Long-term outcomes of hemostatic therapy for variceal bleeding and the challenge pending in the post-direct-acting antivirals era.

Background and study aims: This study evaluated the longterm outcomes of mainly endoscopic hemostatic therapy for gastrointestinal variceal bleeding and of the transition of hemostatic therapy. Patients and methods: Among 1,163 patients treated for gastrointestinal varices between April 2006 and June 2020, a total of 125 patients who underwent emergency hemostatic therapy were enrolled. Survival rates and secondary evaluation points were analyzed. Additionally, patients were classified into two groups: the previous and latter term. Patients' background, therapeutic method, and treatment results were compared between the groups. Results: 94.4% had cirrhosis. The average Child-Pugh score was 8.90. Successful primary hemostasis rate was 98.4%, and 5.6% died within 2 weeks, all with a Child-Pugh score ≥9. The respective 1- and 5-year survival rates for Child-Pugh grade A/B were 81.3% and 55.4%, while those for Child-Pugh grade C were 58.1% and 17.8%. Child-Pugh grade C or hepatocellular carcinoma was significantly associated with poor prognosis. In total, 21.6% experienced variceal re-bleeding; 62.9% of these cases were triggered by continued alcohol consumption. There was no significant difference in survival between patients with and without variceal re-bleeding and in post-treatment survival between the previous and latter terms. In the latter term, the number of cases caused by continued alcohol consumption significantly increased. Conclusions: Multidisciplinary treatment and continuation of proper management after hemostatic therapy for variceal bleeding are crucial. Continued alcohol consumption leads to variceal bleeding and re-bleeding; its proper management, including alcohol abstinence, is one of the major challenges left in the post-directacting antivirals era.

Levels of the oxidative stress marker γ-glutamyltranspeptidase at different stages of nonalcoholic fatty liver disease.

OBJECTIVES: This study investigated oxidative stress in the liver, by determining hepatic expression and serum levels of γ-glutamyltranspeptidase (GGT) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in different stages of nonalcoholic fatty liver disease (NAFLD), and assessed whether GGT can differentiate between the various stages of NAFLD. METHODS: Expression of GGT and 8-OHdG was examined in biopsy specimens by immunohistochemistry, and serum GGT and 8-OHdG levels were measured by enzyme-linked immuno sorbent assays in patients with simple fatty liver (n = 10), nonalcoholic steatohepatitis (NASH; n = 10) and, as a control, in alcoholic liver disease (ALD; n = 10). RESULTS: Hepatic tissue expression of GGT and 8-OHdG was seen in ALD, NASH and fatty liver patients. The percentage of hepatocytes positive for 8-OHdG expression and serum 8-OHdG levels was significantly higher in patients with NASH than simple fatty liver. Serum GGT levels were increased in all cases with ALD, NASH and fatty liver, and correlated significantly with serum levels of 8-OHdG in ALD and NASH, but not in simple fatty liver. CONCLUSIONS: Levels of GGT in fatty liver patients may compensate for mild oxidative stress by repressing 8-OHdG levels and preventing progression to NASH; however further oxidative stress leads to increased levels of 8-OHdG and the development of NASH.

Successful and long-lasting treatment of solar urticaria with ultraviolet A rush hardening therapy.

BACKGROUND: Solar urticaria (SU) is a photodermatosis that is thought to be caused through the effects of mast cell mediators released because of an altered chromophore, possibly a photoallergen recognized by IgE. Phototherapy for SU to induce a tolerant state appears to be most effective, but is often time consuming and provides only short-lived remission. Ultraviolet (UV) A rush hardening has been successful and less time consuming in serum factor-negative patients with SU. However, the mechanism of action and long-lasting effects of UVA rush hardening therapy remain unclear. OBJECTIVES: We aimed to evaluate whether UVA rush hardening exhibits long-lasting therapeutic effects in serum factor-positive patients with SU and to examine the action mechanism of tolerance. METHODS: Two serum factor-positive patients with SU were exposed to multiple UVA irradiations at 1-h intervals per day for 2 or 3 days. Intradermal injection of their in vitro-irradiated autologous serum or compound 48/80 and a prick test for histamine were performed before and after UVA rush hardening. RESULTS: The two serum factor-positive patients with SU benefited greatly from UVA rush hardening, as documented by a marked increase in minimal wealing dose, and remained symptom free without using sunscreen in their daily life. Intradermal injection of in vitro-irradiated autologous serum induced wealing before hardening, but not in tolerized skin after hardening. The responses to compound 48/80 and histamine were unaltered. CONCLUSIONS: UVA rush hardening is an effective and long-lasting treatment even in serum factor-positive patients with SU. The mechanism of tolerance may involve continued blockade of photoallergen binding to IgE on mast cells, rather than depletion of mast cell mediators or histamine tachyphylaxis.

Objective recognition of vascular lesions in Mondor's disease by immunohistochemistry.

BACKGROUND: Mondor's disease (MD) is considered an inflammatory condition of superficial vasculitis that develops mainly in the anterolateral thoracoabdominal wall. The pathogenesis of the disease has been controversial, however, because of the lack of histopathologic methods for differentiating between the small vein and the lymphatic vessel. AIM: To objectively examine the origin of vascular lesions in MD, we investigated the endothelial cells of their blood and lymphatic vessels. METHODS: Immunohistochemical examinations were carried out on specimens involving vascular lesions from 16 patients with MD, using antibodies against von Willebrand factor and human lymphatic vessel endothelial hyaluronan receptor-1, which specifically discriminate between lymphatic and blood vessels. RESULTS: The histopathologic findings clearly showed thrombophlebitis in 14 patients, a lesion originating in the lymphatic vessel in one patient, and sclerosis that consisted of the artery together with veins in another. CONCLUSION: This study suggests that almost all cases of MD are due to thrombophlebitis, with a small minority due to lymphangitis or other conditions. We believe this study will contribute to the better recognition of the factual changes in the condition designated MD.

Effect of scatter and attenuation correction in ROI analysis of brain perfusion scintigraphy: phantom experiment and clinical study in patients with unilateral cerebrovascular disease.

UNLABELLED: The AIM of this study was to evaluate the effect of scatter and attenuation correction in region of interest (ROI) analysis of brain perfusion single-photon emission tomography (SPECT), and to assess the influence of selecting the reference area on the calculation of lesion-to-reference count ratios. PATIENTS, METHODS: Data were collected from a brain phantom and ten patients with unilateral internal carotid artery stenosis. A simultaneous emission and transmission scan was performed after injecting 123I-iodoamphetamine. We reconstructed three SPECT images from common projection data: with scatter correction and nonuniform attenuation correction, with scatter correction and uniform attenuation correction, and with uniform attenuation correction applied to data without scatter correction. Regional count ratios were calculated by using four different reference areas (contralateral intact side, ipsilateral cerebellum, whole brain and hemisphere). RESULTS: Scatter correction improved the accuracy of measuring the count ratios in the phantom experiment. It also yielded marked difference in the count ratio in the clinical study when using the cerebellum, whole brain or hemisphere as the reference. Difference between nonuniform and uniform attenuation correction was not significant in the phantom and clinical studies except when the cerebellar reference was used. Calculation of the lesion-to-normal count ratios referring the same site in the contralateral hemisphere was not dependent on the use of scatter correction or transmission scan-based attenuation correction. CONCLUSION: Scatter correction was indispensable for accurate measurement in most of the ROI analyses. Nonuniform attenuation correction is not necessary when using the reference area other than the cerebellum.

The inhibition spectrum of solar urticaria suppresses the wheal-flare response following intradermal injection with photo-activated autologous serum but not with compound 48/80.

BACKGROUND: The inhibition spectrum (IS) in solar urticaria was identified mainly in Japanese patients with solar urticaria, although the mechanism of action of the IS has not been elucidated. METHODS: Because an intradermal injection of action spectrum (AS)-irradiated serum in a case of solar urticaria induced a wheal response, we studied the responsiveness of the intradermal injection after an IS irradiation. RESULTS: An AS in this patient was composed of visible light shorter than 500 nm, while an IS was composed of visible light longer than 530 nm. When the IS was exposed immediately after the AS irradiation, the wheal response was inhibited. However, when the IS was exposed before the AS irradiation, the wheal response was not inhibited. An intradermal injection of her serum produced no reaction, whereas an intradermal injection of her serum pre-irradiated with visible light induced a wheal flare response. Further examination revealed that the in vivo wheal-inducing activity of her serum irradiated with visible light could be attenuated by post-IS irradiation at the injection site, while the wheal-inducing activity of her visible light-irradiated serum was not inhibited by irradiation of the activated serum with the IS. The wheal-flare response induced by compound 48/80 and histamine was not altered by IS irradiation at the site of skin tests. CONCLUSION: These findings indicate that photoallergens in the patient's serum that are activated by visible light irradiation are responsible for the development of her symptoms and that the IS may suppress the wheal response by inhibiting the binding of the photoallergens to mast cells, not by inactivating the photoallergens and stabilizing mast cells.

Over-expression of E2F-1 in esophageal squamous cell carcinoma correlates with tumor progression.

The transcription factor E2F-1, a downstream regulator of the p16-cyclinD-Rb pathway, is required for cell cycle progression. Evidence shows that overexpression of E2F-1 can either promote or inhibit the development of tumors, depending on tissue or experimental conditions. However, the clinical impact of E2F-1 expression on esophageal squamous cell carcinoma (ESCC) remains unknown. To analyze E2F-1 expression in ESCC, we investigated the immunoreactivity of E2F-1 and its correlation with clinicopathological features in 122 patients who underwent surgical resection for ESCC. Positive E2F-1 immunostaining was detected in 73 patients (59.8%). Positive E2F-1 immunostaining correlated positively with pathologic stage (P = 0.0103), p-Grade (P = 0.0014) and pT (P = 0.0192). The overall survival rate was worse in patients with E2F-1-positive tumors than in patients with E2F-1-negative tumors (P = 0.0290). Over-expression of E2F-1 is associated with tumor progression and a worse prognosis after surgery in ESCC.

DARPP-32 expression arises after a phase of dysplasia in oesophageal squamous cell carcinoma.

This is the first report to correlate DARPP-32 immunoreactivity (dopamine and cAMP-regulated phosphoprotein, M(r) 32 000) to clinicopathological status in human cancer. DARPP-32 is recognised as a neuronal protein. A recent study demonstrated that DARPP-32, and a truncated isoform t-DARPP, are overexpressed in gastric carcinoma during the process of carcinogenesis. The biological function of DARPP-32, however, is still unclear. The purpose of this study was to clarify the roles of DARPP-32 and t-DARPP in oesophageal squamous cell carcinoma (OSCC). Initially, we investigated DARPP-32 and t-DARPP expression in OSCC cell lines by Reverse transcription-polymerase chain reaction and Western blot. DARPP-32 expression was observed in four out of seven (57.1%) cell lines, but t-DARPP expression was not observed in any cell lines. In oesophageal tissue sample, DARPP-32 expression was observed in four out of seven (57.1%) tumour tissues, while t-DARPP was not observed in any tissues. Subsequently, DARPP expression was assessed by immunohistochemistry, using a polyclonal antibody, in tissue sections from 122 patients with primary OSCC. DARPP immunoreactivity was not observed in any normal oesophageal mucous membranes. On the other hand, positive DARPP immunostaining was detected in 37 patients (30.3%) and correlated inversely with pathologic stage (P=0.0284), pT (P=0.0438), pN (P=0.0303) and tumour size (P=0.012). The overall survival rate was worse in patients with DARPP-negative tumours than in patients with DARPP-positive tumours (P=0.0453). Interestingly, DARPP expression was observed in only one out of 45 cases of dysplasia. These observations suggest that DARPP-32 (rather than t-DARPP) expression arises after a phase of dysplasia in OSCC, and that tumours expressing DARPP-32 progress less rapidly than DARPP-32-negative tumours.

Identification and analysis of single-nucleotide polymorphisms in the gemcitabine pharmacologic pathway.

Significant variability in the antitumor efficacy and systemic toxicity of gemcitabine has been observed in cancer patients. However, there are currently no tools for prospective identification of patients at risk for untoward events. This study has identified and validated single-nucleotide polymorphisms (SNP) in genes involved in gemcitabine metabolism and transport. Database mining was conducted to identify SNPs in 14 genes involved in gemcitabine metabolism. Pyrosequencing was utilized to determine the SNP allele frequencies in genomic DNA from European and African populations (n=190). A total of 14 genetic variants (including 12 SNPs) were identified in eight of the gemcitabine metabolic pathway genes. The majority of the database variants were observed in population samples. Nine of the 14 (64%) polymorphisms analyzed have allele frequencies that were found to be significantly different between the European and African populations (P<0.05). This study provides the first step to identify markers for predicting variability in gemcitabine response and toxicity.

Mediastinal bronchial artery aneurysm with hematemesis.

Mediastinal bronchial artery aneurysm is a rare condition which can lead to potentially fatal hemorrhage. In most cases it presents respiratory symptoms due to rupture into pleural parenchyma. But when it develops mediodorsally and compresses the esophagus, it may cause dysphagia or hematemesis. Here we report a case of mediastinal bronchial artery aneurysm which presented with hematemesis. Computed tomography and endoscopic ultrasound showed what seemed to be a submucosal tumor on the esophagus. We were able to correctly diagnose the aneurysm using magnetic resonance imaging and probe thoracoscopy, and were able to successfully treat with transluminal artery embolization.

Functional recovery after simultaneous transplantation with neuro-epithelial stem cells and adjacent mesenchymal tissues into infarcted rat brain.

BACKGROUND: Cerebral infarction results in impairment of motor and cognitive functions. We performed intracranial transplantation of multipotential neuro-epithelial stem cells with mesenchyme into experimentally large ischemic lesions to study their potential to relieve deficits. METHODS: Wistar albino rats were subjected to transient middle cerebral artery occlusion for 60 minutes, producing an extensive ischemic lesion in the ipsilateral striatum and adjacent cerebral cortex. The rat mesencephalic neural plate at the early somite stage (embryonic day 10.5) together with adjacent ventral mesenchyme was used as donor material. We performed histological and immunohistochemical studies, with antibodies against tyrosine hydroxylase, and dopamine- and adenosine 3': 5'-monophosphate-regulated phosphoprotein 32 (DARPP-32; a striatal marker). Micro-angiograms were made by using Microfil silicone rubber. Morris Water-maze learning and treadmill task were employed to evaluate motor and cognitive functions. FINDINGS: A viable non-tumoral mass was recognized in the rat striatum, up to as long as 156 days after transplantation. There were many cells positive for tyrosine hydroxylase or DARPP-32 in the graft. Some of the DARPP-32 positive cells within the graft had extended their dendrites into host tissues. In the micro-angiograms, many fine vessels were observed within the graft and dilated vessels meandered around the graft. Transplanted animals recovered significantly better in motor and cognitive functions than animals injected with only culture medium. INTERPRETATION: Neuro-epithelial stem cells may follow several lines of differentiation; along the naturally genetically programmed line of differentiation, or along other cell lines depending on different environments. Grafting of neuro-epithelial stem cells with mesenchyme may merit a further study as a treatment for cerebral infarction.

Caveolin-I overexpression is a favourable prognostic factor for patients with extrahepatic bile duct carcinoma.

Extrahepatic bile duct carcinoma (EBDC) is a malignancy well known for its poor prognosis. Some clinicopathological prognostic markers have been proposed, but genetic factors have not been well investigated. We have examined expression patterns of caveolin-1, which has been shown to function as a tumour suppressor in vitro, in EBDC using immunohistochemistry. Normal tissues adjacent to the tumour cells did not show immunoreactivity for caveolin-1. A total of 22 of the 60-carcinoma tissue samples (36.7%) studied were positive for caveolin-1. Caveolin-1 immunostaining negatively correlated with the patient's age and pathological T factor (pT) in a statistically significant manner. Multivariate analysis using Cox's proportional hazards model identified caveolin-1 expression as an independent positive prognostic factor. Thus, our study suggests that caveolin-1 expression may be a useful prognostic marker for EBDC.

Localized heat urticaria in a patient is associated with a wealing response to heated autologous serum.

We report a case of localized heat urticaria in a 71-year-old woman who developed weals and loss of consciousness after taking a bath. Exposing her skin to heat at 40 degrees C or immersing her hands in water at 40 degrees C produced urticarial lesions and increased her plasma histamine level. Desensitization with hot water improved her symptoms and normalized her plasma histamine level after heat challenge. An intracutaneous injection of her serum produced no reaction, while an injection of her serum that had been heated at 40 degrees C for 15 min induced a weal flare response. Further examination revealed that the weal-inducing activity of her heated serum remained for at least for 6 h and that treatment of her serum at 60 degrees C for 2 h did not abrogate its weal-inducing activity. These findings indicate that certain materials in her serum that are activated by heat are responsible for the development of her anaphylactic and urticarial reactions and that these reactions may be mediated by histamine.

Impact of caveolin-1 expression on prognosis of pancreatic ductal adenocarcinoma.

Caveolin-1 is a major component of caveolae and plays a regulatory role in several signalling pathways. Caveolin-1 was recently identified as a metastasis-related gene in prostate cancer. The clinical effects of caveolin-1 expression in pancreatic carcinoma, however, remain unknown. In this study, we have investigated the relationship between caveolin-1 expression and the clinicopathologic variables and clinical outcome in 79 patients with pancreatic adenocarcinoma undergoing surgical resection. Caveolin-1 expression was determined by immunohistochemistry, using a polyclonal anti-caveolin-1 antibody. Patients were divided into two groups based on the extent of caveolin-1 expression: a negative expression group (immunoreactivity in less than 50% of cells) and a positive expression group. Positive caveolin-1 immunostaining was detected in 32 cases (40.5% of total), while non-neoplastic ductal epithelium showed little or no staining. Positive caveolin-1 expression was correlated with tumour diameter (P=0.0079), histopathologic grade (P=0.0272) and poor prognosis (P=0.0008). Upon multivariate analysis with Cox's proportional hazards model, positive caveolin-1 expression was shown to be an independent negative predictor for survival (P=0.0358). These results suggest that caveolin-1 overexpression is associated with tumour progression, thereby indicating a poor prognosis for certain patients undergoing surgical resection for pancreatic carcinoma.