Eight-year chronic wound caused by Tarlov's cyst: a case report.

BACKGROUND: Tarlov's cyst is often underdiagnosed since it is difficult to identify without imaging assistance. Herein, we report the case of a young girl who presented with an 8-year history of chronic osteomyelitis of bilateral proximal phalanges and metatarsal bones caused by a Tarlov's cyst that did not contain a nerve root. The chronic wound in the forefoot is an unusual presentation and resulted from the Tarlov's cyst accompanied with tethered conus syndrome. CASE PRESENTATION: A 10-year-old Asian girl presented with an 8-year history of chronic osteomyelitis of bilateral proximal phalanges and metatarsal bones. She received sequestrectomy five times, however the immune function tests were all normal. A neurological examination revealed diminished sensation and a slapping gait pattern. Magnetic resonance imaging (MRI) demonstrated a lobulated cyst at the right aspect of the sacrum (S) 1 to sacrum (S) 3 canal near the dorsal root ganglion. Tethered conus syndrome was highly suspected. She received laminectomy of lumbar (L) 5 and S1-S2, which led to the diagnosis of a right S1-S3 epidural cyst. The final diagnosis from the histopathological examination was a right sacral Tarlov's cyst. The clinical conditions of diminished sensation and slapping gait pattern greatly improved after successful surgical treatment. CONCLUSION: In children who present with a recalcitrant chronic wound in the forefoot accompanied with a slapping gait pattern and foot hypoesthesia to pain, aggressive imaging examinations such as spine MRI should be arranged for further evaluation, especially in immunocompetent children.

Underexpression of Carbamoyl Phosphate Synthetase I as Independent Unfavorable Prognostic Factor in Intrahepatic Cholangiocarcinoma: A Potential Theranostic Biomarker.

Intrahepatic cholangiocarcinoma (IHCC) is the second most common malignant neoplasm of the liver. In spite of the increasing incidence worldwide, it is relatively rare in Western countries. IHCC is relatively common in Eastern and Southeastern Asia. Patients with IHCC are usually diagnosed at an advanced stage, therefore, the clinical outcome is dismal. Dysregulation of urea cycle metabolic enzyme expression is found in different types of cancers. Nevertheless, a comprehensive evaluation of genes related to the urea cycle (i.e., GO:0000050) has not been conducted in IHCC. By performing a comparative analysis of gene expression profiles, we specifically examined genes associated with the urea cycle (GO:0000050) in a publicly accessible transcriptomic dataset (GSE26566). Interestingly, CPS1 was identified as the second most prominently down-regulated gene in this context. Tumor tissues of 182 IHCC patients who underwent curative-intent hepatectomy were enrolled. The expression level of CPS1 protein in our IHCC cohort was assessed by immunohistochemical study. Subsequent to that, statistical analyses were carried out to examine the expression of CPS1 in relation to various clinicopathological factors, as well as to assess its impact on survival outcomes. We noticed that lower immunoreactivity of CPS1 in IHCC was associated with tumor progression (pT status) with statistical significance (p = 0.003). CPS1 underexpression was not only negatively correlated to overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS) and metastasis-free survival (MeFS) in univariate analysis but also an independent prognosticator to forecast poorer clinical outcome for all prognostic indices (OS, DFS, LRFS and MeFs) in patients with IHCC (all p ≤ 0.001). These results support that CPS1 may play a crucial role in IHCC oncogenesis and tumor progression and serve as a novel prognostic factor and a potential diagnostic and theranostic biomarker.

Potential Hepatic Lipid Markers Associated with Nonalcoholic Steatohepatitis and Fibrosis in Morbid Obesity Patients.

This study investigated differences in lipidomic profile features in nonalcoholic steatohepatitis (NASH) between mild and significant liver fibrosis cases among patients with morbid obesity. Wedge liver biopsy was performed during sleeve gastrectomy and significant liver fibrosis was defined as a fibrosis score ≥ 2. We selected patients with NASH with non/mild fibrosis (stage F0-F1; n = 30) and NASH with significant fibrosis (stage F2-F4; n = 30). The results of the liver tissue lipidomic analysis revealed that the fold changes of triglyceride (TG) (52:6); cholesterol ester (CE) (20:1); phosphatidylcholine (PC) (38:0) and (50:8); phosphatidic acid (PA) (40:4); phosphatidylinositol (PI) (49:4); phosphatidylglycerol (PG) (40:2); and sphingomyelin (SM) (35:0) and (37:0) were significantly lower in patients with NASH with F2-F4 than those with NASH with F0-F1 (p < 0.05). However, the fold changes of PC (42:4) were relatively higher in patients with NASH with stage 2-4 fibrosis (p < 0.05). Moreover, predictive models incorporating serum markers levels, ultrasonographic studies, and levels of specific lipid components [PC (42:4) and PG (40:2)] yielded the highest area under receiver operating curve (0.941), suggesting a potential correlation between NASH fibrosis stages and liver lipid accumulation among specific lipid species subclasses. This study demonstrated that the concentrations of particular lipid species in the liver correlate with NASH fibrosis stages and may indicate hepatic steatosis regression or progression in patients with morbid obesity.

Inhibition of Viral Replication Reduces Transcriptionally Active Distinct Hepatitis B Virus Integrations With Implications on Host Gene Dysregulation.

BACKGROUND & AIMS: Hepatocellular carcinogenesis of hepatitis B virus (HBV) infection may arise from integration of viral DNA into the host genome. We aimed to gauge the effect of viral inhibition on transcriptionally active HBV-host integration events and explore the correlation of viral integrations with host gene dysregulation. METHODS: We leveraged data and biospecimens from an interventional trial, in which patients with HBV viremia above 2000 IU/mL and minimally raised serum liver enzyme were randomized to receive tenofovir disoproxil fumarate (TDF) or placebo for 3 years. Total RNA-sequencing was performed on paired liver biopsies taken before and after the 3-year intervention in 119 patients. Virus-host chimeric reads were captured to quantify the number of distinct viral integrations. Dysregulation of a host gene disrupted by viral integration was defined by aberrant expression >2 standard deviations away from samples without viral integration. RESULTS: The TDF (n = 64) and placebo groups (n = 55) were comparable at baseline. Expressed viral integrations were detected in all pre- and posttreatment samples. The number of distinct viral integrations significantly correlated with circulatory biomarkers indicative of viral activities including HBV DNA, RNA, and viral antigens (P < .0003 for all correlations). Moreover, TDF vs placebo achieved a significantly greater reduction in distinct viral integrations, with 3.28-fold and 1.81-fold decreases in the expressed integrations per million reads, respectively (analysis of covariance, P = .037). Besides, viral integrations significantly correlated with host gene dysregulation. CONCLUSION: Inhibition of viral replication reduces the number of transcriptionally active distinct HBV-host DNA integrations in patients with substantial viremia. Given the mutagenic potentials of viral integrations, such treatment effects should be considered in patient management.

Assessment of tumor extension to the ductal system of submucosal glands in patients with superficial esophageal squamous neoplasms: Implications for endoscopic resection.

BACKGROUND: Endoscopic submucosal dissection (ESD) has become the standard treatment for superficial esophageal squamous cell neoplasia (SESCN); however, local recurrence still occurs occasionally even in patients who meet the current curative criteria. Esophageal ducts of the submucosal gland may serve as a pathway for the spread of SESCN to a deeper layer. However, the clinical impact of ductal involvement (DI) in patients undergoing ESD has yet to be investigated. METHODS: We consecutively enrolled patients with SESCN who were treated with ESD. The resected specimens were meticulously reviewed in multiple section slices for the presence and resected margins of DI, and their correlations with clinical factors were evaluated. RESULTS: A total of 210 lesions were analyzed, of which 78 (37.1%) presented with DI. The presence of submucosal invasion, lymphovascular invasion (LVI), and DI were indicators of worse prognosis (P < .05). Deep extended DIs were misdiagnosed as deep submucosal invasive cancer in 4 cases (2%). Of the 185 patients who met the criteria for curative ESD (ie, R0 resection and no deep submucosal invasion or LVI), 11 (5.9%) developed local recurrence/metastasis during a mean follow-up of 55.2 months (range, 6 to 140) months. Compared with patients with without DI, patients with DI had worse recurrence-free survival (P = .008, log-rank test) and a higher local risk of recurrence (12.7% vs 2.5%) after curative ESD (hazard ratio, 4.20; P = .038). CONCLUSIONS: A precise histological assessment of DI in SESCN is crucial after ESD, given that DI is common and associated with worse outcome. Whether total removal of esophageal glands/ducts can improve outcome requires future study.

Once-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase (TORCH-B): a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial.

BACKGROUND: Antiviral therapy for patients with non-cirrhotic chronic hepatitis B and minimally raised alanine aminotransferase (ALT) is controversial. We aimed to investigate the efficacy and safety of tenofovir disoproxil fumarate in reducing the risk of disease progression in this patient population. METHODS: TORCH-B is a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial done at six teaching hospitals in Taiwan that enrolled patients with chronic hepatitis B. Eligible patients were aged 25-70 years and had substantial viraemia (viral DNA >2000 IU/mL) and minimally raised serum ALT concentrations more than one-fold but less than two-fold the upper limit of normal (ULN). Exclusion criteria included liver cirrhosis and previous antiviral treatment. Eligible participants were randomly assigned (1:1), stratified by site with a fixed block size of ten, to receive either 300 mg of oral tenofovir disoproxil fumarate or placebo once daily for 3 years. The participants, investigators, research coordinators, pathologists, laboratory personnel, and staff involved in patient care or assessment were masked to treatment assignment. 0·5 mg/day of oral entecavir was added to rescue acute hepatitis flare. The coprimary outcomes were change in necroinflammation severity on the Knodell scale and change in fibrosis stage on the Ishak scale and were evaluated in the modified intention-to-treat population, which comprised all patients with paired liver biopsies. Safety was evaluated in all patients who were randomly assigned. This trial is registered at ClinicalTrials.gov, NCT01522625, and is completed. FINDINGS: From Jan 30, 2012, to Nov 10, 2015, 875 patients were screened and 160 were randomly assigned to receive either tenofovir disoproxil fumarate (n=79) or placebo (n=81). The coprimary outcomes were assessed in 146 patients (73 in each group). Liver fibrosis progressed (an increase of ≥1 stage) in 19 (26%, 95% CI 17-38) of 73 patients in the tenofovir disoproxil fumarate group and in 34 (47%, 35-59) of 73 patients in the placebo group (relative risk [RR] 0·56, 95% CI 0·35-0·88; p=0·013), whereas necroinflammation progressed (an increase of ≥2 points) in five (7%, 95% CI 2-15) patients in the tenofovir disoproxil fumarate group and in 12 (16%, 9-27) patients in the placebo group (RR 0·42, 95% CI 0·15-1·12; p=0·084). Two (3%) of 79 patients in the tenofovir disoproxil fumarate group and 13 (16%) of 81 patients in the placebo group had acute hepatitis flare requiring add-on entecavir (RR 0·16, 95% CI 0·04-0·68; p=0·013). The two groups were otherwise similar in occurrences of adverse events. No patients died. INTERPRETATION: Tenofovir disoproxil fumarate reduces the risk of progression in liver fibrosis in patients with chronic hepatitis B and minimally raised ALT, but its effect on necroinflammation is non-significant. FUNDING: The Taiwan Ministry of Science and Technology, E-Da Hospital, the Taipei Institute of Pathology, Gilead Sciences.

Interleukin-2 receptor alpha as a biomarker for nonalcoholic fatty liver disease diagnosis.

BACKGROUND: Two recent studies in the adult and pediatric Nonalcoholic Steatohepatitis-Clinical Research Network (NASH-CRN) cohorts have shown that soluble interleukin-2 receptor alpha (IL2RA) levels increased with fibrosis severity. However, no hepatic study has been conducted in Asian morbidly obese patients who underwent bariatric surgery. In this study, we proposed IL2RA as a biomarker for nonalcoholic fatty liver disease (NAFLD) diagnosis and performed immunohistochemistry (IHC) staining of IL2RA. METHODS: This prospective cohort study enrolled 123 morbidly obese patients who underwent bariatric surgery at Taipei Medical University Hospital from October 2016 to June 2018. During bariatric surgery, all patients underwent a wedge liver biopsy under laparoscopic guidance. The diagnoses of NASH and liver fibrosis were made histologically. In IHC of IL2RA, the number of lymphocytes with IL2RA immunoreactivity was counted in five high-power fields (×400, total: 1.19 mm2). RESULTS: Among the 123 patients, the mean age was 35.5 years, mean body mass index (BMI) was 40.6 kg/m2, 87 (70.7%) were female, 25 (20.7%) had diabetes mellitus, and 57 (46.3%; 11 with non-NAFLD and 46 with steatosis) and 66 (53.7%) were included in the non-NASH and NASH groups, respectively. The NASH group had higher IHC of IL2RA than the non-NASH group. In multivariate analysis, IHC of IL2RA (odds ratio, 1.025; 95% confidence interval, 1.006-1.045; p = 0.011) and alanine aminotransferase (ALT; odds ratio, 1.045; 95% confidence interval, 1.018-1.073; p = 0.001) were the independent factors associated with NASH. The area under the receiver operating curve of IL2RA IHC for NASH was 0.627 at the cutoff value of 82 (p = 0.0113). CONCLUSION: IL2RA is significantly associated with NASH in morbidly obese patients and would be a useful biomarker for NASH diagnosis.

Risk factors and pathological characteristics for intraductal tumor spread of submucosal gland in early esophageal squamous cell neoplasia.

The esophageal gland duct may serve as a pathway for the spread of early esophageal squamous cell neoplasia (ESCN) to a deeper layer. Deep intraductal tumor spreading cannot be completely eradicated by ablation therapy. However, the risk factors of ductal involvement (DI) in patients with ESCNs have yet to be investigated. We consecutively enrolled 160 early ESCNs, which were treated with endoscopic submucosal dissection. The resected specimens were reviewed for the number, morphology, resected margin, distribution and extension level of DI, which were then correlated to clinical factors. A total of 317 DIs (median:3, range 1-40 per-lesion) in 61 lesions (38.1%) were identified. Of these lesions, 14 have DIs maximally extended to the level of lamina propria mucosa, 17 to muscularis mucosae, and 30 to the submucosa. Multivariate logistic regression analysis showed that tumors located in the upper esophagus (OR = 2.93, 95% CI, 1.02-8.42), large tumor circumferential extension (OR = 5.39, 95% CI, 1.06-27.47), deep tumor invasion depth (OR = 4.12, 95% CI, 1.81-9.33) and numerous Lugol-voiding lesions in background esophageal mucosa (OR = 2.65, 95% CI, 1.10-6.37) were risk factors for DI. The maximally extended level of ducts involved were significantly correlated with the cancer invasion depth (P < 0.05). Notably, 245 (77%) of the involved ducts were located at the central-trisection of the lesions, and 52% of them (165/317) revealed dilatation of esophageal glandular ducts. Five (1.6%) of the involved ducts revealed cancer cell invasion through the glandular structures. In conclusion, DI is not uncommon in early ESCN and may be a major limitation of endoscopic ablation therapy.

Fibroscan-Based Score to Predict Significant Liver Fibrosis in Morbidly Obese Patients with Nonalcoholic Fatty Liver Disease.

BACKGROUND: The prevalence rate of nonalcoholic fatty liver disease (NAFLD) has been reported in 74 to 90% of morbidly obese patients. This study aims to develop a scoring system that predicts significant liver fibrosis in morbidly obese patients. METHODS: This prospective cohort study involved 123 morbidly obese patients who underwent metabolic surgery at Taipei Medical University Hospital between October 2016 and June 2018. Wedge liver biopsy was performed during surgery, and significant liver fibrosis was defined as a fibrosis score â‰§ 2. Ultrasonography and transient elastography were performed prior to surgery to assess the risk factors associated with significant liver fibrosis. RESULTS: Mean patient age was 35.5 years, mean body mass index (BMI) was 40.6 kg/m2, and 87 (70.7%) were female. Fibrosis staging revealed 28 (22.8%) at stage 2, 14 (11.4%) at stage 3, and 2 (1.6%) at stage 4. Patients were then separated into training (n = 73) and validation (n = 50) cohorts. Multivariate analysis revealed a liver stiffness measurement (LSM) > 7 kPa and aspartate aminotransferase/platelet ratio index (APRI) > 0.40 as independent factors associated with significant liver fibrosis among the training cohort. Fibroscan-base score weighted sum of (1 for presence of APRI > 0.40) + (2 for presence of LSM > 7 kPa) yielded the highest area under receiver operating curve (0.854, P = 0.0001; 0.785, P = 0.0002) compared with other non-invasive markers in the training and validation cohorts, respectively. CONCLUSION: We developed a simple, clinical scoring system incorporating Fibroscan and APRI to predict significant liver fibrosis in morbidly obese patients.

A Novel Role for the Klebsiella pneumoniae Sap (Sensitivity to Antimicrobial Peptides) Transporter in Intestinal Cell Interactions, Innate Immune Responses, Liver Abscess, and Virulence.

Klebsiella pneumoniae is an important human pathogen causing hospital-acquired and community-acquired infections. Systemic K. pneumoniae infections may be preceded by gastrointestinal colonization, but the basis of this bacterium's interaction with the intestinal epithelium remains unclear. Here, we report that the K. pneumoniae Sap (sensitivity to antimicrobial peptides) transporter contributes to bacterial-host cell interactions and in vivo virulence. Gene deletion showed that sapA is required for the adherence of a K. pneumoniae blood isolate to intestinal epithelial, lung epithelial, urinary bladder epithelial, and liver cells. The ΔsapA mutant was deficient for translocation across intestinal epithelial monolayers, macrophage interactions, and induction of proinflammatory cytokines. In a mouse gastrointestinal infection model, ΔsapA yielded significantly decreased bacterial loads in liver, spleen and intestine, reduced liver abscess generation, and decreased mortality. These findings offer new insights into the pathogenic interaction of K. pneumoniae with the host gastrointestinal tract to cause systemic infection.

The in vivo tissue effect of endoscopic balloon-based radiofrequency ablation in treating esophageal squamous cell neoplasia.

BACKGROUND: Endoscopic radiofrequency ablation (RFA) is a rapidly evolving therapeutic modality for early flat esophageal squamous cell neoplasms (ESCNs). However, the in vivo tissue effects of RFA on the esophageal wall are uncertain. METHODS: We prospectively enrolled eight patients with flat-type early ESCNs who were treated with balloon-based RFA. We evaluated the in vivo tissue effect on the esophagus using endoscopic ultrasound (EUS) and the histology of retrieved coagulum. RESULTS: The mean tumor length was 6.1 cm, and six of the eight patients achieved a complete response after primary RFA. Real-time evaluation of the tissue effect showed that the mucosa and submucosal layer were more edematous and thicker after RFA than before the procedure (mean 4.89 vs. 2.04 mm, p<.001), suggesting that the thermal effect of RFA may injure the submucosa. Histological evaluation of retrieved coagulum showed a severe cauterization (burning) effect with extensive cell necrosis; however, four cases had some residual viable neoplastic cells. Even though there were viable cells in the sloughed coagulum, half of the patients still achieved complete remission after RFA. CONCLUSIONS: Our findings suggest that the thermal effect of RFA may injure the submucosal layer and enable neoplastic epithelium to slough off without "burning."