Pathological complete response with FOLFIRINOX therapy for recurrence of pancreatic acinar cell carcinoma.

Pancreatic acinar cell carcinoma (PACC) is a very rare subtype of pancreatic cancer. Due to small number of patients, no standard chemotherapy protocol has been established. We experienced an extremely rare case of PACC with liver metastasis that showed a pathological complete response after modified FOLFIRINOX (mFFX) therapy. A 42-year-old man who underwent distal pancreatectomy for an 80 mm tumor at the pancreatic tail 3 years ago was referred to our hospital in September 2017 for the treatment of a recurrent liver tumor. Percutaneous biopsy revealed an acinar-neuroendocrine carcinoma, similar to the surgical specimen. He received eight cycles of irinotecan plus cisplatin chemotherapy. However, the tumor increased in size, and treatment was switched to mFFX therapy. The tumor in the liver shrank remarkably after nine cycles of mFFX therapy. Conversion surgery was selected, and the patient underwent hepatic left and caudate lobectomy 8 months after administration of mFFX. The resected specimen showed no viable tumor cells, indicating a pathological complete response. The histological diagnosis was reconsidered, and PACC was finally diagnosed via an additional immunohistological review. The patient has remained well with no recurrence for 6 years after surgery. This study is the first to report a case of pathological complete response with mFFX therapy for the recurrence of PACC.

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.

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.

Ampullary Neuroendocrine Neoplasm: Clinicopathological Characteristics and Novel Endoscopic Entity.

BACKGROUND: Neuroendocrine neoplasms of the ampulla of Vater (ampullary NEN) have features of both gastrointestinal and pancreato-biliary (PB) NEN. However, the limited number of studies examining ampullary NEN makes it difficult to clarify their unique characteristics. This study aimed to elucidate the clinical characteristics of ampullary NEN. METHODS: We enrolled 162 patients with PB-NEN diagnosed at Kyushu University Hospital between 2011 and 2020. Clinical features, pathological diagnoses, treatments, and prognoses were retrospectively analyzed. We also compared ampullary NEN with pancreatic NEN (PanNEN). RESULTS: We analyzed 10 ampullary NEN cases and 149 PanNEN cases. The ampullary NEN cases consisted of 4 cases of neuroendocrine tumor Grade 1 (NET G1), 1 NET G2 (Grade 2), and 5 neuroendocrine carcinomas (NECs). The incidences of NEC and cholangitis were significantly higher in ampullary NEN than in PanNEN. All ampullary NETs had a submucosal tumor-like appearance, as identified by endoscopic ultrasound-guided fine needle aspiration. We treated small NET G1 (<10 mm) with endoscopic papillectomy and large NET G1 with pancreaticoduodenectomy. There were no cases of recurrence after resection. All ampullary NECs presented with the characteristic endoscopic finding of a "crater sign" similar to deep-mining ulcers seen in gastric malignant lymphoma. Four cases underwent surgical resection, and 1 case was unresectable. Two patients who underwent multidisciplinary treatment were maintained without recurrence for over 2 years. CONCLUSIONS: Endoscopic findings showed identifiable distinctions between ampullary NETs and NECs.

Incidence and appropriate management of drug-induced interstitial lung disease in Japanese patients with unresectable pancreatic cancer: A multicenter retrospective study.

AIM: Drug-induced interstitial lung disease (DI-ILD) is a serious adverse event during chemotherapy. This study aimed to obtain real-world data of the incidence, clinical characteristics, predictive factors, and prognosis of patients with pancreatic cancer who developed DI-ILD. METHODS: In patients with locally advanced or metastatic pancreatic cancer who underwent standard chemotherapy at our hospital and its participating facilities between April 2014 and March 2019, the clinical features, occurrence rate and clinical course of DI-ILD, and prognosis were retrospectively evaluated. RESULTS: Altogether, 390 patients were finally enrolled. DI-ILD occurred in 24 cases (6.2%). The median period from diagnosis of pancreatic cancer to the onset of DI-ILD was 2.2 months (.6-13.3 months). The rate of DI-ILD onset according to each regimen was 5.8% of gemcitabine (GEM) plus albumin-bound paclitaxel therapy (18/308), 3.8% of GEM (4/106), and 2.3% of FOLFIRINOX (2/88). The incidence of DI-ILD in GEM-based regimens was significantly higher than that in non-GEM-based regimens (p < .01). The median overall survival (OS) of the patients with and without DI-ILD after propensity score matching was 11.5 months and 11.4 months (p = .99), respectively. After the resolution of DI-ILD, no statistical significance in the median OS of the patients with and without subsequent treatment (11.0 vs. 6.8 months, p = .18) was observed. CONCLUSION: DI-ILD is not a rare adverse event in the current standard chemotherapy for pancreatic cancer in Japan. With appropriate management of DI-ILD, the prognosis of patients with DI-ILD can be equivalent to that of patients without DI-ILD.

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.

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.

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.

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.

Predictive factors of operability after neoadjuvant chemotherapy in resectable or borderline resectable pancreatic cancer: a single-center retrospective study.

BACKGROUND/AIMS: Recently neoadjuvant chemotherapy (NAC) for pancreatic cancer has been shown to be superior to upfront surgery, but it remains a matter of debate for resectable cases. In clinical practice, some resectable cases may become unresectable after NAC. This study aimed to reveal the outcomes after NAC and to clarify the characteristics of unresected cases. METHODS: The medical records of 142 patients who underwent NAC between 2016 and 2020 were retrospectively reviewed. Patient characteristics, effectiveness of NAC, and outcomes were compared between the surgical group and non-surgical group (NSG). Furthermore, the risk of recurrence limited to in the patients who received NAC with gemcitabine plus nab-paclitaxel, which were mostly administered in this cohort, following R0/R1 resection was assessed. RESULTS: The overall and R0 resection rates after NAC were 89.1% and 79.7%, respectively. The neutrophil to lymphocyte ratio (NLR) > 2.78 (p = 0.0120) and anatomical borderline resectable pancreatic cancer (p = 0.0044) revealed a statistically significantly correlation with the NSG. On the other hand, NAC week < 8 (p = 0.0285), radiological response, stable disease or progression disease (p = 0.0212), and pathological stage > IIA (P = 0.0003) were significantly associated with recurrence. The tumor response rate was approximately 26.1%, and three patients with ≥ 30% reduction of primary tumor lost excision opportunities because of metastasis, interstitial pneumonia, and vascular invasion. CONCLUSIONS: This study shows incomplete tumor shrinkage benefits, but pre-NAC NLR is a predictive factor for predicting operability after NAC. The NLR can be easily calculated by normal blood test, and can be considered as a suitable marker of operability.

Efficacy of Early Endoscopic Ultrasound-Guided Transluminal Drainage for Postoperative Pancreatic Fistula.

Background: Endoscopic ultrasound-guided transluminal drainage (EUS-TD) is generally performed 4 weeks after disease onset for evacuating pancreatic fluid collections. However, the optimal timing for conducting the procedure in those diagnosed with postoperative pancreatic fistula (POPF) has not been established. We aimed to elucidate the efficacy and safety of early EUS-TD procedures for treating POPF. Methods: We retrospectively reviewed patients diagnosed with POPF who underwent EUS-TD in the Kyushu University Hospital between 2008 and 2019. Clinical features were comparatively analyzed between the two patient groups who underwent either early (≤15 days postoperatively) or late (>15 days postoperatively) EUS-TD. Factors prolonging hospital stay were also analyzed using Cox proportional hazard models. Results: Thirty patients (median age, 64.5 years) were enrolled. The most common initial operation was distal pancreatectomy with splenectomy (60.0%). Median size of POPF was 69.5 (range, 38-145) mm, and median time interval between surgery and EUS-TD was 17.5 (range, 3-232) days. Totally, 47% patients underwent early EUS-TD. Rates of technical success, clinical success, and complications were 100%, 97%, and 6.9%, respectively. No recurrence of POPF occurred during a median follow-up period of 14 months. Clinical characteristics and outcomes were comparable between the early and late drainage patient groups, except for the rates of infection and nonencapsulation of POPF, which were significantly higher in the early drainage group. Performing simultaneous internal and external drainage (hazard ratio (HR): 0.31; 95% confidence interval (CI): 0.11-0.93, p=0.04) and conducting ≥2 treatment sessions (HR: 0.26; 95% CI: 0.08-0.84, p=0.02) were significantly associated with prolonged hospitalization after EUS-TD. Conclusions: EUS-TD is a safe and effective method for managing POPF, regardless of when it is performed in the postoperative period. Once infected POPF occurs, clinicians should not hesitate to perform EUS-TD even within 15 days of the initial operation.

Colonic varices: a rare complication of pancreatic cancer.

A 55-year-old man was diagnosed with pancreatic cancer of the uncus and received chemotherapy (modified FOLFIRINOX). Ten months later, he was admitted to our hospital with massive lower gastrointestinal bleeding. Contrast-enhanced CT showed ascending colon varices caused by the occlusion of the superior mesenteric vein (SMV) due to pancreatic cancer invasion. Colonoscopy revealed tortuous varices with red spots in the ascending colon. The patient received blood transfusions and was discharged; however, he was hospitalized for recurrent massive lower gastrointestinal bleeding 3 months later. During this readmission, we performed the transileocolic vein obliteration method due to SMV stenosis and the absence of an obvious shunt. He experienced an uneventful post-operative recovery, and contrast-enhanced CT after 2 months revealed no recurrence of colonic varices. Ectopic varices are portosystemic venous collaterals resulting from portal hypertension occurring in any locations other than the esophagogastric region. Colonic varices have rarely been reported before. Patients with pancreatic cancer may present with gastrointestinal bleeding caused by tumor bleeding or esophagogastric varices; however, ectopic varices such as colon varices, a rare complication of pancreatic cancer, should be considered in patients with obscure gastrointestinal bleeding.

Natural history and clinical outcomes of pancreatic neuroendocrine neoplasms based on the WHO 2017 classification; a single-center experience of 30 years.

BACKGROUND/OBJECTIVES: This single-center study aimed to evaluate treatment outcomes and long-term prognosis of patients with pancreatic neuroendocrine neoplasms (PanNENs) based on the World Health Organization (WHO) 2017 classification. METHODS: We enrolled 245 patients with PanNENs treated at Kyushu University Hospital between January 1987 and March 2018. PanNENs were categorized according to the WHO 2017 classification or further subdivisions of Ki-67 index. Clinicopathological features, median survival time (MST), and prognostic factors were retrospectively analyzed. RESULTS: The number of PanNENs, especially non-functioning PanNENs, has increased over the last decade. The mean MST of all patients was 202 months; which was longest in patients with NET G1 (n = 145, MST = 261 months) relative to NET G2 (n = 72, 132 months), NET G3 (n = 3, 34 months) and NEC G3 (n = 17, 9 months). Prognosis in patients with surgery as the first-line treatment was significantly better than in those with drug therapy. However, 26% of patients who underwent curative resection developed recurrence after a median time of 28.7 months. In unresectable PanNENs (n = 97), the MST and 5-year survival rate were 78 months and 55.8%, respectively. Poor differentiation, Ki-67 index of >10% and presence of liver metastasis were significant unfavorable predictors. Response to first-line therapy (stable disease/partial response) and three or more treatment regimens were significant favorable predictors for unresectable PanNENs according to multivariate analyses (p < 0.01). CONCLUSIONS: We demonstrated the utility of the WHO 2017 classification for PanNENs in the real clinical setting. For better prognosis in PanNENs, the use of three or more regimens should be considered.

Relapse patterns and predictors of IgG4-related diseases involved with autoimmune pancreatitis: A single-center retrospective study of 115 patients.

OBJECTIVE: Autoimmune pancreatitis is an autoimmune disorder accompanied by clinicopathological manifestations that have been established as immunoglobulin (IgG)4-related diseases (IgG4-RD). Other IgG4-RD are often involved with autoimmune pancreatitis. They sometimes relapse despite a favorable response to steroid therapy. This study aimed to clarify the patterns and risk factors for extrapancreatic relapse. METHODS: We reviewed the data of 115 patients diagnosed with definite autoimmune pancreatitis type 1 and followed up for > 1 year. We analyzed two items: the timing and pattern of extrapancreatic relapse, and risk factors for relapse with three common manifestations: IgG4-related sclerosing cholangitis (SC), IgG4-related dacryoadenitis and sialadenitis (DS), and IgG4-related retroperitoneal fibrosis (RF). RESULTS: Remission was achieved in all patients, except one. The extrapancreatic relapse rates were 11.0%, 19.7%, and 40% within 3, 5, and 10 years, respectively. Of 26 patients with extrapancreatic relapse, nine (34.6%) relapsed with a new IgG4-RD. Based on multivariate analysis, the interval between symptom onset and steroid initiation, and the presence of RF at onset were significant risk factors for relapse with SC and RF, respectively. CONCLUSIONS: Our results indicate that they may be various extrapancreatic relapse patterns especially in autoimmune pancreatitis with other organ involvement. Patients with a delayed initiation of steroids or RF at onset should be carefully followed up as high-risk groups for SC and RF relapse.