A Retrospective Study Investigating the Safety and Efficacy of Nanoliposomal Irinotecan in Elderly Patients with Unresectable Pancreatic Cancer.

Although nanoliposomal irinotecan combined with 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) has been used to treat first-line resistant unresectable pancreatic cancer, the efficacy and safety data among the elderly remain limited. We retrospectively analyzed clinical outcomes among elderly patients. Patients treated with nal-IRI+5-FU/LV were assigned to the elderly (≥75 years) and non-elderly (<75 years) groups. Herein, 85 patients received nal-IRI+5-FU/LV, with 32 assigned to the elderly group. Patient characteristics in the elderly and non-elderly groups were as follows: age: 78.5 (75-88)/71 (48-74), male: 17/32 (53%/60%), performance status (ECOG) 0:9/20 (28%/38%), nal-IRI+5-FU/LV in second line: 23/24 (72%/45%), respectively. A significantly high number of elderly patients exhibited aggravated kidney and hepatic functions. Median overall survival (OS) and progression-free survival (PFS) in the elderly group vs. non-elderly group were 9.4 months vs. 9.9 months (hazard ratio (HR) 1.51, 95% confidence interval (CI) 0.85-2.67, p = 0.16) and 3.4 months vs. 3.7 months (HR 1.41, 95% CI 0.86-2.32, p = 0.17). Both groups exhibited a similar incidence of efficacy and adverse events. There were no significant differences in OS and PFS between groups. We analyzed the C-reactive protein/albumin ratio (CAR) and neutrophil/lymphocyte ratio (NLR) as indicators that could determine eligibility for nal-IRI+5-FU/LV. The median CAR and NLR scores in the ineligible group were 1.17 and 4.23 (p < 0.001 and p = 0.018, respectively). Elderly patients with worse CAR and NLR score could be deemed ineligible for nal-IRI+5-FU/LV.

Impact of neoadjuvant therapy on gut microbiome in patients with resectable/borderline resectable pancreatic ductal adenocarcinoma.

BACKGROUND: /Objectives: Effects of chemotherapy on gut microbiota have been reported in various carcinomas. The current study aimed to evaluate the changes in the gut microbiota before and after neoadjuvant chemotherapy (NAC) in patients with resectable (R) and borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) and understand their clinical implications. METHODS: Twenty patients diagnosed with R/BR-PDAC were included in this study. Stool samples were collected at two points, before and after NAC, for microbiota analysis using 16S ribosomal RNA (16S rRNA) gene sequences. RESULTS: Of the 20 patients, 18 (90%) were treated with gemcitabine plus S-1 as NAC, and the remaining patients received gemcitabine plus nab-paclitaxel and a fluorouracil, leucovorin, irinotecan, and oxaliplatin combination. No significant differences were observed in the α- and ß-diversity before and after NAC. Bacterial diversity was not associated with Evans classification (histological grade of tumor destruction by NAC) or postoperative complications. The relative abundance of Actinobacteria phylum after NAC was significantly lower than that before NAC (P = 0.02). At the genus level, the relative abundance of Bifidobacterium before NAC in patients with Evans grade 2 disease was significantly higher than that in patients with Evans grade 1 disease (P = 0.03). Patients with Evans grade 2 lost significantly more Bifidobacterium than patients with Evans grade 1 (P = 0.01). CONCLUSIONS: The diversity of gut microbiota was neither decreased by NAC for R/BR-PDAC nor associated with postoperative complications. Lower incidence of Bifidobacterium genus before NAC may be associated with a lower pathological response to NAC.

Long-term Outcomes after Steroid Pulse Therapy in Patients with Type 1 Autoimmune Pancreatitis.

Objective Steroid pulse therapy is a regimen involving the intravenous administration of supra-pharmacological doses of corticosteroids in the short term. It is used to treat various inflammatory and autoimmune conditions. However, the strengths and limitations of steroid pulse therapy for induction of remission in type 1 autoimmune pancreatitis (AIP) are unknown. Methods Depending on the steroid therapy regimen administered, the 104 patients with type 1 AIP included in this retrospective study were divided into three groups: conventional oral prednisolone (PSL) regimen (PSL group), intravenous methylprednisolone (IVMP) pulse followed by oral PSL regimen (Pulse+PSL group), and IVMP pulse-alone regimen (Pulse-alone group). We then examined the relapse rate and adverse events among the three groups. Results The Kaplan-Meier estimates of the relapse rate at 36 months after steroid therapy were 13.6% in the PSL group, 13.3% in the Pulse+PSL group, and 46.2% in the Pulse-alone group. The log-rank test revealed that the relapse-free survival in the Pulse-alone group was significantly shorter than that in the PSL (p=0.024) and Pulse+PSL groups (p=0.014). The exacerbation of glucose tolerance after steroid therapy was less frequently observed in the Pulse-alone group (0%) than in the PSL group (17%, p=0.050) and Pulse+PSL groups (26%, p=0.011). Conclusion Although treatment with IVMP pulse alone resulted in unsatisfactory relapse prevention outcomes compared with conventional steroid therapy, the IVMP pulse-alone regimen might be an alternative treatment strategy for type 1 AIP from the perspective of avoiding adverse events from steroids.

A case of type 2 autoimmune pancreatitis with spontaneous remission.

A 70-year-old man with epigastric pain was referred to our hospital. Computed tomography and magnetic resonance imaging showed the diffusely enlarged pancreas compared to his normal pancreas 6 months prior to presentation. Serum levels of IgG4 and amylase were normal, while C-reactive protein was slightly elevated. Endoscopic ultrasound-guided fine-needle biopsy of the pancreas revealed acinar-ductal metaplasia with neutrophil infiltration and without infiltration of IgG4-positive plasma cells. After the clinical diagnosis of type 2 autoimmune pancreatitis (AIP), his symptoms spontaneously improved without steroid therapy. Three months later, radiological findings showed improved pancreas size and serological findings. The pathological diagnosis of type 2 AIP using endoscopic ultrasound-guided fine-needle biopsy is challenging, particularly for proving granulocyte epithelial lesions. This was a valuable type 2 AIP case in which the images before, at the time of onset, and at the time of spontaneous remission were evaluated.

Efficacy and safety of endoscopic stent placement for afferent loop obstruction using a short double-balloon endoscopy.

Background: Afferent loop obstruction (ALO) is a rare mechanical complication that occurs after gastrojejunostomy. Recently the use of double-balloon endoscopy (DBE) can be useful for benign and malignant ALO. Methods: We retrospectively identified 22 patients who underwent DBE for ALO from January 2009 to December 2020. We evaluated the efficacy and safety of short DBE treatment for ALO. Results: Short DBE was able to reach an obstructive site in the afferent limb in all patients (100%) and was able to reach the blind end in 14 patients (64%). The technical success rate was 100%, and the clinical success rate was 95%. Procedure-related adverse events occurred in two patients (9%). In the case of benign ALO, three of nine patients showed improvement in ALO with single stent placement. Two of nine patients improved after the replacement of the plastic stent (PS) two or three times. Four of nine patients continued with the replacement of PS. In the case of malignant ALO, the metallic stent was placed in 10 patients, and eight patients with metallic stents did not experience stent occlusion until they died. Reintervention was attempted in six patients (27%) with benign ALO but was not attempted in malignant ALO. Conclusions: Treatments for ALO using the short DBE was effective and relatively safe because the technical and clinical success rates were very high and there were relatively low complications. Consequently, short DBE could be the first-choice treatment for both benign and malignant ALO.

Intraperitoneal Paclitaxel Treatment for Patients with Pancreatic Ductal Adenocarcinoma with Peritoneal Dissemination Provides a Survival Benefit.

Background: Intraperitoneal chemotherapy using paclitaxel (i.p.-PTX) is expected to be a new therapeutic strategy for patients with pancreatic ductal adenocarcinoma (PDAC) and peritoneal dissemination. We evaluated the survival benefit of i.p.-PTX compared with standard systemic chemotherapy. Methods: Clinical data of 101 consecutive PDAC patients with peritoneal dissemination between 2007 and 2018 were analyzed. All patients were determined to have no other sites of distant organ metastasis to the lung, bone, or liver on contrast-enhanced CT imaging. Patients underwent staging laparoscopy or open laparotomy to confirm pathological evidence of peritoneal dissemination, and to exclude occult liver metastasis. Survival curves were estimated using the Kaplan−Meier method, and differences were compared using the log-rank test. Results: Forty-three patients were treated with i.p.-PTX (i.p.-PTX group) and forty-nine patients received standard systemic chemotherapy (Ctrl group). Nine patients did not receive any treatment (BSC group). The median survival time (MST) in the i.p.-PTX group was significantly longer than that in the Ctrl group (17.9 months vs. 10.2 months, p = 0.006). Negative peritoneal washing cytology was observed in 24 out of 43 patients in the i.p.-PTX group. The i.p.-PTX group tended to have a higher proportion of clinical responses than the Ctrl group (30% vs. 18%, p = 0.183). Conversion surgery was performed in 10 patients in the i.p.-PTX group and 2 patients in the Ctrl group after confirming disappearance of peritoneal dissemination with staging laparoscopy or open laparotomy (p = 0.005). The MST in patients who underwent surgical resection was significantly longer than that in patients who did not (27.4 months vs. 11.3 months; p < 0.0001). Conclusion: i.p.-PTX therapy provided improved survival in PDAC patients with peritoneal dissemination, and conversion surgery enhanced it in patients with favorable responses to chemotherapy. i.p.-PTX might become one of the treatment options to PDAC patients with peritoneal dissemination.

Rectally Administered Low-Dose Diclofenac Has No Effect on Preventing Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis: A Propensity Score Analysis.

OBJECTIVES: We evaluated the preventive effect of low-dose diclofenac (25-50 mg) on post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) by propensity score matching analysis. METHODS: We retrospectively analyzed the data of 515 patients who underwent ERCP for the first time with or without the rectal administration of low-dose diclofenac before the procedure. For the purpose of minimization of the intrinsic selection bias, we compared the incidence rate of PEP between the diclofenac and control group after propensity score matching. RESULTS: Post-ERCP pancreatitis developed in 15 patients (2.9%). There was no significant difference in the incidence of PEP between the diclofenac (2.4%) and control group (3.3%) (P = 0.608). One hundred ninety matched pairs were generated by propensity score matching and analyzed; however, the incidence rate of PEP was the same in both groups (2.1%, P = 1.000). In the subgroup analysis using data of patients with high-risk factors for developing PEP, the incidence rate of PEP was comparable between the diclofenac (3.8%) and control groups (4.0%) (P = 0.917). CONCLUSIONS: In our propensity score analysis, rectal administration of low-dose diclofenac was not shown to be useful in preventing PEP.

Serum free light chain assessment in type 1 autoimmune pancreatitis.

BACKGROUND: /Object: Some patients with type 1 autoimmune pancreatitis (AIP), the pancreatic manifestation of IgG4-related disease, have normal serum IgG4. The aim of this study is to investigate the diagnostic value of measuring serum free light chains (FLCs) in type 1 AIP. MATERIALS AND METHODS: Thirty-seven patients with type 1 AIP, and 21 healthy, 17 alcoholic chronic pancreatitis (ACP), 21 idiopathic chronic pancreatitis (ICP) and 20 pancreatic cancer (PC) patients were enrolled. Serum IgG4 and FLC concentrations were measured using sFLC Freelite assays on a nephelometric analyzer. RESULTS: Active AIP patients have significantly higher serum levels of κ (median 30.97 (12.3-227.0) mg/L) and λFLC (median 20.53 (12.36-102.7) mg/L)) than healthy controls (κFLC; median 12.5 (3.1-52.1) mg/L), λFLC: median 12.45 (5.4-39.5) mg/L) (p < 0.05) correlating with raised serum IgG4, and significantly higher summated FLCs (∑) (median 53.09 (25.0-218.0) mg/L) than ICP patients (median 26.77 (15.0-89.2) mg/L) and healthy controls (median 24.43 (8.5-91.6) mg/L) (p < 0.05). AIP patients (median 1.43 (0.84-3.24)) showed significantly higher κ/λ ratios than ACP (median 0.83 (0.42-1.18)), ICP (median 0.87 (0.47-2.16)), PC patients (median 0.90 (0.48-1.27)) and healthy controls (median 0.963 (0.51-1.32)). There was a correlation between increased κ and λ FLCs levels and the number of affected organs involved in IgG4 related disease. CONCLUSION: Patients with type 1 AIP have increased serum k and λ FLC concentrations, Σ FLC, and κ/λ ratios. These novel biomarkers may be useful in the diagnosis of type 1 AIP and in monitoring disease activity.

Development of Severe Acute Pancreatitis Following Uncovered Metallic Stent Placement: A Rare Case Report.

Self-expandable metallic stents (SEMSs) are widely used for malignant biliary stricture (MBS). Acute pancreatitis is an early complication following SEMS placement. In the present case, the patient developed severe acute pancreatitis after SEMS placement for MBS because of metastatic lymph nodes. Endoscopic retrograde cholangiopancreatography, endoscopic sphincterotomy and an endoscopic nasobiliary drainage tube placement were performed. After seven days, an uncovered SEMS was placed; however, severe acute pancreatitis occurred, and the SEMS was drawn out emergently. In SEMS placement for patients with MBS caused by non-pancreatic cancer, SEMS should be selected carefully while considering each patient's case.

Recent advances of endoscopic retrograde cholangiopancreatography using balloon assisted endoscopy for pancreaticobiliary diseases in patients with surgically altered anatomy: Therapeutic strategy and management of difficult cases.

Endoscopic retrograde cholangiopancreatography (ERCP) is an endoscopic modality established for diagnosis and treatment of pancreaticobiliary diseases. However ERCP in patients with surgically altered anatomy (SAA) has been difficult, and more invasive therapies have been primarily selected. The development of balloon assisted endoscopes (BAEs) innovatively facilitated ERCP in such patients. Recent advances of BAEs and other devices greatly contributed to increasing success of ERCP using BAEs (BAE-ERCP). Furthermore, interventions using Endoscopic Ultrasound (EUS-intervention) have been reported to be useful for pancreaticobiliary diseases in patients with SAA, which provide more options for endoscopic therapies and are also expected as a rescue therapy for difficult cases of BAE-ERCP. In order to thoroughly complete endoscopic treatment for pancreaticobiliary diseases with SAA, it is important to standardize the BAE-ERCP procedures based on the features of respective endoscopes and to establish a strategy for endoscopic treatment which includes analysis of BAE-ERCP difficult cases and selection of cases for rescue therapy. In addition, it is essential to be acquainted with the characteristics of possible adverse events of the procedure and to be able to deal with them for safe accomplishment of endoscopic treatment.

Usefulness of half-covered metallic stent placement in preventing acute cholecystitis complication in pancreatic cancer-induced distal biliary stricture.

BACKGROUND AND AIM: A self-expandable metallic stent (SEMS) is commonly used for biliary stricture caused by pancreatic cancer. Covered SEMS may obstruct the cystic duct, causing acute cholecystitis. This study aimed to determine the outcomes of using a half-covered SEMS with an offset covered portion for preventing cystic duct obstruction. METHODS: Among 80 patients with half-covered SEMS placement for the treatment of pancreatic cancer-induced distal biliary stricture, 74 were followed up. The half-covered SEMS has a total length of 6 or 7 cm, and the offset covered part was 0.5-4.5 or 0.5-5.5 cm, respectively. Intraductal ultrasonography (IDUS) and endoscopic nasobiliary drainage (ENBD) were performed during the initial endoscopic retrograde cholangiopancreatography (ERCP). IDUS findings and ENBD tube cholangiogram confirmed the cystic duct confluence. SEMS placement was performed on the second ERCP or several weeks after the initial tube stent placement. RESULTS: Half-covered SEMS placement was successful in all patients. However, four (5.4%) patients exhibited early complications, including acute cholecystitis in one patient and stent displacement in another. Over 30 days, cholangitis, tumor growth, and stent displacement occurred in nine (11.3%), five (6.3%), and two (2.5%) patients, respectively. The median stent patency was 71.1 weeks, and the median overall survival in patients with and without chemotherapy was 31.8 and 12.2 weeks, respectively. CONCLUSIONS: With confirmation of the cystic duct confluence, half-covered SEMS placement may become a treatment option for distal biliary stricture caused by pancreatic cancer to prevent acute cholecystitis. Half-covered SEMS patency was comparable with that of covered SEMS.

Interleukin-35 promotes the differentiation of regulatory T cells and suppresses Th2 response in IgG4-related type 1 autoimmune pancreatitis.

BACKGROUND: IgG4-related disease (IgG4-RD) is a systemic inflammatory disease, which includes type 1 autoimmune pancreatitis (AIP). Interleukin-35 (IL-35) exhibits immunosuppressive effects in several autoimmune diseases. However, the expression of IL-35 had not been reported so far in type 1 AIP. We evaluated the association between IL-35 and several cytokines, which mediate the function of Tregs in type 1 AIP. METHODS: Plasma was collected from patients with type 1 AIP, alcoholic chronic pancreatitis (ACP), and healthy controls (HC) and assayed for cytokine expression. Total mRNA separated from peripheral blood was isolated from naïve Tregs (nTregs) and effector Tregs (eTregs). EBI3 and IL-12p35 gene expressions were tested in these cells by quantitative PCR. In addition, expression of IL-35 subunits in the pancreatic tissues of patients with type 1 AIP and ACP was analyzed by immunohistochemistry. RESULTS: IL-35 was significantly elevated in type 1 AIP (n = 32) plasma compared with ACP (n = 16) and HC (n = 22), but IL-27 was not. We also detected many cells expressing both EBI3 and IL-12p35 in type 1 AIP tissues. Moreover, in peripheral blood lymphocyte, the percentage of nTregs and eTregs of CD4+ T cells in patients with type 1 AIP (n = 14) compared with HC (n = 15) was significantly decreased and increased, respectively. There were no significant differences of gene expression in patients with type 1 AIP and HC. CONCLUSIONS: This study identified elevated expression of plasma IL-35 and tissue IL-35 subunits in patients with type 1 AIP. This might lead to inflammation suppression via activated eTregs. IL-35 might be associated with this anti-inflammatory role, especially against the Th2 response through several cytokines and the differentiation of Tregs in type 1 AIP.

Extracellular vesicles microRNA analysis in type 1 autoimmune pancreatitis: Increased expression of microRNA-21.

BACKGROUND: The molecular basis of type 1 autoimmune pancreatitis (AIP) remains unclear. Recent attention on the role of extracellular vesicles microRNA (EV miRNA) in immune homeostasis has prompted us to perform an extensive miRNA screening of serum-derived EV in AIP. METHODS: EV miRNA expression was analyzed using microarrays in AIP, chronic pancreatitis (CP), and healthy adult (HC) samples (n = 10 from each group). Differences in signals, > 3 or <1/3 times, represented significant differences in expression. Another cohort of AIP (n = 14), CP (n = 10), and HC (n = 10) samples of EV miRNA was analyzed using reverse-transcription polymerase chain reaction (RT-PCR). miRNA expression in pancreatic tissues was evaluated using in situ hybridization (ISH) in three additional subjects from each group. RESULTS: Signals of eight miRNAs (miR-659-3p, -27a-3p, -99a-5p, -21-5p, -205-5p, -100-5p, -29c-3p, and -125b-1-3p) were significantly higher, while those of two miRNAs (miR-4252 and -5004-5p) were significantly lower in AIP than in HC. EV miR-21-5p was significantly up-regulated in AIP than in HC (P = 0.035) and CP (P = 0.048). The number of miR-21-5p positive inflammatory cells was significantly elevated in AIP than in CP (P = 0.014). CONCLUSIONS: Circulating EVs exhibited altered miRNA expression patterns with elevated miR-21-5p in AIP when compared with those in HC and CP. miR-21-5p was highly expressed in pancreatic inflammatory cells in AIP. Our data suggests that miR-21-5p may be involved in the regulation of effector pathways in the pathophysiology of AIP, thus differentiating AIP from CP.

Clinical implications of elevated serum interleukin-6 in IgG4-related disease.

INTRODUCTION: Some patients with IgG4-related disease (IgG4-RD) exhibit elevated serum interleukin (IL)-6 with excessive inflammatory reactions or with repeating relapse. To date few reports pertaining to clinical implications of elevated serum IL-6 in IgG4-RD patients have been published. The aims of the current retrospective study were to investigate the clinical implications of elevated serum IL-6 in IgG4-RD patients, and to examine whether IL-6 can predict the activity and/or relapse of the disease. MATERIALS AND METHODS: We examined the clinical picture at the onset of 43 patients who were diagnosed with IgG4-RD in our hospital and were able to measure serum IL-6 before steroid treatment. RESULTS: The median level of serum IL-6 was 2.2 pg/mL. There was a significant correlation between IL-6 and C-reactive protein (CRP) level (r = 0.397, p = 0.008), hemoglobin level (r = -0.390, p = 0.010) and albumin level (r = -0.556, p < 0.001). When 43 patients were divided into two groups by using a cut-off IL-6 of 4 pg/mL, the high IL-6 group showed higher age, lower albumin, higher CRP and higher aspartate aminotransferase (AST) (age p = 0.014, albumin p = 0.006, CRP p <0.001, AST p = 0.009). Hepatic swelling and splenomegaly were significantly more prevalent in the high IL-6 group than it was in the low IL-6 group (liver p < 0.001, spleen p = 0.020). Biliary tract involvement tended to admit more in the high IL-6 group (p = 0.060). CONCLUSION: Serum IL-6 level at the onset of IgG4-RD may be significantly correlated with clinical inflammatory parameters and it may also be associated with involvement of the bile duct, liver, and spleen.

Esophageal Large-Cell Neuroendocrine Carcinoma with Inconsistent Response to Treatment in the Primary and Metastatic Lesions.

Esophageal large-cell neuroendocrine carcinoma (NEC) is a rare malignant tumor that is characterized by high-grade malignancy and a poor prognosis. However, the rarity of esophageal NEC has prevented the development of an established treatment, and no reports have described a discrepancy in the effectiveness of cisplatin plus irinotecan between primary and metastatic lesions. A 43-year-old Japanese man was referred to our hospital with refractory epigastralgia. A previous gastrointestinal endoscopy had revealed a 50-mm type 2 tumor in the abdominal esophagus. The pathological findings indicated poorly differentiated squamous cell carcinoma. Contrast-enhanced computed tomography revealed a metastatic liver tumor. One cycle of fluorouracil and cisplatin was not effective, and endoscopy was repeatedly performed. The pathological findings indicated a large-cell malignant tumor with tumor cells that were positive for CD56, synaptophysin, and Ki-67 (> 80%). Based on a diagnosis of esophageal large-cell NEC with a metastatic liver tumor, the patient received cisplatin plus irinotecan biweekly. After 4 months, computed tomography revealed marked shrinkage of the metastatic tumor, but the patient complained of dysphagia. Endoscopy revealed enlargement of the primary tumor, which was then treated using radiotherapy plus fluorouracil and cisplatin. The primary tumor subsequently shrank, and the patient's symptoms were relieved, but the metastatic tumor grew. Thus, chemoradiotherapy could be an option for managing a primary esophageal large-cell NEC that does not respond to chemotherapy alone. However, the possibility of an inconsistent response to therapy in primary and metastatic lesions should be considered.

Successful Multidisciplinary Therapy for Small Cell Carcinomas Arising from the Extrahepatic Bile Duct.

A 74-year-old man was diagnosed with small cell carcinoma arising from the extrahepatic bile duct according to a histological examination of the biopsy specimen obtained during endoscopic retrograde cholangiopancreatography. Additionally, bulky hilar lymphadenopathy was observed, and the patient was treated with the combination of radiation and chemotherapy (cisplatin and irinotecan). Post-therapy, he underwent pancreaticoduodenectomy. The histological examination of the resected specimen revealed no residual cancer cells in the bile duct wall and a small amount of cancer cells in only a single lymph node. Due to this multidisciplinary therapy, the patient showed no signs of recurrence 12 months postoperatively.