Randomized Trial of Vitamin D Supplementation to Prevent Seasonal Influenza and Upper Respiratory Infection in Patients With Inflammatory Bowel Disease.

BACKGROUND: We evaluated whether oral vitamin D supplementation during the winter and early spring reduces the incidence of influenza and upper respiratory infections in patients with inflammatory bowel disease (IBD). METHODS: A randomized, double-blind, controlled trial was conducted to compare the effects of vitamin D supplementation (500 IU/day) and a placebo. The primary outcome was the incidence of influenza; the secondary outcome was the incidence of upper respiratory infection. Prespecified subgroup analyses were performed according to 25-hydroxyvitamin D (25-OHD) levels (low <20 ng/mL or high ≥20 ng/mL) and whether ulcerative colitis (UC) or Crohn's disease (CD) was present. We also used the Lichtiger clinical activity index for patients with UC and the Crohn's Disease Activity Index (CDAI) for patients with CD before and after interventions. RESULTS: We included 223 patients with IBD and randomized them into 2 groups: vitamin D supplementation (n = 108) and placebo (n = 115). The incidence of influenza did not differ between the groups. However, the incidence of upper respiratory infection was significantly lower in the vitamin D group (relative risk [RR], 0.59; 95% confidence interval (CI), 0.35-0.98; P = 0.042). This effect was enhanced in the low 25-OHD level subgroup (RR, 0.36; 95% CI, 0.14-0.90; P = 0.02). With respect to adverse events, the Lichtiger clinical activity index score was significantly worse in the vitamin D group (P = 0.002) and remained significant only in the high 25-OHD level subgroup. CONCLUSIONS: Vitamin D supplementation may have a preventative effect against upper respiratory infection in patients with IBD but may worsen the symptoms of UC.

Molecular targeted photoimmunotherapy for HER2-positive human gastric cancer in combination with chemotherapy results in improved treatment outcomes through different cytotoxic mechanisms.

BACKGROUND: Photoimmunotherapy (PIT) is a novel type of molecular optical imaging-guided cancer phototherapy based on a monoclonal antibody conjugated to a photosensitizer, IR700, in combination with near-infrared (NIR) light. PIT rapidly causes target-specific cell death by inducing cell membrane damages and appears to be highly effective; however, we have previously demonstrated that tumor recurrences were eventually seen in PIT-treated mice, likely owing to inhomogeneous mAb-IR700 conjugate distribution in the tumor, thus limiting the effectiveness of PIT as a monotherapy. Here, we examined the effects of human epidermal growth factor-2 (HER2)-targeted PIT in combination with 5-fluorouracil (5-FU) compared to PIT alone for HER2-expressing human gastric cancer cells. METHODS: NCI-N87 cells, HER2-positive human gastric cancer cells, were used for the experiments. Trastuzumab, a monoclonal antibody directed against HER2, was conjugated to IR700. To assess the short-term cytotoxicity and examine the apoptotic effects upon addition of 5-FU in vitro, we performed LIVE/DEAD and caspase-3 activity assays. Additionally, to explore the effects on long-term growth inhibition, trypan blue dye exclusion assay was performed. NCI-N87 tumor xenograft models were prepared for in vivo treatment studies and the tumor-bearing mice were randomized into various treatment groups. RESULTS: Compared to PIT alone, the combination of HER2-targeted PIT and 5-FU rapidly induced significant cytotoxicity in both the short-term and long-term cytotoxicity assays. While both 5-FU and/or trastuzumab-IR700 conjugate treatment induced an increase in caspase-3 activity, there was no additional increase in caspase-3 activity upon NIR light irradiation after incubation with 5-FU and/or trastuzumab-IR700. The combination of HER2-targeted PIT and 5-FU resulted in greater and longer tumor growth inhibition than PIT monotherapy in vivo. This combined effect of PIT and 5-FU is likely owing to their different mechanisms of inducing tumor cell death, namely necrotic membrane damage by PIT and apoptotic cell death by 5-FU and trastuzumab. CONCLUSIONS: PIT in combination with 5-FU resulted in enhanced antitumor effects compared to PIT alone for HER2-expressing human gastric cancer in vitro and in vivo. This combination photoimmunochemotherapy represents a practical method for treating human gastric cancer and should be investigated further in the clinical setting.

[A case of acquired immunodeficiency syndrome with ileocecal ulcer].

We report a case of a patient with acquired immunodeficiency syndrome (AIDS) and ileocecal ulcer. A 31-year-old man was admitted with chief complaints of decreased body weight and abdominal pain. Colonoscopy revealed a round punched-out ulcer on the ileocecal valve. Initially, we suspected entero-Behçet's disease and simple ulcer as the cause of the ileocecal ulcer. However, after histologic examination of tissue biopsies obtained during colonoscopy, we diagnosed the patient as having cytomegalovirus (CMV) enteritis. Based on the patient's white blood cell depletion and CMV enteritis, we performed a human immunodeficiency virus (HIV) antibody test. The test was positive, and the diagnosis of AIDS was established. The number of patients with AIDS has been increasing in Japan; thus, we should consider the possibility of CMV enteritis and AIDS in young adult patients affected by ileocecal ulcer with no notable history.

Prostaglandin E-major urinary metabolite as a reliable surrogate marker for mucosal inflammation in ulcerative colitis.

BACKGROUND: C-reactive protein (CRP) is used as a biomarker of ulcerative colitis (UC) activity, but CRP levels are sometimes insufficient to reflect UC activity. Therefore, a simple noninvasive biomarker assay with sufficient sensitivity and specificity to accurately reflect UC activity is desired. Since prostaglandin E2 production and colonic inflammation are associated, we evaluated whether prostaglandin E-major urinary metabolite (PGE-MUM) can be used as such a biomarker. METHODS: Patients with UC (n = 99) were enrolled from March 2011 to February 2012. UC activity was evaluated using the simple clinical colitis activity index in 99 patients, Mayo endoscopic scoring (Mayo) in 79 patients, and Matts' grading (Matts) in 64 patients. PGE-MUM levels were measured by radioimmunoassay kit and compared against CRP levels as a control. RESULTS: Both PGE-MUM and CRP levels correlated with UC activity (P < 0.01). Areas under the receiver operating characteristic curves of simple clinical colitis activity index, Mayo, and Matts for PEG-MUM were each higher than for CRP (0.93 > 0.73, 0.90 > 0.77, and 0.89 > 0.75, respectively). In multivariate logistic regression models, PGE-MUM was a significant independent predictor of histologic remission (sensitivity/specificity, 0.82/0.82) when the cutoff value was set to 17.0 µg/g creatinine, but CRP was not (0.69/0.69) (P < 0.01). CONCLUSIONS: Compared with CRP level, PGE-MUM level demonstrated better sensitivity for reflecting UC activity, especially in cases of histologic inflammation, and thus seems to be a better evaluator of mucosal healing. Because this method is simple, quick, and noninvasive, PGE-MUM seems to be a useful biomarker of UC.

Efficacy of zinc-carnosine chelate compound, Polaprezinc, enemas in patients with ulcerative colitis.

OBJECTIVES: Ulcerative colitis (UC) is a chronic, relapsing and remitting intestinal inflammatory disorder. Zinc is known to be efficacious for the repair of damaged tissue and has been shown to protect against gastric ulceration. This study focused on Polaprezinc (PZ), N-(3-aminopropionyl)-L-histidinato zinc, which accelerates ulcer healing through actions such as prostaglandin-independent cytoprotection and antioxidative activity. METHODS: In this randomized, placebo-controlled, investigator-blinded trial, 28 patients with active UC at The Jikei University Hospital were randomly divided into two groups: one treated with a 150 mg PZ enema (n = 18) and the other not treated with a PZ enema (n = 10). All patients received usual induction therapy. Clinical symptoms, endoscopic findings and histological findings were evaluated at entry and one week later. RESULTS: In the PZ group, modified Matts' endoscopic scores were significantly improved after treatment compared to baseline in the rectum (p = 0.004), sigmoid colon (p = 0.03) and descending colon (p = 0.04). In the non-PZ group, scores were not significantly improved in the rectum (p = 0.14) and descending colon (p = 0.34), but were improved in the sigmoid colon (p = 0.04). In the PZ group, the Mayo scores at baseline and at Day 8 were 9.1 ± 1.6 and 5.8 ± 2.7 (p = 0.00004), respectively, and in the placebo group, the scores were 8.9 ± 1.7 and 7.4 ± 2.1 (p = 0.009), respectively. Clinical response or remission was significantly better in the PZ group (71%) than in the placebo group (10%). CONCLUSIONS: A zinc-carnosine chelate compound, PZ, enema may become a useful new add-on treatment to accelerate mucosal healing in UC.

Unusual images of mass-forming intrahepatic cholangiocarcinoma.

We experienced a case of mass-forming intrahepatic cholangiocarcinoma which could not been diagnosed accurately without pathologic findings. A 78-year-old Japanese woman with no particular symptoms was admitted for changes in liver function tests. Ultrasonography revealed a solid liver tumor. When there are no typical imaging features, no pathognomonic clinical findings and no obvious risk factors for any specific hepatic tumor, it may be difficult to make an accurate diagnosis before surgical resection. The lesion was resected on the basis of a high degree of suspicion for malignancy and submitted for pathologic evaluation. Microscopically, the neoplasm was a moderately differentiated adenocarcinoma with abundant fibrous stroma, consistent with a mass-forming cholangiocarcinoma. This case exemplifies the importance of considering the various tumorous and non-tumorous diseases in the differential diagnosis of a liver mass with atypical features, especially when malignancy cannot be excluded.

The utility of balloon enteroscopy in the diagnosis of histiocytic sarcoma of the small intestine: a case report.

The diagnosis of the rare neoplasm histiocytic sarcoma (HS) relies on morphology and the presence of immunophenotypic features of histiocytic lineage. More than 57 cases, including 16 cases involving the gastrointestinal (GI) tract, have been described since the World Health Organization issued its classification system for tumors of hematopoietic and lymphoid tissue in 2001. HS is often diagnosed in its late stages, at which point the prognosis is poor. Only a small proportion of these patients can undergo surgical resection with curative intent. The present report describes how HS can be diagnosed at a stage of favorable prognosis using balloon enteroscopy (BE), thereby enabling surgical resection before the development of metastases. This strategy is reviewed in the setting of a patient with jejunal HS, followed by a discussion of data from 16 other reported cases of GI HS.

Utility of single balloon enteroscopy (SBE) for difficult cases of total colonoscopy.

Balloon enteroscopy (BE) was originally developed for observation of the deep small intestine, and has recently been utilized for difficult cases of total colonoscopy due to reasons such as adhesions and elongation. In this report, we present our experience with single balloon enteroscopy (SBE) to facilitate successful colonoscopy when standard techniques failed. In two cases, early colon cancers were detected in the cecum by SBE and were removed endoscopically or surgically. A third case is discussed in which SBE was attempted but was ultimately not successful. In that case, total colonoscopy was not performed because of looping in the sigmoid and transverse colon. A fourth case in which SBE was performed in order to remove colonic gas in a patient with megacolon. In that case, total colonoscopy could not be completed because the SBE balloon could not "grab" the dilated colon and therefore could not advance. SBE is a useful adjunct to standard colonoscopy in challenging cases, but has limitations and does not always ensure success.

Acute Pancreatitis due to pH-Dependent Mesalazine That Occurred in the Course of Ulcerative Colitis.

We report the case of a 26-year-old male who presented with acute pancreatitis during the course of treatment for pancolitic ulcerative colitis (UC) with a time-dependent mesalazine formulation, prednisolone and azathioprine (AZA). Despite a review of his clinical history and various tests, the cause of pancreatitis could not be determined. Since drug-induced pancreatitis was considered possible, administration of the time-dependent mesalazine preparation and AZA was discontinued, and conservative treatment for acute pancreatitis was performed. The pancreatitis promptly improved with these treatments, but drug lymphocyte stimulation test (DLST) for both the time-dependent mesalazine formulation and AZA was negative. A pH-dependent mesalazine formulation was given for maintenance therapy of UC. Subsequently, as the pancreatitis relapsed, drug-induced pancreatitis was strongly suspected. Administration of mesalazine was discontinued, and pancreatitis was smoothly in remission by conservative treatment. According to the positive DLST result for the pH-dependent mesalazine formulation and the clinical course, a diagnosis of pH-dependent mesalazine-induced pancreatitis due to this formulation was made. During the clinical course of UC, occurrence of drug-induced pancreatitis must always be considered.

Expansion of CD4(+)CD25(+)FoxP3(+) regulatory T cells in hepatitis C virus-related chronic hepatitis, cirrhosis and hepatocellular carcinoma.

AIM: Regulatory T (Treg) cells may play a pivotal role in the persistence of hepatitis C virus (HCV) infection and the development of hepatocellular carcinoma (HCC). Therefore, we examined their frequency in peripheral blood from patients with HCV-positive chronic hepatitis (CH), cirrhosis (LC) and HCC. METHODS: Treg cells were identified as CD4(+), CD25(+) and FoxP3(+) T lymphocytes using three-color FACS. The frequency of Treg cells was expressed as a percentage of the total CD4(+) T lymphocytes, and the phenotype of Treg cells was examined using CD45RA. RESULTS: Treg cells were significantly increased in CH (5.88 +/- 0.19%, n = 76; P < 0.01), LC (6.10 +/- 0.28%, n = 40; P < 0.001) and HCC (6.80 +/- 0.30%, n = 57; P < 0.0001) compared to healthy control (5.13 +/- 0.25%, n = 31). However, Treg cells were not increased with the progression of fibrosis or the grade of inflammations. Treg cells were slightly increased in early-stage HCC (6.91 +/- 0.40%) compared with advanced-stage HCC (6.58 +/- 0.39%), but these results were not statistically significant. In a serial examination, a distinct increase in Treg cells after local therapy for early-stage HCC was a hallmark of early recurrence. Most expanded Treg cells in HCC were CD45RA(-), suggesting that a memory-type Treg population had differentiated in the periphery and not in the thymus. CONCLUSION: We observed an increase in Treg cells in HCV-related chronic liver disease, particularly in HCC, and these cells were shown to be memory-type Treg cells.

[A case of primary small cell carcinoma of the esophagus responding remarkably to carboplatin (CBDCA) + etoposide (VP-16) combination therapy and radiation therapy].

A 78-year-old man was admitted to hour hospital because of dysphagia, and primary small cell carcinoma of the esophagus was diagnosed. Carboplatin (CBDCA) + etoposide (VP-16) combination chemotherapy and radiation therapy was performed. After this therapy, endoscopic examination and computed tomographic scan showed the disappearance of the primary esophageal tumor. Endoscopic examination with biopsy confirmed the disappearance of malignant cells. Severe adverse reactions were not observed during this therapy. This patient is alive without recurrence for 6 years and 3 months. This case seems to provide suggestions on deciding on the operative indications for small cell carcinoma of esophagus.

Etiology of non-B non-C hepatocellular carcinoma in the eastern district of Tokyo.

BACKGROUND: This study was carried out to clarify the carcinogenic factors associated with nonviral hepatocellular carcinoma (HCC). METHODS: A total of 320 HCC patients diagnosed and treated from January 2000 to December 2006 were enrolled. The clinical characteristics of non-B non-C HCC patients were examined to determine possible carcinogenic factors. RESULTS: Of 320 HCC patients, 64 were classified as having non-B non-C HCC. The proportion of non-B non-C HCC increased from 17.8% in 2000 to 28.6% in 2006. Non-B non-C HCC patients had a significantly higher rate of early stage cirrhosis (Child-Pugh classification) than viral HCC patients. Significantly fewer non-B non-C HCC patients had periodic intensive medical assessments than viral HCC patients. Forty-five non-B non-C HCC patients were habitual alcohol drinkers, ten had nonalcoholic fatty liver disease (NAFLD), and seven had no apparent etiology. In habitual drinkers, the stage of underlying liver disease varied widely, while most NAFLD patients had early stage cirrhosis. On the other hand, more than half of the patients with HCC of undetermined etiology had noncirrhotic liver disease. Among habitual drinkers, the underlying liver disease was more progressive, and the T stage was more advanced in those with high daily alcohol intake than in those with low daily alcohol intake. Periodic intensive medical assessments were crucial for detecting early stage HCC. CONCLUSIONS: Alcohol consumption and NAFLD may be important etiological factors in non-B non-C HCC. Periodic medical assessments for all patients with non-B non-C cirrhosis are crucial for early diagnosis and curative therapy.

The effects of the loop diuretics furosemide and torasemide on diuresis in dogs and cats.

Torasemide is a new loop diuretic that combines the effects of furosemide and spironolactone. There are no reports on the effects of torasemide in cats and dogs. This study compared the diuretic effects of furosemide and torasemide in cats and dogs. Cats with pressure overload cardiac hypertrophy were given oral placebo, torasemide 0.3 mg/kg, or furosemide 1 mg/kg or 3 mg/kg. Control and mitral regurgitation dogs were given oral placebo, torasemide 0.2 mg/kg, and furosemide 2 mg/kg for 7 days. Urine samples were obtained at baseline and 1, 2, 3, 4, 5, 6, 8, 12, and 24 hr after each drug dose. Urine volume and urine Na(+) and K(+) were measured. Both furosemide and torasemide increased urine volume 1 hr after administration. Furosemide caused a dose-dependent increase in urine volume that peaked at 2-3 hr in cats and dogs. The diuretic effect of furosemide disappeared 6 hr after administration, while that of torasemide peaked 2-4 hr after administration and persisted for 12 hr in cats and dogs. In MR dogs, torasemide for 7 days significantly decreased urine potassium excretion. Plasma aldosterone increased with torasemide, whereas there was no change with furosemide. In conclusion, about 1/10 concentration of torasemide was as potent as furosemide and had a longer diuretic effect in cats and dogs. These data suggest that torasemide is useful for treating congestive heart failure or edema in cats and dogs.

[The usefulness of MDCT in Crohn's disease].

The usefulness of multidetector-row CT (MDCT) was investigated in 27 patients with Crohn's disease. MDCT depicted characteristic lesions associated with Crohn's disease, including bowel wall thickening, strictures, bowel wall enhancement with contrast, opacity of fatty tissue and mesenteric lymph node enlargement. With respect to delineation of lesion sites, a 76% or higher correlation rate was observed between MDCT and other conventional diagnostic procedures such as colonoscopy, barium enema, small bowel examination, and gastrointestinal endoscopy. The patient were classified as either with active disease or in remission based on the Crohn's disease activity index (CDAI). We then compared MDCT findings in patients with active disease and in remission. A positive correlation (r = 0.70) between CDAI and bowel wall thickening was observed. A comparison of 13 patients with active disease versus 14 patients in remission revealed significant bowel wall thickening, mesenteric lymph node enlargement, and opacity of fatty tissue. MDCT accurately depicted lesions consistent with active Crohn's disease. MDCT is a minimally invasive procedure that is useful in the evaluation of acute active Crohn's disease.