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Hyperplastic nodules (HNs) have been considered to be hyperplastic lesions among Japanese pathologists, although they have not been recognized worldwide. Here, we examined clinicopathological and molecular differences between goblet cell-rich variant hyperplastic polyp (GCHPs), microvesicular variant HPs (MVHPs), and HNs. Patients with hyperplastic lesions including 61 GCHPs, 62 MVHPs, and 19 HNs were enrolled in the present study. The clinicopathological and molecular features examined included the mucin phenotype expression, p53 overexpression, annexin A10, genetic mutations (BRAF and KRAS), and DNA methylation status (low, intermediate, and high methylation epigenotype). In addition, hierarchical cluster analysis was also performed to identify patterns among the histological features. The lesions were stratified into three subgroups and each lesion was assigned into a subgroup. While GCHP was associated with KRAS mutation, MVHP was closely associated with BRAF mutation; no mutation was found in HN. We list specific histological findings that corresponded to each lesion. Finally, there were no significant differences in the methylation status among lesions. The current result shows that both MVHPs and GCHPs have a neoplastic nature whereas HN is non-neoplastic. We suggest that HNs should be distinguished from HPs, in particular GCHPs, in terms of pathological and genetic features.

BACKGROUND Loss-of-function homozygous or compound heterozygous mutations in IL36RN, which encodes interleukin-36 receptor antagonist (IL-36Ra), has been implicated in the pathogenesis of skin disorders. However, the pathogenic role of IL-36Ra in cutaneous ischemia-reperfusion (I/R) injury remains unclear. OBJECTIVES We investigated the role of IL36Ra in cutaneous I/R injury. METHODS We examined I/R injury in Il36rn-/- mice. The area of wounds, numbers of infiltrated cells, apoptotic cells and neutrophil extracellular trap (NET) formation were assessed. The expression levels of various genes were analysed using real-time RT-PCR. The expression of high mobility group box 1 (HMGB1), an endogenous toll-like receptor (TLR) 4 ligand, was confirmed using immunohistology, and serum HMGB1 levels were measured by ELISA. Cytokine production by stimulated cultured J774A.1 and HaCaT cells was examined. RESULTS IL-36Ra deficiency resulted in significantly delayed wound healing and increased neutrophil and macrophage infiltration into the wound tissues. Il36rn-/- mice had increased mRNA expression levels of CXCL1, CXCL2, CCL4, TNF-α, TGF-β, IL-1β, IL-6 and IL-36γ relative to wild-type mice. Apoptosis was identified in keratinocytes by TUNEL assay. HMGB1 expression in the I/R site was decreased in both keratinocytes and adnexal cells, while serum HMGB1 levels were significantly elevated after reperfusion. The mRNA levels of various cytokines, including IL-1β, were elevated in J774A.1 cells through TLR4 signalling by HMGB1 stimulation. In addition, HaCaT cells stimulated with IL-1β showed significantly increased CXCL1, TNF-α, IL-6, IL-36β and IL-36γ mRNA expression. Furthermore, NET formation was increased by IL-36Ra deficiency. Finally, either the blockade of TLR4 signalling by TAK-242 or inhibition of NET formation by Cl-amidine normalized exacerbated I/R injury in Il36rn-/- mice. CONCLUSIONS This study indicated that IL-36Ra deficiency exacerbates cutaneous I/R injury due to excessive inflammatory cell recruitment, NET formation, and excessive cytokine and chemokine production via the TLR4 pathway by HMGB1 released from epidermal apoptotic cells.

Identification of molecular alterations occurring in the adenomatous and carcinomatous components within the same tumor would greatly enhance understanding of the neoplastic progression of colorectal cancer. We examined somatic copy number alterations (SCNAs) and mRNA expression at the corresponding loci involved in the adenoma–carcinoma sequence in the isolated adenomatous and cancer glands of the same tumor in 15 cases of microsatellite‐stable “carcinoma in adenoma,” using genome‐wide SNP and global gene expression arrays. Multiple copy‐neutral loss of heterozygosity events were detected at 4q13.2, 15q15.1, and 14q24.3 in the adenomatous component and at 4q13.2, 15q15.1, and 14q24.3 in the carcinomatous component. There were significant differences in the copy number (CN) gain frequencies at 20q11.21–q13.33, 8q13.3, 8p23.1, and 8q21.2–q22.2 between the adenomatous and carcinomatous components. Finally, we found a high frequency of five genotypes involving CN gain with upregulated expression of the corresponding gene (RPS21, MIR3654, RSP20, SNORD54, or ASPH) in the carcinomatous component, whereas none of these genotypes were detected in the adenomatous component. This finding is interesting in that CN gain with upregulated gene expression may enhance gene function and play a crucial role in the progression of an adenoma into a carcinomatous lesion.

Impetigo herpetiformis (IH) is a rare pustular dermatosis. It can be life-threatening for both the mother and fetus and often causes therapeutic problems. However, there is no specific guideline for the treatment of IH and the evidence regarding the efficacy of treatments for IH has not been established. Herein, we report two cases of IH, which were successfully treated with anti-tumor necrosis factor (TNF)-α drugs. The serum levels of the drugs in the infants and mothers were examined using enzyme-linked immunosorbent assay (ELISA). Case 1 was a 35-year-old, gravida 2, para 1, female patient in week 20 of pregnancy; she was treated with adalimumab (ADA) until delivery. Case 2 was a 26-year-old, gravida 1, para 0, female patient in week 30 of pregnancy; she was treated with certolizumab pegol (CZP) until delivery. In both cases, the skin lesions started regressing considerably after administration of the biologic agents. We examined the serum levels of the biologic agents in the mothers and infants using ELISA. In case 1, the ADA serum level in the infant was as high as that in the mother at birth; it then decreased below the lower limit of quantification at week 12 post-delivery. In case 2, the CZP serum level in the infant was below the lower limit of quantification at birth. In this report, we revealed that biologic agents could be an effective treatment for severe IH and that CZP treatment can be considered safe for the mothers and fetuses.

The aim of this investigation was to evaluate the clinical value of barium enema (BE) examination for the management of colorectal epithelial neoplasms. We reviewed the colonoscopy records at our institution from 2014 to 2019 and identified cases of endoscopically or surgically resected colorectal epithelial neoplasms evaluated by BE, conventional colonoscopy, magnifying narrow-band imaging colonoscopy (M-NBI), and magnifying chromoendoscopy (MCE). The yield of each modality for the diagnosis of massively submucosal invasive (mSM) colorectal cancer was evaluated by a receiver-operating characteristic analysis including the area under the curve (AUC). We analyzed the records of 105 patients (17 adenomas, 53 high-grade dysplasias (HGDs), and 35 cancers). Smooth surface, irregularity in depression, and eccentric deformity on the profile view with BE were observed more frequently in mSM cancers than adenomas/HGDs/slightly submucosal invasive cancers (p

Purpose We report a case of severe choroidal detachments (CDs) in both eyes caused by systemic lupus erythematosus (SLE). Observations The patient was a 50-year-old woman who presented with conjunctival edema in both eyes, visual dysfunction, and generalized fatigue. At the first visit, the best corrected visual acuity (BCVA) was 20/70 OD and 20/70 OS, and the intraocular pressure (IOP) was 22 mmHg OD and 27 mmHg OS. She had serous retinal detachments (SRDs), CDs, ciliary dissections, and a shallow anterior chamber with partial angle closure in both eyes. Systemic findings included hypoalbuminemia, pleural fluid, generalized fatigue, and brown papules on the back and both legs. First, we suspected Vogt-Koyanagi-Harada disease and administered two courses of methylprednisolone pulse therapy, but the CDs in both eyes gradually deteriorated and worsened to the extent that the optic nerve in both eyes could not be observed, and the BCVA deteriorated to 20/200 OD and 6/200 OS. Further multidisciplinary evaluations for diagnosing collagen diseases revealed vasculitis in the skin histopathology examination, positive results for anti-double stranded DNA antibody and anti-SS-A antibody, and hypocomplementemia in the blood examination, and she was diagnosed with severe SLE in the dermatology department. After administration of high dose intravenous γ-globulin therapy, albumin infusion, and intravenous cyclophosphamide pulse therapy, the SRDs and severe CDs improved along with improvement in hypoalbuminemia, pleural fluid, and generalized fatigue. Moreover, the shallow anterior chamber and high IOP improved to normal in both eyes. The CDs and SRDs completely disappeared, and the BCVA improved to 20/13 OU 6 months after the SLE therapy. Conclusion and importance In patients with observed SRDs and CDs accompanying hypoalbuminemia, it is necessary to consider collagen diseases such as SLE.

MicroRNAs (miRNAs) are potential biomarkers of neoplastic lesions, but additional information on dysregulated miRNA expression during progression of the adenoma-adenocarcinoma sequence may be helpful to identify the role of miRNAs in this sequence. We examined the expression levels of 13 miRNAs (hsa-miRNA-19a-3p, hsa-miRNA-21-5p, hsa-miRNA-27a-3p, hsa-miRNA-27b-3p, hsa-miRNA-31-5p, hsa-miRNA-34b-3p, hsa-miRNA-125b-5p, hsa-miRNA-143-3p, miRNA-191-5p, hsa-miRNA-193b-3p, hsa-miRNA-195-5p, hsa-miRNA-206 and hsa-let-7a-5p) that are closely associated with colorectal carcinogenesis in 40 conventional adenomas (tubular and tubulovillous adenomas), 20 intramucosal carcinomas (IMCs) and 60 invasive colorectal cancers (iCRCs) using reverse-transcription polymerase chain reaction. These 120 tumors were divided into two cohorts, that is, cohort 1 (60 cases) and cohort 2 (for validation; 60 cases). We analyzed the expression levels of these miRNAs in the first step (adenoma→IMC) and second step IMC→iCRC) of the adenoma-carcinoma sequence in both cohorts. Although no significant differences in the expression of any of the 13 miRNAs were found between adenomas and IMCs consistently in both cohorts, the expression levels of hsa-miRNA-125b-5p, hsa-miRNA-143-3p, and hsa-miRNA-206 were significantly upregulated in iCRC in both cohorts compared with those in IMC. The current results suggest that certain miRNAs, including hsa-miRNA-125b-5p, hsa-miRNA-143-3p and hsa-miRNA-206, are candidate markers that play critical roles in the progression of IMC to iCRC.

Mutations in BRAF are important events in colorectal serrated lesions and specific genetic markers for the serrated pathway. However, examination of BRAF mutations is not easy in routine histopathologic analyses. Here, the authors examined 73 colorectal serrated lesions, including 21 hyperplastic polyps, 32 traditional serrated adenomas, and 30 sessile serrated lesions, for comparison of BRAF mutation status with immunopositive expression of the anti-BRAF V600E mutation-specific antibody VE1. Thirty-two tubular adenomas (TAs) were examined as controls. In addition, 5 examples of sessile serrated lesion with dysplasia were included. Mutations in BRAF (exon 15; V600E) and KRAS (exon 2) were analyzed in serrated lesions and TAs using pyrosequencing. Finally, the authors compared BRAF mutations with immunohistochemical expression of VE1 antibodies against the BRAF V600E mutation, which was examined based on quantitative analyses and correlations between semiquantitative (0, 1+, or 2+) and quantitative results in colorectal serrated lesions. The cut-off value of VE1 expression (32%) was set based on receiver operating characteristic curve analysis. In the current study, mutations in BRAF were well correlated with VE1 expression in serrated lesions, although no TAs without BRAF mutations were immunopositive. In contrast, serrated lesions and TAs with mutations in KRAS were not stained for VE1 expression. In serrated lesions, although the sensitivity was 96.2% to 100%, the specificity was 90.0% to 100%. In addition, there was also good correlation between semiquantitative and quantitative results. Analysis of BRAF V600E expression may be pathologically useful, particularly in routine histopathologic diagnosis.

We aimed to evaluate the efficacy and safety of nab-paclitaxel in patients with refractory advanced non-small cell lung cancer who failed previous chemotherapy. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0–2 and adequate organ function. Patients received nab-paclitaxel, 100 mg/m2 i.v. on days 1, 8, and 15 every 4 weeks. The primary endpoint was the overall response rate. Secondary endpoints were the progression-free survival time, overall survival, and the toxicity profile. From July 2013 to July 2015, a total of 31 patients were enrolled. Fourteen patients received nab-paclitaxel as a second-line and 17 received it as an over third-line therapy. Each patient received a median of 5 treatment cycles (range, 1–11). The overall response rate was 19.3% (95% confidence interval, 9.1–36.2%) (complete response (n = 0), partial response (n = 6), stable disease (n = 17), and progressive disease (n = 8)). The median progression-free survival time was 4.5 months (95% confidence interval 3.5–6.3 months), median overall survival time was 15.7 months, and 1-year survival rate was 54.8%. Most common grade 3 or 4 non-hematological toxicities were elevated aspartate transaminase level (3.2%) and sensory neuropathy (9.6%). Neutropenia was the most common grade 3 or 4 adverse events (38.6%), and febrile neutropenia developed in 12.9% patients. No treatment-related deaths were observed in this study. Primary endpoint was met. Single agent nab-paclitaxel showed significant clinical efficacy and manageable toxicities for patients with chemorefractory advanced non-small cell lung cancer even if late line setting. UMIN000011696 . The date of registration was July 11th, 2013.

Background Thyrotoxic crisis and pheochromocytoma multisystem crisis are rare, life-threatening, emergency endocrine diseases with various clinical manifestations. Here we report a case of a patient who simultaneously developed thyrotoxic crisis and pheochromocytoma multisystem crisis and required intensive cardiovascular management. Case presentation A 60-year-old Asian man experienced nausea and vomiting, and subsequently developed dyspnea and cold sweats while farming. His serum free thyroxine, free triiodothyronine, and thyrotropin receptor antibody levels were elevated at 2.9 ng/dL, 7.2 pg/dL, and 4.7 IU/L, respectively. Serum thyrotropin levels were suppressed at less than 0.01 μIU/mL. Thyroid echography demonstrated no thyroid swelling (23 × 43 mm). A whole body computed tomography was performed for systemic evaluation. This revealed exophthalmos and a mass of size 57 × 64 mm in the anterior pararenal space. Based on these findings, we made an initial diagnosis of thyrotoxic crisis secondary to exacerbation of Grave’s hyperthyroidism. Treatment was begun with an iodine agent at a dose of 36 mg/day, thiamazole at a dose of 30 mg/day, and hydrocortisone at a dose of 300 mg daily for 3 consecutive days. To control tachycardia, continuous intravenously administered propranolol and diltiazem infusions were given. At the same time, small doses of doxazosin and carvedilol were used for both alpha and beta adrenergic blockade. On hospital day 5, his blood pressure and serum catecholamine concentrations (adrenalin 42,365 pg/mL, dopamine 6409 pg/mL, noradrenalin 72,212 pg/mL) were still high despite higher beta blocker and calcium channel blocker doses. These findings contributed to the diagnosis of pheochromocytoma multisystem crisis with simultaneous thyrotoxic crisis. We increased the doses of doxazosin and carvedilol, which stabilized his hemodynamic status. On hospital day 16, metaiodobenzylguanidine scintigraphy showed high accumulation in the right adrenal gland tumor. After retroperitoneal laparoscopic adrenalectomy on hospital day 33, his condition stabilized. He was discharged on hospital day 58. Conclusions Since he required more intensive cardiovascular management for thyrotoxic crisis, beta blockade was increased under intensive care unit monitoring even though initial alpha blockade is recommended in pheochromocytoma. When these crises occur simultaneously, cardiovascular management can be very challenging.

Background Malignant phyllodes tumors (PTs) of the breast occur infrequently and are difficult to treat with adjuvant therapy. Here, we present a case of a female patient with a huge malignant PT with rapid progression in a short period. Case presentation A 44-year-old woman presented to our hospital with a rapid growth mass in her right breast, measuring 20 cm. She was initially diagnosed as having a borderline phyllodes tumor by core needle biopsy and underwent total mastectomy and artificial dermis was grafted, 20 days later, latissimus dorsi muscle flap and free skin grafting were performed. Two courses of doxorubicin–ifosfamide therapy were administered because of recurrence, but the patient died 4 months after the mastectomy. Conclusions A standard therapeutic strategy for malignant PTs is needed in urgently to reduce the risk of tumor recurrence.

Crizotinib, which is effective in patients with anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer, is sometimes associated with the generation of complex renal cysts. A 56-year-old man with ALK positive adenocarcinoma received crizotinib. Ten months after the introduction of crizotinib, a cystic lesion developed from his right kidney to the iliopsoas muscle, accompanied by fever, anemia, and hypoproteinemia. After 17 months of treatment, crizotinib was switched to alectinib, followed by the recovery of hypoproteinemia and systemic inflammation. Switching to alectinib may be beneficial in patients demonstrating crizotinib-associated complex renal cysts with systemic inflammation and exhaustion.

金沢大学医薬保健学総合研究科先進的地域医療研究講座 = Department of Advanced Research in Community Medicine, To clarify the molecular and clinicopathological characteristics of colorectal serrated lesions, we assessed the DNA methylation of cancer-associated genes in a cohort of BRAF-mutant precancerous lesions from 94 individuals. We then compared those results with the lesions’ clinicopathological features, especially colorectal subsites. The lesions included hyperplastic polyps (n = 16), traditional serrated adenomas (TSAs) (n = 15), TSAs with sessile serrated adenomas (SSAs) (n = 6), SSAs (n = 49) and SSAs with dysplasia (n = 16). The prevalence of lesions exhibiting the CpG island methylator phenotype (CIMP) was lower in the sigmoid colon and rectum than in other bowel subsites, including the cecum, ascending, transverse and descending colon. In addition, several cancer-associated genes showed higher methylation levels within lesions in the proximal to sigmoid colon than in the sigmoid colon and rectum. These results indicate that the methylation status of lesions with BRAF mutation is strongly associated with their location, histological findings and neoplastic pathways. By contrast, no difference in aberrant DNA methylation was observed in normal-appearing background colonic mucosa along the bowel subsites, which may indicate the absence of an epigenetic field defect.

Background: The INPULSIS trials revealed that nintedanib reduced the decline in lung function in patients with idiopathic pulmonary fibrosis. We aimed to evaluate the efficacy and safety of nintedanib in Japanese idiopathic pulmonary fibrosis patients in real-world settings. Method: Medical records of idiopathic pulmonary fibrosis patients, who received treatment with nintedanib in five institutions between July 2015 and June 2017, were reviewed. Patients with % forced vital capacity ⩾50% and % predicted diffusing capacity of the lung carbon monoxide ⩾30% were classified as the moderate group and those with more impaired lung functions as the severe group. Result: Among 158 patients analyzed, 132 (84.6%) were classified as the moderate group and 26 (15.4%) as the severe group. In the moderate group, changes in forced vital capacity in 12 months were significantly different between before and after nintedanib administration (−253 ± 163 vs −125 ± 235 mL; p = 0.0027). In contrast, changes in forced vital capacity in 12 months were not significantly changed by nintedanib treatment in the severe group (−353 ± 250 vs −112 ± 341 mL; p = 0.2374). Incidence of acute exacerbation was higher in the severe group than in the moderate group (30.8% vs 18.9%). The overall survival of the moderate and the severe groups was 17.2 and 10.1 months. Conclusion: In real-world practice, nintedanib showed comparable efficacy to those observed in previous trials. In the severe group, the efficacy of nintedanib might be limited.

This phase I trial was conducted to determine the maximum tolerated dose (MTD) and recommended dose of afatinib for phase II trial in elderly patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. The study used a standard 3 + 3 dose escalation design. Patients aged 75 years or older with advanced NSCLC harboring EGFR mutations were enrolled. The doses of afatinib, which were given once daily, were planned as follows: level 1, 20 mg/day; level 2, 30 mg/day; level 3, 40 mg/day. Dose-limiting toxicity (DLT) was defined as grade 4 hematologic, persistent grade > 2 diarrhea for > 2 days despite concomitant medications or grade 3 non-hematologic toxicity. DLT was evaluated during day 1-28. Fifteen patients were enrolled. Patient characteristics were: male/female 3/12; median age 79 (range 75-87); PS 0/1, 2/13. Six patients have been treated at levels 1 and 3, and three patients at level 2. At level 1, one of six patients experienced grade 3 rush, grade 3 anorexia, and grade 3 infection as DLTs. At level 2, none of three patients experienced a DLT. At level 3, two patients developed grade 3 diarrhea, one of whom also experienced grade 3 anorexia. Most frequent adverse events of any grade were diarrhea, paronychia, rush, and nausea. Most patients at level 2 and 3 required dose reduction in 3 months. MTD was defined as 40 mg/day, and recommended dose for phase II study in elderly patients was 30 mg/day.

Background. Persistent edema is a common complication after the surgical treatment of blepharoptosis; however, no objective methods have been established for evaluating or treating this condition. We focused on the Japanese herbal medicine, Saireito, and evaluated its efficacy in reducing postoperative edema. Methods. This was a prospective, nonrandomized, and controlled study. We evaluated the incidence of postoperative edema in a Control group using a subjective patient-assessed visual analog scales (VASs) to assess swelling, pain, itching, and local warmth and an objective surgeon-assessed VAS to evaluate swelling. Swelling was also assessed by an objective computer-based analysis of digital images. These methods were used to evaluate the effects of Saireito (8.1 g/day) for 8 weeks. Results. A total of 49 patients and 80 eyelids were enrolled. Twenty-nine patients and 48 eyelids were assigned to the Control group, and 20 patients and 32 eyelids were assigned to the Saireito group. Our analysis of the Control group indicated that postoperative edema persisted for up to 8 weeks. On the other hand, the postoperative edema in the Saireito group was mostly eliminated at 8 weeks. The computer-based analysis of digital images showed that the edema tended to be reduced in the Saireito group compared with the Control group. Conclusion. Saireito might be effective for reducing postoperative edema after blepharoptosis surgery and almost completely eliminated it at 8 weeks after surgery. This study was a preliminary and nonrandomized study; therefore, the randomized and placebo-controlled study will be needed in the next step.

Sarcoidosis is an inflammatory granulomatous disease that is systemic, but bone involvement is uncommon. A 68-year-old man was referred to our hospital complaining of right shoulder pain with numbness. Computed tomography revealed systemic lymphadenopathy and multiple bone lesions. Because malignant lymphoma with a mass lesion protruding into the vertebral canal was considered, he underwent urgent radiotherapy. Thereafter, a needle biopsy of the left parasternal node was performed and showed epithelioid granulomas, confirming a diagnosis of sarcoidosis. Since his neurologic symptoms improved, the patient was not given systemic corticosteroids. Radiotherapy may be useful for local control of bone sarcoidosis.

In maxillofacial fields, concave deformity often requires hard tissue augmentation. Various types of materials are used for facial augmentation: Hydroxyapatite is the most ideal material because of its remarkable biocompatibility and ability to maintain the desired form for a long period. This article describes a simple surgical procedure to augment facial concavity with porous hydroxyapatite block (pHA-B) and its clinical applications and potential complications. In this retrospective study, we reviewed 24 patients with facial concave deformity and who underwent surgery using the pHA-B for facial augmentation, from July 1992 to January 2014. These patients underwent 30 pHA-B procedures for facial augmentation and were evaluated for complications and malposition. The study group consisted of 12 male and 12 female patients (age ranged, 15–52 years; mean, 26.7 years). The follow-up periods ranged from 6 to 80 months, with a mean period of 27.3 months. The primary diagnoses of facial concave deformity consisted of 13 congenital craniofacial deformity cases; eight, esthetic contouring; and three, posttraumatic facial deformity. The augmented sites included the malar and parapiriformis areas and the mandible. There was no malpositioning and nor any obvious infection for which removal of the pHA-B was needed. Our surgical treatment for facial concave deformity using pHA-B is simple, minimally invasive, provides the desired result in form, and is safe for the long term. Level of Evidence: Level IV, therapeutic study.

Immunohistochemical screening of Anaplastic lymphoma kinase (ALK) rearrangement has been regarded essential and routinely carried out to select treatment for lung adenocarcinoma. However, difficulty to approach a tumor by transbronchial lung biopsy (TBLB), it often fails to obtain tumor tissues whereas tumor cells are contained in cytology specimens simultaneously obtained when the bronchoscopy is done. Therefore we evaluated the expression of ALK protein by using immunohistochemistry (IHC) on TBLB specimens and immunocytochemistry (ICC) on brushing smear cytology slides in the same cases, and compared the concordance rate of IHC and ICC results. ICC was carried out on routine Papanicolau-stained slides after cytology diagnosis and decolorization. Results Eighteen patients with adenocarcinoma were extracted in the Hirosaki University Hospital and the Hirosaki National Hospital. IHC and ICC results showed a very high concordance rate: sensitivity of ICC in comparison with IHC was 85.7% (6/7), specificity was 100% (11/11), positive predictive value was 100% (6/6), and negative predictive value was 91.6% (11/12). Detection of ALK rearrangement using ICC on routine Papanicolau cytology slides is considered to be advantageous for lung cancer treatments.

Background and Aims Sessile serrated adenoma/polyps (SSA/Ps), which are precursor lesions of colorectal cancer (CRC) with BRAF mutation and the CpG island methylator phenotype (CIMP), develop cytologic dysplasia (CD) during the progression of colorectal tumorigenesis. In the present study we aimed to clarify the endoscopic and molecular signatures of SSA/Ps, with and without CD. Methods A series of 208 serrated lesions, including 41 hyperplastic polyps, 90 SSA/Ps, 33 SSA/Ps with CD, and 44 traditional serrated adenomas, were observed and resected using magnifying endoscopy. BRAF and KRAS mutations and methylation of CIMP markers ( MINT1 , MINT2 , MINT12 , MINT31 , and p16 ) were analyzed through pyrosequencing. Molecular alterations were then compared with endoscopic and pathologic characteristics. Results Among SSA/Ps without CD, the Type II-Open pit pattern (Type II-O), BRAF mutation, and CIMP were tightly associated with a proximal colon location. SSA/Ps in the distal colon infrequently exhibited Type II-O and CIMP. By contrast, most SSA/Ps with CD showed Type II-O plus adenomatous pit patterns (Type III or IV), BRAF mutation, and CIMP, irrespective of their locations. Conclusions Our results suggest that the Type II-O plus III/IV pit pattern is a common feature of SSA/Ps with CD in both the proximal and distal colon and that this pit pattern is a hallmark of serrated lesions at high risk of developing into CRCs.

To the Editor: We read with interest the article by Schmeling, et al 1. They screened a large number of sera from children with antinuclear antibody (ANA)–associated rheumatic disease (AARD) and related conditions, as well as sera from a reference cohort, for anti-dense fine speckled 70 autoantibodies (anti-DFS70ab). They showed that the frequency of anti-DFS70ab in healthy children (3/145, 2.1%) was within the lower range of that reported in adults, but that anti-DFS70ab were found at significantly higher frequencies in children with localized scleroderma (LS; 4/29, 13.8%), juvenile dermatomyositis (JDM; 2/11, 18.2%), and uveitis (3/26, 11.5%). For 331 patients with systemic lupus erythematosus (SLE) and 41 patients with systemic sclerosis, they investigated concomitant AARD-associated autoantibodies and found that only 6 patients with SLE had isolated anti-DFS70ab. This result fits the theory that anti-DFS70ab positivity in AARD is usually associated with additional AARD-related antibodies2. However, because their disease cohort was small, except for SLE and juvenile idiopathic arthritis (JIA; 202 patients), the higher frequency of the antibodies in … Address correspondence to Dr. Y. Muro, Division of Connective Tissue Disease and Autoimmunity, Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. E-mail: ymuro{at}med.nagoya-u.ac.jp

Two cases of dumbbell-shaped lipoma under the zygomatic arch and the therapeutic courses are described. Both tumours were present in the buccal and temporal processes and the isthmus, which showed dumbbell forms occupying temporal and infratemporal fossae on coronal MR images. According to the location, the tumours seemed to be derived from a masticatory fat pad. The tumours were completely excised via a temporal and small cheek skin incision, with no postoperative complications. Over the 5-year follow-up period, both cases have shown good function and aesthetics, and no recurrences have been observed.

Background Lung cancers with anaplastic lymphoma kinase rearrangements are highly sensitive to anaplastic lymphoma kinase tyrosine kinase inhibition, underscoring the notion that such cancers are addicted to anaplastic lymphoma kinase activity. Several anaplastic lymphoma kinase inhibitors have been identified and are being evaluated in clinical trials. However patients with poor performance status (3 or 4) were not involved in these clinical trials, it has been unclear to use anaplastic lymphoma kinase–tyrosine kinase inhibitors for these patients. Here, we report an anaplastic lymphoma kinase-positive non small cell lung cancer patient with performance status 4, who was successfully treated with alectinib. Case presentation We report on a 52-year-old patient diagnosed as non small cell lung cancer harboring echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene. His performance status was 4 because of severe respiratory failure. We treated this patient with alectinib as the first line therapy. Dramatic response was obtained and his performance status improved from 4 to 1 without severe adverse events. Conclusion Alectinib is a therapeutic option for the anaplastic lymphoma kinase positive patients with poor performance status.

Aberrant DNA methylation could potentially serve as a biomarker for colorectal neoplasms. In this study, we assessed the feasibility of using DNA methylation detected in bowel lavage fluid (BLF) for colorectal cancer screening. A total of 508 BLF specimens were collected from patients with colorectal cancer (n = 56), advanced adenoma (n = 53), minor polyp (n = 209), and healthy individuals (n = 190) undergoing colonoscopy. Methylation of 15 genes (miR-1-1, miR-9-1, miR-9-3, miR-34b/c, miR-124-1, miR-124-2, miR-124-3, miR-137, SFRP1, SFRP2, APC, DKK2, WIF1, LOC386758, and ZNF582) was then analyzed in MethyLight assays, after which receiver operating characteristic (ROC) curves were analyzed to assess the diagnostic performance of BLF methylation. Through analyzing BLF specimens in a training set (n = 345), we selected the three genes showing the greatest sensitivity for colorectal cancer detection (miR-124-3, 71.8%; LOC386758, 79.5%; and SFRP1, 74.4%). A scoring system based on the methylation of those three genes (M-score) achieved 82% sensitivity and 79% specificity, and the area under the ROC curve (AUC) was 0.834. The strong performance of this system was then validated in an independent test set (n = 153; AUC = 0.808). No significant correlation was found between M-score and the clinicopathologic features of the colorectal cancers. Our results demonstrate that DNA methylation in BLF specimens may be a useful biomarker for the detection of colorectal cancer. Cancer Prev Res; 7(10); 1002–10. ©2014 AACR.

A case of hemangiopericytoma of the palate is presented. The patient was a 47-year-old woman. She came to our department because of swelling (2×2cm) of the left side of the hard palate, present for 1 year. MR imaging showed an isointense tumor on T 1- and T 2-weighted images, and a dynamic study showed a short time to peak with a rapid washout pattern. The tumor was resected under general anesthesia, and the histopathologic diagnosis was a hemangiopericytoma with no malignant findings. There have been no signs of recurrence or metastasis as of 2 years 2 months after operation.

Fluoride (F) complexes are used in some fields of industry and medicine. F excretion mainly depends on kidney function. Urinary F concentration is measured to monitor the health of workers exposed to F. The toxicokinetics of F were studied by analyzing plasma concentration of F after intravenous injection of 2.86, 5.71 and 8.57 mg/kg into male Wistar rats. A dose-response relationship was recognized between these F doses and renal tissue injury. Blood samples were removed at 0, 10, 20, and 30 min, and after 1, 2, 3, 4, 5, and 6 h after injection. Plasma concentration-vs-time profiles were evaluated by a nonlinear least-squares method for fitting data to polyexponential equations and calculation of relevant pharmacokinetic parameters. Results indicated that a two-compartment model could describe the elimination of F from plasma. The beta rate constant, total plasma clearance (C1) and first-order rate constants (K21, Kel) decreased, and the half-time of the beta-phase (t1/2beta) was significantly prolonged with increasing dose. The kidney is the main target organ for F toxicity. Acute exposure to high doses of F damages renal tissue and causes renal dysfunction. The C1 of F is mainly dependent on renal F excretion. Since severe kidney damage markedly affected the toxicokinetics of F and decreased its elimination, other nephrotoxic indicators and measurement of plasma F concentration are necessary for monitoring high-dose F exposure.

We describe a case of contact stomatitis due to a surgical pack.A 61-year-old woman had the upper right first premolar extracted by a local dentist on January 22, 1999. Thereafter, she had pain associated with gingival recession at the upper right canine. For treatment, surgical packs were applied to the upper right canine region on February 17. From February 20, swelling developed in the right upper lip and cheek and reddening and pain developed at the right margin of the tongue. The patient was referred to our department on February 23. The swelling was edematous, and blood examination found no signs of inflammation. Interview of the patient suggested an allergic reaction to the surgical pack. We therefore referred the patient to the department of dermatology to undergo patch testing. There were no abnormalities with the powder and control, but reddening was noted 48 hours after the liquid had been applied to the skin of the back (evaluated as +), and blisters were seen after 72 hours (evaluated as+3). These findings resulted in a diagnosis of contat stomatitis caused by the surgical pack liquid.

Su1531 Comparison of Quality of Bowel Preparation Between 4L Polyethylene Glycol and 2L Polyethylene Glycol Plus Ascorbic Acid With and Without Simethicone a Preliminary Report Sun Mi Kang*, Eun Young Kim, Si Hye Kim, Byung Seok Kim, Jimin Han, Jin Tae Jung, Joong Goo Kwon, Chang Hyeong Lee, Ho Gak Kim Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea (the Republic of) Background/Aim: Optimal bowel preparation is essential for the high quality colonoscopic procedure. Polyethylene glycol based solution is the most commonly used bowel preparation agent. This study has investigated the quality of bowl preparation between two preparation regimen with and without supplemetal use of simethicone. Methods: Prospective, single-blind, randomized comparative study was carried out from a single center. Patients were randomly assigned into 4 groups: 4L polyethylene glycol(4L-PEG), 4L PEG with simethicone(4L-PEG+S), 2L polyethylene glycol plus ascorbic acid(2L-PEG-Asc), 2L PEG-Asc with simethicone(2L-PEG-Asc+S). In groups with simethicone, patients took 400mg of simethicone after second split dose of PEG based solution. Boston Bowel Preparation Scale was used to evaluate the quality of bowel preparation. Degree of bubble formation was recorded for three colonic segments (the right side of the colon-including the cecum and ascending colon/ the transverse section of the colon-including the hepatic and splenic flexures/ and the left side of the colon-including the descending colon, sigmoid colon, and rectum) during the withdrawal of colonoscope. Adenoma detection rate (ADR) and polyp detection rate (PDR) were compared between the groups. Tolerability and willingness to repeat colonoscopy with same preparation regimen were also evaluated by using the questionnaire. Results: Overall, 191 patients were enrolled and randomly allocated to the 4 groups. There was no significant difference in the degree of bowel cleansing according to the preparation regimen (Boston Bowel Preparation Scale: 4L-PEG/4L-PEG+S/2L-PEG-Asc/2L-PEG-Asc+S 6.581/6.571/6.54/ 6.98, PZ0.350). Degree of foam and bubble formation was significantly decreased in both simethicone groups (total bubble grade score: 4L-PEG+S/2L-PEG-Asc+S 5.633/ 5.633 vs 4L-PEG/2L-PEG-Asc 4.93/4.98, PZ0.002). In the subgroup analysis, female showed more significant improvement in the bubble score: 4L-PEG+S/2L-PEGAsc+S 5.923/5.733 vs 4L-PEG/2L-PEG-Asc 4.636/5.125, PZ0.000). ADR and PDR were 39%/35%/38%/36% and 56%/54%/53%/52% respectively for 4L-PEG/4L-PEG+S/2LPEG-Asc/2L-PEG-Asc+S. Patients had more satisfaction with 2L PEG-Asc regimen (2LPEG-Asc/2L-PEG-Asc+S 92%/89.8% vs 4L-PEG/4L-PEG+S 74.42%/69.39%, PZ0.007). The patients were more willing to repeat colonoscopy with 2L PEG-Asc (2L-PEG-Asc/ 2L PEG-Asc+S 94%/85.71% vs 4L-PEG/4LPEG+S 62.79%/63.2739%, PZ0.000). Conclusions: Low volume PEG-Asc showed similar effectiveness in bowel preparation compared to large volume PEG. Supplemental use of simethicone decreased the occurrence of foam and bubbles, especially in female. 2L PEG-Asc regimen was better tolerated and patients were willing to repeat colonoscopy with 2L PEG-Asc regimen.

A human pancreatic beta-cell line that is functionally equivalent to primary beta-cells has not been available. We established a reversibly immortalized human beta-cell clone (NAKT-15) by transfection of primary human beta-cells with a retroviral vector containing simian virus 40 large T-antigen (SV40T) and human telomerase reverse transcriptase (hTERT) cDNAs flanked by paired loxP recombination targets, which allow deletion of SV40T and TERT by Cre recombinase. Reverted NAKT-15 cells expressed beta-cell transcription factors (Isl-1, Pax 6, Nkx 6.1, Pdx-1), prohormone convertases 1/3 and 2, and secretory granule proteins, and secreted insulin in response to glucose, similar to normal human islets. Transplantation of NAKT-15 cells into streptozotocin-induced diabetic severe combined immunodeficiency mice resulted in perfect control of blood glucose within 2 weeks; mice remained normoglycemic for longer than 30 weeks. The establishment of this cell line is one step toward a potential cure of diabetes by transplantation.

Background Thymic carcinoma is a rare neoplasm of the thymus. Systemic chemotherapy is an important therapeutic modality for thymic carcinoma. However, no standard chemotherapy for this carcinoma has yet been established. The usefulness of second-line or later-line chemotherapy has remained unclear. A case of relapsed thymic carcinoma that was successfully treated by S-1 as second-line chemotherapy is reported herein. Case presentation A 73-year-old man diagnosed as having thymic carcinoma was treated with three cycles of first-line chemotherapy with ADOC (cisplatin, doxorubicin, vincristine, and cyclophosphamide) and additional radiotherapy (50 Gy). Since his serum cytokeratin 19 fragment level increased suddenly after 3 months of stable disease, he was considered to have progressive disease, and was given S-1 as chemotherapy. Two months later, he had partial response, and the S-1 treatment has been continued since July 2009. Progression-free survival of greater than 4 years was obtained with S-1. Conclusion A case of relapsed thymic carcinoma that was treated with S-1, and continues to show a long progression-free survival with good quality of life on treatment is described. S-1 might be an active agent against relapsed thymic carcinoma.

Background Lung cancer is the leading cause of cancer-related death worldwide. Epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitor (TKI) is used for the patients with EGFR-mutant lung cancer. Recently, phase III studies in the patients with EGFR-mutant demonstrated that EGFR-TKI monotherapy improved progression-free survival compared with platinum-doublet chemotherapy. The echinoderm microtubule-associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion oncogene represents one of the newest molecular targets in non-small cell lung cancer (NSCLC). Patients who harbor EML4-ALK fusions have been associated with a lack of EGFR or KRAS mutations. Case presentation We report a 39-year-old patient diagnosed as adenocarcinoma harboring EGFR mutation and EML4-ALK fusion gene. We treated this patient with erlotinib as the third line therapy, but no clinical benefit was obtained. Conclusion We experienced a rare case with EGFR mutation and EML4-ALK. Any clinical benefit using EGFR-TKI was not obtained in our case. The therapeutic choice for the patients with more than one driver mutations is unclear. We needs further understanding of the lung cancer molecular biology and the biomarker infomation.

Construction of a safe and functional bioartificial pancreas (BAP) that provides an adequate environment for islet cells may be an important approach to treating diabetic patients. Various types of BAP devices have been developed, but most of them involve extravascular implantation of islets in microcapsules or diffusion chambers. These devices have poor diffusive exchange between the islets and blood, and often rupture. To overcome these problems, we developed a new type of BAP composed of polyethylene-vinyl alcohol (EVAL) hollow fibers that are permeable to glucose and insulin and a poly-amino-urethane-coated, non-woven polytetrafluoroethylene (PTFE) fabric that allows cell adhesion. Porcine islets attached to the surface of the PTFE fabric, but not to the surface of the EVAL hollow fibers, allowing nutrient and oxygen exchange between blood flowing inside the fibers and cells outside. We inoculated this BAP with porcine islets and connected it to the circulation of totally pancreatectomized diabetic pigs. We found that blood glucose levels were reduced to a normal range and general health was improved, resulting in longer survival times. In addition, regulation of insulin secretion from the BAP was properly controlled in response to glucose both in vitro and in vivo. These results indicate that our newly developed BAP may be a potential therapy for the treatment of diabetes in humans.

Background Septic arthritis of the sternoclavicular joint is rare. It can be associated with serious complications such as osteomyelitis, chest wall abscess, and mediastinitis. In this report, we describe a case of an otherwise healthy adult with septic arthritis of the sternoclavicular joint with chest wall abscess. Case presentation A 68-year-old Japanese man presented to our hospital complaining of pain and erythema near the right sternoclavicular joint. Despite 1 week of oral antibiotics, his symptoms did not improve. Computed tomography revealed an abscess with air around the right pectoralis major muscle. After being transferred to a tertiary hospital, emergency surgery was performed. Operative findings included necrotic tissue around the right sternoclavicular joint and sternoclavicular joint destruction, which was debrided and packed open. Methicillin-susceptible Staphylococcus aureus was identified in blood and wound cultures. Negative pressure wound therapy and hyperbaric oxygen therapy were performed for infection control and wound healing. The patient’s general condition improved, and good granulation tissue developed. The wound was closed using a V-Y flap on hospital day 48. The patient has been free of relapse for 3 years. Conclusions Septic arthritis of the sternoclavicular joint is an unusual infection, especially in otherwise healthy adults. Because it is associated with serious complications such as chest wall abscess, prompt diagnosis and appropriate treatment are required.

Background To overcome the absorption of traditional fat grafting, techniques for adipose-derived regenerative cell (ADRC)-enriched fat grafting are currently being adapted for practical application. The Celution®800/CRS (Cytori Therapeutics, San Diego, CA) has enabled rapid grafting of the patient’s own freshly harvested ADRCs without requiring a culturing step. However, the optimal cell concentration and the effects of ADRCs on the characteristics of grafted fat after free fat grafting remain unclear. Methods ADRCs were isolated and purified from human fat tissue using the Celution®800/CRS. Animals that received fat grafting without the addition of ADRCs were designated the control group (group A). The number of ADRCs per grafted fat volume (mL) was adjusted to 3 × 105, 1.5 × 106, and 3 × 106 cells/mL (groups B, C, and D, respectively), mixed with free fat, and transplanted as ADRC-enriched fat grafting. These mixtures were transplanted subcutaneously into BALB/C Jcl-nu/nu mice. The volume of grafted fat was determined 5 months after transplantation, and histological assessments were performed. Results ADRC-enriched fat grafting resulted in decreased fat absorption and the formation of greater numbers of new blood vessels in the grafted fat. The optimal ADRC concentration in this study was found to be 3 × 105 cells/mL (group B), with higher concentrations resulting in increased cyst and fibril formation in the grafted fat. Conclusions This study used the Celution®800/CRS for free fat grafting and demonstrated that the concentration of transplanted ADRCs affected the engraftment and quality of the grafted fat.