Serum tumor antigen REG4 as a diagnostic biomarker in pancreatic ductal adenocarcinoma

Background and Aims

Serum biomarkers for the early detection of pancreatic cancer are not currently available. We evaluated the usefulness of a novel serum marker, REG4, in the diagnosis of pancreatic cancer, as compared to carbohydrate antigen (CA) 19-9.

Methods

We collected pretherapeutic sera from 92 patients with pancreatic cancer, as well as sera from 28 patients with other pancreatic tumors, 11 patients with pancreatitis, and 69 healthy controls. Serum levels of REG4 were measured using a standard sandwich enzyme-linked immunosorbent assay (ELISA).

Results

Compared with healthy controls, serum levels of REG4 were higher in pancreatic cancer patients (P < 0.001), and in patients with pancreatitis (P < 0.001). Receiver operating characteristic (ROC) analysis indicated that serum REG4 performed better than serum CA19-9 for distinguishing patients with pancreatic cancer from healthy controls [areas under the curve (AUC) for REG4 and CA19-9 were 0.922 and 0.884, respectively]. When we validated the study, the sensitivity of REG4 for pancreatic cancer was 94.9%, specificity was 64.0%, and accuracy was 77.5% for the REG4 cutoff value of 3.49 ng/ml. No correlation was seen between serum REG4 and CA19-9 levels, with the sensitivity, specificity, and accuracy of the combined markers reaching 100.0, 60.0, and 77.5%, respectively. No significant differences were seen among any stages of pancreatic cancer. In surgical specimens, immunohistochemical analysis found a correlation between serum REG4 levels and REG4 expression in pancreatic cancers.

Conclusions

REG4 is expressed in pancreatic cancer, and serum levels of REG4 offer a useful indicator for distinguishing between patients with pancreatic cancer and healthy subjects. Serum REG4 has potential for use as a screening serum marker for pancreatic cancers, including early-stage cancers.     

A screening for essential cell growth-related genes involved in arsenite toxicity in Saccharomyces cerevisiae

Genes that are essential for growth in yeast were screened to identify those involved in arsenite sensitivity. We found that the knockdown of YPT1, ERG8, or RKI1 enhanced arsenite sensitivity in yeast.     

Systemic cytokine response in moribund mice of streptococcal toxic shock syndrome model

Streptococcus pyogenes causes severe invasive disease in humans, including streptococcal toxic shock syndrome (STSS). We previously reported a mouse model that is similar to human STSS. When mice were infected intramuscularly with 10⁷ CFU of S. pyogenes, all of them survived acute phase of infection. After 20 or more days of infection, a number of them died suddenly accompanied by S. pyogenes bacteremia. We call this phenomenon “delayed death”. We analyzed the serum cytokine levels of mice with delayed death, and compared them with those of mice who died in the acute phase of intravenous S. pyogenes infection. The serum levels of TNF-α and IFN-γ in mice of delayed death were more than 100 times higher than those in acute death mice. IL-10 and IL-12, which were not detected in acute death, were also significantly higher in mice of delayed death. IL-6 and MCP-1 (CCL-2) were elevated in both groups of mice. It was noteworthy that not only pro-inflammatory cytokines but also anti-inflammatory cytokines were elevated in delayed death. We also found that intravenous TNF-α injection accelerated delayed death, suggesting that an increase of serum TNF-α induced S. pyogenes bacteremia in our mouse model.     

Functional dissociation in right inferior frontal cortex during performance of go/no-go task

The contribution of the right inferior frontal cortex to responseinhibition has been demonstrated by previous studies of neuropsychology,electrophysiology, and neuroimaging. The inferior frontal cortexis also known to be activated during processing of infrequentstimuli such as stimulus-driven attention. Response inhibitionhas most often been investigated using the go/no-go task, andthe no-go trials are usually given infrequently to enhance prepotentresponse tendency. Thus, it has not been clarified whether theinferior frontal activation during the go/no-go task is associatedwith response inhibition or processing of infrequent stimuli.In the present functional magnetic resonance imaging study,we employed not only frequent-go trials but also infrequent-gotrials that were presented as infrequently as the no-go trials.The imaging results demonstrated that the posterior inferiorfrontal gyrus (pIFG) was activated during response inhibitionas revealed by the no-go vs. infrequent-go trials, whereas theinferior frontal junction (IFJ) region was activated primarilyduring processing of infrequent stimuli as revealed by the infrequent-goversus frequent-go trials. These results indicate that the pIFGand IFJ within the inferior frontal cortex are spatially closebut are associated with different cognitive control processesin the go/no-go paradigm.     

Clinical analysis of eight patients with primary follicular lymphoma in the duodenum

We performed a clinical analysis on 8 patients with primary follicular lymphoma in the duodenum taken from among 26 cases of primary gastrointestinal malignant lymphoma treated in our division. The median age was 60 years (range 48 to 82 yr). The ratio of males to females was 4:4. The chief complaints were no symptoms in 4 cases, heartburn in 2 cases, lower abdominal pain in 1 case, and back pain in 1 case. All patients were in clinical stage I EA. Gastroendoscopic findings showed multiple whitish granules around the ampulla of Vater in all patients. Involvement of the site in 6 cases was only located at the second portion; lesions in the other 2 cases were located at the second portion, and at the third portion or fourth portion, respectively. A histological study showed follicular lymphoma grade 1, and an immunohistological study demonstrated that the lymphoma cells were positive for CD79a, CD10, CD20, and bcl-2. Five patients were positive for the FISH analysis fusion signal of IgH/bcl-2 genes. Rituximab with CHOP therapy was performed for 7 patients. Seven patients are currently alive, and one died of uterine cancer. At the medium-term 39 month-follow-up, 7 patients were in complete remission, and 1 patient was in partial remission. Rituximab with CHOP (CVP) therapy is a possible treatment for primary follicular lymphoma in the duodenum. Further consideration of appropriate therapy for this disease might be necessary.     

Objective Assessment of Erythema caused by Metal Patch Testing using an Erythema Index Meter

The patch test is the most reliable method for diagnosing a metal allergy. However, interpretation of patch test results depends on the experience of the investigator and on the conditions of the individual patient. In the case of patch tests for metal salts, irritant reactions such as pustular or follicular reactions are quite common. Therefore, one must be careful not to interpret irritant reactions as allergic responses, and objective standards to evaluate erythema in patch tests need to be established.In the present study, we attempted to objectively evaluate patch test results for metal salts using an erythema index meter. We used the Erythema Index Difference (EID) (patch test site erythema index (EI) minus the mean EI of healthy skin outside the patch test area and at the unit tape site) rather than the EI itself in order to eliminate the effects of the patch test unit and individual differences. We measured the EID over time in patients with suspected metal allergies to various metals. Significant differences in EID were observed among ++ assessments, + assessments and irritant reactions based on International Contact Dermatitis Research Group (ICDRG) standards. In considering changes in EID over time, allergic and irritant reactions can be discriminated with high sensitivity (73.3%) and specificity (91.2%).These results suggest that the measurement of erythema over time with an erythema index meter is useful for the objective assessment of metal patch test reactions.     

Relation between neutrophil counts on admission, microvascular injury, and left ventricular functional recovery in patients with an anterior wall first acute myocardial infarction treated with primary coronary angioplasty

Increased neutrophil counts have been associated with an increased risk of adverse clinical events after acute myocardial infarction (AMI). We examined the association of neutrophil counts on admission with degree of microvascular injury and left ventricular functional recovery after primary coronary angioplasty in AMI. We studied 116 patients with a first anterior wall AMI who underwent primary coronary angioplasty within 12 hours of onset. Patients were categorized into 3 groups based on initial neutrophil count: low (<5,000/mm(3)), intermediate (5,000 to 10,000/mm(3)), and high (>10,000/mm(3)). Coronary flow velocity parameters were assessed immediately after reperfusion using a Doppler guidewire. We defined severe microvascular injury as the presence of systolic flow reversal and a diastolic deceleration time <600 ms. Echocardiographic wall motion was analyzed before revascularization and 4 weeks after revascularization. In patients with a high neutrophil count, systolic flow reversal was more frequently observed, diastolic deceleration time was shorter, and coronary flow reserve was lower. By regression analysis, neutrophil count significantly correlated with diastolic deceleration time (r = -0.38, p <0.0001), coronary flow reserve (r = -0.33, p = 0.0004), and score for change in wall motion (r = -0.36, p = 0.0004). Multivariate analysis showed that neutrophil count on admission was an independent predictor of severe microvascular injury (odds ratio 2.94, p = 0.02). In conclusion, neutrophilia on admission is associated with impaired microvascular reperfusion and poor functional recovery after primary coronary angioplasty.