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Abstract Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.

Abstract Background Duke pancreatic mono-clonal antigen type 2 (DUPAN-II) is a famous tumour maker for pancreatic cancer (PC) as well as carbohydrate antigen 19–9 (CA19-9). We evaluated the clinical implications of DUPAN-II levels as a biological indicator for PC during preoperative chemoradiation therapy (CRT). Methods This retrospective analysis included data from 221 consecutive patients with resectable and borderline resectable PC at diagnosis who underwent preoperative CRT between 2008 and 2017. We focused on 73 patients with elevated pre-CRT DUPAN-II levels (> 230 U/mL; more than 1.5 times the cut-off value for the normal range). Pre- and post-CRT DUPAN-II levels and the changes in DUPAN-II ratio were measured. Results Univariate analysis identified normalisation of DUPAN-II levels after CRT as a significant prognostic factor (hazard ratio [HR] = 2.06, confidence interval [CI] = 1.03–4.24, p = 0.042). Total normalisation ratio was 49% (n = 36). Overall survival (OS) in patients with normalised DUPAN-II levels was significantly longer than that in 73 patients with elevated levels (5-year survival, 55% vs. 21%, p = 0.032) and in 60 patients who underwent tumour resection (5-year survival, 59% vs. 26%, p = 0.039). Conclusion Normalisation of DUPAN-II levels during preoperative CRT was a significant prognostic factor and could be an indicator to monitor treatment efficacy and predict patient prognosis.

Abstract Background Pancreatic cancer (PC) is a highly lethal malignancy, even if surgical resection is possible (median survival:

Abstract Type I interferon (IFN) plays a crucial role in innate and adaptive immunity, and aberrant IFN responses are involved in systemic autoimmune diseases, such as systemic lupus erythematosus (SLE) and dermatomyositis (DM). Type I IFNs can be induced by transcribed retrotransposons. The regulation of retrotransposons and type I IFN and the downstream IFN pathways in SLE, DM, and autoimmune blistering disease (AIBD) were investigated. The gene expression levels of retrotransposons, including LINE-1, type I-III IFNs, and IFN-stimulated genes (ISGs) in peripheral blood cells from patients with DM (n = 24), SLE (n = 19), AIBD (n = 14) and healthy controls (HCs, n = 10) were assessed by quantitative polymerase chain reaction. Upregulation of retrotransposons and IFNs was detected in DM patient samples, as is characteristic, compared to HCs; however, ISGs were not uniformly upregulated. In contrast, retrotransposons and IFNs, except for type II IFN, such as IFN-γ, were not upregulated in SLE. In AIBD, only some retrotransposons and type I interferons were upregulated. The DM, SLE, and AIBD samples showed coordinated expression of retrotransposons and type I IFNs and distinct spectra of IFN signaling. A positive correlation between LINE-1 and IFN-β1 was also detected in human cell lines. These factors may participate in the development of these autoimmune diseases.

Pregnancy-associated cervicocephalic arterial dissection is rare, and its pathophysiology remains poorly understood. Despite the hypothesized contribution to pathogenesis, connective tissue diseases and genetic factors are rarely identified in clinical cases. We describe a case of postpartum arterial dissection involving all four cervicocephalic arteries resulting in acute cerebral infarction. The patient underwent successful endovascular thrombectomy and angioplasty and recovered fully without sequelae. Genetic screening for connective tissue diseases identified a heterozygous missense COL5A1 variant with unknown clinical significance. Two genetically related family members later developed arterial abnormalities, and one of them tested positive for the same COL5A1 gene variant as our patient, while the other was scheduled for genetic testing. The extensive clinical presentation of our patient and the prevalence of arterial abnormalities in her family warrant further assessment of the association between the identified COL5A1 gene variant and the pathogenesis of arterial dissections.

Abstract Background and Aim There are no previous reports describing the prognostic significance of the residual intraductal carcinoma component (carcinoma in situ [CIS]) following preoperative treatment for pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to investigate the prognostic significance of a minimal residual CIS in cases with complete absence of an invasive component after preoperative treatment for PDAC. Methods Eighty‐one of 594 PDAC patients with preoperative treatment and subsequent surgery in our institute showed remarkable remission in the invasive component, which included 48 patients with the minimal residual invasive component (Min‐inv group) and 33 with absence of an invasive component (No‐inv group). We assessed the survival of these patients in association with the presence or absence of an invasive component and intraductal CIS. Results Five‐year overall survival in the No‐inv group patients was significantly better than that of the Min‐inv group patients (82%/66%, P = .041). Among the 33 patients in the No‐inv group, residual CIS was observed in 16 patients (CIS‐positive group), and the remaining 17 patients had no residual CIS (CIS‐negative group). There was no significant difference in survival between patients in the CIS‐positive and CIS‐negative groups (92%/78%, P = .31). Conclusions Residual CIS in the absence of an invasive component after preoperative treatment does not yield a prognostic impact after receiving perioperative treatment for PDAC. It might be reasonable to define pathological complete response (pCR) from the prognostic standpoint as follows: pCR is the complete absence of an invasive carcinoma component regardless of residual CIS.

We herein present the first case of nanoparticle albumin-bound paclitaxel (nab-paclitaxel)- and/or gemcitabine-induced scleroderma accompanied by acanthosis nigricans-like skin changes in a 54-year-old Japanese male. He was diagnosed with pancreatic cancer and received 17 courses of nab-paclitaxel and gemcitabine chemotherapy. Edema and skin sclerosis in his legs appeared after the first and third course, respectively. Histological examination of the hyperkeratotic lesion of the ankle revealed hyperkeratosis, acanthosis, papillomatosis, increased number of melanocytes in the basal layer, and dermal fibrosis. Awareness of the clinical characteristics of nab-paclitaxel- and/or gemcitabine-induced scleroderma accompanied by acanthosis nigricans-like skin changes is important for dermatologists to establish an accurate diagnosis.

Background: Hereditary angioedema (HAE) is a rare but life-threatening condition. HAE types I and II (HAE-1/2) result from C1-inhibitor (C1–INH) deficiency. However, recent genetic analysis has established a new type of HAE with normal C1–INH (HAEnC1-INH). The mutations of factor XII, plasminogen, angiopoietin 1, and kininogen 1 genes may be the cause of HAEnC1-INH. Nevertheless, other causative molecules (HAE-unknown) may be involved. The Japanese therapeutic environment for HAE has been improving owing to the self-subcutaneous injection of icatibant, which was approved for the treatment of acute attack and enables early therapy. Erythema marginatum (EM) is a visible prodromal symptom which occasionally occurs prior to an angioedema attack; hence, recognizing the risk of an acute attack is important for early treatment. However, the detailed characteristics of EM remain unclear. In this study, we first investigated the clinical manifestations of EM in Japanese patients with HAE. Methods: A 20-point survey was developed and distributed to 40 physicians to gather clinical data on EM from patients with HAE. Results: Data on 68 patients with HAE (58 patients with HAE-1/2 and 10 patients with HAE-unknown) were collected. Of the patients with HAE-1/2, 53.4% experienced EM, whereas 43.1% did not. The forearm was the most frequent area of EM (64.5%), followed by the abdomen (29.0%) and upper arm and precordium (19.3%). Of the HAE-1/2 patients with EM, 41.9% always had angioedema following EM, while 29.0% always had colocalization of EM with angioedema. Moreover, 3.2% showed a correlation between the awareness of EM and severity of an angioedema attack. In 60.9% of HAE-1/2 patients with EM, the interval between the awareness of EM and appearance of angioedema was

Purpose: Programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) targeted therapies have shown promising survival outcomes in several human neoplasms. However, it is unclear whether the expression of PD-L1 can be correlated to any clinical and pathologic variables in patients with cutaneous angiosarcoma (CA). The aim of this study was to evaluate the clinicopathological significance of PD-L1 expression in CA patients. Materials and Methods: Data from 52 patients with CA were retrospectively reviewed. PD-L1 expression, tumor proliferation determined by Ki-67 index, and immunohistochemical evaluation of tumor-infiltrating lymphocytes, CD4+ and CD8+, were used to determine correlation with clinicopathological variables. Results: PD-L1 was positively expressed in 40% of all patients. PD-L1 expression was significantly associated with tumor cell proliferation. Multivariate analysis confirmed that high levels of CD8+ tumor-infiltrating lymphocytes were a significant predictor in patients with clinical stage I CA and the positive expression of PD-L1 was an independent prognostic factor in predicting worse outcome. Conclusion: PD-L1 expression is a novel pathologic marker for predicting worse outcome in patients with CA.

The efficacy and safety of botulinum toxin B (BTX-B) for treatment of Raynaud’s phenomenon and digital ulcers in patients with systemic sclerosis was assessed. A total of 45 patients with systemic sclerosis who had Raynaud’s phenomenon were blinded and divided randomly into 4 groups: a no-treatment control group, and 3 treatment groups, using 250, 1,000 or 2,000 international units (U) of BTX-B injections in the hand with more severe symptoms. Four weeks after injection, pain/numbness visual analogue scale scores and Raynaud’s score in the groups treated with 1,000 and 2,000 U BTX-B were significantly lower than in the control group and the group treated with 250 U BTX-B. These beneficial effects were sustained until 16 weeks after the single injection. At 4 weeks after injection skin temperature recovery in the group treated with 2,000 U BTX-B was significantly improved. The numbers of digital ulcers in the groups treated with 1,000 and 2,000 U BTX-B were significantly lower than in the control group. In conclusion, 1,000 and 2,000 U BTX-B injections significantly suppressed the activity of Raynaud’s phenomenon and digital ulcers in patients with SSc without serious adverse events.

Arteriovenous malformations (AVM) are congenital vascular lesions fed by arterial feeders originating from branches of the internal carotid artery (ICA) or vertebrobasilar artery. We experienced unique AVMs arising in the midline Galenic region, receiving blood supply from the ICA/vertebral artery systems and the external carotid artery system. We retrospectively reviewed data on eight patients who had an AVM arising in the Galenic region and were treated in the University of Tokyo Hospital between 1990 and 2019. The median age at diagnosis was 62 years. Three cases (38%) presented with obstructive hydrocephalus due to aqueduct obstruction caused by an engorged vein of Galen. In all cases, feeders from dural arteries were present and the vein of Galen was the primary drainer. All patients underwent stereotactic radiosurgery. Five patients were followed for > two years; nidus obliteration was confirmed in one, and > 75% shrinkage was confirmed in three, while one patient died due to hemorrhage. Altogether, AVMs arising in the Galenic region are rare and exhibit several peculiar characteristics including the presence of dural feeders, an older age at presentation and presentation with obstructive hydrocephalus.

Pancreatic acinar cell carcinoma (ACC) is a rare tumor, and its pathophysiology has not been well understood. Treatment strategies for hepatic metastasis originating from ACC remain controversial. We report the case of a 66-year-old woman who had undergone total pancreatectomy from ACC 7 years prior to clinical presentation. Contrast-enhanced computed tomography imaging revealed a tumorous lesion measuring 7 cm in length and 1 cm in diameter and extending along the intrahepatic bile duct (B6), which showed mild enhancement in the early phase and modest washout in the late phase. This lesion was diagnosed as hepatic metastasis primarily in the form of a bile duct tumor thrombus originating from the prior ACC by the pathological evaluation of the fine needle biopsy specimen. The patient underwent preoperative gemcitabine-based chemoradiation therapy followed by subsequent surgical resection, which included subsegmentectomy (S6) of the liver and complete removal of the bile duct tumor thrombus. The patient has had no recurrence during the past 8 months since her last surgery. Multimodal treatment including preoperative chemoradiation therapy might be beneficial especially for marginally resectable cases of ACC.

We report the unique case of a 69-year-old man with an extra-gastrointestinal stromal tumor (EGIST) in the lesser omentum. Based on the location of the tumor and the radiological findings, we made a provisional diagnosis of hepatic cavernous hemangioma in the lateral segment. However, after 5 years of follow-up, tumor growth was noted and the patient underwent a laparotomy. The tumor was located in the lesser omentum and resected en bloc with its fused lesser omentum and an adherent portion of the liver. The pathology results indicated an EGIST with microscopic proliferation of epithelioid cells in the lesser omentum; the tumor was immunohistochemically negative for KIT staining and positive for CD34 and PKC theta. Because of the rarity of mitotic figures and the low Ki-67 labeling, the tumor was diagnosed as a KIT-negative EGIST with a low malignant potential. The patient was followed up without receiving imatinib mesylate treatment and has remained free of any signs of recurrence for 26 months. The present case report describes a very rare lesser omental KIT-negative EGIST.

We report herein a case of idiopathic adrenal hematoma. A 59-year-old Japanese man was referred to our hospital for evaluation of a 7.0 cm mass in the right upper abdominal cavity. The tumor was suspected to originate from either the posterior segment of the liver or the right adrenal gland. His chief complaint was weight loss of 8 kg over the previous 6 months. He had no past medical history and took no medications, including no anticoagulants. Laboratory data were almost normal except for a slight elevation of PIVKA-II. The origin of the tumor was found to be the adrenal gland, as angiography revealed the blood supply to the mass to derive from the right superior and inferior adrenal arteries. A fine needle biopsy of the lesion was unable to confirm the diagnosis. Open right adrenalectomy was performed. The histopathological findings of the surgical specimen revealed a hematoma with normal adrenal tissue. In the absence of any obvious etiology, the diagnosis was idiopathic adrenal hematoma.

Hepatocellular carcinoma (HCC) rarely originates in extrahepatic liver tissue. Laparoscopic resection is widely used to treat HCC. This report presents a case of a patient with ectopic HCC arising in the left triangular ligament of the liver that was successfully treated by laparoscopic resection. A 59-year-old female presented with an elevated serum alpha-fetoprotein (AFP) level (2,508 ng/ml). Dynamic computed tomography demonstrated a tumor measuring 20 mm in diameter below the left diaphragm just adjacent to the spleen. The tumor showed contrast enhancement in the hepatic arterial phase and became less dense than the liver parenchyma in the portal phase. The patient was diagnosed with ectopic HCC arising in the left diaphragm and laparoscopic surgery was performed. The tumor was located in the left triangular ligament of the liver and had a stalk between the tumor and the liver. The tumor was resected, and the final diagnosis was moderately differentiated ectopic HCC arising in the left triangular ligament of the liver. The patient had an uneventful postoperative recovery and has experienced no recurrence over 18 months after the operation.

Blood circulation function of peripheral blood vessels in skin dermis was evaluated employing an optical sensor with a pressurization mechanism using the blood outflow and reflow characteristics. The device contains a light source and an optical sensor. When applied to the skin surface, it first exerts the primary pressure (higher than the systolic blood pressure), causing an outflow of blood from the dermal peripheral blood vessels. After two heartbeats, the pressure is lowered (secondary pressure) and blood reflows into the peripheral blood vessels. Hemoglobin concentration, which changes during blood outflow and reflow, is derived from the received light intensity using the Beer-Lambert law. This method was evaluated in 26 healthy female volunteers and 26 female scleroderma patients. In order to evaluate the blood circulation function of the peripheral blood vessels of scleroderma patients, pressurization sequence which consists of primary pressure followed by secondary pressure was adopted. Blood reflow during the first heartbeat period after applying the secondary pressure of 40mmHg was (mean±SD) 0.059±0.05%mm for scleroderma patients and 0.173±0.104%mm for healthy volunteers. Blood reflow was significantly lower in scleroderma patients than in healthy volunteers (p

In spite of intensive and increasingly successful attempts to determine the multiple steps involved in colorectal carcinogenesis, the mechanisms responsible for metastasis of colorectal tumors to the liver remain to be clarified. To identify genes that are candidates for involvement in the metastatic process, we analyzed genome-wide expression profiles of 10 primary colorectal cancers and their corresponding metastatic lesions by means of a cDNA microarray consisting of 9121 human genes. This analysis identified 40 genes whose expression was commonly upregulated in metastatic lesions, and 7 that were commonly downregulated. The upregulated genes encoded proteins involved in cell adhesion, or remodeling of the actin cytoskeleton. Investigation of the functions of more of the altered genes should improve our understanding of metastasis and may identify diagnostic markers and/or novel molecular targets for prevention or therapy of metastatic lesions.

OBJECTIVE: To assess the utility of circulating adhesion molecule levels as a prognostic indicator of disease progression in systemic sclerosis (SSc) patients with early onset disease. METHODS: Ninety-two Japanese patients with early onset SSc presenting with diffuse skin sclerosis and/or interstitial lung disease were registered in a multicentre, observational study. Concentrations of intercellular adhesion molecule (ICAM) -1, E-selectin, L-selectin, and P-selectin in serum samples from all patients were measured by enzyme-linked immunosorbent asssay (ELISA). In 39 patients, adhesion molecule levels were measured each year for four years. The ability of baseline adhesion molecule levels to predict subsequent progression and severity in clinical and laboratory features were evaluated statistically. RESULTS: At their first visit, serum levels of ICAM-1, E-selection, P-selectin were significantly elevated and serum L-selectin levels were significantly reduced in patients with SSc compared with healthy controls. Overall, serum ICAM-1 levels at each time point were significantly inversely associated with the %vital capacity (VC) of the same time and subsequent years by univariate analysis. The initial serum ICAM-1 levels were significantly inversely associated with the %VC at the fourth year by multiple regression analysis. The initial serum P-selectin levels were significantly associated with the health assessment questionnaire disability index (HAQ-DI) at the fourth year by multiple regression analysis. Initial adhesion molecule levels were not significantly associated with other clinical features including skin thickness score. Baseline adhesion molecule levels were not significantly associated with subsequent rate of change of clinical parameters. CONCLUSION: In patients with SSc, serum levels of ICAM-1 and P-selectin may serve as prognostic indicators of respiratory dysfunction and physical disability, respectively. Further longitudinal studies of larger populations are needed to confirm these findings.

Recent studies applying high-throughput sequencing technologies have identified several recurrently mutated genes and pathways in multiple cancer genomes. However, transcriptional consequences from these genomic alterations in cancer genome remain unclear. In this study, we performed integrated and comparative analyses of whole genomes and transcriptomes of 22 hepatitis B virus (HBV)-related hepatocellular carcinomas (HCCs) and their matched controls. Comparison of whole genome sequence (WGS) and RNA-Seq revealed much evidence that various types of genomic mutations triggered diverse transcriptional changes. Not only splice-site mutations, but also silent mutations in coding regions, deep intronic mutations and structural changes caused splicing aberrations. HBV integrations generated diverse patterns of virus-human fusion transcripts depending on affected gene, such as TERT, CDK15, FN1 and MLL4. Structural variations could drive over-expression of genes such as WNT ligands, with/without creating gene fusions. Furthermore, by taking account of genomic mutations causing transcriptional aberrations, we could improve the sensitivity of deleterious mutation detection in known cancer driver genes (TP53, AXIN1, ARID2, RPS6KA3), and identified recurrent disruptions in putative cancer driver genes such as HNF4A, CPS1, TSC1 and THRAP3 in HCCs. These findings indicate genomic alterations in cancer genome have diverse transcriptomic effects, and integrated analysis of WGS and RNA-Seq can facilitate the interpretation of a large number of genomic alterations detected in cancer genome.

We report a 55-year-old Japanese woman with a two-month history of multiple pruritic erythema and erosion on her face and neck. Based on the clinical appearance, we initially diagnosed her as having pemphigus erythematosus. However, the results of a histopathological examination and a direct immunofluorescence study did not support the initial diagnosis. Additionally, anti-desmoglein 1 and 3 antibodies were all negative. Subsequently, a microscopic examination of scales revealed filaments of fungi and a fungal culture was negative for macroconidium. Using molecular biology techniques, we identified the fungus as Microsporum canis, which causes a zoonotic infection. The immune reaction to the fungi could be drastic and therefore, the eruption sometimes displays atypical clinical manifestations.

Objective: To investigate the long-term dynamics of recurrence risk and the significance of prognostic variables using conditional recurrence-free survival (C-RFS) analysis in neoadjuvant treatment (NAT) for resectable (R) and borderline resectable (BR) pancreatic cancer (PC). Background: C-RFS analysis assesses the probability of achieving additional RFS according to the RFS already accrued. Methods: Patients with NAT and subsequent resection for R/BRPC were enrolled. In the C-RFS analysis, the actual 5-year RFS (5yRFS) rate was calculated separately in the subgroup that had already gained a given amount of RFS. The significance levels of prognostic variables associated with 5yRFS were assessed regarding their time-dependent dynamics in a conditional fashion. Results: Among the total 397 patients, 160 survived for more than 5 years without recurrence after surgery (actual 5yRFS rate: 45%). The probability of 5yRFS incrementally increased based on the RFS already accrued. Pathological nodal and vascular involvement were significant influencers of 5yRFS. The patients with nodal involvement consistently remained at significantly higher risk of recurrence than those without, even after 5yRFS, whereas positivity of vascular involvement was significantly associated with the risk of recurrence only during the early postoperative period and lost its significance after 3yRFS accrued. Conclusions: In NAT for R/BRPC, the probability of gaining additional RFS increases as a function of RFS already accrued, and the significance of prognostic variables time-dependently evolves in their own patterns during the long-term postoperative period. [ABSTRACT FROM AUTHOR]