Downregulation of SMOC1 is associated with progression of colorectal traditional serrated adenomas.

BACKGROUND: Aberrant DNA methylation is prevalent in colorectal serrated lesions. We previously reported that the CpG island of SMOC1 is frequently methylated in traditional serrated adenomas (TSAs) and colorectal cancers (CRCs) but is rarely methylated in sessile serrated lesions (SSLs). In the present study, we aimed to further characterize the expression of SMOC1 in early colorectal lesions. METHODS: SMOC1 expression was analyzed immunohistochemically in a series of colorectal tumors (n = 199) and adjacent normal colonic tissues (n = 112). RESULTS: SMOC1 was abundantly expressed in normal colon and SSLs while it was significantly downregulated in TSAs, advanced adenomas and cancers. Mean immunohistochemistry scores were as follows: normal colon, 24.2; hyperplastic polyp (HP), 18.9; SSL, 23.8; SSL with dysplasia (SSLD)/SSL with early invasive cancer (EIC), 15.8; TSA, 5.4; TSA with high grade dysplasia (HGD)/EIC, 4.7; non-advanced adenoma, 21.4; advanced adenoma, 11.9; EIC, 10.9. Higher levels SMOC1 expression correlated positively with proximal colon locations and flat tumoral morphology, reflecting its abundant expression in SSLs. Among TSAs that contained both flat and protruding components, levels of SMOC1 expression were significantly lower in the protruding components. CONCLUSION: Our results suggest that reduced expression of SMOC1 is associated with progression of TSAs and conventional adenomas and that SMOC1 expression may be a biomarker for diagnosis of serrated lesions and risk prediction in colorectal tumors.

Gel immersion endoscopic ultrasonography for ampullary tumors.

Toyonaga and colleagues present gel immersion endoscopic ultrasonography for ampullary tumors. They propose that gel immersion endoscopic ultrasonography is usefulness in evaluating of ampurally tumors because it allows clear and stable observation for an extended period with a low filling gel volume without papilla compression of the duodenal papilla.

Listeria monocytogenes Ankle Osteomyelitis in a Patient with Rheumatoid Arthritis on Adalimumab: A Report and Literature Review of Listeria monocytogenes Osteomyelitis.

Localized Listeria infection predominantly occurs in the prosthetic and hip joints. We herein report a case of Listeria monocytogenes ankle osteomyelitis in a 73-year-old man receiving adalimumab who was transferred to our hospital because of suspected rheumatoid arthritis (RA) flare. He reported a four-month history of left ankle swelling. A surgical biopsy revealed L. monocytogenes osteomyelitis in the left tibia and talus bones. The patient was successfully treated with antibiotics and surgical debridement. Thus, infection due to L. monocytogenes can present as ankle osteomyelitis in immunocompromised patients and may mimic an RA flare.

Comprehensive molecular profiling of pulmonary pleomorphic carcinoma.

Information regarding the molecular features of pulmonary pleomorphic carcinoma (PPC) is insufficient. Here, we performed next-generation sequencing to determine the genomic and transcriptomic profiles of PPC. We sequenced the DNAs and RNAs of 78 specimens from 52 patients with PPC. We analyzed 15 PPC cases to identify intratumoral differences in gene alterations, tumor mutation burden (TMB), RNA expression, and PD-L1 expression between epithelial and sarcomatoid components. The genomic alterations of six cases of primary tumors and corresponding metastatic tumors were analyzed. KRAS mutations (27%) were the most common driver mutations, followed by EGFR (8%), and MET (8%) mutations. Epithelial and sarcomatoid components shared activating driver mutations, and there were no significant differences in CD274 expression or TMB between the two components. However, PD-L1 was highly expressed in the sarcomatoid component of several cases compared with the epithelial component. Primary and metastatic tumors shared oncogenic mutations among genes such as KRAS and TP53, and additional alterations including NOTCH4 mutations were specifically identified in the metastatic regions. Our data suggest that therapies targeting activating driver mutations may be effective for patients with PPC and that immune checkpoint inhibitors of PPC may be recommended after careful assessment of PD-L1 expression in each epithelial and sarcomatoid component.

An intact boundary between the tumor and inner hypoechoic layer discriminates T1 lesions among sessile elevated gallbladder cancers.

BACKGROUND: The depth of invasion determines the surgical method for treating gallbladder cancer (GBC). However, the preoperative correct diagnosis of invasion depth, especially discrimination of T1 lesions among sessile elevated GBCs, is difficult. We investigated the utility of preoperative endoscopic ultrasound (EUS) findings for diagnosing the invasion depth. METHODS: We studied a sessile elevated GBC specimen diagnosed as a T1 lesion before developing our study protocol. EUS evidenced an intact boundary between the tumor and the inner hypoechoic layer (the intact boundary sign). To evaluate the potential of using this sign to diagnose T1 GBC as a primary outcome indicator, we retrospectively analyzed patients who underwent surgical resection of sessile elevated GBCs between April 2009 and March 2020. RESULTS: Of the 26 surgically resected sessile elevated GBC specimens, 20 were included and six were excluded due to difficulty in evaluating the overall tumor or layer structure. The Kappa coefficient for interobserver agreement regarding the intact boundary sign was 0.733. The sensitivity and specificity of the sign for diagnosing T1 lesions were 0.857 and 1.000, respectively. CONCLUSION: This new EUS finding could guide the accurate diagnosis of T1 lesions in patients with sessile elevated GBC.

Histopathologic features and fragmentation of polyps with cold snare defect protrusions.

BACKGROUND AND AIMS: Cold snare defect protrusions (CSDPs) include muscularis mucosa (MM) and submucosa tissue. CSDPs are thought to result from fragmentation of the specimen during shallow excision. Our aim in this study was to clarify whether CSDPs are associated with polyp fragmentation. METHODS: We retrospectively analyzed 1026 neoplastic colorectal polyps resected by cold snare polypectomy for which the presence or absence of CSDPs was assessed from the endoscopic image. All prepared specimens were reviewed and assessed for the presence or absence of polyp fragmentation, and the proportion of MM on the stump was measured. In addition, the risk factors for CSDP occurrence were evaluated. RESULTS: CSDPs occurred in 116 of the 1026 polyps (11.3%). Polyp fragmentation was significantly associated with the occurrence of CSDP on univariate analysis (odds ratio [OR], 3.74; P < .001) and multivariate analysis (OR, 3.13; P < .001). The proportion of MM >50% was significantly lower in the CSDP group than in the non-CSDP group (51.5% vs 70.9%, P < .001). CSDPs were significantly associated with a large polyp size (OR, 1.32; P = .007) and a large specimen size (OR, 1.24; P < .001) on multivariate analysis. CONCLUSIONS: The occurrence of CSDP was associated with less MM on the stump and fragmentation of the specimen. Clinically, the presence of CSDP is a good indicator of polyp fragmentation.

Immunoglobulin A vasculitis in a patient with neurofibromatosis type 1 / Vasculitis por inmunoglobulina A en un paciente con neurofibromatosis tipo 1

No disponible

Computer-aided classification of hepatocellular ballooning in liver biopsies from patients with NASH using persistent homology.

BACKGROUND AND OBJECTIVE: Hepatocellular ballooning is an important histological parameter in the diagnosis of nonalcoholic steatohepatitis (NASH), and it is considered to be a morphological pattern that indicates the severity and the progression to cirrhosis and liver-related deaths. There remains uncertainty about the pathological criteria for evaluating the spectrum of non-alcoholic fatty liver disease (NAFLD) in liver biopsies. We introduce persistence images as novel mathematical descriptors for the classification of ballooning degeneration in the pathological diagnosis. METHODS: We implemented and tested a topological data analysis methodology combined with linear machine learning techniques and applied this to the classification of tissue images into NAFLD subtypes using Matteoni classification in liver biopsies. RESULTS: Digital images of hematoxylin- and eosin-stained specimens with a pathologist's visual assessment were obtained from 79 patients who were clinically diagnosed with NAFLD. We obtained accuracy rates of more than 90% for the classification between NASH and non-NASH NAFLD groups. The highest area under the curve from the receiver operating characteristic analysis was 0.946 for the classification of NASH and NAFL2 (type 2 of Matteoni classification), when both 0- and 1-dimensional persistence images were used. CONCLUSIONS: Our methodology using persistent homology provides quantitative measurements of the topological features in liver biopsies of NAFLD groups with considerable accuracy.

Endoscopic ultrasound-guided fine needle aspiration for diagnosing pancreatic mass in patients with surgically altered upper gastrointestinal anatomy.

BACKGROUND AND AIMS: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has been established as a safe and accurate method for diagnosing a pancreatic mass; however, EUS-FNA for patients with surgically altered upper gastrointestinal (UGI) anatomy has not yet been investigated sufficiently. Therefore, the feasibility and safety of EUS-FNA in these patients were retrospectively investigated. METHODS: Patients in whom EUS-FNA was performed between March 2008 and April 2017 were retrospectively investigated in terms of EUS-FNA technical success, procedure time, diagnostic accuracies of cytology and histology, and procedure-related adverse events. RESULTS: Twenty-five EUS-FNAs were performed for 15 pancreatic body-to-tail and 10 head lesions. All patients underwent EUS-FNA successfully; however, changing of the echoendoscope to a forward-viewing echoendoscope and preplacement of a nasobiliary catheter by balloon-assisted enteroscopy for guidance were needed in one and two cases, respectively. The median procedure time was 26 min (range, 16-70). The diagnostic accuracies were 76%, 84%, and 88% for cytology, histology, and combined use, respectively. Adverse events were not observed. CONCLUSIONS: Endoscopic ultrasound-guided FNA is a safe and efficient method for diagnosing a pancreatic mass even in patients with surgically altered UGI anatomy. Nevertheless, some sophisticated techniques are required for pancreatic head lesions if reaching the duodenum after passing through the jejunal limb is required for visualization of the pancreatic mass.

Unusual manifestation of monoclonal gammopathy of undetermined significance: a false serum creatinine elevation.

A 72-year-old Japanese man with diabetes mellitus and hypertension presented with an acutely elevated serum creatinine level, from 1.02 to 4.13 mg/dL over 2 months as measured by the enzymatic method by pure-auto S CRE-N®. Renal biopsy could not identify the etiology of the elevating sCr. However, an elevated total protein level (8.2 g/dL) and lowering of the BUN and sCr ratio from 14.5 to 2.7 were found, and bone marrow biopsy showed less than 10% lymphoplasmacytic infiltration, compatible with monoclonal gammopathy of undetermined significance. The diagnosis of a false serum creatinine elevation due to monoclonal gammopathy of undetermined significance was confirmed with the serum cystatin C level at 1.05 mg/dL and the creatinine level of 0.97 mg/dL using Shikarikid-S CRE® method. Although cases of monoclonal gammopathy of undetermined significance with a false serum creatinine elevation as an initial presentation are rare, this condition should be considered in patients with paraproteinemia; measuring the renal function using cystatin C is important in such patients.

Metachronous intraductal papillary mucinous neoplasms disseminate via the pancreatic duct following resection.

Metachronous development of intraductal papillary mucinous neoplasms in the remnant pancreas following resection is a significant clinical burden. Our aim was to characterize the clinicopathological and molecular features of the patients with metachronous tumor development to identify predictive factors and the possible route(s) of dissemination. Seventy-four patients who underwent resection of intraductal papillary mucinous neoplasms with no invasive compartment or associated carcinoma were retrospectively analyzed. In patients with metachronous tumor development, targeted sequencing of 18 genes associated with pancreatic tumorigenesis and immunohistochemical detection of four proteins (p53, SMAD4, p16, and ß-catenin) were performed on both primary and metachronous tumors. The distributions of microscopic neoplastic lesions were examined at surgical margins and in apparently normal tissue apart from the primary tumor. During the median follow-up period of 52 months, 9 patients (12%) developed metachronous tumors in the remnant pancreas. Primary tumors located in the body/tail of the pancreas (odds ratio, 15; 95% confidence interval, 1.6-131) and of the pancreatobiliary type (odds ratio, 6.1; 95% confidence interval, 1.1-35.7) were identified as significant risk factors for subsequent metachronous tumor development. Eight of the nine patients shared molecular aberrations between their primary and metachronous tumors, suggesting migrations from the primary tumor to the pancreatic duct as the cause of metachronous tumor development. Our data suggest that these post-resection metachronous tumors develop by skip dissemination of the primary tumor, potentially via the pancreatic duct. The development of strategies to better predict and prevent this form of tumor progression is necessary.

Pathways of Progression From Intraductal Papillary Mucinous Neoplasm to Pancreatic Ductal Adenocarcinoma Based on Molecular Features.

BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are regarded as precursors of pancreatic ductal adenocarcinomas (PDAs), but little is known about the mechanism of progression. This makes it challenging to assess cancer risk in patients with IPMNs. We investigated associations of IPMNs with concurrent PDAs by genetic and histologic analyses. METHODS: We obtained 30 pancreatic tissues with concurrent PDAs and IPMNs, and 168 lesions, including incipient foci, were mapped, microdissected, and analyzed for mutations in 18 pancreatic cancer-associated genes and expression of tumor suppressors. RESULTS: We determined the clonal relatedness of lesions, based on driver mutations shared by PDAs and concurrent IPMNs, and classified the lesions into 3 subtypes. Twelve PDAs contained driver mutations shared by all concurrent IPMNs, which we called the sequential subtype. This subset was characterized by less diversity in incipient foci with frequent GNAS mutations. Eleven PDAs contained some driver mutations that were shared with concurrent IPMNs, which we called the branch-off subtype. In this subtype, PDAs and IPMNs had identical KRAS mutations but different GNAS mutations, although the lesions were adjacent. Whole-exome sequencing and methylation analysis of these lesions indicated clonal origin with later divergence. Ten PDAs had driver mutations not found in concurrent IPMNs, called the de novo subtype. Expression profiles of TP53 and SMAD4 increased our ability to differentiate these subtypes compared with sequencing data alone. The branch-off and de novo subtypes had substantial heterogeneity among early clones, such as differences in KRAS mutations. Patients with PDAs of the branch-off subtype had a longer times of disease-free survival than patients with PDAs of the de novo or the sequential subtypes. CONCLUSIONS: Detailed histologic and genetic analysis of PDAs and concurrent IPMNs identified 3 different pathways by which IPMNs progress to PDAs-we call these the sequential, branch-off, and de novo subtypes. Subtypes might be associated with clinical and pathologic features and be used to select surveillance programs for patients with IPMNs.

Cystic Duct Metastasis from Renal Cell Carcinoma.

We herein report a 69-year-old man who underwent right nephrectomy 1 year previously to remove renal cell carcinoma (RCC). On our examinations, contrast-enhanced computed tomography revealed a tumor with intensive early enhancement near the cystic duct of the gallbladder. Endoscopic ultrasonography showed a low echoic mass in the cystic duct. We diagnosed the patient's condition as cystic duct metastasis from RCC and performed open cholecystectomy. Histopathology indicated a metastatic tumor of clear cell RCC in the cystic duct wall. In patients with a medical history of RCC, hypervascular lesions suggest the possibility of metastasis. Therefore, detailed imaging examinations should be performed.

Magnetic Resonance Imaging Grading System for Preoperative Diagnosis of Leiomyomas and Uterine Smooth Muscle Tumors.

STUDY OBJECTIVE: To evaluate a new magnetic resonance imaging (MRI) grading system for preoperative differentiation between benign and variant-type uterine leiomyomas including smooth muscle tumors of uncertain malignant potential (STUMPs). DESIGN: Retrospective analysis (Canadian Task Force classification III). SETTING: Teaching hospital (Teine Keijinkai Hospital). PATIENTS: Three-hundred thirteen patient medical records were retrospectively reviewed if treated for uterine myomas and diagnosed with variant type leiomyomas or STUMPs (n = 27) or benign, typical leiomyomas (n = 286) and treated between January 2012 and December 2014. INTERVENTION: Uterine myoma classifications using MRI findings according to a 5-grade system (grades I-V) based on 3 elements. MEASUREMENTS AND MAIN RESULTS: Uterine myoma MRI classifications were based on 3 elements: T2-weighted imaging (high or low), diffusion-weighted imaging (high or low), and apparent diffusion coefficient values (high or low; apparent diffusion coefficient < 1.5 × 10-3 mm2/sec was considered low). Grades I to II were designated as typical or benign leiomyomas, grade III as degenerated leiomyomas, and grades IV to V as variant type leiomyomas or STUMPs. Accuracy levels were 98.9%, 100%, 94.3%, 58.8%, and 41.9% for grades I through V lesions, respectively. The grades were divided into 2 groups to discriminate benign leiomyomas and STUMPs (grades I-III were considered negative and grades IV-V positive). Grades IV to V scored 85.2% for sensitivity, 91.3% for specificity, 47.9% positive predictive value, 98.5% negative predictive value, a 9.745 positive likelihood ratio, and a .162 negative likelihood ratio. CONCLUSION: This novel MRI grading system for uterine myomas may be beneficial in differentiating benign leiomyomas from STUMPs or variant type leiomyomas and could be a future effective presurgical assessment tool.

Effect of topical rebamipide on goblet cells in the lid wiper of human conjunctiva.

It has been demonstrated that topical administration of rebamipide, which is an antiulcer agent, increases the mucin level of the tear film and ameliorates ocular surface conditions such as lid wiper epitheliopathy. The aim of the present study was to analyze the changes in goblet cell number, cell proliferation, and epidermal growth factor receptor (EGFR) induced by topical rebamipide addition to the lid wiper of humans. A total of 30 eyelid tissue samples were obtained during involutional entropion surgeries, fixed in paraformaldehyde, embedded in paraffin and divided into two groups: Rebamipide or non-rebamipide. The tissues in the rebamipide group were obtained from patients who had a medical history of topical rebamipide use prior to surgery. The number of goblet cells was counted under light microscopy. A total of 22 eyelid tissue samples were further examined using immunohistochemistry with anti-Ki-67 and anti-EGFR antibodies to evaluate cell proliferation and EGFR expression, respectively. Histologically, the lid wiper and palpebral conjunctiva were clearly identified in the tissues. The number of goblet cells was significantly higher in the rebamipide group compared with the non-rebamipide group (P=0.0367). There was no significant difference in lid wiper cell proliferation between the rebamipide and non-rebamipide groups. Immunohistochemistry revealed that EGFR levels in the lid wiper epithelial cells were significantly higher in the rebamipide group compared with the non-rebamipide group (P=0.0237). These results suggest that topical rebamipide application increases the number of goblet cells in the lid wiper, which in turn upregulates the expression of EGFR. These findings may be clinically relevant and provide a therapeutic basis for the treatment of ocular disease such as dry eye and lid wiper epitheliopathy.

A case of extrahepatic growth-type hepatocellular carcinoma presenting with bleeding from colonic metastasis.

A 60-year-old woman visited our hospital due to hematochezia. Colonoscopy revealed a 50-mm-diameter submucosal tumor with ulceration of the left side of the transverse colon, and magnetic resonance imaging (MRI) demonstrated the presence of small hepatic nodules. Submucosal tumor of the colon with liver metastasis was therefore diagnosed. To prevent tumor bleeding, we performed partial transverse colectomy. The histopathological diagnosis was moderately differentiated hepatocellular carcinoma presenting as a submucosal tumor with a high frequency of vascular invasion. Computed tomography (CT) angiography revealed a 40-mm-diameter confluent multinodular-type hepatocellular carcinoma with outward spread from segment II and multiple intrahepatic metastases. Our final diagnosis was hepatocellular carcinoma with hematogenous colon metastasis.