[Undistinguishable Cryptococcus-related granulomatous lesion from carcinoma in the tail of the pancreas: a case report].

Abdominal computed tomography revealed a 19×13mm delayed enhancing mass and dilation of the distal pancreatic duct in the head of the pancreas. Magnetic resonance cholangiopancreatography showed pancreatic duct stenosis in the tail of the pancreas. Endoscopic retrograde pancreatography revealed an abrupt interruption of the main pancreatic duct at the tail of the pancreas. We could not assess the distal side of the pancreatic stenosis due to the large extent of obstruction. The pancreatic head mass was diagnosed as adenocarcinoma using endoscopic ultrasound-fine needle aspiration biopsy. However, we could not determine whether the pancreatic duct stenosis in the tail of the pancreas was malignant. Nevertheless, we performed a total pancreatectomy with splenectomy. Histological examination showed poorly differentiated adenocarcinoma in the pancreatic head mass but the pancreatic duct stenosis in the tail of the pancreas was diagnosed as pancreatic granuloma caused by Cryptococcus. Fungal infections may reportedly promote the development of pancreatic cancer, as further suggested by this case of cryptococcal infection.

Comparing the Efficacy and Safety of Gemcitabine plus Nab-Paclitaxel versus Gemcitabine Alone in Older Adults with Unresectable Pancreatic Cancer.

BACKGROUND: Gemcitabine plus nab-paclitaxel (GnP) has been a standard treatment for unresectable pancreatic cancer (uPC); however, the current treatment status and usefulness in older adults with uPC remain unclear. Therefore, we aimed to investigate the patient background and compare the efficacy and safety of GnP versus other treatments in older adults with uPC. PATIENTS AND METHODS: In this prospective observational study, we enrolled 233 eligible patients aged ≥76 years with pathologically proven, clinically uPC, and no history of chemotherapy from 55 Japanese centers during September 2018-September 2019. The main endpoints were overall survival (OS), progression-free survival (PFS), and safety. Geriatric assessments were performed upon registration and after 3 months. To adjust for confounders, we conducted propensity score-matched analyses. RESULTS: GnP, gemcitabine alone (Gem), best supportive care, and other therapies were administered to 116, 72, 16, and 29 patients, respectively. In the propensity score-matched analysis, 42 patients each were selected from the GnP and Gem groups. The median OS was longer in the GnP group than in the Gem group (12.2 vs. 9.4 months; hazard ratio [HR], 0.65; 95% CI, 0.37-1.13). The median PFS was significantly longer in the GnP group than in the Gem group (9.2 vs. 3.7 months; HR, 0.38; 95% CI, 0.23-0.64). The incidence of severe adverse events was higher with GnP than with Gem; however, the difference was not significant. CONCLUSION: GnP is more efficacious than Gem in patients aged ≥76 years with uPC despite demonstrating a higher incidence of severe adverse events.

Feasibility and Efficacy of Endoscopic Ultrasound-Guided Hepaticogastrostomy Without Dilation: A Propensity Score Matching Analysis.

BACKGROUND: Recently, endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) procedures have been gradually established; nonetheless, some adverse events (AEs) have been reported. Dilation procedures using a non-cautery or cautery device increase the incidence of AEs in EUS-HGS. AIMS: We evaluated EUS-HGS procedures without dilation and the factors associated with dilation. METHODS: We enrolled 79 patients who underwent EUS-HGS between July 2015 and March 2021 at two centers, 72 of whom had technical success (72/79, 91%). During the EUS-HGS procedures, we defined patients without dilation procedures as the dilation (-) group. We divided the patients into two groups: the dilation (+) (35 patients) and dilation (-) (37 patients) groups. We performed a propensity score matching analysis to adjust for confounding bias between the two groups. Multivariable logistic regression analysis was conducted to identify factors associated with dilation. RESULTS: There was no difference in clinical success rate between the dilation (+) and dilation (-) groups (91% vs. 95%, P = 0.545). The AE rate (P = 0.013) and long procedure time (P = 0.017) were significantly higher in the dilation (+) group than in the dilation (-) group before and after propensity score matching. Factors associated with dilation were plastic stent placement (odds ratio [OR], 6.96; 95% confidence interval [CI], 1.68-28.7; P = 0.007) and puncture angle of ≤ 90° (OR, 44.6; 95% CI, 5.1-390; P < 0.001). CONCLUSIONS: A dilation procedure in EUS-HGS may not always be necessary. However, patients with an angle of ≤ 90° between the needle and intrahepatic biliary tract or plastic stent deployment require dilation procedures.

[Massive biliary hemorrhage due to rupture of pseudoaneurysm after endoscopic biliary plastic stenting for pancreatic cancer].

A 51-year-old woman underwent endoscopic biliary drainage with a plastic stent for obstructive jaundice due to unresectable pancreatic head cancer. During chemotherapy following heavy ion therapy for the cancer, she presented with acute cholangitis and massive rectal bleeding. The massive hemorrhage was caused by rupture of the biliary duct due to a pseudoaneurysm in the right hepatic artery. The position of the aneurysm coincided with the liver-side end of the plastic stent. Sustained irritation of the arterial and bile duct walls by the stent was considered to have contributed to formation of the aneurysm.

Utility of chromogranin B compared with chromogranin A as a biomarker in Japanese patients with pancreatic neuroendocrine tumors.

OBJECTIVE: Currently, serum chromogranin A is a well-established biomarker for pancreatic neuroendocrine tumors; however, other pancreatic diseases, oral use of a proton pump inhibitor and renal impairment can affect chromogranin A. Meanwhile, chromogranin B, belonging to the same granin family as chromogranin A, is not fully examined in these conditions. The present study aimed to evaluate the utility of chromogranin B as a pancreatic neuroendocrine tumor biomarker. METHODS: Serum chromogranin B levels were determined by radioimmunoassay and serum chromogranin A levels by enzyme-linked immunosorbent assay in pancreatic neuroendocrine tumor (n = 91) and other pancreatic conditions, and in healthy people (n = 104), to assess the relationships with clinical features. RESULTS: The diagnostic ability of chromogranin B was as good as chromogranin A. The area under the curve was 0.79 for chromogranin B (sensitivity/specificity: 72%/77%), and 0.78 for chromogranin A (sensitivity/specificity: 79%/64%). Chromogranin B was not affected by proton pump inhibitor use and age, which affected chromogranin A. The number of cases without liver metastases was larger in pancreatic neuroendocrine tumor patients with positive chromogranin B and negative chromogranin A. Though chromogranin A significantly elevated cases with proton pump inhibitor treatment and had positive correlation with age, chromogranin B did not have the tendencies. However, both chromogranin B and chromogranin A elevated in the case with renal impairment. In addition, the logistic regression analysis showed that chromogranin B was superior to chromogranin A in differentiation of pancreatic neuroendocrine tumor from other pancreatic diseases. CONCLUSIONS: Compared with chromogranin A, chromogranin B may be more useful during proton pump inhibitor treatment and can detect tumors without liver metastases. In addition, chromogranin B may be an excellent biomarker when differentiation of pancreatic neuroendocrine tumor from other pancreatic diseases is required.

Efficacy of endoscopic ultrasonography and endoscopic ultrasonography-guided fine-needle aspiration for the diagnosis and grading of pancreatic neuroendocrine tumors.

BACKGROUND AND AIM: Pancreatic neuroendocrine tumors (pNETs) are histologically categorized according to the WHO 2010 classification by their mitotic index or Ki-67 index as G1, G2, or G3. The present study examined the efficacy of endoscopic ultrasonography (EUS) and EUS-guided fine-needle aspiration (EUS-FNA) in the diagnosis and grading of pNET. METHODS: We retrospectively reviewed 61 pNETs in 51 patients who underwent EUS between January 2007 and June 2014. All lesions were pathologically diagnosed by surgical resection or EUS-FNA. We evaluated the detection rates of EUS for pNET and sensitivity of EUS-FNA, and compared the Ki-67 index between EUS-FNA samples and surgical specimens. EUS findings were compared between G1 and G2/G3 tumors. RESULTS: EUS showed significantly higher sensitivity (96.7%) for identifying pNET than CT (85.2%), MRI (70.2%), and ultrasonography (75.5%). The sensitivity of EUS-FNA for the diagnosis of pNET was 89.2%. The concordance rate of WHO classification between EUS-FNA and surgical specimens was 69.2% (9/13). The concordance rate was relatively high (87.5%, 5/6) in tumors <20 mm but lower (57.1%; 4/7) in tumors ≥20 mm. Regarding EUS findings, G2/G3 tumors were more likely to be large (>20 mm), heterogeneous, and have main pancreatic duct (MPD) obstruction than G1 tumors. Multivariate analysis showed large diameter and MPD obstruction were significantly associated with G2/G3 tumors. CONCLUSIONS: EUS and EUS-FNA are highly sensitive and accurate diagnostic methods for pNET. Characteristic EUS findings such as large tumor size and MPD obstruction are suggestive of G2/G3 tumors and would be helpful for grading pNETs.

Long-term outcomes and prognostic factors in 78 Japanese patients with advanced pancreatic neuroendocrine neoplasms: a single-center retrospective study.

OBJECTIVE: Despite an increase in the number of Japanese patients with pancreatic neuroendocrine neoplasms, long-term outcomes and prognostic factors, especially for those with advanced disease, remain unclear. METHODS: We retrospectively reviewed the medical records of 78 patients with unresectable pancreatic neuroendocrine neoplasms treated at our hospital from January 1987 to March 2015. Survival analyses were performed using Kaplan-Meier methods. Prognostic significance of several clinicopathological factors were analyzed by univariate and multivariate analyses using a Cox regression model. RESULTS: Median overall survivals of pancreatic neuroendocrine tumor (n = 64) and pancreatic neuroendocrine carcinoma (n = 14) were 83.7 and 9.1 months, respectively (hazard ratio: 0.02, 95% confidence interval: 0.01-0.08, P < 0.001). Although no significant differences were observed using a Ki-67 cut-off value of 2% (hazard ratio: 0.46, 95% confidence interval: 0.16-1.13, P = 0.0989), a Ki-67 cut-off of 10% was a significant predictor in patients with pancreatic neuroendocrine tumor (hazard ratio: 9.95, 95% confidence interval, 3.01-32.97, P < 0.001). Treatment after the advent of targeted therapy (hazard ratio: 0.07, 95% confidence interval: 0.03-0.19, P < 0.001) and the presence of bone metastases (hazard ratio: 4.38, 95% confidence interval: 1.42-11.29, P = 0.013) were significant prognostic factors in patients with pancreatic neuroendocrine tumor evaluated by univariate analysis. Multivariate analysis also revealed that a Ki-67 index ≥10% (hazard ratio: 38.8, 95% confidence interval: 8.42-226.62, P < 0.001), approval of targeted therapy (hazard ratio: 0.02, 95% confidence interval: 0.00-0.11, P < 0.001) and bone metastases (hazard ratio: 5.56, 95% confidence interval: 1.10-24.00, P = 0.039) were independent prognostic factors. CONCLUSIONS: We elucidated the long-term outcomes and prognostic factors in Japanese patients with advanced pancreatic neuroendocrine neoplasms.

[Gemcitabine in Combination with Cisplatin in Patients with Unresectable Advanced or Recurrent Biliary Tract Cancer--A Multicenter Prospective Observational Study in Fukuoka].

The standard chemotherapy for the treatment of unresectable advanced and recurrent biliary tract cancers is considered gemcitabine plus cisplatin (GC) on the basis of favorable results reported in the ABC-02 study from the UK and the BT22 study from Japan. However, the GC cohort of the BT22 study consisted of only 42 patients, and we considered it necessary to confirm the effectiveness and safety of GC chemotherapy in a multicenter prospective observational study in Fukuoka. Thirty-seven patients were enrolled in this study, including two patients with recurrent disease. The median patient age was 67.5 years (range, 43-84 years). Twelve patients had intrahepatic cholangiocarcinoma, 13 patients had extrahepatic cholangiocarcinoma, and 12 patients had gallbladder cancer. The median survival time (MST) was 14.9 months, the 1-year survival rate was 54.5%, and the median progression free survival (PFS) was 7.7 months. No chemotherapy-related deaths occurred, and Grade 3/4 adverse events were mainly hematological events including leucopenia in 13 (35.1%) patients and neutropenia in 12 (32.4%). The MST, 1-year survival rate, median PFS, and rate of Grade 3/4 adverse events in our study were similar to those of the BT22 study. In conclusion, this multicenter prospective observational study confirms the effectiveness and safety of GC chemotherapy for the treatment of unresectable advanced and recurrent biliary tract cancers.

ERK pathway and sheddases play an essential role in ethanol-induced CX3CL1 release in pancreatic stellate cells.

The clinical course of chronic pancreatitis (CP) worsens with drinking, and pancreatic stellate cells (PSCs) have an important role in the pathogenesis of alcoholic CP. Chemokines recruit inflammatory cells, resulting in chronic pancreatic inflammation. Although serum levels of fractalkine (CX3CL1) are significantly elevated in patients with alcoholic CP, the mechanism of this elevation remains unclear. This study aims to determine the effects of cytokines, pathogen-associated molecular patterns (PAMPs), and ethanol and its metabolites on CX3CL1 secretion by PSCs. Male Wistar/Bonn Kobori (WBN/Kob) rats aged 15 to 20 weeks were used as rodent models of CP in vivo. PSCs were isolated from 6-week-old male Wistar rats. The effects of cytokines, PAMPs, and ethanol and its metabolites on chemokine production and activation of signaling pathways in PSCs in vitro were examined by real-time reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and enzyme-linked immunosorbent assay. Expression of CX3CL1 and matrix metalloprotease (MMP)-2 was increased in the pancreas of WBN/Kob rats. The rat PSCs expressed CX3CL1, MMP-2, and a disintegrin and metalloprotease domain (ADAM) 17. Cytokines and PAMPs induced CX3CL1 release and activated extracellular signal-regulated kinase (ERK), MMP-9, and ADAM17. CX3CL1 release was suppressed by specific inhibitors of ERK, MMP, and ADAM, and ERK was associated with CX3CL1 transcription. Ethanol and phorbol myristate acetate synergistically increased CX3CL1 release. Real-time PCR and western blotting confirmed the synergistic activation of ERK and ADAM17. Ethanol synergistically increased CX3CL1 release via ERK and ADAM17 activation in PSCs. In conclusion, we demonstrated for the first time that ethanol synergistically increased CX3CL1 release from PSCs at least in part through activation of ERK mitogen-activated protein kinase and ADAM17. This might be one of the mechanisms of serum CX3CL1 elevation and disease progression in patients with alcoholic CP.

Machine learning-based model for prediction and feature analysis of recurrence in pancreatic neuroendocrine tumors G1/G2.

BACKGROUND: Pancreatic neuroendocrine neoplasms (PanNENs) are a heterogeneous group of tumors. Although the prognosis of resected PanNENs is generally considered to be good, a relatively high recurrence rate has been reported. Given the scarcity of large-scale reports about PanNEN recurrence due to their rarity, we aimed to identify the predictors for recurrence in patients with resected PanNENs to improve prognosis. METHODS: We established a multicenter database of 573 patients with PanNENs, who underwent resection between January 1987 and July 2020 at 22 Japanese centers, mainly in the Kyushu region. We evaluated the clinical characteristics of 371 patients with localized non-functioning pancreatic neuroendocrine tumors (G1/G2). We also constructed a machine learning-based prediction model to analyze the important features to determine recurrence. RESULTS: Fifty-two patients experienced recurrence (14.0%) during the follow-up period, with the median time of recurrence being 33.7 months. The random survival forest (RSF) model showed better predictive performance than the Cox proportional hazards regression model in terms of the Harrell's C-index (0.841 vs. 0.820). The Ki-67 index, residual tumor, WHO grade, tumor size, and lymph node metastasis were the top five predictors in the RSF model; tumor size above 20 mm was the watershed with increased recurrence probability, whereas the 5-year disease-free survival rate decreased linearly as the Ki-67 index increased. CONCLUSIONS: Our study revealed the characteristics of resected PanNENs in real-world clinical practice. Machine learning techniques can be powerful analytical tools that provide new insights into the relationship between the Ki-67 index or tumor size and recurrence.

[A case of Cowden disease with a germline mutation in exon5 of PTEN gene diagnosed based on typical esophageal multiple polypoid lesions observed on a medical checkup].

A man in his fifties had a medical checkup. Mucosal papillomatosis in his oral cavity and palmoplantar keratosis were observed. Esophagogastroduodenoscopy revealed multiple polypoid lesions both in the esophagus and stomach. In addition, colonoscopy showed schwannoma in the rectum. He underwent an operation for adenomatous goiter. At first his typical esophageal multiple polypoid lesion was a diagnostic cue to Cowden disease (CD). Other clinical findings convinced us that he was suffering from CD. He was, then, diagnosed as CD according to the criteria of International Cowden Consortium although he had no family medical history suspicious of CD. Interestingly, genetic testing revealed that the patient had a germline mutation in exon5 of PTEN on chromosome 10. It was a point mutation of C to T transition at codon130, resulting in nonsense mutation (CGA→TGA). A close follow-up, especially cancer surveillance, is necessary for him since CD is associated with a high risk of developing malignant disease. It is noted that the typical esophageal features can be a diagnostic cue to CD, as shown in the present case.

Discrepancy in the Ki67 labeling index of brain and orbital metastatic lesions from gastrointestinal neuroendocrine tumors: A case report.

Proliferative activity examined by Ki67 labeling index (LI) plays pivotal role for managing gastrointestinal neuroendocrine tumor (GI-NET). Few reports indicated the intra-patient heterogeneity of Ki67-LI among metastatic tumor sites. We report a case of brain and orbital metastases from GI-NET that showed discrepancy of the Ki67-LI. A 71 year-old woman who was diagnosed as GI-NET with liver and bone metastases and performed medical therapy, had headache, right exophthalmos, and pain of right eye and was referred to our department. Magnetic resonance image revealed that tumors in the left occipital region and right orbit. We diagnosed as metastatic brain and orbital tumors from GI-NET. Surgical removal of both symptomatic lesions was performed and the diagnosis was pathologically confirmed. Immunohistochemical studies revealed the discrepancy of the Ki67-LI of the lesions (brain tumor: 8% versus orbital tumor: 22%). Sampling of multiple metastatic sites may prevent underestimate tumor proliferative activity.

The feasibility of percutaneous transhepatic gallbladder aspiration for acute cholecystitis after self-expandable metallic stent placement for malignant biliary obstruction: a 10-year retrospective analysis in a single center.

BACKGROUND/AIMS: Patients with acute cholecystitis (AC) after metallic stent (MS) placement for malignant biliary obstruction (MBO) have a high surgical risk. We performed percutaneous transhepatic gallbladder aspiration (PTGBA) as the first treatment for AC. We aimed to identify the risk factors for AC after MS placement and the poor response factors of PTGBA. METHODS: We enrolled 401 patients who underwent MS placement for MBO between April 2011 and March 2020. The incidence of AC was 10.7%. Of these 43 patients, 37 underwent PTGBA as the first treatment. The patients' responses to PTGBA were divided into good and poor response groups. RESULTS: There were 20 patients in good response group and 17 patients in poor response group. Risk factors for cholecystitis after MS placement included cystic duct obstruction (p<0.001) and covered MS (p<0.001). Cystic duct obstruction (p=0.003) and uncovered MS (p=0.011) demonstrated significantly poor responses to PTGBA. Cystic duct obstruction is a risk factor for cholecystitis and poor response factor for PTGBA, whereas covered MS is a risk factor for cholecystitis and an uncovered MS is a poor response factor of PTGBA for cholecystitis. CONCLUSION: The onset and poor response factors of AC after MS placement were different between covered and uncovered MS. PTGBA can be a viable option for AC after MS placement, especially in patients with covered MS.

The Glasgow Prognostic Score and stricture site can predict prognosis after endoscopic duodenal stent placement for malignant gastric outlet obstruction.

Endoscopic duodenal stent (DS) placement for malignant gastric outlet obstruction (GOO) is rapidly increasing in clinical practice; however, the most suitable patient candidates for DS placement have not been determined. One hundred and thirty-five patients with GOO who underwent DS placement in three Japanese referral centers between January 2010 and October 2019 were retrospectively evaluated. Overall survival (OS) after DS placement, technical/clinical success rates, adverse events, and predictive factors affecting OS after DS placement were also analyzed. The median OS after DS placement of all patients was 81 (7-901) days. Technical and clinical success rates were 99.3% and 83.7%, respectively. The GOO Scoring System score significantly increased before and after DS placement (0.9 vs. 2.7, P < 0.001). The procedure-related complication rate was 6.0%. All 19 patients (14.1%) with stent occlusion underwent endoscopic re-intervention successfully. Multivariate analyses revealed chemotherapy after DS placement (P = 0.01), stricture site in D3 (distal part of the papilla) (P = 0.01), and a Glasgow Prognostic Score (GPS) of 0-1 before duodenal stent placement (P < 0.001) were factors significantly associated with prolonged OS. In conclusion, patients with a GPS of 0-1 and D3 stricture who are tolerant of chemotherapy are suitable candidates for DS placement.

Discrepancy in the Ki67 labeling index of brain and orbital metastatic lesions from gastrointestinal neuroendocrine tumors: A case report.

Proliferative activity examined by Ki67 labeling index (LI) plays pivotal role for managing gastrointestinal neuroendocrine tumor (GI-NET). Few reports indicated the intra-patient heterogeneity of Ki67-LI among metastatic tumor sites. We report a case of brain and orbital metastases from GI-NET that showed discrepancy of the Ki67-LI. A 71 year-old woman who was diagnosed as GI-NET with liver and bone metastases and performed medical therapy, had headache, right exophthalmos, and pain of right eye and was referred to our department. Magnetic resonance image revealed that tumors in the left occipital region and right orbit. We diagnosed as metastatic brain and orbital tumors from GI-NET. Surgical removal of both symptomatic lesions was performed and the diagnosis was pathologically confirmed. Immunohistochemical studies revealed the discrepancy of the Ki67-LI of the lesions (brain tumor: 8% versus orbital tumor: 22%). Sampling of multiple metastatic sites may prevent underestimate tumor proliferative activity.