Diaphragmatic clear cell carcinoma with Lynch syndrome after surgery for atypical endometrial hyperplasia and ovarian endometriosis: A case report.

Clear cell carcinoma (CCC) of the diaphragm is rare, with an origin that is reported to be associated with malignant transformation of extraperitoneal endometriosis. Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome caused by germline pathogenic variants in one of the DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2. Women with LS have a significantly increased lifetime risk of endometrial and ovarian cancer. CCC is a common histology of endometriosis- and LS-associated malignancy. The present study describes the case of a 51-year-old woman with an intra-abdominal mass found during a routine physical examination. The patient had undergone total hysterectomy and bilateral adnexectomy for atypical endometrial hyperplasia (AEH) and ovarian endometriosis, respectively, 3 years previously. Enhanced computed tomography showed a mass on the surface of the liver. Laparoscopic examination of the abdominal cavity revealed a tumor on the underside of the right diaphragm, which was then surgically excised. Pathological examination of the excised tumor, along with immunohistochemistry, led to a diagnosis of CCC. Since LS was suspected due to the genetic family history of the patient, microsatellite instability analysis was performed on the diaphragmatic tumor, and the results were positive. Immunohistochemistry was performed for MMR proteins in AEH and CCC cells, both of which revealed loss of MSH2 and MSH6 expression. Following detailed genetic counseling, genetic testing of MMR genes was performed, revealing a germline pathogenic variant in MSH2 (c.1000C>T, p.Gln344*), thus confirming the diagnosis of LS. To the best of our knowledge, this is the first case report of concurrent diaphragmatic CCC and LS. Patients with LS and endometriosis are at risk of developing ovarian cancer or intra-abdominal malignant tumors. In addition, immunohistochemistry screening for MMR proteins should be considered in patients with AEH and a family history of LS-related cancer, to enable early clinical intervention in cases of endometrial cancer.

Enhanced expression of neopterin in valve tissue of bicuspid aortic stenosis.

Background: Aortic valve stenosis (AS) occurs in bicuspid aortic valve (BAV) patients at a relatively young age compared to tricuspid aortic valve (TAV) patients. However, the underlying cause of this phenomenon remains unknown. Neopterin, which is a by-product of the guanosine triphosphate (GTP) pathway, enhances the oxidative potential of reactive oxygen species. To clarify the role of neopterin in the aortic valve, we immunohistochemically studied the presence of neopterin in aortic valve specimens from patients with AS harboring either TAV or BAV. Methods: Frozen aortic valve samples were surgically obtained from 68 patients with severe AS with TAV (n=34) and BAV (n=34). Normal aortic valves were obtained from cadavers who died of non-cardiovascular causes as controls (n=9). Samples were immunohistochemically stained with antibodies against smooth muscle cells, macrophages, T lymphocytes, neopterin, and 4-hydroxy-2-nonenal (4-HNE). Results: Quantitative analysis showed that the percentage of macrophages, 4-HNE- and neopterin-positive macrophage score, and the number of T lymphocytes were significantly higher in BAV patients than in TAV patients (macrophages, P=0.013; T lymphocytes, P=0.011; neopterin, P<0.001; 4-HNE, P=0.008). Double immunostaining for neopterin and macrophages demonstrated that most neopterin-positive cells were macrophages in BAV patients. Conclusions: Neopterin accumulation in macrophages may increase oxidative stress and contribute to the early onset of AS in BAV.

5'­isomiR is the most abundant sequence of miR­1246, a candidate biomarker of lung cancer, in serum.

MicroRNA (miRNA/miR) 5'­isoforms (5'­isomiRs) differ from canonical sequences registered in the microRNA database in the length of their 5' ends. The 'seed sequence' of miRNAs that bind to target mRNAs is 2­8 nucleotides from the 5' end; thus, shifts at the 5' end can cause a 'seed shift'. Accumulating data from miRNA deep sequencing have revealed that, in a substantial number of miRNAs, sequences corresponding to specific isomiRs, not the canonical form, are the most abundant. Studies have so far focused on circulating miRNAs as either markers or intercellular communication factors. miR­1246 is abundant in the serum and is a candidate diagnostic and prognostic marker for esophageal squamous cell carcinoma, pancreatic cancer, hepatocellular carcinoma, colorectal adenocarcinoma and non­small cell lung cancer (NSCLC). The present study analyzed the 5'­end of serum miR­1246 by fragment analysis and found that a 5'­isomiR, which is two bases shorter than the canonical sequence, was the most abundant sequence in patients with NSCLC as well as healthy donors. To quantify the 5'­isomiR, 5'­isomiR­specific primers based on primers for allele specific­PCR were used, primarily because commercially available methods for miRNA Reverse transcription­quantitative PCR cannot discriminate among sequences, especially those located at the 5' end of miRNA. The total miR­1246 levels were significantly increased in patients with NSCLC; by contrast, the level of the canonical sequence was significantly decreased. Significant positive correlations were observed between the total miR­1246 levels and the 5'­isomiR levels, but not that of the canonical sequence. These results imply that the increase in levels of serum miR­1246 in patients with NSCLC depends on increase of the 5'­isomiR.

Successful management of pelvic recurrence of MSI-High endometrial cancer by total pelvic exenteration followed by administration of pembrolizumab:A case report.

Surgery can be curative treatment for pelvic locoregional recurrence of endometrial cancer; however, a cure is contingent on complete resection. Here, we report the case of a patient in whom recurrent endometrial tumor remained in the pelvis after resection; long-term control was achieved with postoperative administration of pembrolizumab.The patient had recurrent endometrial cancer of stage IA and was treated with chemotherapy and radiation, but tumor persisted in the pelvic cavity. We therefore attempted total pelvic exenteration, but the tumor was adherent to the pelvic wall and complete resection could not be achieved. However, postoperative administration of pembrolizumab controlled the residual tumor for more than two years without regrowth. We believe that since the resected tumor was MSI-High, the residual tumor responded well to pembrolizumab. It is not known whether cytoreductive surgery contributes to a long-term response to pembrolizumab, but at least in our patient, pembrolizumab appeared to be a very effective drug therapy for MSI-High endometrial cancer that was refractory to chemotherapy and radiotherapy.

A rare case of recurrent ovarian cancer with TPM3-NTRK1 gene rearrangement: A case report.

NTRK gene fusion is rare in gynecological cancer. Entrectinib is a novel targeted drug, which is a potent inhibitor of TRK A, B and C. The present case report described a case of recurrent ovarian cancer with TPM3-NTRK1 rearrangement, which was detected by next-generation sequencing (NGS) and treated with entrectinib. A 56-year-old woman was diagnosed as having stage IV ovarian cancer with positive pleural fluid cytology. Neoadjuvant chemotherapy and interval debulking surgery, followed by chemotherapy, were performed. A total of 10 months after completion of chemotherapy, the disease recurred and the patient was treated with multimodal therapy for recurrence. DNA-based NGS detected TPM3-NTRK1 rearrangement and entrectinib therapy was initiated; however, the disease progressed despite 6 weeks of entrectinib administration, and 1 month after discontinuation of entrectinib, the patient died. After their death, immunohistochemistry with a pan-Trk monoclonal antibody was performed to determine the expression levels of TRK; however, immunohistochemistry was negative for TRK. In conclusion, the present case report described a rare case of recurrent ovarian cancer with TPM3-NTRK1 gene fusion, in which entrectinib was not effective. While NTRK gene fusion was detected by DNA-based NGS, immunohistochemistry was negative for TRK. These findings indicated that immunohistochemistry may be required for confirmation of TRK protein expression prior to entrectinib administration.

Rare Hereditary Gynecological Cancer Syndromes.

Hereditary cancer syndromes, which are characterized by onset at an early age and an increased risk of developing certain tumors, are caused by germline pathogenic variants in tumor suppressor genes and are mostly inherited in an autosomal dominant manner. Therefore, hereditary cancer syndromes have been used as powerful models to identify and characterize susceptibility genes associated with cancer. Furthermore, clarification of the association between genotypes and phenotypes in one disease has provided insights into the etiology of other seemingly different diseases. Molecular genetic discoveries from the study of hereditary cancer syndrome have not only changed the methods of diagnosis and management, but have also shed light on the molecular regulatory pathways that are important in the development and treatment of sporadic tumors. The main cancer susceptibility syndromes that involve gynecologic cancers include hereditary breast and ovarian cancer syndrome as well as Lynch syndrome. However, in addition to these two hereditary cancer syndromes, there are several other hereditary syndromes associated with gynecologic cancers. In the present review, we provide an overview of the clinical features, and discuss the molecular genetics, of four rare hereditary gynecological cancer syndromes; Cowden syndrome, Peutz-Jeghers syndrome, DICER1 syndrome and rhabdoid tumor predisposition syndrome 2.

Successful pregnancy and term delivery after treatment of unicornuate uterus with non-communicating rudimentary horn pregnancy with local methotrexate injection followed by laparoscopic resection: a case report and literature review.

BACKGROUND: Pregnancy in a rudimentary horn is an extremely rare type of ectopic pregnancy. A rudimentary uterine horn pregnancy is associated with a risk of spontaneous rupture and bleeding during surgery due to the increased uterine blood flow. Recent advances in imaging modalities have enabled laparoscopic surgery to be performed in cases without rupture in the early stages of pregnancy. However, there are few reports of successful pregnancies and deliveries after treatment of rudimentary horn pregnancies. We report the successful management of a case of non-communicating rudimentary horn pregnancy by local injection of methotrexate followed by complete laparoscopic excision along with a review of the literature. CASE PRESENTATION: The patient was a 29-year-old Japanese woman, gravida 2, nullipara. She was diagnosed with a left unicornuate uterus with a right non-communicating rudimentary horn on hysterosalpingography and magnetic resonance imaging. A gestational sac with a heartbeat was observed in the right rudimentary uterine horn at 6 weeks of gestation. A diagnosis of ectopic pregnancy in a non-communicating rudimentary horn was made. Color Doppler detected multiple blood flow signals around the gestational sac, which were clearly increased compared to the left unicornuate uterus. Her serum human chorionic gonadotropin level was 104,619 mIU/ml. A 100 mg methotrexate injection into the gestational sac was administered, and laparoscopic surgery was performed on day 48 after the methotrexate treatment. The right rudimentary horn and fallopian tube were successfully excised with minimal bleeding. A spontaneous normal pregnancy was established 6 months after the surgery. The pregnancy was uneventful, and a baby girl was born by elective cesarean section at 38w0d. CONCLUSION: Combined local methotrexate injection and laparoscopic surgery are safe treatment options for patients with a unicornuate uterus with a non-communicating rudimentary horn pregnancy.

Successful Management of Platinum-resistant Ovarian Cancer by Weekly Nedaplatin Followed by Olaparib: Three Case Reports.

BACKGROUND: Treatment for platinum-resistant ovarian cancer is difficult and challenging because available chemotherapeutic agents only offer short survival improvements. The efficacy of re-treatment with platinum-based agents including nedaplatin for platinum-resistant patients has not been fully investigated. CASE REPORT: We describe herein three cases of heavily treated platinum-resistant ovarian cancer that were successfully treated with weekly nedaplatin followed by olaparib. After becoming platinum-resistant, the cases were treated with non-platinum chemotherapies. Following these regimens, weekly nedaplatin was introduced, followed by olaparib. At the time of writing, survival since the start of weekly nedaplatin was 30 months for case 1, 20 months for case 2, and 17 months for case 3, with all patients showing no evidence of disease. CONCLUSION: Weekly nedaplatin followed by olaparib might represent a good treatment option for platinum-resistant ovarian cancer and is a solid candidate for further evaluation.

Successful management of preoperatively diagnosed torsion of a subserosal uterine fibroid by pneumoperitoneum laparoscopic single-port surgery.

OBJECTIVE: Preoperative diagnosis and successful management of acute torsion of a subserosal fibroid by using appropriate imaging modalities and single-port laparoscopic surgery. CASE REPORT: A 44-year-old nulliparous woman presented with lower abdominal pain. Computed tomography and magnetic resonance imaging with contrast enhancement revealed a tumor in the pouch of Douglas with a low contrast at the center and thin-rim enhancement. Torsion of a uterine subserosal fibroid was diagnosed preoperatively. Laparoscopic single-port surgery by pneumoperitoneum was performed. Torsion of the pedicle attached to the uterine wall was excised by bipolar coagulation and cut with scissors. The extirpated fibroid was extracted from the umbilical wound. The pneumoperitoneum single-port laparoscopic surgery was completed as a gynecologic emergency operation. CONCLUSION: Torsional uterine fibroids are difficult to diagnose preoperatively as symptoms are nonspecific and need emergent surgical management as an acute abdomen. Preoperative diagnosis using appropriate imaging modalities is important to perform single-port laparoscopic surgery.

Pelvic Exenteration as Potential Cure and Symptom Relief in Advanced and Recurrent Gynaecological Cancer.

BACKGROUND/AIM: Pelvic exenteration is a radical procedure for certain advanced or recurrent gynaecological cancers, performed with curative or palliative intent. Its validity has evolved as operative mortality and morbidity have improved. This surgery was evaluated to determine the validity of these claims. PATIENTS AND METHODS: The details of surgery and outcomes of 13 patients who underwent pelvic exenteration (6 curative intent, 7 palliative intent) for advanced or recurrent gynaecological cancers in our Department were retrospectively evaluated. RESULTS: There were no significant differences in blood loss, surgical time, hospital stay, and complications between curative pelvic exenteration and palliative pelvic exenteration. The curative intent group had a good prognosis; the palliative-intent group showed a trend to a worse prognosis. All patients' symptoms were relieved, but in patients with short survival, symptom relief lasted for up to 3 months. CONCLUSION: Pelvic exenteration is an acceptable and valuable procedure for gynaecological cancers.

Neointimal coverage after second generation drug-eluting stent implantation has a relationship with pre-existing atherosclerotic lesion characteristics.

The relationship between preexisting atherosclerotic lesion characteristics and neointimal thickness after second-generation drug-eluting stent (DES) placement is still unknown. Thus, we evaluated that relationship using optical coherence tomography (OCT).A single-center, retrospective, observational study was conducted. Patients with stable angina or asymptomatic myocardial ischemia who received percutaneous coronary intervention for a de novo lesion using a second-generation DES under frequency domain OCT guidance and underwent follow-up coronary angiography (CAG) and OCT between December 2010 and December 2015 were included. The relationship between the neointimal thickness on the stent strut and the plaque characteristics was retrospectively evaluated using OCT immediately after stent implantation and at the time of follow-up CAG.We analyzed 3459 struts from 20 stents in 15 patients. The mean follow-up period was 264 days. In the follow-up study, no angiographic in-stent restenosis was found. Of the 3459 struts, 3315 (95.8%) were covered with neointima. The median neointimal thicknesses of the stent struts on calcified, fibrous, and lipid-rich lesions were 20 µm (interquartile range [IQR], 10-50 µm), 70 µm (40-140 µm; P < .001), and 90 µm (50-170 µm; P < .001), respectively. These differences were observed regardless of the type of second-generation DES used.Most of the stent struts were covered with neointima. The neointimal thickness after the second-generation DES implantation had a close relationship with the preexisting atherosclerotic lesion characteristics. In this study, we found differences in arterial healing processes due to underlying plaque; therefore, evaluating the lesion characteristics by OCT may predict the risk for future restenosis and thrombosis.

Serum levels of candidate microRNA diagnostic markers differ among the stages of non-small-cell lung cancer.

Circulating microRNAs (miRNAs) are promising markers for cancer diagnosis and prognosis. Numerous studies evaluating miRNAs as markers for non-small cell lung cancer (NSCLC) have been conducted in recent years; however, the majority of candidate markers proposed via individual studies were inconsistent and no marker miRNAs for the diagnosis of early stage NSCLC have been established. In the present study, miR-145, miR-20a, miR-21 and miR-223, which were previously reported as candidate diagnostic markers of NSCLC, were re-evaluated. The serum levels of these miRNAs were quantified in 56 patients with stage I-IV NSCLC using the TaqMan microRNA assays and separately compared the levels at each stage with those in 26 control patients. The level of miR-145 was significantly reduced in patients with NSCLC, regardless of clinical stage, and its level increased following tumor resection in patients with stage I-II disease. These results indicate that miR-145 is relevant as a diagnostic marker for stages I-IV NSCLC. Additionally, the levels of miR-20a and miR-21 demonstrated notable differences among patients at different clinical stages. These miRNAs distinguished patients in a number of, but not all, stages of NSCLC from cancer-free control patients. These results indicated that it is essential to analyze miRNA levels at each stage separately in order to evaluate marker miRNAs for NSCLC diagnosis.

Neopterin and Cardiovascular Events Following Coronary Stent Implantation in Patients with Stable Angina Pectoris.

AIM: Neopterin is an activation marker for monocytes/macrophages. We prospectively investigated the predictive value of plasma neopterin levels on 2-year and long-term cardiovascular events in patients with stable angina pectoris (SAP) undergoing coronary stent implantation. METHODS: We studied 123 consecutive patients with SAP who underwent primary coronary stenting (44 patients with bare metal stent: BMS group and 79 with drug-eluting stent: DES group). Plasma neopterin levels were measured on admission using HPLC. Moreover, one frozen coronary artery specimen after DES and three frozen coronary specimens after BMS were obtained by autopsy or endarterectomy, followed by immunohistochemical staining for neopterin. RESULTS: Plasma neopterin levels were significantly higher in patients with cardiovascular events than in those without them (P＜0.001). In subgroup analyses, higher levels of plasma neopterin in patients with cardiovascular events (P＜0.001) and a positive correlation between neopterin levels and late lumen loss after stenting (P =0.008) were observed in the BMS group but not in the DES group (P=0.53 and P=0.17, respectively). In long-term cardiovascular events, multivariate Cox regression analysis identified the significance of the high-neopterin group as independent determinants of cardiovascular events (hazard ratio, 2.225; 95% CI, 1.283-3.857; P =0.004). Immunohistochemical staining showed abundant neopterin-positive macrophages in the neointima after BMS implantation but no neopterin-positive macrophages in the neointima after DES implantation. CONCLUSION: These findings suggest that neopterin is associated with cardiovascular events after coronary stent implantation in patients with SAP. However, there might be a strong association between neopterin and cardiovascular events after BMS but not after DES in these patients.

Identification of miR-305, a microRNA that promotes aging, and its target mRNAs in Drosophila.

MicroRNAs (miRNAs) are involved in the regulation of important biological processes. Here, we describe a novel Drosophila miRNAs involved in aging. We selected eight Drosophila miRNAs, displaying high homology with seed sequences of aging-related miRNAs characterized in other species, and investigated whether the over-expression of these miRNAs affected aging in Drosophila adult flies. The lifespan of adults over-expressing miR-305, a miRNA showing high homology with miR-239 in C. elegans, was significantly shorter. Conversely, a reduction in miR-305 expression led to a longer lifespan than that in control flies. miR-305 over-expression accelerated the impairment of locomotor activity and promoted the age-dependent accumulation of poly-ubiquitinated protein aggregates in the muscle, as flies aged. Thus, we show that the ectopic expression of miR-305 has a deleterious effect on aging in Drosophila. To identify the targets of miR-305, we performed RNA-Seq. We discovered several mRNAs encoding antimicrobial peptides and insulin-like peptides, whose expression changed in adults upon miR-305 over-expression. We further confirmed, by qRT-PCR, that miR-305 over-expression significantly decreases the mRNA levels of four antimicrobial peptides. As these mRNAs contain multiple sequences matching the seed sequence of miR-305, we speculate that a reduction in target mRNA levels, caused by ectopic miRNA expression, promotes aging.

Enhanced expression of natriuretic peptide receptor A and B in neutrophils of culprit lesions in patients with acute myocardial infarction.

Natriuretic peptides and their specific receptors have been suggested to have regulatory effects on smooth muscle cell (SMC) growth and inflammatory cell reactions. However, the roles of natriuretic peptide receptor A (NPR­A) and B (NPR­B) in unstable plaques remain to be studied in detail. Frozen sections from 82 coronary artery segments were used. These segments were obtained at autopsy from 13 patients with acute myocardial infarction (AMI; 7 ruptured and 6 eroded plaques) and from 30 patients with non­cardiovascular diseases. Antibodies against SMCs, endothelial cells, macrophages, neutrophils, NPR­A, NPR­B and neutral endopeptidase (NEP) were used. Neutrophil infiltration was identified in all lesions with plaque rupture or erosion. Double immunostaining identified that the majority of NPR­A­ or NPR­B­positive cells were neutrophils in ruptured and eroded plaques. Using morphometric analysis, no significant difference was observed in the percentage of NPR­A­ and NPR­B­positive cells between ruptured and eroded plaques, while the number of NEP­positive neutrophils in ruptured plaques was significantly higher compared with eroded plaques (P<0.0001). These results of the distinct presence of NPR­A­ and NPR­B­positive cells in unstable plaques underlying AMI suggested that natriuretic peptides serve a role in regulating plaque instability in humans.

Relationship between tissue Doppler measurements of left ventricular diastolic function and silent brain infarction in patients with non-valvular atrial fibrillation.

AIMS: Left ventricular (LV) diastolic function assessed by tissue Doppler imaging (TDI) is reported to be associated with left atrial (LA) blood stasis in patients with non-valvular atrial fibrillation (AF). This study aimed to evaluate the relationship of diastolic TDI parameters with silent brain infarction (SBI) on brain magnetic resonance imaging (MRI), and in turn the risks of subsequent stroke or dementia, in non-valvular AF patients. METHODS AND RESULTS: The study population consisted of 171 neurologically asymptomatic patients with non-valvular AF who underwent transoesophageal echocardiography (TOE) (128 men; mean age, 63 ± 11 years). We measured diastolic TDI parameters by transthoracic echocardiography, and also screened for SBI employing brain MRI. Early transmitral flow velocity (E) and mitral annular velocity by TDI (e') were measured, and E/e' ratios were calculated. An increased tertile of the E/e' ratio was significantly related to high prevalences of LA abnormalities detected by TOE (32% vs. 12% vs. 9%; P =0.002) and SBI on brain MRI (46% vs. 23% vs. 14%; P < 0.001). In multivariate logistic regression analyses after adjustment for age, hypertension, chronic kidney disease, and CHA2DS2-VASc score ≥2, the E/e' ratio ≥12.4 was found to be an independent predictor of the presence of SBI (OR 3.98, 95% CI 1.74-9.07; P = 0.001). CONCLUSIONS: Impaired LV diastolic function evaluated by increased E/e' ratio was closely associated with the presence of SBI independent of CHA2DS2-VASc score. TDI measurements are non-invasive and useful for risk stratification of the early stage of cerebral damages in patients with non-valvular AF.

Serum Mac-2 binding protein is a novel biomarker for chronic pancreatitis.

AIM: To determine the efficacy of Mac-2 binding protein (Mac-2bp) for diagnosis of chronic pancreatitis. METHODS: Fifty-nine healthy volunteers (HV), 162 patients with chronic pancreatitis (CP), and 94 patients with pancreatic ductal adenocarcinoma (PDAC) were enrolled in this study. We measured serum Mac-2bp using our developed enzyme-linked immunosorbent assay kit. Additional biochemical variables were measured using an automated analyzer (including aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase, triglyceride, C-reactive protein, and amylase levels) or chemiluminescent enzyme immunoassay (carbohydrate antigen 19-9 and carcinoembryonic antigen). The ability of Mac-2bp to predict CP diagnosis accurately was assessed using receiver operating characteristic (ROC) analyses. RESULTS: Serum Mac-2bp levels were significantly increased in CP patients compared to HV (P < 0.0001) and PDAC patients (P < 0.0001). Area under the ROC curve values of Mac-2bp for the discrimination of CP from HV and PDAC were 0.727 and 0.784, respectively. Multivariate analyses demonstrated that serum Mac-2bp levels were independent determinants for CP diagnosis from HV and PDAC patients. Immunohistological staining showed that Mac-2bp was expressed faintly in the pancreas tissues of both CP and PDAC patients. Serum aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase, and triglyceride levels were significantly higher in patients with CP or PDAC. Serum Mac-2bp levels were highly correlated with protein levels of alanine aminotransferase, γ-glutamyltransferase, and C-reactive protein, but not amylase, suggesting that the damaged liver produces Mac-2bp. CONCLUSION: Measurement of serum Mac-2bp may be a novel and useful biomarker for CP diagnosis as well as liver fibrosis in the general population.

Specific increase in serum core-fucosylated haptoglobin in patients with chronic pancreatitis.

BACKGROUND/OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all malignancies, and its diagnosis in early stages is the most important prognostic factor. Chronic pancreatitis (CP), a common background of PDAC occurrence, is morphologically defined as progressive pancreatic fibrosis and inflammation accompanied by pancreatic exocrine cell atrophy. We recently found that inflammation and fibrosis are independent characteristic histological changes in noncancerous lesions in PDAC patients despite the absence of a past history of clinical CP. Subclinical CP is an important background for PDAC occurrence. Therefore, there is an urgent need to develop a noninvasive and reliable biomarker for CP diagnosis. METHODS: Fifty-nine healthy volunteers (HV), 159 patients with CP, and 83 patients with PDAC were enrolled in this study. We measured serum total fucosylated haptoglobin (Fuc-Hpt) and core-Fuc-Hpt levels using lectin-antibody enzyme-linked immunosorbent assay kits that we developed. In these kits, total Fuc-Hpt and core-Fuc-Hpt were measured using Aleuria aurantia lectin and Pholiota squarrosa lectin, respectively. RESULTS: Serum Fuc-Hpt levels were significantly increased in CP patients compared to HV (P < 0.0001) and were further increased in PDAC patients (P < 0.0001). Interestingly, serum core-Fuc-Hpt levels were significantly higher in CP patients compared to HV (P < 0.0001) and PDAC patients (P < 0.0001). Multivariate analyses demonstrated that total serum core-Fuc-Hpt was an independent determinant for CP diagnosis, but Fuc-Hpt was not. CONCLUSIONS: A dramatic change in oligosaccharides was observed in serum haptoglobin between CP and PDAC. Serum core-Fuc-Hpt may be a novel and useful biomarker for CP diagnosis.

Predictors of silent brain infarction on magnetic resonance imaging in patients with nonvalvular atrial fibrillation: A transesophageal echocardiographic study.

BACKGROUND: Silent brain infarction (SBI) is often found in patients with atrial fibrillation (AF) and may be related to cognitive decline. We investigated the predictors of SBI on brain magnetic resonance imaging (MRI) using transesophageal echocardiography (TEE) in patients with nonvalvular AF. METHODS: The study population consisted of 103 neurologically asymptomatic patients with nonvalvular AF who underwent TEE before transcatheter AF ablation (76 men; mean age 63 ± 10 years). Left atrial (LA) abnormalities such as LA thrombus, spontaneous echo contrast, or abnormal LA appendage emptying velocity (<20 cm/s) and complex plaques in the aortic arch defined as large plaques ≥4 mm thickness, ulcerated plaques, or mobile plaques were evaluated by TEE. All patients were screened for SBI by brain MRI. RESULTS: Of 103 patients, 31 (30%) showed SBI on brain MRI. Most lesions were multiple (61%) and small (<15 mm) in diameter (84%). Patients with SBI had a higher prevalence of LA abnormalities (45% vs 14%; P < .001) and complex arch plaques (45% vs 7%; P < .001) compared with those without SBI. In a multivariate logistic regression analysis including age and CHADS2 score ≥2, LA abnormalities (odds ratio 4.13; 95% CI 1.34-12.72; P = .014) and complex arch plaques (odds ratio 4.82; 95% CI 1.23-18.92; P = .024) were independent predictors of SBI. CONCLUSIONS: Left atrial abnormalities and complex arch plaques detected by TEE were closely associated with the presence of SBI on brain MRI, suggesting that microembolization of small thrombi derived from the fibrillating LA or advanced aortic atherosclerotic lesions may be important causes of SBI in patients with nonvalvular AF.