Pancreatic injury in patients treated with immune checkpoint inhibitors: a retrospective multicenterstudy.

BACKGROUND: Immune checkpoint inhibitor-related pancreatic injury (ICI-PI) is a rare occurrence, which has not been reported in detail. We conducted a retrospective multicenter study to determine the clinical characteristics, risk factors, and treatment of ICI-PI. METHODS: We reviewed the medical records of patients who received ICIs for malignant tumors between April 2014 and April 2019 at 16 participating hospitals. Patients with elevated pancreatic enzymes or pancreatitis were identified and classified using the Common terminology Criteria for Adverse Events (CTCAE) ver.5.0). The number of patients with pancreatic enzyme elevation was determined and those with pancreatic enzyme elevation of ≥ grade 3 according to CTCAE ver.5.0, or pancreatitis underwent detailed analysis for ICI-PI. RESULTS: The study enrolled 1069 patients. Nineteen patients (1.8%) had ICI-PI, 5 (0.5%) of whom also had pancreatitis. Four patients had mild pancreatitis, whereas 1 patient had severe pancreatitis, culminating in death. Steroid therapy was administered to 7 of 19 patients, which led to ICI-PI improvement in 5 patients. On the other hand, ICI-PI improved in 9 of 12 patients who were not administered steroid therapy. Six of the 14 patients with ICI-PI improvement were rechallenged with ICI, and ICI-PI relapse occurred in only 1 patient (16.7%), which improved with ICI discontinuation and steroid therapy. CONCLUSIONS: ICI-PI is a rare occurrence, with a low incidence of pancreatitis, which followed a very serious course in one patient. Although the benefit of steroid therapy for ICI-PI is unclear, ICI rechallenge is acceptable after improvement of ICI-PI without pancreatitis.

Relapse and side effects of steroid therapy beyond 3 years in autoimmune pancreatitis: A multicenter retrospective study.

BACKGROUND: The impact of extended steroid administration on patients with autoimmune pancreatitis after a 3-year maintenance period remains poorly understood. This study analyzed the advantage and disadvantage of continuing steroid therapy beyond 3 years. METHODS: In this retrospective multicenter study across 17 institutions, patients who successfully completed 3 years of maintenance therapy without experiencing relapse were categorized into two groups: the maintenance therapy discontinuation group, who discontinued steroid therapy after the initial 3-year period, and maintenance therapy continuation group, who continued steroid therapy beyond 3 years. The cumulative relapse rate after 3 years of maintenance therapy was the primary outcome. Relapse predictors were compared using the Gray test for cumulative relapse incidence by specific factor. RESULTS: Of 211 patients, 105 experienced no relapse during the 3-year maintenance therapy and were divided into two groups: 69 in the maintenance therapy discontinuation group and 36 in the maintenance therapy continuation group. The relapse rate was lower in the maintenance therapy continuation group than in the maintenance therapy discontinuation group (P = 0.035). Predictors of relapse after 3 years included cessation of maintenance therapy (hazard ratio [HR] = 3.76; 95 % confidence interval [CI] = 1.07-13.3, P = 0.040) and renal involvement (HR = 2.88; 95 % CI = 1.04-7.99, P = 0.042). The maintenance therapy continuation group showed a significantly higher prevalence of macrovascular complications, compared with the maintenance therapy discontinuation group (P = 0.005). CONCLUSIONS: Cessation of steroid maintenance therapy and renal involvement were predictors of relapse after 3 years of maintenance therapy. However, the long-term use of steroids may increase the risk of macrovascular complications.

A novel fully covered metal stent for unresectable malignant distal biliary obstruction: results of a multicenter prospective study.

Background/Aims: Endoscopic self-expandable metal stent (SEMS) placement is currently the standard technique for treating unresectable malignant distal biliary obstructions (MDBO). Therefore, covered SEMS with longer stent patency and fewer migrations are required. This study aimed to assess the clinical performance of a novel, fully covered SEMS for unresectable MDBO. Methods: This was a multicenter single-arm prospective study. The primary outcome was a non-obstruction rate at 6 months. The secondary outcomes were overall survival (OS), recurrent biliary obstruction (RBO), time to RBO (TRBO), technical and clinical success, and adverse events. Results: A total of 73 patients were enrolled in this study. The non-obstruction rate at 6 months was 61%. The median OS and TRBO were 233 and 216 days, respectively. The technical and clinical success rates were 100% and 97%, respectively. Furthermore, the rate of occurrence of RBO and adverse events was 49% and 21%, respectively. The length of bile duct stenosis (<2.2 cm) was the only significant risk factor for stent migration. Conclusions: The non-obstruction rate of a novel fully covered SEMS for MDBO is comparable to that reported earlier but shorter than expected. Short bile duct stenosis is a significant risk factor for stent migration.

Summary of the current status of clinically diagnosed cases of Schnitzler syndrome in Japan.

BACKGROUND: Schnitzler syndrome is a rare disorder with chronic urticaria, and there is no report summarizing the current status in Japan. METHODS: A nationwide survey of major dermatology departments in Japan was conducted in 2019. We further performed a systematic search of PubMed and Ichushi-Web, using the keywords "Schnitzler syndrome" and "Japan" then contacted the corresponding authors or physicians for further information. RESULTS: Excluding duplicates, a total of 36 clinically diagnosed cases were identified from 1994 through the spring of 2022, with a male to female ratio of 1:1. The median age of onset was 56.5 years. It took 3.3 years from the first symptom, mostly urticaria, to reach the final diagnosis. The current status of 30 cases was ascertained; two patients developed B-cell lymphoma. SchS treatment was generally effective with high doses of corticosteroids, but symptoms sometimes recurred after tapering. Colchicine was administered in 17 cases and was effective in 8, but showed no effect in the others. Tocilizumab, used in six cases, improved laboratory abnormalities and symptoms, but lost its efficacy after several years. Rituximab, used in five cases, was effective in reducing serum IgM levels or lymphoma mass, but not in inflammatory symptoms. Four cases were treated with IL-1 targeting therapy, either anakinra or canakinumab, and achieved complete remission, except one case with diffuse large B-cell lymphoma. CONCLUSIONS: Since Schnitzler syndrome is a rare disease, the continuous collection and long-term follow-up of clinical information is essential for its appropriate treatment and further understanding of its pathophysiology.

Clinical outcome of conservatively managed pancreatic intraductal papillary mucinous neoplasms with mural nodules and main duct dilation.

BACKGROUND: Surgical resection of intraductal papillary mucinous neoplasm (IPMN) is strongly recommended for patients exhibiting high-risk stigmata (HRS). However, determining surgical indications for elderly patients with comorbidities is challenging, as clinical outcomes are not well characterized. This multicenter observational study elucidated the clinical outcomes of patients with IPMN exhibiting HRS who did not undergo surgery. METHODS: This study enrolled 101 IPMN patients exhibiting HRS with follow-up observations at 11 hospitals in Japan (2011-2016). The median observation period was 37 months (maximum: 86 months). Primary outcomes were estimated 5-year overall survival (OS) and disease-specific survival (DSS). Survival was also stratified based on HRS features. RESULTS: Of 101 patients, 32 (31.7%) had the main pancreatic duct (MPD) measuring ≥ 10 mm and 80 (79.2%) had mural nodules measuring ≥ 5 mm. The estimated 5-year OS and DSS were 74% and 91%, respectively. In the stratified analysis, the co-presence of MPD ≥ 10 mm and mural nodules ≥ 5 mm or mural nodule ≥ 10 mm were related to worse 5-year DSS (MPD ≥ 10 mm and mural nodules ≥ 5 mm vs other characteristics: 60% vs 95%, log-rank test: p = 0.049; mural nodules ≥ 10 mm vs < 10 mm: 77% vs 95%, log-rank test: p = 0.003). CONCLUSIONS: The estimated 5-year DSS of conservatively managed IPMN patients with mural nodules and main duct dilation was 91%. Only IPMN patients with plural HRS or large nodule formation might have an increased mortality risk. This is an important insight that can help facilitate appropriate clinical decision-making, especially in the elderly or high-surgical risk IPMN patients.

Serum apolipoprotein A2 isoforms in autoimmune pancreatitis.

Recently, apolipoprotein A2 (apoA2) isoforms have been reported as candidate serum/plasma biomarkers of pancreatic cancer. However, the distribution of apoA2 isoforms in patients with autoimmune pancreatitis (AIP) has not been investigated yet. In this study, we evaluated the distribution of serum apoA2 isoforms; i.e., homodimer apoA2-ATQ/ATQ, heterodimer apoA2-ATQ/AT, and homodimer apoA2-AT/AT, in AIP patients and healthy volunteers (HV) using enzyme-linked immunosorbent assays, and the clinical characteristics and serum levels of each apoA2 isoform in 32 AIP patients and 38 HV were investigated. The calculated apoA2-ATQ/AT levels of the AIP patients were significantly lower than those of the HV, which agreed with results obtained for patients with pancreatic cancer. Interestingly, most of the AIP patients exhibited high levels of apoA2-ATQ along with low levels of apoA2-AT, indicating that the processing of the C-terminal regions of apoA2 dimer was inhibited in the AIP patients. This specific distribution of serum apoA2 isoforms might provide important information about the disease states of AIP patients and aid the differential diagnosis of AIP versus pancreatic cancer.

Coexistence of keloids and pilomatricoma in a patient with Rubinstein-Taybi syndrome.

Rubinstein-Taybi syndrome (RTS) is an autosomaldominant hereditary disease, which contains many skeletal and organ anomalies as well as mental retardation. Although high incidence of keloids in RTS is known, it is difficult to find a detailed report on the clinical features of keloids. In the following letter, we report an RTS patient fulfilling diagnostic criteria whosuffered from both keloids and pilomatricoma. We also performed a literature search, which identified the possible involvement of the Wnt/ß-catenin signaling pathway in the pathogenesis of these two skin lesions.

Utility of Autonomic Function Tests to Differentiate Dementia with Lewy Bodies and Parkinson Disease with Dementia from Alzheimer Disease.

OBJECTIVE: We studied autonomic disturbance in patients with dementia with Lewy bodies (DLB), Parkinson disease with dementia (PDD), Alzheimer disease (AD), to determine whether autonomic function tests can be used to distinguish these disorders. METHODS: Autonomic function was tested in 56 patients with DLB, 37 patients with PDD, and 59 patients with AD by using the sympathetic skin response, coefficient of variation in R-R interval, the head-up tilt test, serum norepinephrine concentration, and 123I-meta-iodobenzylguanidine cardiac scintigraphy. Symptoms of autonomic dysfunction, such as constipation, urinary symptoms, and orthostatic hypotension, were also noted. RESULTS: The groups did not differ on baseline characteristics other than those associated with Parkinsonism and dementia. All patients with DLB and PDD had some dysautonomia, whereas rates were much lower for patients with AD (19%). Significantly more DLB and PDD patients than AD patients showed abnormalities on autonomic function tests. CONCLUSIONS: Autonomic function tests might be quite useful to distinguish DLB and PDD from AD.

Pancreatic inflammation and atrophy are not associated with pancreatic cancer concomitant with intraductal papillary mucinous neoplasm.

BACKGROUND: Inflammation-induced carcinogenesis in pancreatic ductal adenocarcinoma (PDAC) has been reported; however, its involvement in PDAC with intraductal papillary mucinous neoplasm (IPMN) remains unclear. We herein investigated the relationship between pancreatic atrophy and inflammation and the incidence of PDAC concomitant with IPMN. METHODS: This study included 178 consecutive patients who underwent surgical resection for PDAC with IPMN (N = 21) and IPMN (N = 157) between April 2001 and October 2016. A multivariable logistic regression analysis was conducted to assess the relationship between pancreatic inflammation and atrophy and the incidence of PDAC concomitant with IPMN, with adjustments for clinical characteristics and imaging features. Pathological pancreatic inflammation and atrophy were evaluated in resected specimens. RESULTS: High degrees of pancreatic inflammation and atrophy were not associated with the incidence of PDAC with IPMN (multivariable odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.07 to 3.33, P = .52, adjusted by clinical characteristics, OR = 0.9, 95% CI = 0.10 to 5.86, P = .91, adjusted by imaging studies; OR = 0.2, 95% CI = 0.009 to 1.31, P = .10, adjusted by clinical characteristics, OR = 0.2, 95% CI = 0.01 to 1.43, P = .12, adjusted by imaging studies, respectively). CONCLUSIONS: Pancreatic inflammation and atrophy were not associated with pancreatic cancer concomitant with IPMN.

Chronic Pancreatitis Finding by Endoscopic Ultrasonography in the Pancreatic Parenchyma of Intraductal Papillary Mucinous Neoplasms Is Associated with Invasive Intraductal Papillary Mucinous Carcinoma.

BACKGROUND/OBJECTIVES: The recent guideline for intraductal papillary mucinous neoplasms (IPMNs) focuses on morphological features of the lesion as signs of malignant transformation, but ignores the background pancreatic parenchyma, including features of chronic pancreatitis (CP), which is a risk factor for pancreatic malignancies. Endoscopic ultrasonography frequently reveals evidence of CP (EUS-CP findings) in the background pancreatic parenchyma of patients with IPMNs. Therefore, we investigated whether background EUS-CP findings were associated with malignant IPMN. METHODS: The clinical data of 69 consecutive patients with IPMNs who underwent preoperative EUS and surgical resection between April 2010 and October 2014 were collected prospectively. The association of EUS-CP findings (total number of EUS-CP findings; 0 vs. ≥1) with invasive IPMN was examined. The association of EUS-CP findings with pathological changes of the background pancreatic parenchyma (atrophy/inflammation/fibrosis) was also examined. RESULTS: Among patients with EUS-CP findings, invasive intraductal papillary mucinous carcinoma (IPMC) was significantly more frequent than among patients without EUS-CP findings (42.5% [17/40] vs. 3.4% [1/29], p = 0.0002). In addition, patients with EUS-CP findings had higher grades of pancreatic atrophy and inflammation than patients without EUS-CP findings (atrophy: 72.5% [29/40] vs. 34.5% [10/29], p = 0.003; inflammation: 45.0% [18/40] vs. 20.7% [6/29], p = 0.04). CONCLUSIONS: In IPMN patients, detection of EUS-CP findings in the background pancreatic parenchyma was associated with a higher prevalence of invasive IPMC. Accordingly, EUS examination should not only assess the morphological features of the lesion itself, but also EUS-CP findings in the background parenchyma.

Smoking Status and the Incidence of Pancreatic Cancer Concomitant With Intraductal Papillary Mucinous Neoplasm.

OBJECTIVES: The effect of smoking status on the incidence of pancreatic ductal adenocarcinoma (PDAC) concomitant with intraductal papillary mucinous neoplasm (IPMN) has not been clarified. This study investigated the association of smoking status with PDAC concomitant with IPMN. METHODS: The subjects were 124 consecutive patients undergoing resection of IPMNs (intraductal papillary mucinous adenoma (IPMA): N = 77, invasive IPMN: N = 31, and PDAC with IPMN: N = 16) between April 2008 and October 2015. The associations between smoking status (never/former/current smoker) or cumulative pack-years (0-19/20-39/≥40) and the incidence of PDAC concomitant with IPMN or invasive IPMN were evaluated. RESULTS: Current smoking, not former smoking, was associated with the incidence of PDAC concomitant with IPMN (PDAC with IPMN vs IPMN alone; P = 0.004, PDAC with IPMN vs IPMA; P = 0.004, PDAC with IPMN vs invasive IPMN; P = 0.04, respectively), but not that of invasive IPMN (invasive IPMN vs IPMA; P = 0.85). Cumulative pack-years were higher in patients who had PDAC concomitant with IPMN than in patients with invasive IPMN (P = 0.04). Cumulative pack-years were not associated with smoking status (current vs former). CONCLUSIONS: Current smoking, not former smoking, was associated with the incidence of PDAC concomitant with IPMN. Cessation of smoking may be recommended for patients with IPMN.

Association between serum SPan-1 and lymph node metastasis in invasive intraductal papillary mucinous neoplasm of the pancreas.

BACKGROUND AND AIM: Lymph node metastasis predicts poorer prognoses in patients with invasive intraductal papillary mucinous neoplasms of the pancreas (IPMNs). Factors associated with lymph node metastasis of invasive IPMN remain unclear. Therefore, this study aimed to define factors associated with lymph node metastasis of invasive IPMN. METHODS: Between June 2000 to August 2015, 156 consecutive patients with IPMN underwent surgical resection at Kobe University Hospital, and were enrolled in this study. The relationship between lymph node metastasis and clinical characteristics, including imaging studies and serum tumor markers, was evaluated. A multivariate logistic regression analysis was performed to assess the relationship between serum tumor markers and the presence of lymph node metastasis of IPMN, adjusted for clinical characteristics. RESULTS: Lymph node metastasis was observed in 7.7% (12/156) of IPMNs via a pathological examination. The multivariate logistic regression analysis revealed that serum SPan-1 was associated with the presence of lymph node metastasis of IPMN (odds ratio [OR] = 7.32; 95% confidence interval [CI] = 1.10 to 56.0; P = 0.04). In addition, survival was poorer among serum SPan-1-positive patients than SPan-1 negative patients (Log-rank test; P = 0.0002). Lymph node enlargement was detected preoperatively on computed tomography scans in only 16.7% (2/12) of cases that were positive for lymph node metastasis. CONCLUSIONS: Elevated serum SPan-1 was associated with lymph node metastasis in this cohort of patients who underwent resection for invasive IPMN.

History of Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis and Acute Pancreatitis as Risk Factors for Post-ERCP Pancreatitis.

BACKGROUND: Previous pancreatitis is a definite patient-related risk factor for pancreatitis after endoscopic retrograde cholangiopancreatography (post-ERCP pancreatitis: PEP). However, the effects of differences in the history of PEP and acute pancreatitis on the occurrence of PEP have not been fully investigated. We examined the relationship between previous PEP or previous acute pancreatitis and procedural factors associated with PEP. METHODS: Clinical data on 1,334 consecutive patients undergoing ERCP between April 2006 and June 2010 were collected. A multivariate logistic regression analysis was conducted to assess the relationship between PEP and the cannulation time (<15 min vs. ≥15 min) or total procedure time (<30 min vs. ≥30 min) according to previous pancreatitis (previous PEP: pPEP or previous acute pancreatitis: pAP), with adjustments for clinical characteristics. RESULTS: Longer cannulation times (≥15 min) correlated with the occurrence of PEP in the pPEP group (OR=2.97; 95% CI=1.10 to 8.43, P=0.03) and in patients without previous pancreatitis (non-preP group) (OR=2.43; 95% CI=1.41 to 4.14, P= 0.002), but not in the pAP group (OR=2.78; 95% CI=0.50 to 22.42, P= 0.25). In contrast, longer procedure times correlated with the occurrence of PEP in the pAP group (OR=3.93; 95% CI=1.11 to 16.5, P= 0.03), but not in the pPEP group (OR=2.79; 95% CI=0.92 to 9.18, P= 0.068) or non-preP group (OR=0.71; 95% CI=0.39 to 1.24, P= 0.23). CONCLUSIONS: A higher risk of PEP with previous PEP was associated with longer cannulation times, whereas a higher risk of PEP with previous acute pancreatitis was associated with longer procedure times.

Predictive value of low serum pancreatic enzymes in invasive intraductal papillary mucinous neoplasms.

BACKGROUND: Despite evidence suggesting a role of chronic pancreatitis in pancreatic carcinogenesis, its relationship with invasive intraductal papillary mucinous neoplasms (IPMN) remains unclear. Low levels of pancreatic enzymes are predictive markers of advanced chronic pancreatitis. We investigated whether low pancreatic enzyme levels were associated with a higher incidence of invasive IPMN. METHODS: This study included 146 consecutive patients who underwent surgical resection of IPMN between April 2001 and October 2014. Multivariable logistic regression analysis was conducted to assess the association between serum pancreatic enzymes and the incidence of invasive IPMN, with adjustment for clinical characteristics including alcohol consumption. The association of serum pancreatic enzymes with pathological pancreatic atrophy and inflammation in areas adjacent to or distant from the tumor was also evaluated. RESULTS: Low serum levels of pancreatic amylase and lipase were associated with a higher incidence of invasive IPMN (multivariable odds ratio [OR] = 9.6, 95% confidence interval [CI] = 2.99 to 35.1, P = 0.0001; OR = 14.2, 95% CI = 2.77 to 112, P = 0.001, respectively). Low serum pancreatic amylase and lipase levels were also associated with higher grade pancreatic atrophy in areas adjacent to the tumor (P = 0.011 and P = 0.017, respectively) and in areas distant from the tumor (P = 0.0002 and P = 0.001, respectively). Furthermore, low serum pancreatic amylase and lipase levels were associated with higher grade inflammation in areas distant from the tumor (P < 0.0001 and P = 0.001, respectively). CONCLUSIONS: Low serum pancreatic enzymes may be a predictive marker of invasive IPMN. Excessive alcohol consumption did not influence the association of low pancreatic enzyme levels with invasive IPMN.

An ex vivo model employing keloid-derived cell-seeded collagen sponges for therapy development.

The most distinctive feature of keloid is the extreme deposition of extracellular matrix, including collagens and proteoglycans (PGs). The focus of this study was the PG versican, which presumably defines keloid volume because of its ability to retain large amounts of water through its component glycosaminoglycans (GAGs). The excessive deposition of versican in keloids was examined by immunohistochemical analysis and by upregulation of the versican gene in these lesions by real-time PCR. The latter showed that mesenchymal cells derived from keloid lesion (KL) cells continue to exhibit above-normal versican production in culture. To establish a model of GAG deposition in keloids, collagen sponges seeded with KL cells (KL-SPos) were implanted in the subcutaneous space of nude mice. After 1 month, the KL-SPos were significantly heavier than the fibroblast (Fb)-seeded sponges (Fb-SPos). This ex vivo model was subsequently used to examine an inhibitory ability of IL-1ß that was identified to reduce versican in vitro. IL-1ß or chondroitinase ABC, when injected directly, successfully reduced the weight of the KL-SPos. Thus, on the basis of the change in weight of the seeded sponges, this ex vivo model can be used to test therapies aimed at reducing or inhibiting keloid formation and to study the pathogenesis of this aberrant response.