mildly cool water (n = 47) and control (n = 47) groups. We used 20 mL of 15°C water for the mildly cool water. The primary outcome was the proportion of subjects with improved peristalsis after treatment. In the rodent proximal colon, we evaluated the intraluminal pressure and performed video imaging of the rodent proximal colon with cool water administration into the colonic lumen. Clinical trial registry website (Trial No. UMIN-CTR; UMIN000030725).In the randomized controlled trial, after treatment, the proportion of subjects with no peristalsis with cool water was significantly higher than that in the placebo group (44.7% vs 23.4%;For the first time, this study demonstrates that cool temperature-dependent suppression of colonic peristalsis may be associated with TRPM8 activation.

We investigated the efficacy of a Wilms' tumor gene 1 (WT1) vaccine combined with gemcitabine (GEMWT1) and compared it with gemcitabine (GEM) monotherapy for advanced pancreatic ductal adenocarcinoma (PDAC) in a randomized phase II study. We randomly assigned HLA-A*02:01– or HLA-A*24:02–positive patients with advanced PDAC to receive GEMWT1 or GEM. We assessed WT1-specific immune responses via delayed-type hypersensitivity (DTH) to the WT1 peptide and a tetramer assay to detect WT1-specific cytotoxic T lymphocytes (WT1-CTL). Of 91 patients enrolled, 85 were evaluable (GEMWT1: n = 42; GEM: n = 43). GEMWT1 prolonged progression-free survival [PFS; hazard ratio (HR), 0.66; P = 0.084] and improved overall survival rate at 1 year (1-year OS%; GEMWT1: 35.7%; GEM: 20.9%). However, the difference in OS was not significant (HR: 0.82; P = 0.363). These effects were particularly evident in metastatic PDAC (PFS: HR 0.51, P = 0.0017; 1-year OS%: GEMWT1 27.3%; GEM 11.8%). The combination was well tolerated, with no unexpected serious adverse events. In patients with metastatic PDAC, PFS in the DTH-positive GEMWT1 group was significantly prolonged, with a better HR of 0.27 compared with the GEM group, whereas PFS in the DTH-negative GEMWT1 group was similar to that in the GEM group (HR 0.86; P = 0.001). DTH positivity was associated with an increase in WT1-CTLs induced by the WT1 vaccine. GEM plus the WT1 vaccine prolonged PFS and may improve 1-year OS% in advanced PDAC. These clinical effects were associated with the induction of WT1-specific immune responses. Cancer Immunol Res; 6(3); 320–31. ©2018 AACR.

FACT-G subscale by treatment group

Background and Purpose— The treatment and prognosis of acute large vessel occlusion with mild symptoms have not been sufficiently studied. The present study aimed to investigate the clinical or radiological predictors of clinical outcome in patients with stroke with mild symptoms due to acute large vessel occlusion. Methods— Of 2420 patients with acute large vessel occlusion in the RESCUE-Japan Registry 2 (Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism-Japan Registry 2), a multicenter prospective registry in Japan, patients with modified Rankin Scale scores of 0 to 2 before onset and initial National Institutes of Health Stroke Scale (NIHSS) scores of 0 to 5 were examined in post hoc analysis. We examined the clinical and radiological characteristics associated with a favorable outcome (modified Rankin Scale score, 0–2 at 90 days) using multivariate analysis, as well as the factors associated with a favorable outcome in patients treated with endovascular therapy. Results— We analyzed 272 patients (median age, 73 years; median NIHSS score on admission, 3). Eighty-six (31.6%) patients were treated with intravenous recombinant tissue-type plasminogen activator, 54 (19.9%) underwent endovascular therapy, and 208 (76.5%) showed a favorable outcome. In multivariate analysis, age P Conclusions— Younger age, lower initial NIHSS score, intravenous recombinant tissue-type plasminogen activator, and absence of hyperglycemia were independently associated with a favorable outcome in patients with acute large vessel occlusion with low NIHSS scores. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02419794.

Mesalamine is a key drug in the treatment of ulcerative colitis (UC) for both induction and maintenance therapy. On the other hand, it is known that there are some cases of mesalamine intolerance that are difficult to distinguish from symptoms due to aggravation of UC. The aim of this study is to investigate the clinical characteristic of mesalamine intolerance in UC. A retrospective, observational study was conducted. We enrolled 31 patients who were diagnosed as mesalamine intolerance between April 2015 to March 2020. We examined clinical features, time to onset, drug types of mesalamine, DLST positive rate, colonoscopy findings, disease activity, and clinical course after diagnosis. The average dose of mesalamine was 3.69 g and DLST-positive was 57.1%. Within the first 2 weeks from the start of mesalamine, 51.6% showed symptoms of intolerance. The serum CRP level was relatively high at ≥10.0 mg/dl in 53.6% of the cases. There was no difference in clinical background, symptoms, or laboratory findings between patients with DLST-positive and negative. In this study, we clarified the clinical characteristics of mesalamine intolerant patients, and found no difference in the clinical background or success rate of desensitization therapy between positive and negative DLST cases.

Recently, CAD EYE (Fujifilm, Tokyo, Japan), an artificial intelligence for the lesion recognition (CADe) and the optical diagnosis (CADx) of colorectal polyps, was released. We evaluated the function of CADe and CADx of CAD EYE. In this single-center retrospective study, we examined consecutive polyps ≤ 10 mm detected from March to April 2021 to determine whether CAD EYE could recognize them live with both normal- and high-speed observation using white-light imaging (WLI) and linked-color imaging (LCI). We then examined whether the polyps were neoplastic or hyperplastic live with magnified or non-magnified blue-laser imaging (BLI-LASER) or blue-light imaging (BLI-LED) under CAD EYE, comparing the retrospective evaluations with 5 experts and 5 trainees using still images. All polyps were histopathologically examined. We analyzed 100 polyps (mean size 3.9 ± 2.6 mm; 55 neoplastic and 45 hyperplastic lesions) in 25 patients. Regarding CADe, the respective detection rates of CAD EYE with normal- and high-speed observation were 85.0% and 67.0% for WLI (p = 0.002) and 89.0% and 75.0% for LCI (p = 0.009). Regarding CADx for differentiating neoplastic and hyperplastic lesions, the diagnostic accuracy values of CAD EYE with non-magnified and magnified BLI-LASER/LED were 88.8% and 87.8%. Regarding magnified BLI-LASER/LED, the diagnostic accuracy value of CAD EYE was not significantly different from that of experts (92.0%, p = 0.17), but that of trainees (79.0%, p = 0.04). We also found no significant differences in CADe or CADx between LED (53 lesions) and LASER (47 lesions). CAD EYE was a helpful tool for CADe and CADx in clinical practice.

BACKGROUND Rapid urinary trypsinogen-2 dipstick test and levels of urinary trypsinogen-2 and trypsinogen activation peptide (TAP) concentration have been reported as prognostic markers for the diagnosis of acute pancreatitis. AIM To reconfirm the validity of all these markers in the diagnosis of acute pancreatitis by undertaking a multi-center study in Japan. METHODS Patients with acute abdominal pain were recruited from 17 medical institutions in Japan from April 2009 to December 2012. Urinary and serum samples were collected twice, at enrollment and on the following day for measuring target markers. The diagnosis and severity assessment of acute pancreatitis were assessed based on prognostic factors and computed tomography (CT) Grade of the Japanese Ministry of Health, Labour, and Welfare criteria. RESULTS A total of 94 patients were enrolled during the study period. The trypsinogen-2 dipstick test was positive in 57 of 78 patients with acute pancreatitis (sensitivity, 73.1%) and in 6 of 16 patients with abdominal pain but without any evidence of acute pancreatitis (specificity, 62.5%). The area under the curve (AUC) score of urinary trypsinogen-2 according to prognostic factors was 0.704, which was highest in all parameter. The AUC scores of urinary trypsinogen-2 and TAP according to CT Grade were 0.701 and 0.692, respectively, which shows higher than other pancreatic enzymes. The levels of urinary trypsinogen-2 and TAP were significantly higher in patients with extended extra-pancreatic inflammation as evaluated by CT Grade. CONCLUSION We reconfirmed urinary trypsinogen-2 dipstick test is useful as a marker for the diagnosis of acute pancreatitis. Urinary trypsinogen-2 and TAP may be considered as useful markers to determine extra-pancreatic inflammation in acute pancreatitis.

BACKGROUNDIdiopathic dissecting cerebral aneurysms (IDCAs) are male dominant but are extremely rare in children. Many IDCAs in children are located in the posterior cerebral artery and the supraclinoid internal cervical artery. No cases of IDCA of the distal anterior cerebral artery (ACA) have been reported.OBSERVATIONSA previously healthy 7-month-old boy experienced afebrile seizures and presented at the authors’ hospital 1 week after the first seizure. He was not feeling well but had no neurological deficits. The authors diagnosed a ruptured aneurysm of the right distal ACA based on imaging results. He underwent emergency craniotomy to prevent re-rupture of the aneurysm. Using intraoperative indocyanine green videoangiography, the authors confirmed peripheral blood flow and then performed aneurysmectomy. Pathological examination of the aneurysm revealed a thickened intima, fragmentation of the internal elastic lamina, and a hematoma in the aneurysmal wall. The authors ultimately diagnosed IDCA because no cause was indicated, including a history of trauma. The boy recovered after surgery and was subsequently discharged with no complications.LESSONSThe authors reported, for the first time, IDCA of the distal ACA in an infant. The trapping technique is often used for giant fusiform aneurysms in infants. Indocyanine green videoangiography is useful for evaluating peripheral blood flow during trapping in this case.

We studied the injection-locking properties of a resonant-tunneling-diode terahertz oscillator in the small-signal injection regime with a frequency-stabilized continuous THz wave. The linewidth of the emission spectrum dramatically decreased to less than 120 mHz (HWHM) from 4.4 MHz in the free running state as a result of the injection locking. We experimentally determined the amplitude of injection voltage at the antenna caused by the injected THz wave. The locking range was proportional to the injection amplitude and consistent with Adler's model. As increasing the injection amplitude, we observed decrease of the noise component in the power spectrum, which manifests the free-running state, and alternative increase of the injection-locked component. The noise component and the injection-locked component had the same power at the threshold injection amplitude as small as $5\times10^{-4}$ of the oscillation amplitude. This threshold behavior can be qualitatively explained by Maffezzoni's model of noise reduction in general limit-cycle oscillators., The following article has been submitted to APL Photonics

Background Statins have been associated with reduced recurrence and better functional outcomes in patients with acute ischemic stroke. However, the effect of statins in patients with acute large vessel occlusion (LVO) is not well scrutinized. Methods and Results RESCUE (Recovery by Endovascular Salvage for Cerebral Ultra‐Acute Embolism)‐Japan Registry 2, a physician‐initiated registry, enrolled 2420 consecutive patients with acute LVO who were admitted to 46 centers across Japan within 24 hours of onset. We compared patients with and without statin use after acute LVO onset (statin group and nonstatin group, respectively) in terms of the modified Rankin scale at 90 days. We estimated that the odds ratios for the primary outcome was modified Rankin scale and we estimated the odds ratios for a 1‐scale lower modified Rankin scale adjusting for confounders. After excluding 12 patients without LVO and 9 patients without follow‐up, the mean age of 2399 patients was 75.9 years; men accounted for 55% of patients. Statins were administered to 447 (19%) patients after acute LVO onset. Patients in the statin group had more atherothrombotic cerebral infarctions (34.2% versus 12.1%, P P P P =0.02). The mortality at 90 days was lower in the statin group (4.7%) than the nonstatin group (12.5%; P P =0.02). Conclusions Statin administration after acute LVO onset is significantly associated with better functional outcome and mortality at 90 days.

Inflammation-based prognostic indicators have been developed to predict the prognosis in patients with pancreatic cancer. However, prognostic indices have not been established in patients with unresectable pancreatic cancer, including those without indication for chemotherapy at diagnosis. This study aimed to identify the predictors in all patients with unresectable pancreatic cancer. We retrospectively analyzed data of 119 patients with unresectable pancreatic cancer from June 2006 to September 2018. The following laboratory parameters were evaluated: the Glasgow Prognostic Score (GPS), modified GPS, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), C-reactive protein albumin (CRP/Alb) ratio, and prognostic nutritional index (PNI). We performed time-dependent receiver operating characteristic analysis, overall survival (OS) analysis, and univariate and multivariate analyses to determine the prognostic factors in patients with unresectable pancreatic cancer. The cut-off value for NLR was determined to be 3.74. The 6-month OS rates in low and high NLR groups were 75.5% and 18.8% (P P = 0.003), metastatic pancreatic cancer (P = 0.037), no treatment (P P P P P P = 0.002), high CRP/Alb ratio (P P P = 0.046), no treatment (P P = 0.002), and high NLR (P

Simple Summary The psoas muscle mass index (PMI) is a simplified tool used in the quantification of skeletal muscle. The aim of our study was to investigate whether the PMI at diagnosis or its decrease during chemotherapy can influence the prognosis of unresectable pancreatic cancer. The median overall survival (OS) was 278.0 (95% confidence interval (CI), 199.1–356.9) days in the high-PMI group, and 221.0 (95% CI, 90.9–351.1) days in the low-PMI group (p = 0.329). The median OS was 347.0 (95% CI, 289.1–404.9) days in the group without PMI decrease and 172.0 (95% CI, 129.8–214.2) days in the group with PMI decrease (p = 0.001). We determined that the PMI at diagnosis was not associated with OS in patients with unresectable pancreatic cancer receiving systemic chemotherapy, whereas PMI decrease during chemotherapy influenced the OS. Abstract The impact of the psoas muscle mass index (PMI) on survival is still poorly understood in unresectable pancreatic cancer. Thus, we aimed to investigate whether the PMI at diagnosis or its decrease during chemotherapy can influence the prognosis of unresectable pancreatic cancer. The data of 100 patients were analyzed, and they were divided into two groups according to the median PMI in each sex. Subsequently, 72 patients undergoing computed tomography (CT) within 30–100 days from CT at diagnosis were evaluated in terms of PMI change rate, and divided into two groups based on the median. We evaluated the clinical characteristics and outcomes in terms of the PMI at diagnosis or its decrease during chemotherapy. The median PMI was 5.00 in males, and 3.66 in females. The median overall survival (OS) was 278.0 days in the high-PMI group and 221.0 days in the low-PMI group (p = 0.329). The median PMI change rate was −2.4%. The median OS was 347.0 days in the group without PMI decrease and 172.0 days in the group with PMI decrease (p = 0.001). We determined that a pivotal prognostic factor was not the PMI at diagnosis, but rather PMI decrease during chemotherapy in unresectable pancreatic cancer.

Background and Objectives: Differential diagnosis to estimate the malignant potential of gastric submucosal tumor (g-SMT) is important for decision-making. This study evaluated the use of a 20G needle with a core trap for EUS-guided fine-needle biopsy (EUS-FNB) for g-SMT. Methods: This multicentric prospective trial was registered in the University Hospital Medical Information Network (UMIN000021410). Consecutive patients with g-SMT who presented at one of the nine Japanese Referral Centers between June 2017 and November 2018 were enrolled. All patients underwent EUS-FNB using a 20G needle with a core trap. Samples obtained with the first-needle pass were used for central pathological review. EUS-FNB was evaluated in terms of (i) technical success rate, (ii) adequacy for histological evaluation, (iii) rate of complications, (iv) accuracy for histological diagnosis of gastrointestinal stromal tumor (GIST), and (v) concordance between GIST mitotic index determined by EUS-FNB and after tumor resection. Results: The study included 52 patients. The technical success rate of EUS-FNB was 100%. The adequacy rate for histological evaluation was 90.4% (P < 0.001). There were no complications related to EUS-FNB. Of the 38/52 patients who underwent surgical resection, 36 were finally diagnosed with GIST. The sensitivity, specificity, and accuracy of EUS-FNB for the histological diagnosis of g-SMT were 80.6%, 100%, and 81.6%, respectively. The concordance rate between the mitotic index on EUS-FNB and that after analysis of the resected tumor was 89.7%. Conclusions: EUS-FNB using a 20G needle with a core trap is feasible, providing histological samples of sufficient quality for diagnosing g-SMT.

Chronic pancreatitis is considered to be an irreversible progressive chronic inflammatory disease. The etiology and pathology of chronic pancreatitis are complex; therefore, it is important to correctly understand the stage and pathology and provide appropriate treatment accordingly. The newly revised Clinical Practice Guidelines of Chronic Pancreatitis 2015 consist of four chapters, i.e., diagnosis, staging, treatment, and prognosis, and includes a total of 65 clinical questions. These guidelines have aimed at providing certain directions and clinically practical contents for the management of chronic pancreatitis, preferentially adopting clinically useful articles. These revised guidelines also refer to early chronic pancreatitis based on the Criteria for the Diagnosis of Chronic Pancreatitis 2009. They include such items as health insurance coverage of high-titer lipase preparations and extracorporeal shock wave lithotripsy, new antidiabetic drugs, and the definition of and treatment approach to pancreatic pseudocyst. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the publication of the first edition.

[This corrects the article DOI: 10.1371/journal.pone.0209448.].

Increasing the performance of submucosal injection materials (SIMs) is important for endoscopic therapy of early gastrointestinal cancer. It is essential to establish an ex vivo model that can evaluate SIM performance accurately, for developing high-performance SIMs. In our previous study, we developed a new ex vivo model that can be used to evaluate the performance of various SIMs in detail by applying constant tension to the specimen's ends. We also confirmed that the proposed new ex vivo model allows accurate submucosal elevation height (SEH) measurement under uniform conditions and detailed comparisons of the performances of various types of SIMs. Here, we describe the new ex vivo model and explain the detailed setup methodology of this model. Since all parts of the new model were easy to obtain, the setup of the new model could be completed quickly. SEH of various SIMs could be measured more accurately by using the new model. The critical factor that determines SIM performance can be identified using the new model. SIM development speed will drastically increase after the factor has been identified.

Background Endovascular therapy has been shown to be effective in patients with acute cerebral large‐vessel occlusion, but real‐world efficacies are unknown. Methods and Results We conducted a prospective registry at 46 centers between October 2014 and January 2017. Eligible patients were those who were aged 20 years or older, with acute cerebral large‐vessel occlusion, and who were hospitalized within 24 hours of the onset. We enrolled both consecutive patients who were treated with or without endovascular therapy. Endovascular therapy included thrombectomy, balloon angioplasty, stenting, local fibrinolysis, and piercing. The primary outcome was a favorable outcome as defined by a modified Rankin Scale of 0 to 2 at 90 days after onset. Secondary outcomes were modified Rankin Scale of 0 to 1 and mortality. Safety outcomes were intracerebral hemorrhage or a recurrence of ischemic stroke. We constructed the 2242 (1121 each) propensity score–matched patients cohort based on a propensity score for endovascular therapy and estimated the adjusted odds ratio, followed by sensitivity analyses on original 2399 (1278 in endovascular therapy versus 1121 in no endovascular therapy) patients. In the propensity score–matched cohort, favorable outcomes were observed in 35.3% and 30.7% of patients in the endovascular therapy and no endovascular therapy groups, respectively ( P= 0.02). The adjusted odds ratio for the favorable outcome was 1.44 (95% confidence interval, 1.10–1.86, P =0.007). The efficacy of endovascular therapy in achieving favorable outcomes did not differ between our subgroups and in the sensitivity analyses. Conclusions Endovascular therapy decreased disabilities at 90 days in real‐world patients with acute cerebral large‐vessel occlusion. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT02419794.

Alcohol-based disinfectants play an important role in the prevention of healthcare-acquired infection (HAI). We investigated whether pathogens present in mucus acquire resistance to alcohol-based disinfectants, and elucidated the underlying mechanism. Both the resistance of influenza A virus and Escherichia coli to alcohol-based disinfectants or ultraviolet irradiation and the diffusion rate of ethanol were determined in artificial mucus or sputum samples obtained from 27 individuals with acute upper respiratory infection. Pathogens in mucus (artificial mucus or sputum samples) were not completely inactivated by alcohol-based disinfectants (survival rate >10%), suggesting that the alcohol-based disinfectants were ineffective. Pathogen survival and mucus viscosity were strongly correlated (correlation coefficient >0.7, P

In fracture treatment, biological bone union generally depends on the bone's natural fracture healing capacity, even in surgically treated cases. Hydroxyapatite/collagen composite (HAp/Col) has high osteoconductivity and stimulates osteogenic progenitors. Furthermore, it has the potent capacity to adsorb bone morphogenetic proteins (BMPs). In this study, we prepared an injectable HAp/Col paste and evaluated its augmentation of bone union. Furthermore, the effect of HAp/Col paste combined with BMP-2 was also evaluated. We used a rat femur osteotomy model with a defect size of 1 mm. Male Wistar rats were assigned to one of the following four groups; a control group without any implant, a HAp/Col implant group, a group that received an absorbable collagen sponge (ACS) implant impregnated with BMP-2 (1 μg), and a group that received a HAp/Col implant impregnated with BMP-2 implant. Micro-CT analysis, three-point bending tests, and histological evaluation were performed. Bone union was achieved in two of eight cases in the HAp/Col group, five of eight cases in the ACS + BMP-2 group, and all cases in the HAp/Col + BMP-2 group at 8 weeks post-surgery. The control group did not achieve bone union. In addition, in the HAp/Col + BMP-2 group, the biomechanical strength of the fused femurs was comparable to that of the contralateral intact femur; the ratio of the mechanical load at the breaking point of the osteotomy side relative to that of the contralateral side was 1.00 ± 0.151 (SD). These results indicate that HAp/Col paste with or without BMP-2 augments bone union. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:129-137, 2018.

We investigated the efficacy of a Wilms' tumor gene 1 (WT1) vaccine combined with gemcitabine (GEMWT1) and compared it with gemcitabine (GEM) monotherapy for advanced pancreatic ductal adenocarcinoma (PDAC) in a randomized phase II study. We randomly assigned HLA-A*02:01– or HLA-A*24:02–positive patients with advanced PDAC to receive GEMWT1 or GEM. We assessed WT1-specific immune responses via delayed-type hypersensitivity (DTH) to the WT1 peptide and a tetramer assay to detect WT1-specific cytotoxic T lymphocytes (WT1-CTL). Of 91 patients enrolled, 85 were evaluable (GEMWT1: n = 42; GEM: n = 43). GEMWT1 prolonged progression-free survival [PFS; hazard ratio (HR), 0.66; P = 0.084] and improved overall survival rate at 1 year (1-year OS%; GEMWT1: 35.7%; GEM: 20.9%). However, the difference in OS was not significant (HR: 0.82; P = 0.363). These effects were particularly evident in metastatic PDAC (PFS: HR 0.51, P = 0.0017; 1-year OS%: GEMWT1 27.3%; GEM 11.8%). The combination was well tolerated, with no unexpected serious adverse events. In patients with metastatic PDAC, PFS in the DTH-positive GEMWT1 group was significantly prolonged, with a better HR of 0.27 compared with the GEM group, whereas PFS in the DTH-negative GEMWT1 group was similar to that in the GEM group (HR 0.86; P = 0.001). DTH positivity was associated with an increase in WT1-CTLs induced by the WT1 vaccine. GEM plus the WT1 vaccine prolonged PFS and may improve 1-year OS% in advanced PDAC. These clinical effects were associated with the induction of WT1-specific immune responses. Cancer Immunol Res; 6(3); 320–31. ©2018 AACR.

Although viral RNA or infectious virions have been detected in the feces of individuals infected with human influenza A and B viruses (IAV/IBV), the mechanism of viral survival in the gastrointestinal tract remains unclear. We developed a model that attempts to recapitulate the conditions encountered by a swallowed virus. While IAV/IBV are vulnerable to simulated digestive juices (gastric acid and bile/pancreatic juice), highly viscous mucus protects viral RNA and virions, allowing the virus to retain its infectivity. Our results suggest that virions and RNA present in swallowed mucus are not inactivated or degraded by the gastrointestinal environment, allowing their detection in feces.

ObjectiveCorticosteroid has been established as the standard therapy for autoimmune pancreatitis (AIP), but the requirement for maintenance corticosteroid therapy is controversial. We conducted a randomised controlled trial to clarify the efficacy of maintenance corticosteroid therapy in patients with AIP.DesignWe conducted a multicentre, tertiary setting, randomised controlled trial. After the induction of remission with the initial oral prednisolone (PSL) treatment, maintenance therapy with PSL at 5–7.5 mg/day was continued for 3 years or withdrawn at 26 weeks. The primary endpoint was relapse-free survival over 3 years and the secondary endpoint was serious corticosteroid-related complications. All analyses were performed on an intention-to-treat basis.ResultsBetween April 2009 and March 2012, 49 patients with AIP were randomly assigned to the maintenance therapy group (n=30) or the cessation group (n=19). Baseline characteristics were not different between the two groups. Relapses occurred within 3 years in 11 out of 19 (57.9%) patients assigned to the cessation group, and in 7 of 30 (23.3%) patients in the maintenance therapy group. The relapse rate over 3 years was significantly lower in the maintenance therapy group than that in the cessation group (p=0.011). The relapse-free survival was significantly longer in the maintenance therapy group than that in the cessation group (p=0.007). No serious corticosteroid-related complications requiring discontinuation of PSL were observed.ConclusionsMaintenance corticosteroid therapy for 3 years may decrease relapses in patients with AIP compared with those who discontinued the therapy at 26 weeks.Trial registration numberUMIN000001818; Results.

We previously demonstrated the importance of quality management procedures for the handling of human bone marrow stromal cells (hBMSCs) and provided evidence for the existence of osteogenic inhibitor molecules in BMSCs. One candidate inhibitor is the ephrin type-A receptor 5 (EphA5), which is expressed in hBMSCs and upregulated during long-term culture. In this study, forced expression of EphA5 diminished the expression of osteoblast phenotypic markers. Downregulation of endogenous EphA5 by dexamethasone treatment promoted osteoblast marker expression. EphA5 could be involved in the normal growth regulation of BMSCs and could be a potential marker for replicative senescence. Although Eph forward signaling stimulated by ephrin-B-Fc promoted the expression of ALP mRNA in BMSCs, exogenous addition of EphA5-Fc did not affect the ALP level. The mechanism underlying the silencing of EphA5 in early cultures remains unclear. EphA5 promoter was barely methylated in hBMSCs while histone deacetylation could partially suppress EphA5 expression in early-passage cultures. In repeatedly passaged cultures, the upregulation of EphA5 independent of methylation could competitively inhibit osteogenic signal transduction pathways such as EphB forward signaling. Elucidation of the potential inhibitory function of EphA5 in hBMSCs may provide an alternative approach for lineage differentiation in cell therapy strategies and regenerative medicine.

Aim The purpose of this study was to clarify whether fatty pancreas might lead to impaired pancreatic endocrine or exocrine function. Material and methods The study involved 109 participants who had undergone the glucagon stimulation test and N-benzoyl-L-tyros-p-amino benzoic acid (BT-PABA) test to assess pancreatic function as well as unenhanced abdominal computed tomography (CT). Pancreatic endocrine impairment was defined as ΔC peptide immunoreactivity less than 2 [mmol/L] in the glucagon stimulation test, and pancreatic exocrine impairment was defined as a urinary PABA excretion rate less than 70% on the BT-PABA test. We defined as the mean CT value of pancreas / CT value of spleen (P/S ratio) as a marker to assess fatty pancreas. We analyzed the association between fatty pancreas and pancreatic impairment using the logistic regression model. The odds ratio (OR) is shown per 0.1 unit. Results Pancreatic endocrine function was impaired in 33.0% of the participants, and 56.9% of those were regarded as having pancreatic exocrine impairment. The P/S ratio was significantly correlated with pancreatic endocrine impairment in univariate analysis (OR = 0.61, 95% confidence interval (CI) = 0.43–0.83, P = 0.0013) and multivariate analysis (OR = 0.38, 95% CI = 0.22–0.61, P < .0001) for all participants. Similar significant relationships were observed in both univariate (OR = 0.70, 95% CI = 0.49–0.99, P = 0.04) and multivariate (OR = 0.39, 95% CI = 0.21–0.66, P = 0.0002) analyses for the participants without diabetes (n = 93). The amount of pancreatic fat was not associated with exocrine impairment in univariate analysis (OR = 0.80, 95% CI = 0.59–1.06, P = 0.12). Conclusion Fatty pancreas was associated with pancreatic endocrine impairment but did not have a clear relationship with pancreatic exocrine impairment.

UNLABELLED:We evaluated whether dexamethasone augments the osteogenic capability of bone marrow-derived stromal cells (BMSCs) and muscle tissue-derived stromal cells (MuSCs), both of which are thought to contribute to ectopic bone formation induced by bone morphogenetic protein-2 (BMP-2), and determined the underlying mechanisms. Rat BMSCs and MuSCs were cultured in growth media with or without 10-7 M dexamethasone and then differentiated under osteogenic conditions with dexamethasone and BMP-2. The effects of dexamethasone on cell proliferation and osteogenic differentiation, and also on ectopic bone formation induced by BMP-2, were analyzed. Dexamethasone affected not only the proliferation rate but also the subpopulation composition of BMSCs and MuSCs, and subsequently augmented their osteogenic capacity during osteogenic differentiation. During osteogenic induction by BMP-2, dexamethasone also markedly affected cell proliferation in both BMSCs and MuSCs. In an in vivo ectopic bone formation model, bone formation in muscle-implanted scaffolds containing dexamethasone and BMP-2 was more than two fold higher than that in scaffolds containing BMP-2 alone. Our results suggest that dexamethasone potently enhances the osteogenic capability of BMP-2 and may thus decrease the quantity of BMP-2 required for clinical application, thereby reducing the complications caused by excessive doses of BMP-2. HIGHLIGHTS:1. Dexamethasone induced selective proliferation of bone marrow- and muscle-derived cells with higher differentiation potential. 2. Dexamethasone enhanced the osteogenic capability of bone marrow- and muscle-derived cells by altering the subpopulation composition. 3. Dexamethasone augmented ectopic bone formation induced by bone morphogenetic protein-2.

To investigate the origin of argyrophil small cell carcinoma (ASCC) of the uterine cervix, we examined the influence of dibutyryl cyclic adenosine 3',5'-monophosphate (dB-cAMP), a known differentiation inducer, on the characteristics of an ASCC cell line, TC-YIK, which has been shown to be a useful in vitro experimental model of ASCC. In TC-YIK cells after treatment with dB-cAMP, two specific antigenic markers of macrophages, CD14 and human leukocyte antigen-DR, were detected by flow cytometric analysis. In addition, interferon-gamma mRNA was detected by reverse transcription-polymerase chain reaction and interferon-gamma protein was detected by ELISA. More than 90% of the cells stained positive for alpha-naphthyl butyrate esterase, 1% of the cells showed phagocytotic activity against Micrococcus lysodeikticus, and 22% of the cells had M. lysodeikticus adsorbed on their surface. Furthermore, granulocyte-macrophage colony stimulating factor accelerated the proliferation of TC-YIK cells. These results indicate that dB-cAMP promotes differentiation of ASCC cells to macrophages. In contrast, less than 10% of the cells showed stellate morphology, suggesting differentiation to neuronal cells after treatment with dB-cAMP, as reported previously. Thus, TC-YIK cells have been shown to differentiate both into macrophage lineage cells and neuronal cells, suggesting that ASCC originates from undifferentiated stem cells.