Metabolic Syndrome Accelerates the Age-Related Increase of Intraductal Papillary Mucinous Neoplasm of the Pancreas.

OBJECTIVES: Aging is associated with a high prevalence of pancreatic cysts and intraductal papillary mucinous neoplasms (IPMNs). Metabolic syndrome (MS) may increase the risk of neoplasms, including those that develop in the pancreas. However, the influence of factors associated with MS on the development of IPMN remains unclear. METHODS: A total of 9363 patients who underwent abdominal ultrasound examinations between April 2012 and May 2013 were included in this study. Multivariate logistic regression analysis was performed to identify factors associated with the presence of IPMN by age. RESULTS: Pancreatic cysts were detected in 198 of 9363 patients, of whom 129 were found to have IPMNs. The presence of IPMN significantly correlated with age (10-year increments; odds ratio, 2.73; 95% CI, 2.28-3.29; P < 0.001). High body mass index, history of smoking, hyperlipidemia, hypertension, and MS were associated with a higher prevalence of IPMN with advancing age. In multivariate analysis, the presence of IPMN was more frequent in elderly patients with MS (odds ratio, 3.14; 95% CI, 3.14-6.72; P = 0.003). CONCLUSIONS: The present study suggests that the incidence of IPMN increases with age and is accelerated in the presence of MS.

The impact of nutritional status in nivolumab-treated patients with advanced esophageal cancer.

Although phase III trials have reported improved overall survival in patients with advanced esophageal squamous cell carcinoma following treatment with nivolumab, as compared with chemotherapy (paclitaxel or docetaxel), the treatment was effective only in a limited number of patients. Therefore, the aim of this study is to determine whether there is a correlation between nutritional status (Glasgow prognostic score, prognostic nutritional index, and neutrophil-to-lymphocyte ratio) and prognosis of advanced esophageal cancer in patients treated with taxane or nivolumab therapy. The medical records of 35 patients who received taxane monotherapy (paclitaxel or docetaxel), for advanced esophageal cancer between October 2016 and November 2018 (taxane cohort) were reviewed. The clinical data of 37 patients who received nivolumab therapy between March 2020 and September 2021 (nivolumab cohort) were collected. The median overall survival was 9.1 months for the taxane cohort and 12.5 months for the nivolumab cohort. In the nivolumab cohort, patients with good nutritional status had significantly better median overall survival than those with poor nutritional status (18.1 vs. 7.6 months, respectively, p = 0.009, classified by prognostic nutritional index, 15.5 vs. 4.3 months, respectively, p = 0.012, classified by Glasgow prognostic score), whereas the prognosis of the patients treated with taxane therapy was less affected by the nutritional status. This suggests that the pretreatment nutritional status of patients with advanced esophageal cancer is a key factor for successful outcomes, especially for treatment with nivolumab.

Integrated analysis of tertiary lymphoid structures in relation to tumor-infiltrating lymphocytes and patient survival in pancreatic ductal adenocarcinoma.

BACKGROUND: Tertiary lymphoid structure (TLS) reflects an intense immune response against cancer, which correlates with favorable patient survival. However, the association of TLS with tumor-infiltrating lymphocytes (TILs) and clinical outcomes has not been investigated comprehensively in pancreatic ductal adenocarcinoma (PDAC). METHODS: We utilized an integrative molecular pathological epidemiology database on 162 cases with resected PDAC, and examined TLS in relation to levels of TILs, patient survival, and treatment response. In whole-section slides, we assessed the formation of TLS and conducted immunohistochemistry for tumor-infiltrating T cells (CD4, CD8, CD45RO, and FOXP3). As confounding factors, we assessed alterations of four main driver genes (KRAS, TP53, CDKN2A [p16], and SMAD4) using next-generation sequencing and immunohistochemistry, and tumor CD274 (PD-L1) expression assessed by immunohistochemistry. RESULTS: TLSs were found in 112 patients with PDAC (69.1%). TLS was associated with high levels of CD4+ TILs (multivariable odds ratio [OR], 3.50; 95% confidence interval [CI] 1.65-7.80; P = 0.0002), CD8+ TILs (multivariable OR, 11.0; 95% CI 4.57-29.7, P < 0.0001) and CD45RO+ TILs (multivariable OR, 2.65; 95% CI 1.25-5.80, P = 0.01), but not with levels of FOXP3+ TILs. TLS was associated with longer pancreatic cancer-specific survival (multivariable hazard ratio, 0.37; 95% CI 0.25-0.56, P < 0.0001) and favorable outcomes of adjuvant S-1-treatment. TLS was not associated with driver gene alterations but tumor CD274 negative expression. CONCLUSIONS: Our comprehensive data supports the surrogacy of TLS for vigorous anti-tumor immune response characterized by high levels of helper and cytotoxic T cells and their prognostic role.

Comprehensive Analysis of Molecular Biologic Characteristics of Pancreatic Ductal Adenocarcinoma Concomitant with Intraductal Papillary Mucinous Neoplasm.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) concomitant with intraductal papillary mucinous neoplasm (IPMN) is defined as PDAC occurring apart from IPMN. This study comprehensively investigated the molecular biologic characteristics of PDAC concomitant with IPMN in major genetic alterations, tumor microenvironment, and prognosis by contrast with those of conventional PDAC. METHODS: The study retrospectively reviewed the data of 158 surgically resected PDAC patients. The driver gene alteration status (KRAS, TP53, CDKN2A, SMAD4, and GNAS) together with the immune and fibrotic status in tumor was evaluated. The prognosis of PDAC concomitant with IPMN and that of conventional PDAC also were compared. RESULTS: No statistically significant difference was found between PDAC concomitant with IPMN and conventional PDAC in the alteration frequency analysis of the major driver genes and the immune and fibrotic status in the tumor microenvironment. Overall survival and disease-free survival between patients who had PDAC concomitant with IPMN and those who had conventional PDAC did not show statistically significant differences in propensity-matched subjects. Furthermore, the co-existence of IPMN was not a poor prognostic factor in the multivariable-adjusted Cox proportional hazards model (hazard ratio, 0.95; 95 % confidence interval, 0.51-1.78). CONCLUSIONS: In this study, PDAC concomitant with IPMN had tumor characteristics similar to those of conventional PDAC in terms of the major driver gene alterations, tumor microenvironment, and prognosis.

An autopsy case of severe acute pancreatitis induced by administration of pazopanib following nivolumab.

Drug-induced pancreatitis is often mild to moderate in severity, but severe and even fatal cases can occur. Here, we report a 74-year-old woman undergoing chemotherapy for recurrent renal cell carcinoma, who presented with abdominal pain after administration of pazopanib following nivolumab and was diagnosed with severe acute pancreatitis. Administration of methylprednisolone and conservative treatment were initiated, but clinical findings and laboratory tests rapidly worsened. When she died, an autopsy was performed. The autopsy findings suggested the possibility of pancreatitis as immune-related adverse events. To the best of our knowledge, no fatal cases of acute pancreatitis due to nivolumab or pazopanib have been reported. We considered that the effects of nivolumab were sustained in the pancreas, and pazopanib administration might have worsened the toxicity.

Acute pancreatitis in intraductal papillary mucinous neoplasms correlates with pancreatic volume and epithelial subtypes.

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is associated with acute pancreatitis (AP) in some cases, however its causes have not been fully elucidated. We investigated the association of the incidence of AP with epithelial subtypes and pancreatic volume in IPMN. METHODS: This retrospective study included 182 consecutive surgically resected IPMN patients between January 2000 and December 2018. The relationship between the incidence of AP and epithelial subtypes of IPMN and pancreatic volume was investigated. Epithelial subtypes of IPMN were classified into gastric (G type: N = 116), intestinal (I type: N = 49), pancreatobiliary (PB type: N = 14), and oncocytic types (O type: N = 3). Pancreatic volume of the contrast-enhanced computed tomography scan was measured using Ziostation2 software. Histological pancreatic parenchymal atrophy was also evaluated. RESULTS: AP occurred more frequently in I-types (I-type vs. G-type, 22.4% [11/49] vs 3.4% [4/116], P = 0.003) and PB-types (PB type vs. G-type, 35.7% [5/14] vs. 3.4% [4/116], P = 0.007) in comparison with G-types, which constituted the majority of the resected IPMNs. AP occurred more frequently in I-type patients with high pancreatic volumes (I-type with high pancreatic volume vs. I-type with low pancreatic volume, 37.0% [10/27] vs. 4.7% [1/21], P = 0.02). However, histological atrophy did not show an additional influence on the association between the incidence of AP and epithelial subtypes. The elevation of serum pancreatic enzymes was not significantly related to epithelial subtypes. CONCLUSION: Epithelial subtypes and the degree of pancreatic volume may be closely associated with the incidence of AP in IPMN.

Prediction of pancreatic atrophy after steroid therapy using equilibrium-phase contrast computed tomography imaging in autoimmune pancreatitis.

BACKGROUND AND AIMS: Imaging tools for predicting pancreatic atrophy after steroid therapy in autoimmune pancreatitis (AIP) have not been established. As delayed equilibrium-phase contrast enhancement in computed tomography (CE-CT) may reflect interstitial fibrosis, we evaluated the ability of equilibrium-phase CT imaging for predicting pancreatic atrophy. METHODS: Forty-six steroid-treated AIP patients who underwent contrast-enhanced CT at our university hospital were included in this retrospective study. CT attenuation (Hounsfield units [HU]) values in noncontrast images (NC) and equilibrium-phase images (EP) and the differences in HU values between NC and EP images (SUB) were measured. Pancreatic volume was measured in CE-CT before (Volpre) and after (Volpost) steroid therapy. The volume reduction rate was calculated. The relationships of CT values with pancreatic atrophy, Volpost, volume reduction rate, and diabetes exacerbation were investigated. RESULTS: CT values in the EP and SUB images before steroid therapy were associated with pancreatic atrophy after steroid therapy (atrophy vs nonatrophy 114.5 ± 12.8 vs 99.5 ± 11.1, P = 0.0002; 70.9 ± 14.72 vs 57.2 ± 13.1, P = 0.003, respectively), but CT values in NC images were not (P = 0.42). CT values in EP and SUB images before steroid therapy were correlated with Volpost (EP images r = -0.70, P = 0.002; SUB images r = -0.68, P = 0.03) and volume reduction rate after steroid therapy (EP images: r = -0.55, P < 0.0001; SUB images r = -0.45, P = 0.002). Diabetes exacerbation was associated with higher EP and SUB values (P = 0.009 and P = 0.04, respectively). CONCLUSION: Equilibrium-phase contrast CT imaging may facilitate prediction of pancreatic atrophy after steroid therapy in AIP.

A case of high-grade pancreatic intraepithelial neoplasia diagnosed based on focal pancreatic parenchymal atrophy after acute pancreatitis.

A 60-year-old male visited a previous hospital with upper abdominal pain. He was diagnosed with localized mild acute pancreatitis. Three months later, abdominal contrast-enhanced computed tomography showed focal parenchymal atrophy of the pancreas with distal pancreatic duct dilation. No obvious solid mass could be found at the site of the pancreatic duct stenosis on imaging examinations. Endoscopic retrograde pancreatography showed focal mild stenosis with distal pancreatic duct dilation in the tail of the pancreas. Carcinoma in situ of the pancreas was strongly suspected, especially based on the presence of focal atrophy of the pancreas around the site of stenosis of the main pancreatic duct and the distal pancreatic duct dilation. Laparoscopic distal pancreatectomy was performed. Histologically, high-grade pancreatic intraepithelial neoplasia was found in the epithelium of the stenotic main pancreatic duct and its branches. This case suggests that localized acute pancreatitis and focal atrophy of the pancreas with distal dilation of the pancreatic duct could be important clinical manifestations of pancreatic carcinoma in situ.

A Case in which an Intraductal Papillary Neoplasm of the Bile Duct Was Surgically Resected 12 Years after the Initial Diagnosis.

A 66-year-old Japanese man was referred to our hospital with multiple giant liver cysts. The cysts had already been detected as multiple 3-cm cysts with small nodules at another hospital 12 years prior to this presentation. The cysts were diagnosed as an intraductal papillary neoplasms of the bile duct (IPNB) occupying the right lobe of the liver. Extended right lobectomy was performed. Based on the pathological findings, the tumor was diagnosed to be an oncocytic-type IPNB with minimal invasion. This experience suggests that the progression of IPNBs occur relatively slowly. The present case might provide important information for understanding the natural history of IPNBs.

Eosinophilic Cholangitis Without Biliary Stricture After the Treatment of Eosinophilic Esophagitis.

Eosinophilic cholangitis (EC) is an uncommon, benign, self-limiting disease, which typically causes bile duct stricture with eosinophil infiltration. We report the case of a 70-year-old woman who presented with abdominal pain diagnosed with EC after treatment for eosinophilic esophagitis. All previous reported cases of EC had bile duct stricture seen on magnetic resonance cholangiopancreatography or cholangiogram during endoscopic retrograde cholangiopancreatography, but only wall thickness of the common bile duct was noted in our case. Although rare, EC should be considered when wall thickening of the bile duct is observed, even without stricture.

Significance of pancreatic calcification on preoperative computed tomography of intraductal papillary mucinous neoplasms.

BACKGROUND AND AIM: Chronic pancreatitis is a risk factor for pancreatic cancer. Pancreatic calcification is a characteristic of chronic pancreatitis; however, its significance for intraductal papillary mucinous neoplasm (IPMN) oncogenesis remains unknown. Therefore, we investigated the relationship between pancreatic calcification and invasive IPMN. METHODS: This study included 157 patients who underwent resection for IPMN between April 2001 and October 2016 (intraductal papillary mucinous adenoma, n = 76; noninvasive intraductal papillary mucinous carcinoma [IPMC], n = 32; and invasive IPMC, n = 49). We divided the subjects on the basis of the presence/absence of pancreatic calcification on preoperative computed tomography (CT). The factors associated with pancreatic calcification were investigated in univariate analyses. Then, multivariate logistic regression analyses of the relationship between pancreatic calcification and invasive IPMC (after adjusting for clinical or imaging characteristics) were conducted. RESULTS: Preoperative CT revealed pancreatic calcification in 17.2% (27/157) of the resected IPMN. In the univariate analyses, jaundice, high serum carbohydrate antigen 19-9 levels, and invasive IPMC were significantly associated with pancreatic calcification (4/27 [14.8%] vs 4/130 [3.1%], 0.01; 12/27 [44.4%] vs 31/130 [23.8%], 0.03; and 15/27 [55.6%] vs 34/130 [26.2%], 0.001, respectively). Pancreatic calcification was significantly associated with invasive IPMC (multivariate odds ratio = 2.88, 95% confidence interval [95% CI] = 1.15-7.21, 0.03, adjusted for clinical characteristics; odds ratio = 5.50, 95% CI = 1.98-15.3, 0.001, adjusted for imaging characteristics). CONCLUSIONS: Pancreatic calcification on CT is associated with invasive IPMC. Pancreatic calcification might be a predictor of invasive IPMC.

Clinical outcomes of ampullary neoplasms in resected margin positive or uncertain cases after endoscopic papillectomy.

BACKGROUND: Endoscopic papillectomy (EP) for benign ampullary neoplasms could be a less-invasive alternative to pancreatoduodenectomy (PD). There are some problems and limitations with EP. The post-EP resection margins of ampullary tumors are often positive or uncertain because of the burning effect of EP. The clinical outcomes of resected margin positive or uncertain cases after EP remain unknown. AIM: To investigate the clinical outcomes of resected margin positive or uncertain cases after EP. METHODS: Between January 2007 and October 2018, all patients with ampullary tumors who underwent EP at Kobe University Hospital were included in this study. The indications for EP were as follows: adenoma, as determined by preoperative endoscopic biopsy, without bile/pancreatic duct extension, according to endoscopic ultrasound or intraductal ultrasound. The clinical outcomes of resected margin positive or uncertain cases after EP were retrospectively investigated. RESULTS: Of the 45 patients, 29 were male, and 16 were female. The mean age of the patients was 65 years old. Forty-one patients (89.5%) underwent en bloc resection, and 4 patients (10.5%) underwent piecemeal resection. After EP, 33 tumors were histopathologically diagnosed as adenoma, and 12 were diagnosed as adenocarcinoma. The resected margins were positive or uncertain in 24 patients (53.3%). Of these cases, 15 and 9 were diagnosed as adenoma and adenocarcinoma, respectively. Follow-up observation was selected for all adenomas and 5 adenocarcinomas. In the remaining 4 adenocarcinoma cases, additional PD was performed. Additional PD was performed in 4 cases, and residual carcinoma was found after the additional PD in 1 of these cases. In the follow-up period, local tumor recurrence was detected in 3 cases. Two of these cases involved primary EP-diagnosed adenoma. The recurrent tumors were also adenomas detected by biopsy. The remaining case involved primary EP-diagnosed adenocarcinoma. The recurrent tumor was also an adenocarcinoma. All of the recurrent tumors were successfully treated with argon plasma coagulation (APC). There was no local or lymph node recurrence after the APC. The post-APC follow-up periods lasted for 57.1 to 133.8 mo. No ampullary tumor-related deaths occurred in all patients. CONCLUSION: Resected margin positive or uncertain cases after EP could be managed by endoscopic treatment including APC, even in cases of adenocarcinoma. EP could become an effective less-invasive first-line treatment for early stage ampullary tumors.

Evaluation of efficacy of pancreatic juice cytology for risk classification according to international consensus guidelines in patients with intraductal papillary mucinous neoplasm; a retrospective study.

OBJECTIVES: Pancreatic juice cytology (PJC) for intraductal papillary mucinous neoplasm (IPMN) is a possible tool to enhance preoperative diagnostic ability by improving risk classification for malignant IPMN, but its efficacy is controversial. This study evaluated the efficacy of PJC for risk classification according to international guidelines. METHODS: We retrospectively analyzed 127 IPMN patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) preoperatively. PJC was performed in 125 of the 127 cases. High-risk stigmata (HRS, n = 57), worrisome features (WF, n = 64), and other characteristics (n = 6) were classified according to the 2017 international guidelines. RESULTS: Among the 127 IPMN patients, 71 (55.9%) had malignant IPMN (invasive and non-invasive intraductal papillary mucinous carcinoma). The accuracy of WF for classifying malignant IPMN was increased by the addition of PJC, but the accuracy of HRS was not (WF to WF + PJC: 33.1% [42/127] to 48.8% [61/125], HRS to HRS + PJC: 65.4% [83/127] to 52.8% [66/125]). Post-ERCP pancreatitis (PEP) occurred in 32 (25.2%) of 127 IPMN patients. Severe PEP was not detected. Significant risk factors for PEP were female sex, obesity, and endoscopic naso-pancreatic drainage (ENPD) (P = .03, P = .0006, and P = .02, respectively). In patients with ENPD tube placement, a main pancreatic duct size of <5 mm was a significant risk factor for PEP (P = .02). CONCLUSION: PJC could increase the accuracy of WF for classifying malignant IPMN. The additive effect of PJC for risk classification may be limited, however, and it is not recommended for all IPMN cases due to the high frequency of PEP.

All-optical dynamic photonic bandgap control in an all-solid double-clad tellurite photonic bandgap fiber.

All-optical dynamic photonic bandgap (PBG) control by an optical Kerr effect (OKE) is investigated in an all-solid double-clad tellurite photonic bandgap fiber (PBGF) which is fabricated based on TeO2-Li2O-WO3-MoO3-Nb2O5 (TLWMN, high-index rod) glass, TeO2-ZnO-Na2O-La2O3 (TZNL, inner cladding) glass, and TeO2-ZnO-Li2O-K2O-Al2O3-P2O5 (TZLKAP, outer cladding) glass. To the best of our knowledge, this is the first demonstration of all-optical dynamic PBG control in optical fibers. This PBGF has a high nonlinear refractive index which can lead to a significant OKE and induce the generation of all-optical dynamic PBG control. The transmission spectrum is simulated with the pump peak power increasing from 0 to 300 kW, which shows an obvious PBG shift. Dynamic PBG control is demonstrated both numerically and experimentally at the pump peak power of 200 kW (ON or OFF) at the signal of 1570 nm.