Current understanding of precursors to pancreatic cancer

Precursors to pancreatic cancer have been investigated for a century. Previous studies have revealed three distinct precursors,i.e. mucinous cystic neoplasm (MCN), intraductal papillary mucinous neoplasm (IPMN), and pancreatic intraepithelial neoplasia (PanIN), harboring identical or similar genetic alterations as does invasive pancreatic carcinoma. The current understanding of precursors to pancreatic cancer can be illustrated by progressive pathways from noninvasive MCN, IPMN, and PanIN toward invasive carcinoma. MCNs consist of ovarian‐type stroma and epithelial lining with varying grades of atypia, and are occasionally associated with invasive adenocarcinoma. The epithelium of noninvasive IPMNs shows a variety of different directions of differentiation, including gastric, intestinal, pancreatobiliary (PB), and oncocytic types. IPMNs can also harbor varying grades of architectural and cytologic atypia. IPMNs confined to branch ducts are mostly the gastric type, and IPMNs involving the main ducts are often intestinal type, while PB and oncocytic types are rare. Small (<1 cm) IPMNs of the gastric type are not always morphologically distinguishable from low‐grade PanINs. Mucin expression profiles suggest intestinal‐type IPMNs progress to mucinous noncystic (colloid) carcinoma, while PB‐type IPMNs progress toward ductal adenocarcinoma. It is a well‐described paradigm that PanIN lesions progress toward ductal adenocarcinoma through step‐wise genetic alterations. The activation of Hedgehog and Notch signaling pathways in PanIN lesions as well as in pancreatic adenocarcinoma suggest that developmental pathways may be disregulated during carcinogenesis of the pancreas. Further study is needed to elucidate the pathways from precursors toward invasive carcinoma of the pancreas.     

Efficacy of Corrected Rapid Turnover Protein Increment Index (CRII) for Early Detection of Improvement of Nutrition Status in Patients with Malnutrition

Serum prealbumin level is useful for assessment of changes in nutritional status but it is markedly affected by the inflammation. In this study, we examined the efficacy of the corrected rapid turnover protein increment index (CRII) for prealbumin, which is calculated as [prealbumin level/C-reactive protein (CRP) level on the assessment day]/[prealbumin level/CRP level on the day of starting nutritional care], for prediction of improvement of nutritional status in patients with malnutrition. The subjects were 50 hospitalized patients with low albuminemia, who were receiving nutritional care. Serum concentrations of albumin, prealbumin and CRP were measured every week for 5 weeks. We defined patients whose serum albumin level was elevated by more than 0.2 g/dl after 5 weeks as those showing improved nutritional status. There was a significant difference in the prealbumin level between improved and unimproved patients at 5 weeks after the start of nutritional support. On the other hand, the prealbumin CRII value showed a significant difference between the groups at 1 and 2 weeks after the start of nutritional support. In conclusion, assessment of prealbumin CRII is useful for early prediction of improved nutritional status in patients with malnutrition.     

Clinical importance of precursor lesions in the pancreas

Three distinct noninvasive precursor lesions to invasive ductal adenocarcinoma of the pancreas have been described. These include the mucinous cystic neoplasm, intraductal papillary mucinous neoplasm, and pancreatic intraepithelial neoplasia. The early detection and treatment of these lesions can interrupt the progression of a curable noninvasive precursor to an almost uniformly deadly invasive cancer.     

High yellow color intensity by angioscopy with quantitative colorimetry to identify high-risk features in culprit lesions of patients with acute coronary syndromes

High yellow color intensity (HYCI) regions of atherosclerotic plaque, determined by angioscopy with quantitative colorimetry, are associated with lipid cores underneath thin fibrous caps in ex vivo tissue samples. To determine whether HYCI regions of coronary plaque are associated with disruption or thrombus in living patients, quantitative colorimetry was applied to angioscopy, and the color of culprit lesions was measured in patients with acute coronary syndromes. In 46 patients with acute coronary syndromes (acute myocardial infarction, n = 14; unstable angina pectoris [UAP] with culprit thrombus, n = 16; and UAP without culprit thrombus, n = 16), the recorded angioscopic images of culprit lesions were analyzed using a quantitative colorimetric method based on the L*a*b* color space applied to angioscopy (positive b* = yellow color intensity). HYCI was defined as b* value >23. Plaque disruption was significantly more prevalent in 19 of 24 HYCI regions (79%) than in 9 of 22 non-HYCI regions (41%) (p = 0.007). Culprit HYCI regions were prevalent in patients with myocardial infarction (11 of 14 [79%]), followed by those with UAP with thrombus (9 of 16 [56%]) and UAP without thrombus (4 of 16 [25%]) (p = 0.01 for trend), and were significantly more prevalent in 66% of patients with myocardial infarction and UAP with thrombus compared with 25% of those with UAP without thrombus (p = 0.007). In conclusion, HYCI regions of coronary plaque may be indicative of high-risk lesions vulnerable to thrombosis. Coronary angioscopy with quantitative colorimetry could be used to study the association between high-risk coronary lesions and future cardiovascular events.     

Nocturnal gastric acid breakthrough during the administration of rabeprazole and ranitidine in Helicobacter pylori-negative subjects: effects of different regimens

Background. Nocturnal gastric acid breakthrough (NAB) is defined as nocturnal intragastric pH less than 4 for more than 1h during proton pump inhibitor (PPI) administration. A bedtime dose of an H2 receptor antagonist (H2RA) inhibites NAB, but the efficacy of the H2RA decreases with continuous administration. We carried out the present study to investigate the effect of 14-day H2RA administration on NAB. Methods. Ten male volunteers without Helicobacter pylori infection received four different 14-day regimens of rabeprazole and ranitidine (study a, morning dose of 20mg rabeprazole; study b, morning dose of 20mg rabeprazole with a single bedtime dose of 150mg ranitidine only on the last day; study c, continuous 20mg morning dose of rabeprazole and 150mg at bedtime; study d, morning and evening doses of 10mg rabeprazole). Ambulatory 24-h gastric pH monitoring was conducted on the last day of each regimen. Results. NAB in studies a, b, c, and d was observed in 9, 1, 4, and 4 subjects, respectively, and the longest periods of nocturnal gastric pH at less than 4.0 were 102.5, 14.0, 37.5, and 52.5min, respectively (study b vs study c, P < 0.05). Conclusions. The continuous inhibitory effect of ranitidine combined with rabeprazole on nocturnal gastric acid secretion declined during 14-day-long administration in H. Pylori-negative subjects. Split dosing of rabeprazole was more effective than the single morning dose for inhibiting nocturnal gastric acid secretion.     

Geranylgeranylacetone stimulates mucin synthesis in cultured guinea pig gastric pit cells by inducing a neuronal nitric oxide synthase

Nitric oxide (NO) has been considered to play an important role in the regulation of blood flow, mucosal integrity, and mucus production in the stomach. We investigated the stimulatory actions of epidermal growth factor (EGF) and a cytoprotective compound, geranylgeranylacetone (GGA), on mucin synthesis in guinea pig gastric pre-pit cells, maintained in a serum-free culture system. GGA increased [³H]glucosamine uptake and the accumulation of mucus granules positive for galactose oxidase-Schiff reaction in the cells. This stimulatory action of GGA was equivalent to that of EGF, but GGA did not stimulate the cell growth. Both EGF and GGA increased the release of NO degeneration products, NO₂ ⁻ and NO₃ ⁻. The [³H]glucosamine uptake was completely inhibited by the non-selective NO synthase (NOS) inhibitors, N ^G -nitro-l-arginine and N ^G -monomethyl-l-arginine, and it was only partially inhibited by a more selective inhibitor for inducible NOS isoform (iNOS), aminoguanidine. Northern blotting with a cDNA probe for rat iNOS, and Western blotting with a polyclonal antibody against iNOS, demonstrated that GGA did not up-regulate the iNOS mRNA expression nor induce its protein. In contrast, GGA and EGF induced neuronal NOS, but not endothelial NOS, which was confirmed by immunoblot analyses with antibodies against these constitutive NOS isoforms. Thus, the present experiments suggests that GGA, as well as EGF, stimulates mucin synthesis at least in part through an NO-dependent pathway, leading to an increase in the integrity of the gastric mucosa. Received: September 7, 1999 / Accepted: March 24, 2000     

Comparison of neointimal coverage by optical coherence tomography of a sirolimus-eluting stent versus a bare-metal stent three months after implantation

No detailed data regarding neointimal coverage of bare-metal stents (BMSs) at 3 months after implantation was reported to date. This investigation was designed to evaluate the neointimal coverage of BMSs compared with sirolimus-eluting stents (SESs) using optical coherence tomography. A prospective optical coherence tomographic follow-up examination was performed 3 months after stent implantation for patients who underwent BMS (n = 16) or SES implantation (n = 24). Neointimal hyperplasia (NIH) thickness on each stent strut and percentage of NIH area in each cross section were measured. Malapposition of stent struts to the vessel wall and the existence of in-stent thrombi were also evaluated. There were 5,076 struts of SESs and 2,875 struts of BMSs identified. NIH thickness and percentage of NIH area in the BMS group were higher than in the SES group (351 +/- 248 vs 31 +/- 39 mum; p <0.0001; 45.0 +/- 14% vs 10.0 +/- 4%; p <0.0001, respectively). The frequency of uncovered struts was higher in the SES group than the BMS group (15% vs 0.1%; p <0.0001). Malapposed struts were observed more frequently in the SES group than the BMS group (15% vs 1.1%; p <0.0001). In conclusion, there was no difference in incidence of in-stent thrombus between the 2 groups (14% vs 0%; p = 0.23). The present study showed almost all BMS struts to be well covered at a 3-month follow-up, suggesting that patients receiving BMS stents may not require dual-antiplatelet therapy >3 months after implantation.     

Phytosterols dissolved in diacylglycerol oil reinforce the cholesterol-lowering effect of low-dose pravastatin treatment

Background and aimsDietary therapy using phytosterols can reinforce statin treatment; however the value of a low-dose combination of those agents remains to be investigated. Plant sterols (PS), dissolved in diacylglycerol (DAG) oil, (PS/DAG) can be effective at a relatively low dose. The objective of the present study was to examine the effect of PS/DAG oil on blood cholesterol concentrations in hypercholesterolemic outpatients on low-dose pravastatin (10 mg/day).Methods and resultsThe patients (n = 61) were randomly assigned to one of three groups, who consumed TAG (control), DAG or PS/DAG oil. The average intake of PS from the PS/DAG oil during the test period was significantly higher than that for TAG and DAG oils (502 vs. 49 and 38 mg/day, P < 0.05). Significant cholesterol-lowering effects from the baseline were observed in the case of the PS/DAG oil treatment alone. Changes in low-density lipoprotein (LDL) cholesterol were inversely correlated with baseline serum campesterol concentrations (r = −0.560, P < 0.05), but not baseline LDL cholesterol concentrations. In addition, serum apolipoprotein B concentrations were reduced to a greater extent in subjects with high versus low levels of baseline campesterol (−13.2 mg/dL vs. −3.1 mg/dL, P < 0.05). Furthermore, there was a mild, but significant reduction in serum lipoprotein (a) concentration from the baseline (−5.9 mg/dL), which was correlated with the reduction in serum apolipoprotein B concentration (r = 0.596, P < 0.05).ConclusionA low-dose combination of PS/DAG oil and pravastatin may be a useful strategy for further ameliorating blood cholesterol and lipoprotein (a) concentrations for hypercholesterolemic patients with a low response to pravastatin.     

Conversion to Silodosin in Men on Conventional α1‐Blockers for Symptomatic Benign Prostatic Hyperplasia

Objectives: α₁‐blockers have commonly been used as first‐line medical therapy for symptomatic benign prostatic hyperplasia (BPH). Recently, a highly selective α_1A‐adrenoceptor antagonist, silodosin, was developed in Japan. We examined the efficacy and safety of conversion from conventional α₁‐blockers to silodosin in men with BPH. Methods: Conversion to silodosin was proposed to consecutive patients on conventional α₁‐blockers for symptomatic BPH for at least 6 months. The effects of conversion were examined by the International Prostate Symptom Score, quality of life index, overactive bladder symptom score, peak flow rate, residual urine volume, and adverse events at 12 weeks. The efficacy of silodosin was also evaluated by patients' impression. Results: Eighty‐one men underwent conversion, for the most part because of dissatisfaction with the efficacy of their current treatment in improving nocturia or weak stream. The International Prostate Symptom Score total score significantly improved from 12.7 ± 5.9 at baseline to 10.6 ± 5.4 at 4 weeks (P < 0.001) and 10.9 ± 5.8 at 12 weeks (P < 0.01). The progress was mostly due to improvement in voiding symptoms, although reduction of storage symptoms was also significant. The quality of life index also significantly decreased with conversion to silodosin. Efficacy as judged by patients' impression was 76% (37/49) at 12 weeks of treatment. None of the overactive bladder symptom score, peak flow rate, and residual urine volume exhibited significant change. No serious adverse events were observed during the study period. Conclusion: Conversion to silodosin may be beneficial in men who are dissatisfied with conventional α₁‐blockers for BPH, and be particularly useful in improving voiding symptoms.     

Impact of statin therapy on renal function and long-term prognosis in acute coronary syndrome patients with chronic kidney disease

A recent study showed that statins reduce cardiovascular events in stable coronary artery disease patients with chronic kidney disease (CKD). However, it remains unclear whether acute coronary syndrome (ACS) patients with CKD benefit from statins. A total of 501 patients with ACS who underwent successful percutaneous coronary intervention were investigated and CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/minute/1.73 m(2) at discharge. Three hundred and twenty-four of 501 patients (64.7%) had CKD and 173 patients (34.5%) received statins. The patients with CKD were older and had higher blood pressure than those without CKD. With a mean follow-up of 5.2 years, irrespective of treatment assignment, 74 patients with CKD experienced cardiac events (22.8%) in comparison to 25 without CKD (14.1%, HR 1.81; 95% CI 1.15-2.84, P = 0.0095). Cardiac events occurred in only 18 of the patients with CKD treated with statins (16.2%) and in 56 of those treated with CKD without statins (26.3%, HR 0.58; 95% CI 0.34-0.98, P = 0.039), whereas, no significant reduction of the events was observed in the patients without CKD treated with statins versus without having statins (P = 0.130). These data indicate that statin therapy reduces cardiac events in ACS patients with CKD.