Low serum pancreatic amylase levels as a novel latent risk factor for colorectal adenoma in non-alcohol drinkers.

BACKGROUND AND AIM: Obesity, insulin resistance, and metabolic alterations increase the risk of colorectal cancer and adenoma (CRA). Non-alcoholic fatty liver disease (NAFLD) or pancreatic disease (NAFPD) shares many risk factors with CRA that may have significant roles in its development; however, the relationship between CRA and NAFLD/NAFPD remains unclear. METHODS: This cross-sectional study recruited 712 eligible participants without current drinking who had undergone total colonoscopy as part of a health checkup. These participants were classified into a CRA group (n = 236) and a control group (n = 439), which consisted of individuals without CRA and a history of polyp resection. NAFLD and NAFPD were diagnosed based on abdominal ultrasonography findings. RESULTS: Non-alcoholic fatty liver disease was observed more frequently in individuals with CRA than in the control group (55.9% vs 41.6%, P < 0.01). There was no significant association between NAFPD and CRA; however, serum pancreatic amylase (P-amylase) levels were significantly lower in individuals with CRA. Although NAFLD was one of the factors increasing the presence of CRA (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.07-2.10), low P-amylase levels were significantly associated with the presence of CRA (OR, 1.73; 95% CI, 1.04-2.88) independent of age, sex, current smoking, obesity, metabolic alterations including insulin resistance, and NAFLD. CONCLUSIONS: Low serum P-amylase levels were a possible independent risk factor for CRA in the present study. The latent pancreatic exocrine-endocrine-gut relationship was considered a novel pathway involved in obesity-related CRA development, in non-alcoholic individuals.

Association between High Levels of Circulating Chemerin and Colorectal Adenoma in Men.

BACKGROUND: Obesity and metabolic syndrome are considered the risk factors of colorectal adenoma (CRA) and colorectal cancer (CRC). Chemerin is a novel adipocytokine associated with the development of gastric cancer, esophageal cancer, hepatocellular carcinoma, and CRC. However, the relationship between chemerin levels and CRA remains unclear. OBJECTIVE: This study is aimed at investigating the -association between serum chemerin levels and the development of CRA. METHODS: We conducted a total colonoscopy-based cross-sectional case-control study of 80 male patients with CRA and 80 male age-matched control individuals without CRA, according to their endoscopic findings. Serum chemerin concentrations were measured using a sandwich enzyme-linked immunosorbent assay kit, and the OR of CRA was calculated via logistic regression analysis. RESULTS: The mean serum chemerin level of the CRA group was significantly higher than that of the control group (7.9 ± 0.41 vs. 5.16 ± 0.34 ng/mL, p < 0.001). Serum chemerin level was positively correlated to the development of CRA (r = 0.34). Multivariate logistic regression analysis revealed that a high chemerin level was independently associated with the development of CRA (OR 2.82, 95% CI 1.39-5.72). CONCLUSIONS: Our findings indicated that increased serum chemerin levels are positively associated with the presence of CRA in men. Chemerin may play an important role in the development of CRA.

Medium-chain triglycerides supplement therapy with a low-carbohydrate formula can supply energy and enhance ammonia detoxification in the hepatocytes of patients with adult-onset type II citrullinemia.

Citrin, encoded by SLC25A13, constitutes the malate-aspartate shuttle, the main NADH-shuttle in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). Citrin deficiency is predicted to impair hepatic glycolysis and de novo lipogenesis, resulting in hepatic energy deficit. Secondary decrease in hepatic argininosuccinate synthetase (ASS1) expression has been considered a cause of hyperammonemia in CTLN2. We previously reported that medium-chain triglyceride (MCT) supplement therapy with a low-carbohydrate formula was effective in CTLN2 to prevent a relapse of hyperammonemic encephalopathy. We present the therapy for six CTLN2 patients. All the patients' general condition steadily improved and five patients with hyperammonemic encephalopathy recovered from unconsciousness in a few days. Before the treatment, plasma glutamine levels did not increase over the normal range and rather decreased to lower than the normal range in some patients. The treatment promptly decreased the blood ammonia level, which was accompanied by a decrease in plasma citrulline levels and an increase in plasma glutamine levels. These findings indicated that hyperammonemia was not only caused by the impairment of ureagenesis at ASS1 step, but was also associated with an impairment of glutamine synthetase (GS) ammonia-detoxification system in the hepatocytes. There was no decrease in the GS expressing hepatocytes. MCT supplement with a low-carbohydrate formula can supply the energy and/or substrates for ASS1 and GS, and enhance ammonia detoxification in hepatocytes. Histological improvement in the hepatic steatosis and ASS1-expression was also observed in a patient after long-term treatment.

Young Patient with X-linked Agammaglobulinemia Presents with Advanced Gastric Cancer and Extensive Atrophic Gastritis.

X-linked agammaglobulinemia (XLA) is associated with an increased risk of gastrointestinal cancers including gastric cancer (GC). We herein report the case of a 30-year-old male patient with XLA who developed GC and extensive atrophic gastritis. He tested positive in the urea breath test, thus indicating the presence of Helicobacter pylori. Distal gastrectomy and chemotherapy were performed without any complications; however, the died two years after this diagnosis. Immunoglobulin deficiency makes these patients susceptible to progressive atrophic gastritis and the associated risk of GC. Therefore, patients with XLA are advised to undergo an evaluation for Helicobacter pylori infection as well as monitoring for GC.

Modulation of AMPK/ TET2/ 5-hmC axis in response to metabolic alterations as a novel pathway for obesity-related colorectal cancer development.

Obesity is a major risk factor for colorectal cancer (CRC). Sustained hyperglycemia destabilizes tumor suppressor ten-eleven translocation (TET) 2, which is a substrate of AMPK, thereby dysregulating 5-hydroxymethylcytosine (5-hmC). However, the role played by this novel pathway in the development of obesity-related CRC is unclear. In this study, we aimed to evaluate the expression levels of TET2 and 5-hmC in obesity-related CRC and the effects of TET2 expression on the proliferation of CRC cells. To this end, surgically resected CRC samples from seven obese patients (Ob-CRC) and seven non-obese patients (nOb-CRC) were analyzed, and expression levels of the TET family and 5-hmC were compared between the groups. A decrease was observed in TET2 mRNA levels and 5-hmC levels in Ob-CRC compared to that in nOb-CRC. Furthermore, we used CRC cell lines to investigate the relationship between insulin, proliferation, and TET expression and AMPK. In cell lines, glucose and insulin treatments suppressed the expression of TET2 and increased cell proliferation. Downregulation of TET2 using siRNA also induced cell proliferation. An AMPK activator inhibited insulin- or glucose-stimulated cell proliferation and restored TET2 expression. We propose the AMPK-TET2-5-hmC axis as a novel pathway and potential therapeutic target in obesity-related CRC development.

Linked color imaging improves the diagnostic accuracy of eosinophilic esophagitis.

Objectives: To assess the usefulness of linked color imaging (LCI), a recently developed image-enhanced endoscopy technique, in the endoscopic diagnosis of eosinophilic esophagitis (EoE). Methods: Thirty white light images (WLIs) and 30 WLI+LCI images collected from patients with and without EoE were randomly and blindly reviewed by 10 endoscopists, including four experts (Exs) and six non-Exs. Edema, ring, exudate furrows, and strictures were rated on the adjusted EoE endoscopic reference score; the diagnosis of EoE was assessed. Using the kappa value, inter- and intra-observer agreements were analyzed among endoscopists. Results: WLI+LCI images had a higher diagnostic accuracy for EoE than WLIs (0.85 vs. 0.70, respectively), especially in non-Exs or endoscopists with no experience with EoE patients. Inter-observer agreement for WLI+LCI images statistically surpassed WLIs for furrows (kappa, 0.73 vs. 0.67, respectively; p = 0.0013), stricture (kappa, 0.51 vs. 0.39, respectively; p = 0.0072), and diagnosis (kappa, 0.67 vs. 0.57, respectively; p < 0.0001) of EoE. The increase in inter-observer agreement in WLI+LCI images allowed for a reduction in the differences between the Exs and non-Ex endoscopists. Intra-observer agreement for WLI+LCI images surpassed WLIs for a ring (kappa, 0.62 vs. 0.43, p = 0.0052), and a similar trend was found in exudates, furrows, and diagnosis irrespective of the Exs or non-Exs. Conclusions: LCI can contribute to the improvement of the endoscopic diagnosis for EoE, with "moderate" to "substantial" consistency, by enhancing the visibility of abnormal findings, leading to reduced diagnostic disparities among endoscopists.

Atypical jejunal follicular lymphoma with severe stricture.

The typical macroscopic appearance of gastrointestinal follicular lymphoma (FL) are multiple white granules or small white polyps, called multiple lymphomatous polyposis type, and subsequent mass lesions with or without ulceration; however, an ulcer type with a stricture is extremely rare. We report a case of a 79-year-old male with severe jejunal stricture due to FL with an uncommon chromosomal translocation t(2;18)(p12;q21). The patient was treated with jejunectomy subsequent rituximab monotherapy with a favorable response. The presence of the stricture made its endoscopic diagnosis confusing; however, it was certainly accompanied by the distinctive white granules on the surface of the tumor as seen in typical FL. With the possibility of an FL with stricture in mind, it is important to collect subtle endoscopic findings of the surrounding mucosa carefully, in order to arrive at an accurate endoscopic diagnosis and eventually to the proper therapeutic option.

Small-bowel Capsule Endoscopic Features in Patients with Eosinophilic Gastroenteritis: Three Case Reports.

Eosinophilic gastroenteritis (EGE) is an uncommon disease characterized by eosinophilic infiltration of the gastrointestinal tract in the absence of secondary causes and presents with a variety of gastrointestinal manifestations. Important diagnostic evidence for EGE can be provided by endoscopy; however, the specific small-bowel capsule endoscopic (SBCE) findings remain unknown. We herein report the SBCE findings of three cases of EGE as well as those of the previous cases. The most common findings in patients with EGE were multiple erythema and erosions with surrounding redness on SBCE; these findings should be considered for the diagnostic evaluation for EGE.

Novel genomic alteration in superficial esophageal squamous cell neoplasms in non-smoker non-drinker females.

Alcohol consumption and smoking pose a significant risk for esophageal squamous cell neoplasia (ESCN) development in males; however, ESCN is often diagnosed in non-drinking and non-smoking females. The mechanisms underlying these differences remain elusive, and understanding them can potentially identify novel pathways involved in ESCN development. We performed short-read sequencing to identify somatic variants on a cancer panel targeting 409 genes using DNA extracted from the superficial squamous cell carcinoma (ESCC) tissues and adjacent non-neoplastic epithelium (NE), and immunohistochemical staining of the protein encoded by the target gene. All male patients (n = 117) were drinkers or smokers, whereas 45% of the female patients (n = 33) were not. Somatic variants were compared among three age-matched groups: 13 female ESCC patients with smoking and drinking habits (known-risk group, F-KR), 13 female ESCC patients without these habits (unknown-risk group, F-UR), and 27 males with ESCC and smoking and drinking habits (M-KR). In the NE, the frequencies of CDKN2A variants were significantly higher in F-UR than in F-KR and M-KR. In both ESCC and NE, p14ARF was significantly overexpressed in F-UR than in the other groups. In conclusion, CDKN2A might be important in ESCC development, independent of known risk factors.

Characteristics of the gut microbiome profile in obese patients with colorectal cancer.

BACKGROUND AND AIM: Obesity affects the gut microbiome, which in turn increases the risk for colorectal cancer. Several studies have shown the mechanisms by which some bacteria may influence the development of colorectal cancer; however, gut microbiome characteristics in obese patients with colorectal cancer remain unclear. Therefore, this study evaluated their gut microbiome profile and its relationship with metabolic markers. METHODS: The study assessed fecal samples from 36 consecutive patients with colorectal cancer and 38 controls without colorectal cancer. To identify microbiotic variations between patients with colorectal cancer and controls, as well as between nonobese and obese individuals, 16S rRNA gene amplicon sequencing was performed. RESULTS: Principal coordinate analysis showed significant differences in the overall structure of the microbiome among the study groups. The α-diversity, assessed by the Chao1 index or Shannon index, was higher in patients with colorectal cancer versus controls. The relative abundance of the genera Enterococcus, Capnocytophaga, and Polaribacter was significantly altered in obese patients with colorectal cancer, whose serum low-density lipoprotein concentrations were positively correlated with the abundance of the genus Enterococcus; among the most abundant species was Enterococcus faecalis, observed at lower levels in obese versus nonobese patients. CONCLUSIONS: This study demonstrated several compositional alterations of the gut microbiome in patients with colorectal cancer and showed that a reduced presence of E. faecalis may be associated with obesity-related colorectal cancer development. The gut microbiome may provide novel insights into the potential mechanisms in obesity-related colorectal carcinogenesis.

Cronkhite-Canada Syndrome Associated with Gastric Outlet Obstruction and Membranous Nephropathy: A Case Report and Review of the Literature.

A 47-year-old man presented with dysgeusia, anorexia, and diarrhea. An endoscopic evaluation showed widespread gastrointestinal nodular inflammation and polyps. The pathological findings were consistent with Cronkhite-Canada Syndrome (CCS). Prednisolone therapy resulted in clinical improvement. However, CCS relapse complicated with gastric obstruction was observed during drug tapering. Although his symptoms disappeared after the reintroduction of steroids, he developed membranous nephritis. Additional cyclosporine A (CyA) treatment dramatically improved his proteinuria and residual gastrointestinal polyposis. The clinical symptoms resolved with steroid treatment, while CyA was effective for both CCS lesions and membranous nephropathy. CyA might therefore be a potential treatment option for CCS associated with membranous nephropathy.

Clinical Features of Esophageal Eosinophilia According to Endoscopic Phenotypes.

Objective Esophageal eosinophilia (EE), a histological hallmark of eosinophilic esophagitis, is classified into two endoscopic phenotypes: localized and diffuse EE. Our aim was to determine the prevalence of EE localized in the lower esophagus and to describe its clinical features in comparison with diffuse EE. Methods Data from 81 consecutive patients with EE were retrospectively investigated. EE was histologically defined as ≥15 eosinophils per high-power field. Based on the endoscopic appearance with a histological assessment, EE was classified as either diffuse or localized type. We compared the clinical features, including the medical treatment and natural course, between the two types. Results Of the 81 patients, 52 (64.2%) had diffuse EE, and 29 (35.8%) had localized EE. Among men patients, localized EE was significantly more common than diffuse EE. In localized EE, dysphagia and food impaction were less prevalent, and the presence of rings was significantly less common than in diffuse EE. Acid-suppressive therapy was administered to only 3 of the 29 patients with localized EE. In asymptomatic patients, especially those with localized EE, endoscopic abnormalities did not worsen but rather improved in some findings, such as with regard to furrows or exudate, during the natural course of three years without medical treatment. Conclusion Localized EE has a strong predilection for men patients and accounted for more than one third of all cases of EE. This condition appears to be less symptomatic and necessitates milder medical treatment than diffuse EE and might not worsen progressively.

Somatic alterations and mutational burden are potential predictive factors for metachronous development of early gastric cancer.

The risk of developing metachronous gastric cancer (MGC) following curative endoscopic submucosal dissection (ESD) of early gastric cancer (EGC) remains even after eradicating Helicobacter pylori (HP) successfully. We screened initial EGC and adjacent non-cancerous mucosa ESD-resected specimens for somatic variants of 409 cancer-related genes, assessing their mutational burden (MB) to predict molecular markers for metachronous post-ESD development. We compared variants between ten patients diagnosed with MGC more than 3 years after ESD and ten age-matched patients who did not have MGC developments after successful HP eradication. We found no significant background differences between the two groups. In adjacent non-cancerous mucosa, the MB tended to be higher in the patients with metachronous developments than in the others. Somatic genomic alterations of RECQL4, JAK3, ARID1A, and MAGI1 genes were significantly associated with MGC development. The criteria including both the MB and their variants, which had potential significant values for predicting MGC. In conclusion, combined of assessing specific somatic variants and MB may be useful for predicting MGC development. This study included a limited number of subjects; however, our novel findings may encourage further exploration of the significance of the molecular features of EGC that predict MGC development, thereby promoting focused follow-up strategies and helping elucidate the mechanisms.

Esophageal intramural pseudodiverticulosis complicated with severe stricture requiring surgical resection.

Esophageal intramural pseudodiverticulosis (EIPD) is an uncommon benign disorder leading to esophageal strictures. The etiology remains unknown; however, anti-fungal treatments or endoscopic balloon dilation can improve early esophageal strictures and these rarely require surgical treatment. We report a case of a 46-year-old male with a 6 cm-long esophageal stricture due to EIPD, which did not improve following treatment with an anti-fungal agent, eventually causing aspiration pneumonia. Therefore, we performed a thoraco-laparoscopic esophagectomy, and his symptoms were improved after surgery. This case suggests that a surgical treatment should be considered in patients with extensive, severe strictures attributable to EIPD.

Pedicle Galeo-pericranial Flap Augmentation in Salvage Frontotemporal Cranioplasty: Additional 'Neurosurgeon-friendly' Reconstruction Technique of Aesthetic Neurosurgery in Superficial Temporal Artery Branch Compromised Host.

This technical note aims to demonstrate the usefulness, indications and its limitations of augmentation technique by bipedicle galeo-pericranial rotation flap and by monopedicle galeo-pericranial flap, both in STA (superficial temporal artery) branch compromised hosts in salvage frontotemporal cranioplasty. Although these flaps are not always idealistically vascularized owing to accidental injuries to the STA branches during previous surgeries, they are properly augmenting after salvage frontotemporal craniotomy when infection is not active. The procedure is indicated for salvage frontotemporal craniotomy when vasculature is needed at the surgical site, such as beneath the skin incision line in a thin injured scalp, onto the titanium plates or beneath the fragile fibrous scar. We do not apply this technique by neurosurgeons alone where infection is active or if the host is irradiated. This technique is recommended as a reconstructive aesthetic neurosurgical procedure. It is a 'neurosurgeon-friendly' simple procedure, as it does not require any special tools or complicated techniques.

Enhancement of cancer radiation therapy by use of adenovirus-mediated secretable glucose-regulated protein 94/gp96 expression.

Tumor-derived glucose-regulated protein 94 (GRP94/gp96) has shown great promise as a tumor vaccine. However, current protein-based approaches require the availability of large quantities of tumor tissue, which are often not possible. In addition, the efficacy of immunotherapy is often not ideal when used alone. In this study, we explored the therapeutic efficacy of a combined GRP94/gp96-based genetic immunotherapy and radiation therapy strategy in the weakly immunogenic and highly metastatic 4T1 murine mammary cancer model. An adenovirus encoding a modified, secretable form of GRP94 gene (AdsGRP94) was constructed and evaluated in various antitumor experiments. Lethally irradiated, virus-infected cells were used as vaccines. Adenoviral vectors were also injected directly into tumors in conjunction with tumor irradiation. Vaccination with lethally irradiated, AdsGRP94-infected 4T1 cells completely prevented subsequent tumor growth from challenge inoculations of as many as 10(7) cells per mouse. In established tumor models, vaccinations alone had minimal effect on local and metastatic tumor growth. However, when vaccination was combined with radiation therapy and i.t. AdsGRP94 injections, local tumor growth and pulmonary metastasis were markedly inhibited. In some cases, complete tumor regression was observed. In these cases, the mice were resistant to subsequent tumor challenge and remain tumor free up to 10 months after initial therapy. Our results indicate that combined AdsGRP94-based immunotherapy and radiation therapy may be a potentially effective strategy for cancer treatment.

Enhancement of hypoxia-induced tumor cell death in vitro and radiation therapy in vivo by use of small interfering RNA targeted to hypoxia-inducible factor-1alpha.

Hypoxia-inducible factor-1alpha (HIF-1alpha) is an important transcriptional factor that is activated when mammalian cells experience hypoxia, a tumor microenvironmental condition that plays pivotal roles in tumor progression and treatment. In this study, we examined the idea of down-regulating HIF-1alpha in tumor cells for therapeutic gain. We show that the expression levels of HIF-1alpha can be significantly attenuated by use of the recently established small interfering RNA technology in combination with adenovirus-mediated gene transfer. Down-regulation of the HIF-1alpha protein enhanced hypoxia-mediated tumor cell apoptosis in vitro. Subcutaneous tumor growth was also prevented from cells with attenuated HIF-1alpha expression. In addition, intratumoral injection of adenovirus encoding the HIF-1alpha-targeted small interfering RNA had a small but significant effect on tumor growth when combined with ionizing radiation. Therefore, our results provide proof of HIF-1alpha as an effective target for anticancer therapy. They also suggest that an adenovirus-based small interfering RNA gene transfer approach may be a potentially effective adjuvant strategy for cancer treatment.

A primary CNS lymphoma in spontaneous remission for 3.5 years after initial detection of the lesions by MRI.

We describe the clinicopathological features of a patient with an autopsy-proven primary CNS lymphoma, who had a relatively long remission period after onset. A 61-year-old man experienced disorientation and gait disturbance. A ventriculoperitoneal shunt operation was performed, based on the diagnosis of hydrocephalus due to aqueductal stenosis, after which his symptoms subsided. Three months later, T2-weighted magnetic resonance imaging (MRI) revealed high-intensity lesions in the corpus callosum and tectum. However, he remained asymptomatic for the next three and a half years, during which periodic MRI studies constantly detected the lesions. At the age of 65 years, he suffered respiratory and consciousness disturbances, and his general condition gradually deteriorated. MRI studies disclosed that the callosal lesion had spontaneously disappeared, whereas the tectal lesion had developed to become an enhanced linear lesion with a tendency to spread on the dorsal side of the brain stem. Examination of the cerebrospinal fluid disclosed a markedly elevated beta2-microglobulin content, and a tentative diagnosis of malignant lymphoma was made. Steroid pulse therapy had little effect, and the patient died four years after presentation. Examination at autopsy disclosed a malignant, large B-cell lymphoma that had diffusely infiltrated the cerebrum and brain stem. In the corpus callosum, a small number of residual lymphoma cells were seen around the vessels. Therefore, the initially detected lesions in the corpus callosum and tectum might have been attributable to lymphoma, and the unusual clinical and radiological features of this case provide further information that might aid in diagnosis and help to ensure prompt treatment.

Severe tension pneumocephalus caused by opening of the frontal sinus by head injury 7 years after initial craniotomy--case report.

A 46-year-old man presented with severe tension pneumocephalus triggered by mild head injury 7 years after craniotomy. He had a history of subarachnoid hemorrhage due to ruptured anterior communicating artery aneurysm, coating of the aneurysm performed via a craniotomy, and a ventriculoperitoneal (VP) shunt inserted. He fell from bed in a rehabilitation hospital. Eight hours after the injury, he became comatose and suffered general convulsion. He was then transferred to our hospital. Radiography and computed tomography (CT) revealed a large amount of intracranial air and a widely opened frontal sinus. On the day of admission, the shunt tube was ligated. Surgery was performed to repair the dura mater and close the frontal sinus. Postoperative CT revealed reduction in the amount of air and frontal sinus obstruction. The patient had a good postoperative course without meningitis. Tension pneumocephalus may occur as a complication several years after a craniotomy because of the chronic lowering of intracranial pressure induced by a VP shunt. Complete frontal sinus repair is important during the initial craniotomy.