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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Oncolytic virus-mediated tumor radiosensitization in mice through DNA-PKcs-specific shRNA.

One of the key issues in cancer radiotherapy research is to sensitize tumor cells to the cell killing effects of ionizing radiation while leaving normal tissues intact. One potential approach to achieve this is through tumor-specific targeting of DNA repair genes. In this study, we engineered a replication-deficient adenovirus encoding a mini shRNA gene targeted to the DNA-PKcs gene, which is involved in double strand break DNA repair, and evaluated its anti-tumor efficacy in combination with radiotherapy. Our shRNA-encoding adenovirus showed significant efficacy in down-regulating the levels of the DNA-PKcs protein that was accompanied by increased radiation sensitivity in the human HCT116 colon cancer cells. However, when delivered intratumorally to xenograft human tumors, minimal anti-tumor effects of the virus were seen either alone or in combination with radiation therapy, suggesting an inefficiency of the non-replicative adenovirus in delivering shRNA genes to the tumor mass. When a conditionally replicative adenovirus targeted to telomerase-positive tumor cells was used in conjunction with the DNA-PKcs-targeted shRNA-encoding non-replicative adenovirus, the efficiency of tumor-specific anti-DNA-PKcs shRNA gene expression was enhanced significantly. Most importantly, this enhanced shRNA expression led to significant anti-tumor efficacy of concurrently delivered radiation therapy. Our results suggest our shRNA-based DNA-PKcs- targeting approach in combination with tumor-targeting replicative adenovirus is a promising method to sensitize solid tumors to radiation therapy.

The features of dry eye disease in a Japanese elderly population.

PURPOSE: The purpose of this study is to assess the features of dry eye disease in a Japanese elderly population. METHODS: One hundred thirteen left eyes of 113 pensioners (50 males, 63 females; mean age, 67.5 +/- 5.7 years) aged over 60 years were recruited in this study. The subjects underwent careful slit-lamp examinations of the conjunctiva, ocular surface, and the eye lids. Tear film breakup time (BUT) examinations, Schirmer test-I, and fluorescein staining of the ocular surface and transillumination of the eyelids were also performed. Dry eye symptomatology was assessed with a symptom questionnaire. Japanese Dry Eye Diagnostic Criteria were used in this study. RESULTS: Ocular tiredness, irritation, dryness, and foreign body sensation were the most frequently reported symptoms by the patients. A total of 73.5% of the eyes had definite dry eyes. A total of 39.8% of the eyes had a Schirmer test reading <5 mm. Mean Schirmer test value was 9.4 +/- 7.8 mm. The mean BUT score was 4.0 +/- 2.8 seconds. A total of 76.9% of the eyes had positive fluorescein staining of the cornea. Meibomian gland dysfunction and conjunctivochalasis were found as frequent factors in relation to dry eye disease with meibomian grand dropout showing positive correlation with tear instability. CONCLUSION: Qualitative and quantitative disorders of the tear film were far more common than recognized in this population of elderly subjects, meibomian gland dysfunction being the most common associate of the tear film disorder and dry eye status. Conjunctivochalasis (conjunctival laxity), although commonly associated with dry eye disease in the elderly, was observed not to be related to age or gender in this study.

High intensity focused ultrasound-induced gene activation in solid tumors.

In this work, the activation of heat-sensitive trans-gene by high-intensity focused ultrasound (HIFU) in a tumor model was investigated. 4T1 cancer cells (2 x 10(6)) were inoculated subcutaneously in the hind limbs of Balb/C mice. The tumors were subsequently transducted on day 10 by intratumoral injection of a heat-sensitive adenovirus vector (Adeno-hsp70B-Luc at 2 x 10(8) pfu/tumor). On day 11, the tumors were heated to a peak temperature of 55, 65, 75, or 85 degrees C within 10-30 s at multiple sites around the center of the tumor by a 1.1- or 3.3-MHz HIFU transducer. Inducible luciferase gene expression was increased from 15-fold to 120-fold of the control group following 1.1-MHz HIFU exposure. Maximum gene activation (120-fold) was produced at a peak temperature of 65-75 degrees C one day following HIFU exposure and decayed to baseline within 7 days. HIFU-induced gene activation (75 degrees C-10 s) could be further improved by using a 3.3-MHz transducer and a dense scan strategy to 170-fold. Thermal stress, rather than nonthermal mechanical stress, was identified as the primary physical mechanism for HIFU-induced gene activation in vivo. Overall, these observations open up the possibility for combining HIFU thermal ablation with heat-regulated gene therapy for cancer treatment.

High intensity focused ultrasound-induced gene activation in sublethally injured tumor cells in vitro.

Cultured human cervical cancer (HeLa) and rat mammary carcinoma (R3230Ac) cells were transfected with vectors encoding green fluorescent protein (GFP) under the control of hsp70B promoter. Aliquots of 10-microl transfected cells (5 x 10(7) cells/ml) were placed in 0.2-ml thin-wall polymerase chain reaction tubes and exposed to 1.1-MHz high intensity focused ultrasound (HIFU) at a peak negative pressure P- = 2.68 MPa. By adjusting the duty cycle of the HIFU transducer, the cell suspensions were heated to a peak temperature from 50 to 70 degrees C in 1-10 s. Exposure dependent cell viability and gene activation were evaluated. For a 5-s HIFU exposure, cell viability dropped from 95% at 50 degrees C to 13% at 70 degrees C. Concomitantly, gene activation in sublethally injured tumor cells increased from 4% at 50 degrees C to 41% at 70 degrees C. A similar trend was observed at 60 degrees C peak temperature as the exposure time increased from 1 to 5 s. Further increase of exposure duration to 10 s led to significantly reduced cell viability and lower overall gene activation in exposed cells. Altogether, maximum HIFU-induced gene activation was achieved at 60 degrees C in 5 s. Under these experimental conditions, HIFU-induced gene activation was found to be produced primarily by thermal rather than mechanical stresses.