Efficacy and safety of streptozocin-based chemotherapy for gastroenteropancreatic neuroendocrine tumors in Japanese clinical practice.

BACKGROUND: Streptozocin has been used to treat neuroendocrine tumors in Europe and the USA; however, its actual status in Japan has not been fully clarified owing to the rarity of this disease and the relatively recent approval of streptozocin in Japan. METHODS: We retrospectively analyzed 53 patients with gastroenteropancreatic neuroendocrine tumors who were treated with streptozocin-based chemotherapy at two Japanese hospitals between January 2004 and June 2023. RESULTS: The overall response and disease control rates were 27.7 and 74.5%, respectively, and the median progression-free survival and overall survival were 7.1 and 20.3 months, respectively. Performance status ≥1 showed a significant negative correlation with progression-free survival, and performance status ≥1 and liver tumor burden ≥25% showed a significant negative correlation with overall survival. No significant differences were observed in the treatment response between pancreatic and gastrointestinal neuroendocrine tumors. No treatment-related serious adverse events were observed; however, 87.7% of patients expressed a decrease in the estimated glomerular filtration rate, which negatively correlated with the duration of streptozocin treatment (r = 0.43, P = 0.0020). In the streptozocin re-administration group (n = 5), no differences were found in efficacy between the initial and second streptozocin treatments. CONCLUSIONS: Although streptozocin is a safe, streptozocin-induced renal dysfunction is a dilemma in streptozocin responders. Streptozocin may benefit patients with gastroenteropancreatic neuroendocrine tumors, especially those with a good performance status; however, in some cases, planned streptozocin withdrawal or switching to other drugs should be considered.

[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.

Circulating CD8+CD122+ T cells as a prognostic indicator of pancreatic cancer.

PURPOSE: The distribution of tissue infiltrating lymphocytes has been shown to affect the prognosis of patients with pancreatic cancer in some previous studies. However, the role of peripheral lymphocytes in pancreatic cancer remains debated. The purpose of this study was to analyze the peripheral subtypes of T lymphocytes, and establish their association with the prognosis of patients with pancreatic cancer. METHODS: Blood and tissue samples were collected from patients with metastatic pancreatic cancer (n = 54), resectable pancreatic cancer (n = 12), and benign pancreatic cysts (n = 52) between April 2019 and January 2022 and analyzed. RESULTS: Patients with metastatic pancreatic cancer had a larger proportion of both tumor-suppressive and tumor-promoting cells than those with benign pancreatic cysts. In addition, the proportion of peripheral CD4+ T cells positively correlated with the survival of patients with metastatic pancreatic cancer, and the proportion of peripheral CD8+CD122+ T cells was associated with early mortality (< 90 days). After chemotherapy, CD8+CD122+ T cells decreased in patients who had a partial response or stable disease. Moreover, by analyzing resected specimens, we first proved that the existence of CD8+CD122+ T cells in a tumor microenvironment (TME) depends on their proportion in peripheral blood. CONCLUSION: Circulating CD8+CD122+ T cells can be a prognostic indicator in patients with pancreatic cancer.

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.

A clinical analysis on functioning pancreatic neuroendocrine tumors (focusing on VIPomas): a single-center experience.

VIPomas are generally rare functioning pancreatic neuroendocrine tumors (PanNETs) that cause watery diarrhea, hypokalemia, and achlorhydria. Due to their extreme rarity, the clinicopathological features and outcomes of VIPomas have not been well reported. This study aimed to determine the diagnostic and therapeutic characteristics and prognosis of VIPomas and to compare them with other PanNETs at a Japanese reference hospital. Medical records of 293 patients with PanNETs were collected. Patient and tumor characteristics and outcomes were retrospectively reviewed. This cohort had only 1.4% (four patients) of patients with VIPomas, and three of these patients changed from non-functioning (NF-) PanNETs during their disease course. Recurrences of hormonal symptoms were observed in all patients despite the initial controls, and all of them died from their disease, more specifically mainly from hormonal symptoms. Compared to the other PanNETs, VIPomas were all located at the pancreatic tail, were larger, and had a higher Ki-67 index and more metastasis. The median survival time was significantly shorter for patients with VIPoma than for those with NF-PanNET (5.9 vs. 26.7 years, p < 0.0001), insulinoma (21.8 years, p < 0.0001), and gastrinoma (12.3 years, p = 0.0325). This study presents the possibility of shifting from non-symptomatic to symptomatic VIPomas as they grow or of transforming from NF-PanNETs to VIPomas. VIPomas should be considered in patients with relatively large NF-PanNETs, especially those located in the pancreatic tail, when diarrhea is continuously observed. As hormonal symptoms are an important cause of death in VIPomas, long-term symptomatic control, which is relatively difficult, is of great significance.

[A case of a patient with bile secretion disorder for whom an egg yolk lecithin-containing liquid diet was used for enteral nutrition].

For elderly people who are difficult to operate, percutaneous transhepatic gallbladder drainage (PTGBD) is conducted instead. In PTGBD, the bile is drained externally and impaired absorption of fat is a concern. Egg yolk lecithin, which is a fat emulsifier, is not easily broken in emulsion even under a low-pH condition, and the emulsified state is stable. Even in bile duct ligation rats, the emulsifier in egg yolk lecithin emulsion is reported to be superior to lipid absorption using other emulsifiers. Emulsification with egg yolk lecithin may possibly contribute to improvement of nutrition during biliary excretion disorders such as external drainage. We report a case of good progress with enteral nutrition with egg yolk lecithin-mixed liquid diet after PTGBD for acute cholecystitis. The patient was an 80-year-old man with a history of myocardial infarction and dementia. He was diagnosed with calculous cholecystitis, and conservative treatment was started. His cholecystitis was exacerbated, and PTGBD was performed on day 12 of the disease. On imaging, the lower extremities of the duodenum were edematous because of the spread of inflammation. Glutamine preparation alone was administered after resuming fasting. A liquid diet containing egg yolk lecithin, 200 ml of K-LEC (1 kcal/ml), was started from day 23, and was administered three times daily. Liquid diet dose was increased to 1,200 kcal/day with added dietary fiber on day 29. The patient's overall condition improved, and transthyretin level and body weight increased. Thereafter, after swallowing training, the patient was switched to oral meal intake from day 37.

Rac1-mediated indentation of resting neurons promotes the chain migration of new neurons in the rostral migratory stream of post-natal mouse brain.

New neurons generated in the ventricular-subventricular zone in the post-natal brain travel toward the olfactory bulb by using a collective cell migration process called 'chain migration.' These new neurons show a saltatory movement of their soma, suggesting that each neuron cycles through periods of 'rest' during migration. Here, we investigated the role of the resting neurons in chain migration using post-natal mouse brain, and found that they undergo a dynamic morphological change, in which a deep indentation forms in the cell body. Inhibition of Rac1 activity resulted in less indentation of the new neurons in vivo. Live cell imaging using a Förster resonance energy transfer biosensor revealed that Rac1 was activated at the sites of contact between actively migrating and resting new neurons. On the cell surface of resting neurons, Rac1 activation coincided with the formation of the indentation. Furthermore, Rac1 knockdown prevented the indentation from forming and impaired migration along the resting neurons. These results suggest that Rac1 regulates a morphological change in the resting neurons, which allows them to serve as a migratory scaffold, and thereby non-cell-autonomously promotes chain migration.

Multicenter study comparing EUS-guided hepaticogastrostomy and ERCP for malignant biliary obstruction in patients with accessible papillae.

BACKGROUND: One advantage of endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) is that it is difficult for reflux cholangitis, caused by duodenal pressure increasing due to duodenal obstruction, to occur. In addition, since stent deployment is performed away from the malignant stricture site, longer stent patency than with endoscopic retrograde cholangiopancreatography (ERCP) may be obtained. However, no study has previously compared EUS-HGS and ERCP for patients without duodenal obstruction or surgically altered anatomy. The aim of the present study was to compare clinical outcomes between EUS-HGS and ERCP in normal anatomy patients without duodenal obstruction. METHOD: In the ERCP group, patients who initially underwent biliary drainage were included. In the EUS-HGS group, patients who underwent EUS-HGS due to failed biliary cannulation were included. Patients with an inaccessible papilla, such as with surgically altered anatomy or duodenal obstruction, were excluded. RESULTS: A total of 314 patients who underwent ERCP and EUS-HGS were enrolled in this study. Of the 314 patients, 289 underwent biliary stenting under ERCP guidance, and 25 patients underwent biliary stenting under EUS-HGS. After propensity score-matching analysis, the adverse event rate tended to be lower in the EUS-HGS group than in the ERCP group. Although overall survival was not significantly different between the EUS-HGS and ERCP groups (p = .228), stent patency was significantly longer in the EUS-HGS group (median 366.0 days) than in the ERCP group (median 76.5 days). CONCLUSIONS: EUS-HGS had a lower adverse event rate, shorter procedure time, and longer stent patency than ERCP in cases of normal anatomy without duodenal obstruction.

Patient-derived organoids of pancreatic ductal adenocarcinoma for subtype determination and clinical outcome prediction.

BACKGROUND: Recently, two molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) have been proposed: the "Classical" and "Basal-like" subtypes, with the former showing better clinical outcomes than the latter. However, the "molecular" classification has not been applied in real-world clinical practice. This study aimed to establish patient-derived organoids (PDOs) for PDAC and evaluate their application in subtype classification and clinical outcome prediction. METHODS: We utilized tumor samples acquired through endoscopic ultrasound-guided fine-needle biopsy and established a PDO library for subsequent use in morphological assessments, RNA-seq analyses, and in vitro drug response assays. We also conducted a prospective clinical study to evaluate whether analysis using PDOs can predict treatment response and prognosis. RESULTS: PDOs of PDAC were established at a high efficiency (> 70%) with at least 100,000 live cells. Morphologically, PDOs were classified as gland-like structures (GL type) and densely proliferating inside (DP type) less than 2 weeks after tissue sampling. RNA-seq analysis revealed that the "morphological" subtype (GL vs. DP) corresponded to the "molecular" subtype ("Classical" vs. "Basal-like"). The "morphological" classification predicted the clinical treatment response and prognosis; the median overall survival of patients with GL type was significantly longer than that with DP type (P < 0.005). The GL type showed a better response to gemcitabine than the DP type in vitro, whereas the drug response of the DP type was improved by the combination of ERK inhibitor and chloroquine. CONCLUSIONS: PDAC PDOs help in subtype determination and clinical outcome prediction, thereby facilitating the bench-to-bedside precision medicine for PDAC.

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.