Predicted Prognosis of Patients with Pancreatic Cancer by Machine Learning.

PURPOSE: Pancreatic cancer remains a disease of high mortality despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic cancers. MUC1 and MUC4 expression are related to the aggressive behavior of human neoplasms and a poor patient outcome. In contrast, MUC2 is a tumor suppressor, and we have previously reported that MUC2 is a favorable prognostic factor in pancreatic neoplasia. This study investigates whether the methylation status of three mucin genes from postoperative tissue specimens from patients with pancreatic neoplasms could serve as a predictive biomarker for outcome after surgery. EXPERIMENTAL DESIGN: We evaluated the methylation status of MUC1, MUC2, and MUC4 promoter regions in pancreatic tissue samples from 191 patients with various pancreatic lesions using methylation-specific electrophoresis. Then, integrating these results and clinicopathologic features, we used support vector machine-, neural network-, and multinomial-based methods to develop a prognostic classifier. RESULTS: Significant differences were identified between the positive- and negative-prediction classifiers of patients in 5-year overall survival (OS) in the cross-validation test. Multivariate analysis revealed that these prognostic classifiers were independent prognostic factors analyzed by not only neoplastic tissues but also nonneoplastic tissues. These classifiers had higher predictive accuracy for OS than tumor size, lymph node metastasis, distant metastasis, and age and can complement the prognostic value of the TNM staging system. CONCLUSIONS: Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with pancreatic ductal adenocarcinoma.

Granulomatous/sarcoid-like reactions in the setting of programmed cell death-1 inhibition: a potential mimic of disease recurrence.

Nivolumab and pembrolizumab are humanized IgG4 monoclonal antibodies against programmed cell death 1 (PD-1). Although these agents are effective in treating advanced melanoma, non-small-cell lung carcinoma, and other types of cancers, various adverse events have been reported. Cutaneous adverse events are particularly prevalent and, while granulomatous/sarcoid-like reactions are uncommon, they are increasingly recognized as immune-related adverse events associated with immune checkpoint inhibitors. Herein, we report two cases of granulomatous/sarcoid-like reaction with foreign material, mimicking metastatic malignancy after PD-1 inhibitor treatment. Clinicians should be aware of the existence of cutaneous lesions and perform biopsy if needed to prevent misdiagnosis and unnecessary adjustments to immunotherapy.

Expression of MUC4 mucin is observed mainly in the intestinal type of intraductal papillary mucinous neoplasm of the pancreas.

OBJECTIVES: This study aimed to examine expression profile of MUC4 in intraductal papillary mucinous neoplasm of the pancreas (IPMN). METHODS: We performed immunohistochemistry (IHC) of MUC4 in 142 IPMNs, with evaluation of the specificity of 2 anti-MUC4 monoclonal antibodies, 8G7 and 1G8, in cancer cell lines. RESULTS: Monoclonal antibody 8G7 showed a clear immunoreactivity, whereas MAb 1G8 did not show any immunoreactivity, in the Western blotting and IHC for human pancreatic carcinoma cell lines expressing MUC4 messenger RNA. However, IHC signals detected by both monoclonal antibodies were observed in the tissue specimens. The expression rates of MUC4/8G7 detected by MAb 8G7 and MUC4/1G8 detected by MAb 1G8 in the intestinal-type IPMNs were significantly higher than those in the gastric-type IPMNs. In the intestinal-type IPMNs, MUC4/8G7 was expressed mainly in the cytoplasm of the neoplastic cells, whereas MUC4/1G8 was expressed mainly at the cell apexes. Even in the gastric-type IPMNs with rare MUC4 expression in the low-grade dysplasia, both MUC4 expression rates increased when dysplasia advanced. CONCLUSIONS: A significantly higher expression of MUC4 in intestinal-type IPMNs than in gastric-type IPMNs will be one of the biomarkers to discriminate between the intestinal-type IPMNs with high malignancy potential from gastric-type IPMNs with low malignancy potential.

MUC4 and MUC1 expression in adenocarcinoma of the stomach correlates with vessel invasion and lymph node metastasis: an immunohistochemical study of early gastric cancer.

We have previously reported that MUC4 expression is a poor prognostic factor in various carcinomas. Our previous study also showed that MUC1 expression in gastric cancers, including the early and advanced stages is a poor prognostic factor. In the present study, the expression profiles of MUC4 and MUC1 were examined by immunohistochemistry (IHC) using two anti-MUC4 monoclonal antibodies (MAbs), 8G7 and 1G8, and anti-MUC1 MAb DF3 in 104 gastrectomy specimens of early gastric adenocarcinoma with submucosal invasion (pT1b2), including 197 histological subtype lesions. Before the IHC study of the human specimens, we evaluated the specificity of the two MAbs by Western blotting and IHC of two MUC4 mRNA expressing gastric cancer cell lines. MAb 8G7 reacted clearly, whereas MAb 1G8 did not show any reactivity, in either Western blotting or IHC. In the IHC of the gastric cancers, the expression rates of MUC4/8G7 detected by MAb 8G7, MUC4/1G8 detected by MAb 1G8 and MUC1/DF3 detected by MAb DF3 in well differentiated types (70%, 38/54; 67%, 36/54; 52%, 28/54) were significantly higher than those in poorly differentiated types (18%, 10/55; 36%, 20/55; 13%, 7/55) (P<0.0001; P = 0.0021; P<0.0001), respectively. The MUC4/8G7 expression was related with lymphatic invasion (r = 0.304, P = 0.033). On the other hand, the MUC4/1G8 expression was related with lymphatic invasion (r = 0.395, P = 0.001) and lymph node metastasis (r = 0.296, P = 0.045). The MUC1/DF3 expression was related with lymphatic invasion (r = 0.357, P = 0.032) and venous invasion (r = 0.377, P = 0.024). In conclusion, the expression of MUC4 as well as MUC1 in early gastric cancers is a useful marker to predict poor prognostic factors related with vessel invasion.

A novel anti-MUC1 antibody against the MUC1 cytoplasmic tail domain: use in sensitive identification of poorly differentiated cells in adenocarcinoma of the stomach.

BACKGROUND: Isolated cancer cells of non-solid type poorly differentiated adenocarcinoma (por2) or signet-ring cell carcinoma (sig) are frequently seen in scirrhous gastric cancers with a very poor prognosis. These cells are often scattered in granulation tissue or desmoplastic fibrotic tissue and tend to be overlooked in routine pathological examination. We aimed to raise a novel antibody that can identify the isolated cancer cells easily. METHODS: Because the MUC1 cytoplasmic tail domain (CTD) has many biological roles including tumor progression and cell adhesion disturbance and is expected to be expressed in isolated cancer cells, we raised a novel monoclonal antibody (MAb) MUC1-014E against an intracellular nonrepeating 19-amino-acid sequence (RYVPPSSTDRSPYEKVSAG: N-1217-1235-C) of the MUC1 CTD, using a synthetic peptide including the 7-amino-acid epitope (STDRSPY: N-1223-1229-C). RESULTS: In the immunohistochemical staining of 107 gastrectomy specimens including 48 por2 and 31 sig lesions, the MAb MUC1-014E showed high rates of positive staining (≥5% of carcinoma cells stained) for por2 (100%) and sig (97%), and of the highest intensity staining (4+, ≥75% of carcinoma cells stained) for por2 (100%) and sig (90%). In the 89 biopsy specimens including 82 por2 and 38 sig lesions, the MAb MUC1-014E showed high rates of positive staining for por2 (100%) and sig (100%) and of 4+ staining for por2 (87%) and sig (84%). All the rates were significantly higher than those with cytokeratins (AE1/AE3 or CAM5.2). CONCLUSIONS: The MAb MUC1-014E is very useful for accurate detection of isolated cancer cells in scirrhous gastric cancers.

Terminal stage cardiac findings in patients with cardiac Fabry disease: an electrocardiographic, echocardiographic, and autopsy study.

OBJECTIVES: Fabry disease is caused by deficiency of alpha-galactosidase A, and typically causes multi-organ dysfunction. Patients with manifestations limited to the heart, mainly left ventricular hypertrophy (LVH), have been reported as a disease variation. We have reported a 3% prevalence of this cardiac variant in men with LVH, which we designated 'cardiac Fabry disease'. The purposes of this study were to evaluate the terminal stage cardiac manifestations and autopsy findings in patients with cardiac Fabry disease. METHODS: We examined seven terminal stage patients with cardiac Fabry disease. During hospitalization, standard 12-lead electrocardiograms, Holter electrocardiograms, and echocardiograms were obtained. Autopsies were performed and macroscopic along with microscopic findings were evaluated. RESULTS: Six patients died of heart failure and one of ventricular fibrillation. Electrocardiograms revealed the presence of conduction abnormalities and nonsustained ventricular tachycardia. Echocardiograms and autopsy findings revealed LVH in all patients. Localized basal posterior wall thinning of the left ventricle was detected in the six patients who died of heart failure. All patients had severe left ventricular dysfunction. Histologically, myocardial cells, but not cardiac vascular endothelial cells, showed glycosphingolipid accumulation. No accumulation was observed in other organs or in systemic vascular endothelial cells. CONCLUSIONS: Severe left ventricular dysfunction with associated conduction disturbances and ventricular arrhythmias occur in patients with terminal stage cardiac Fabry disease. Furthermore, LVH is present and associated with thinning of the base of the left ventricular posterior wall. In contrast to typical Fabry disease, accumulation of glycosphingolipids was observed in myocardial cells but not in other organs.

Mucin expression profile in pancreatic cancer and the precursor lesions.

In this review article, we demonstrate the mucin expression profile in normal tissue, invasive ductal carcinoma (IDC), two subtypes of intraductal papillary-mucinous neoplasm (IPMN dark cell type and IPMN clear cell type), pancreatic intraepithelial neoplasia (PanIN), and mucinous cystic neoplasm (MCN) of the pancreas. In MUC1, there are various glycoforms, such as poorly glycosylated MUC1, sialylated MUC1, and fully glycosylated MUC1. IDCs showed high expression of all the glycoforms of MUC1. IPMNs dark cell type showed no expression or low expression of all the glycoforms of MUC1. IPMNs clear cell type showed low expression of poorly glycosylated MUC1, but expression of sialylated MUC1 and fully glycosylated MUC1. Expression of MUC2 was negative in IDCs, high in IPMNs dark cell type and low in IPMNs clear cell type. MUC5AC was highly expressed in IDCs, IPMNs dark cell type, and IPMNs clear cell type. MUC6 expression was higher in IPMNs clear cell type than in IDCs and IPMNs dark cell type. Our recent study demonstrated that high expression of MUC4 in IDCs is correlated with a poor outcome for patients. In PanINs, expression of both MUC5AC and MUC6 are an early event, whereas up-regulation of MUC1 is a late event. MCNs do not look as if they will show a specific mucin expression profile according to the literature review.

[End-stage cardiac manifestations and autopsy findings in patients with cardiac fabry disease].

BACKGROUND: Fabry disease is an X-linked recessive disorder resulting from a deficiency of alpha-galactosidase A with multi-organ dysfunction. Patients with manifestations limited to the heart have been reported recently as a disease variant. We have previously reported a 3% prevalence of this cardiac variant in men with left ventricular hypertrophy, which we designated cardiac Fabry disease. The purposes of the current study were to evaluate the end-stage cardiac manifestations and autopsy findings in patients with cardiac Fabry disease. METHODS AND RESULTS: We evaluated five autopsied male patients with cardiac Fabry disease. One died of ventricular fibrillation and four of heart failure. Electrocardiograms obtained at hospitalization revealed the presence of conduction abnormalities and nonsustained ventricular tachycardia. Echocardiograms and autopsy findings showed the presence of left ventricular hypertrophy in all patients. Localized thinning of the basal posterior wall of the left ventricle was detected in four patients who died of heart failure. All patients had severe left ventricular dysfunction. Histologically, myocardial cells showed glycosphingolipid accumulation in all of the patients but no accumulation was observed in other organs or in systemic vascular endothelial cells. CONCLUSIONS: Severe left ventricular dysfunction, conduction disturbances and ventricular arrhythmias occur in end-stage cardiac Fabry patients. Furthermore, left ventricular hypertrophy commonly associated with thinning of the base of the left ventricular posterior wall is present. The accumulation of glycosphingolipids can be observed in myocardial cells but not in other organs.

The expression of several types of mucin is related to the biological behavior of pancreatic neoplasms.

BACKGROUND/PURPOSE: Mucins are high molecular weight glycoproteins that have oligosaccharides attached to the apomucin protein backbone by O-glycosidic linkages. Here, we report the expression of MUC1 mucin (membrane-bound mucin), MUC2 mucin (intestinal-type secretory mucin), and MUC5AC mucin (gastric-type secretory mucin) in invasive ductal carcinomas (IDCs; n = 46) and intraductal papillary-mucinous neoplasms (IPMNs; n = 33) of the pancreas, and the relationship of this expression with malignant potential. METHODS: To clarify the precise expression pattern of mucins in IPMNs, we classified IPMNs into three histologic subtypes; IPMN-dark cell type ( n = 19), IPMN-clear cell type ( n = 10), and IPMN-compact cell type ( n = 4). RESULTS: IDC, with a poor outcome, showed a pattern of MUC1(+), MUC2(-), and MUC5AC(+ or -). In contrast, IPMN-dark cell type tumors, with a fairly favorable outcome, showed a pattern of MUC1(-), MUC2(+), and MUC5AC (+), and IPMN-clear cell type tumors, with a favorable outcome, showed a pattern of MUC1(-), MUC2(-), and MUC5AC(+). On the other hand, IPMN-compact cell type tumors showed a pattern of MUC1(+), MUC2 (-), and MUC5AC(+). In IPMN-dark cell type tumors with carcinomatous change showing invasive growth, the invasive areas acquired a characteristic of MUC1 expression that was usually seen in IDC, although their main noninvasive lesions showed no MUC1 expression. The IPMN-compact cell type tumors usually showed high cellular atypia and frequent MUC1 expression, even in the noninvasive areas. CONCLUSIONS: Our study of the mucin expression pattern in IDC and IPMN shows that this pattern may be related to the biological behavior of pancreatic tumors and their malignant potential.

New classification of pancreatic intraductal papillary-mucinous tumour by mucin expression: its relationship with potential for malignancy.

In previous studies of the expression of MUC1 (membrane-bound type mucin) and MUC2 (intestinal type secretory mucin) in pancreatic tumours, invasive ductal carcinoma (IDC) usually showed MUC1+ and MUC2- expression, whereas intraductal papillary-mucinous tumour (IPMT) showed MUC1- and MUC2+ expression. Recently, however, many IPMTs have been collected, a considerable number of which have shown MUC1- and MUC2- expression. In the present study, the clinicopathological features were examined of 18 IPMTs with MUC2+ and 32 IPMTs with MUC2-, and their potential for malignancy was compared. Most of the IPMTs with MUC2+ were composed of dark columnar cells, whereas most of the IPMTs with MUC2- were composed of clear columnar cells. The incidence of carcinomatous change and invasive proliferation of the carcinoma in the MUC2+ tumours was significantly higher than in the MUC2- tumours. The clinical outcome for the patients with IPMT showing the MUC2+ pattern tended to be worse than for those with IPMT showing the MUC2- pattern, although the overall outcome for the two types of IPMT was significantly better than for those with IDC. Because of the differences in mucin expression pattern, morphological appearance and potential for malignancy between the two types of IPMT, we believe that they belong to different neoplastic lineages and that it may be reasonable to classify them as different entities, although the WHO classification contains a single clinicopathological entity of IPMT forming an adenoma-carcinoma sequence. In conclusion, our classification of IPMTs by MUC2 expression pattern may be of value in the better assessment of the biological behaviour of IPMTs and their potential for malignancy.

Recurrent nonocclusive mesenteric ischemia after resection of iliac artery aneurysm.

A case of recurrent nonocclusive mesenteric ischemia in a patient with isolated internal iliac artery aneurysm penetrating the sigmoid colon is described. On the day after the aneurysm and the sigmoid colon had been resected, the patient developed necrosis of the left hemicolon. Fourteen and nineteen days after left hemicolectomy, massive intestinal bleedings occurred, requiring ileectomy. On the basis of operative findings of good pulsation of visceral arterial branches; angiography showing patent mesenteric vessels with some spasms; and pathological findings suggesting mesenteric ischemia, these ischemic events were diagnosed as nonocclusive mesenteric ischemia. Low-output syndrome induced by massive intestinal bleeding and atrial fibrillation and sepsis were responsible for the establishment of the nonocclusive mesenteric ischemia. Development of disseminated intravascular coagulation and continuous administration of diuretics for acute renal failure seemed to have further perturbed the mesenteric circulation. The patient died of subsequent multiple organ failure 4 months after the first operation. We should pay more attention to nonocclusive mesenteric ischemia in patients with mesenteric ischemia, and strict circulatory management during the perioperative period is essential in these patients.