Factors Affecting Nonfunctioning Small Pancreatic Neuroendocrine Neoplasms and Proposed New Treatment Strategies.

BACKGROUND & AIMS: Despite previously reported treatment strategies for nonfunctioning small (≤20 mm) pancreatic neuroendocrine neoplasms (pNENs), uncertainties persist. We aimed to evaluate the surgically resected cases of nonfunctioning small pNENs (NF-spNENs) in a large Japanese cohort to elucidate an optimal treatment strategy for NF-spNENs. METHODS: In this Japanese multicenter study, data were retrospectively collected from patients who underwent pancreatectomy between January 1996 and December 2019, were pathologically diagnosed with pNEN, and were treated according to the World Health Organization 2019 classification. Overall, 1490 patients met the eligibility criteria, and 1014 were included in the analysis cohort. RESULTS: In the analysis cohort, 606 patients (59.8%) had NF-spNENs, with 82% classified as grade 1 (NET-G1) and 18% as grade 2 (NET-G2) or higher. The incidence of lymph node metastasis (N1) by grade was significantly higher in NET-G2 (G1: 3.1% vs G2: 15.0%). Independent factors contributing to N1 were NET-G2 or higher and tumor diameter ≥15 mm. The predictive ability of tumor size for N1 was high. Independent factors contributing to recurrence included multiple lesions, NET-G2 or higher, tumor diameter ≥15 mm, and N1. However, the independent factor contributing to survival was tumor grade (NET-G2 or higher). The appropriate timing for surgical resection of NET-G1 and NET-G2 or higher was when tumors were >20 and >10 mm, respectively. For neoplasms with unknown preoperative grades, tumor size >15 mm was considered appropriate. CONCLUSIONS: NF-spNENs are heterogeneous with varying levels of malignancy. Therefore, treatment strategies based on tumor size alone can be unreliable; personalized treatment strategies that consider tumor grading are preferable.

Multicenter validation study of a treatment selection MAP for pancreatic neuroendocrine tumors.

BACKGROUND: Somatostatin analogs, molecular-targeted agents and cytotoxic anticancer agents are available as therapeutic agents for the systemic treatment of pancreatic neuroendocrine tumors, and we have developed a first-line treatment selection MAP to enable selection of the optimal treatment strategy for pancreatic neuroendocrine tumors. The purpose of this study was to validate the usefulness of the treatment selection MAP. METHODS: Patients who had received systemic therapy for a pancreatic neuroendocrine tumor between January 2017 and December 2020 were compared according to whether they had been treated as recommended by the MAP (matched patients) or not (unmatched patients) to determine whether better outcomes were achieved by the matched patients. The primary endpoint was progression-free survival of the matched group and unmatched groups in the somatostatin analog, molecular-targeted agent and cytotoxic anticancer agents areas of the MAP. RESULTS: There were 41 (55%) MAP-matched patients in all areas among the 74 patients registered at seven hospitals. The MAP-matched rates were 100, 77 and 38% in the somatostatin analog area, molecular-targeted agent area and cytotoxic anticancer agents area, respectively. All of the unmatched patients had been selected for less intensive treatment. The median progression-free survival in the matched group and unmatched group in the molecular-targeted agent area of the MAP were 46.6 and 15.4 months, respectively, and a multivariate analysis identified MAP-matched (hazard ratio 0.18 [95% confidence interval: 0.04-0.87], P = 0.032) as the only significant independent favorable predictive factor. CONCLUSION: The usefulness of the MAP for treatment selection was validated in the molecular-targeted agent area of the MAP.

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.

Long-Term Proton Pump Inhibitor-Acid Suppressive Treatment Can Cause Vitamin B12 Deficiency in Zollinger-Ellison Syndrome (ZES) Patients.

Whether the long-term treatment of patients with proton pump inhibitors (PPIs) with different diseases [GERD, Zollinger-Ellison syndrome (ZES), etc.] can result in vitamin B12 (VB12) deficiency is controversial. In this study, in 175 patients undergoing long-term ZES treatment with anti-acid therapies, drug-induced control acid secretory rates were correlated with the presence/absence of VB12 deficiency, determined by assessing serum VB12 levels, measurements of VB12 body stores (blood methylmalonic acid (MMA) and total homocysteine[tHYC]), and other features of ZES. After a mean of 10.2 yrs. of any acid treatment (5.6 yrs. with PPIs), 21% had VB12 deficiency with significantly lower serum and body VB12 levels (p < 0.0001). The presence of VB12 deficiency did not correlate with any feature of ZES but was associated with a 12-fold lower acid control rate, a 2-fold higher acid control pH (6.4 vs. 3.7), and acid control secretory rates below those required for the activation of pepsin (pH > 3.5). Over a 5-yr period, the patients with VB12 deficiency had a higher rate of achlorhydria (73% vs. 24%) and a lower rate of normal acid secretion (0% vs. 49%). In conclusion, in ZES patients, chronic long-term PPI treatment results in marked acid hyposecretion, resulting in decreased serum VB12 levels and decreased VB12-body stores, which can result in VB12 deficiency.

Optimal first-line treatment strategies of systemic therapy for unresectable gastrointestinal neuroendocrine tumors based on the opinions of Japanese experts.

There are several options for systemic therapy of gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), including somatostatin analogues (SSA), molecular-targeted agents, cytotoxic agents, and peptide receptor radionuclide therapy. However, the effectiveness of each agent varies according to the primary site. Although SSA and everolimus are key drugs used for systemic therapy of neuroendocrine tumors arising from the gastrointestinal tract (GI-NET), the optimal strategy for selecting among these modalities remains unexplored. Japanese experts on GI-NET discussed and determined optimal first-line treatment strategies based on the results of previously reported pivotal trials. The consensus was reached that tumor aggressiveness and prognosis can be predicted using hepatic tumor load and Ki-67 labeling index, which are thought to be clinically important factors when selecting systemic therapy for unresectable GI-NET. SSA therapy is considered appropriate for patients with a low hepatic tumor load and low Ki-67 value and everolimus for those with contraindications to SSA therapy. There was also agreement that the treatment strategy should be determined according to whether the origin is in the midgut, considering the biological differences. Based on this strategy, the experts have tentatively created treatment maps and applied them in representative cases of unresectable GI-NET. Japanese experts proposed tentative maps for optimal first-line treatment in patients with unresectable GI-NET. Further investigation is warranted to validate the usefulness of these maps.

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.

Postprocedure serum amylase or lipase levels predict postendoscopic retrograde cholangiopancreatography pancreatitis: Meta-analysis of diagnostic test accuracy studies and utility assessment.

OBJECTIVES: We aimed to clarify the clinical utility of measuring serum pancreatic enzymes after endoscopic retrograde cholangiopancreatography (ERCP) for the purpose of predicting post-ERCP pancreatitis (PEP) by a meta-analysis of diagnostic test accuracy studies. METHODS: Studies on the prediction accuracy of PEP by serum amylase or lipase measured at 2, 3, and 4 h after ERCP were collected. A literature search was performed in PubMed and the Cochrane Library database for studies published between January 1980 and March 2023. The quality of individual studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2. Data were analyzed using Meta-DiSc 2.0 software. RESULTS: We searched the databases and identified 20 observational studies (12,313 participants). PEPs were defined according to criteria by Cotton or modified Cotton, revised Atlanta criteria, or the Japanese criteria. Meta-analysis of eight studies (4389 participants) showed a pooled sensitivity of 71.1% (95% confidence interval [CI] 56.1-82.5) and pooled specificity of 91.2% (95% CI 85.9-94.6) for the serum amylase cut-off value at 3 times the upper limit of normal (ULN). Another meta-analysis of five studies (1970 participants) showed a pooled sensitivity of 85.8% (95% CI 61.9-95.7) and pooled specificity of 85.3% (95% CI 81.9-88.1) for the serum lipase cut-off value at 3 times ULN. CONCLUSION: Despite a high risk of bias due to various reference standards, this updated meta-analysis and the utility assessment by a decision tree showed the utility of serum amylase or lipase levels more than 3 times ULN measured 2-4 h after ERCP for predicting PEP.

Phase I/II study of streptozocin monotherapy in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: This phase I/II study was conducted to evaluate the efficacy, safety and pharmacokinetics of streptozocin (STZ) in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors. METHODS: Twenty-two patients received up to 4 cycles of intravenous STZ at either 500 mg/m2 once daily for 5 consecutive days every 6 weeks (daily regimen) or at 1000-1500 mg/m2 once weekly for 6 weeks (weekly regimen). Tumor response was evaluated using the modified RECIST criteria ver. 1.1, and adverse events were assessed by grade according to the National Cancer Institute CTCAE (ver. 4.0). RESULTS: Fourteen (63.6%) patients completed the study protocol. No patients had complete response; partial response in 2 (9.1%), stable disease in 17 (77.3%), non-complete response/non-progressive disease in 2 (9.1%) and only 1 (4.5%) had non-evaluable disease. Excluding the latter, the response rate in the daily and weekly regimens was 6.7% (1/15) and 16.7% (1/6), respectively, with an overall response rate of 9.5% (2/21). However, the best overall response in each patient showed that the disease control rate was 100%.Adverse events occurred in all 22 patients, including 17 grade 3 adverse events in 11 patients; however, no grade 4 or 5 adverse events were reported. Prophylactic hydration and antiemetic treatment reduced the severity and incidence of nephrotoxicity, nausea and vomiting. Plasma STZ concentrations decreased rapidly after termination of infusion, with a half-life of 32-40 min. Neither repeated administration nor dose increases affected pharmacokinetic parameters. CONCLUSIONS: STZ may be a useful option for Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.

Nationwide registry for patients with neuroendocrine neoplasm of pancreas, gastrointestinal tract, lungs, bronchi, or thymus in Japan.

BACKGROUND: Neuroendocrine neoplasm (NEN) is a comparatively rare tumor that has been considered indolent. Due to these characteristics, detailed epidemiological data have not been analyzed in Japan. To elucidate the present status of NEN diagnosis and treatment in Japan, we started a registry cohort study in January 2015. METHODS: Patients pathologically diagnosed with NENs of the pancreas, gastrointestinal tract, lungs, bronchi, or thymus after January 2012 were enrolled in this registry after the date of ethics review committee approval in each hospital or institute. Follow-up was continued for enrolled patients. RESULTS: During 5 years of enrollment between January 2015 and December 2019, a total of 1526 participants from 63 departments were enrolled in this registry (mean, 305.2 participants/year), covering approximately 5.8% of the annual incidence of NENs in Japan. For pancreatic NEN, 41.9% of patients had metastasis and the dominant metastatic site was the liver, at twice the rate of lymph node metastasis in the current registry. In contrast, the frequency of lymph node metastasis from gastrointestinal (GI)-NEN was similar to that of the liver. The distribution of WHO 2019-based grades varied according to the primary site. Low-to-intermediate grade (G1-G2) was dominant for duodenal, jejunal/ileal, rectal, and pancreatic NENs, whereas high grade (G3 or NEC) was dominant for esophageal, stomach, and colon NENs. For PanNENs, G3 and NEC accounted only for 1.6% and 2.9%, respectively. CONCLUSIONS: These cohort data provide crucial information for clinical research to clarify the characteristics of NENs in Japan.

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.

Multiple Endocrine Neoplasia Type 1 and the Pancreas: Diagnosis and Treatment of Functioning and Non-Functioning Pancreatic and Duodenal Neuroendocrine Neoplasia within the MEN1 Syndrome - An International Consensus Statement.

The better understanding of the biological behavior of multiple endocrine neoplasia type 1 (MEN1) organ manifestations and the increase in clinical experience warrant a revision of previously published guidelines. Duodenopancreatic neuroendocrine neoplasias (DP-NENs) are still the second most common manifestation in MEN1 and, besides NENs of the thymus, remain a leading cause of death. DP-NENs are thus of main interest in the effort to reevaluate recommendations for their diagnosis and treatment. Especially over the last 2 years, more clinical experience has documented the follow-up of treated and untreated (natural-course) DP-NENs. It was the aim of the international consortium of experts in endocrinology, genetics, radiology, surgery, gastroenterology, and oncology to systematically review the literature and to present a consensus statement based on the highest levels of evidence. Reviewing the literature published over the past decade, the focus was on the diagnosis of F- and NF-DP-NENs within the MEN1 syndrome in an effort to further standardize and improve treatment and follow-up, as well as to establish a "logbook" for the diagnosis and treatment of DP-NENs. This shall help further reduce complications and improve long-term treatment results in these rare tumors. The following international consensus statement builds upon the previously published guidelines of 2001 and 2012 and attempts to supplement the recommendations issued by various national and international societies.

Recent epidemiology of patients with gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NEN) in Japan: a population-based study.

BACKGROUND: The worldwide prevalence and incidence of neuroendocrine neoplasms (NEN) have been increasing recently, although few studies have analyzed data on the current situation of NENs in Japan. Here, the Japan Neuroendocrine Tumor Society (JNETS) planned to investigate the recent incidence and distribution of these tumors using data from the national cancer registry started in 2016. This study examined the incidence and distribution of primary sites as well as rate of advanced disease from this population-based registry. METHODS: A retrospective, population-based study using data from the national cancer registry in Japan (NCR) was conducted to evaluate patients with gastro-entero-pancreatic NEN (GEP-NEN) in 2016. Associated population data were used to determine annual age-adjusted incidences. RESULTS: A total of 6735 individuals were diagnosed with GEP-NEN in Japan in 2016. Annual onset incidence was 0.70/100,000 for pancreatic NEN and 2.84/100,000 for gastrointestinal NEN. NEN in the ileum accounted for only 1% of total GEP-NENs in Japan. Most NENs in the esophagus or lungs were neuroendocrine carcinomas (NECs), while the majority of those in the duodenum, ileum, appendix and rectum were grade 1 neuroendocrine tumors (NETs). Median age at initial diagnosis was in between 60 to 65. Tumors in the duodenum, appendix and rectum were mostly limited to local, while those in the esophagus, stomach and colon tended to show distant metastasis. In Japan, initial treatment for GEP-NENs was resection even if the tumor was NEC. CONCLUSIONS: This is the first report of a national registry-based incidence and distribution of GEP-NEN in Japan. These data will serve as an important first step to determining the exact etiology and trends for this pathology in Japan.

Optimal strategy of systemic treatment for unresectable pancreatic neuroendocrine tumors based upon opinion of Japanese experts.

BACKGROUND/OBJECTIVES: A number of therapeutic agents have been reported to be clinically useful for the management of the patients with unresectable pancreatic neuroendocrine tumors (PanNETs) including somatostatin analogues, molecular-targeted agents and cytotoxic agents. However, the optimal strategy for selection among those treatment modalities above in these patients has remained unexplored. METHODS: Japanese experts for PanNET discussed and determined the optimal treatment strategies according to the results of previously reported studies. RESULTS: The tumor volume of liver metastases and the Ki-67 labeling index were unanimously accepted as indicators of the tumor burden and tumor aggressiveness, respectively, which are two most clinically pivotal factors for determining the strategy of systemic treatment for unresectable PanNETs. In addition, for those with a relatively small tumor burden and slow disease progression, somatostatin analogues were selected as the first-line treatment agents. For those with a relatively large tumor burden and rapid tumor progression, cytotoxic agents were selected, possibly aiming at tumor shrinkage. For those of intermediate tumor volume and/or growth rate, molecular-targeted agents were selected as the first choice. Based on this strategy discussed among the experts, we tentatively prepared a MAP for proposing optimal treatment strategy and examined its validity in some patients with unresectable PanNETs. Results validated the usefulness of this MAP proposed for patients harbouring unresectable PanNETs. CONCLUSION: We herein propose a tentative MAP for optimal treatment selection for the patients harbouring unresectable PanNETs. Further large scale studies are, however, warranted to validate the usefulness of this MAP proposed in this study.

Pancreatic neuroendocrine carcinoma G3 may be heterogeneous and could be classified into two distinct groups.

BACKGROUND/OBJECTIVES: Pancreatic neuroendocrine carcinoma (PanNEC)-G3 often presents along with genetic abnormalities such as KRAS, RB1, and TP53 mutations. However, the association between these genetic findings and response to chemotherapy and prognosis has not been clarified. This study aimed to clarify the clinicopathological features of PanNEC-G3. METHODS: We performed a subgroup analysis of the Japanese PanNEN-G3 study (multicenter, retrospective study), which revealed that Rb loss and KRAS mutation were predictors of the response to platinum-based regimen in PanNEN-G3. We re-classified WHO grades of PanNENs using the 2017 WHO classification and then analyzed the clinicopathological features and prognostic factors in 49 patients with PanNEC-G3. RESULTS: The rates of Rb loss and KRAS mutation in PanNEC-G3 were 54.5% and 48.7%, respectively. Patients with Rb loss and/or KRAS mutation showed a higher response rate to first-line platinum-based regimen than those without Rb loss or KRAS mutation (object response rate 70.0% vs 33.3%, odds ratio 9.22; 95% CI 1.26-67.3, P = 0.029), but tended to have shorter overall survival rates than those without Rb loss or KRAS mutation (median 239 vs 473 days, hazard ratio 2.11; 95% CI 0.92-4.86, P = 0.077). CONCLUSIONS: Patients with PanNEC-G3 have varied clinical outcomes for platinum-based regimen. When grouped based on Rb loss and KRAS mutation, there seemed to be two groups with distinct prognoses and responses to the platinum-based regimen. PanNEC-G3 could, therefore, be classified into two distinct groups based on immunohistochemical and genetic findings.

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.

Surgery for Pancreatic Neuroendocrine Tumor G3 and Carcinoma G3 Should be Considered Separately.

BACKGROUND: The role of surgery in pancreatic neuroendocrine neoplasm grade 3 (pNEN-G3) treatment remains unclear. We aimed to clarify the role of surgery for pNEN-G3, which has recently been reclassified as pancreatic neuroendocrine tumor-G3 (pNET-G3) and pancreatic neuroendocrine carcinoma-G3 (pNEC-G3), with and without metastases, respectively. METHODS: We analyzed a subgroup of patients from the Japanese pancreatic NEC study, a Japanese multicenter case-series study of pNEN-G3. Pathologists subclassified 67 patients as having pNET-G3 or pNEC-G3 based on morphological features. We compared the overall survival (OS) rates among patients who were grouped according to whether they had undergone tumor-targeted surgery for tumors without (SwoM) or with (SwM) metastases, or non-surgical procedures (NS). RESULTS: Data from 21 patients with pNET-G3 (SwoM, n = 6; SwM, n = 5; NS, n = 10) and 46 patients with pNEC-G3 (SwoM, n = 8; SwM, n = 5; NS, n = 33) were analyzed. OS of patients with pNET-G3 was significantly longer after SwoM and SwM than with NS (p = 0.018 and p = 0.022). In contrast, OS did not significantly differ between either SwoM or SwM and NS (p = 0.093 and p = 0.489) among patients with pNEC-G3. CONCLUSION: The role of surgery should be considered separately for pNET-G3 and pNEC-G3. Although SwoM and SwM can be considered for pNET-G3, caution is advised before considering SwM and SwoM for pNEC-G3.

Correction to: Phase II study of sunitinib in Japanese patients with unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumor.

In the original publication of this article, the license subtype should be CC BY and not CC BY-NC.

Efficacy and safety of sunitinib in Japanese patients with progressive, advanced/metastatic, well-differentiated, unresectable pancreatic neuroendocrine tumors: final analyses from a Phase II study.

BACKGROUND: In an interim analysis of a Phase II trial in Japanese patients with pancreatic neuroendocrine tumors (panNETs), sunitinib demonstrated antitumor activity with an objective response rate (ORR) of 50% (95% confidence interval [CI], 21-79) and a median progression-free survival (PFS) of 16.8 months (95% CI, 9.3-26.2). Here, we report the final analyses of efficacy and safety, as well as additional analyses, from this Phase II study. METHODS: This was a multicenter, open-label, Phase II trial (NCT01121562) of sunitinib in Japanese patients with panNETs. Patients received oral sunitinib 37.5 mg/day on a continuous daily dosing schedule. Dose modifications were permitted. The primary endpoint was clinical benefit rate (CBR). Secondary endpoints included ORR, PFS, overall survival (OS), safety and pharmacokinetics. RESULTS: Of 12 patients enrolled and treated, all discontinued treatment-the majority (n = 8) owing to disease progression. Most patients were male (n = 8), <65 years of age (n = 11) and had a non-functional tumor (n = 10). The median (range) number of days on drug was 323.5 (22-727). The CBR (95% CI) was 75.0% (42.8-94.5). ORR (95% CI) was 50.0% (21.1-78.9). Median (95% CI) PFS was 16.8 (9.3-26.2) months; however, median (95% CI) OS was not reached (22.0-not estimable). Most common adverse events (AEs; all-causality) were diarrhea (n = 10; 83.3%), hand-foot syndrome (n = 8; 66.7%) and hypertension (n = 8; 66.7%). CONCLUSIONS: These results support the efficacy and safety of sunitinib in Japanese patients with panNETs. Appropriate AE management through dose reduction and interruption may prolong sunitinib treatment and maximize its efficacy.

Insights into Effects/Risks of Chronic Hypergastrinemia and Lifelong PPI Treatment in Man Based on Studies of Patients with Zollinger-Ellison Syndrome.

The use of proton pump inhibitors (PPIs) over the last 30 years has rapidly increased both in the United States and worldwide. PPIs are not only very widely used both for approved indications (peptic ulcer disease, gastroesophageal reflux disease (GERD), Helicobacter pylori eradication regimens, stress ulcer prevention), but are also one of the most frequently off-label used drugs (25-70% of total). An increasing number of patients with moderate to advanced gastroesophageal reflux disease are remaining on PPI indefinitely. Whereas numerous studies show PPIs remain effective and safe, most of these studies are <5 years of duration and little data exist for >10 years of treatment. Recently, based primarily on observational/epidemiological studies, there have been an increasing number of reports raising issues about safety and side-effects with very long-term chronic treatment. Some of these safety issues are related to the possible long-term effects of chronic hypergastrinemia, which occurs in all patients taking chronic PPIs, others are related to the hypo-/achlorhydria that frequently occurs with chronic PPI treatment, and in others the mechanisms are unclear. These issues have raised considerable controversy in large part because of lack of long-term PPI treatment data (>10-20 years). Zollinger-Ellison syndrome (ZES) is caused by ectopic secretion of gastrin from a neuroendocrine tumor resulting in severe acid hypersecretion requiring life-long antisecretory treatment with PPIs, which are the drugs of choice. Because in <30% of patients with ZES, a long-term cure is not possible, these patients have life-long hypergastrinemia and require life-long treatment with PPIs. Therefore, ZES patients have been proposed as a good model of the long-term effects of hypergastrinemia in man as well as the effects/side-effects of very long-term PPI treatment. In this article, the insights from studies on ZES into these controversial issues with pertinence to chronic PPI use in non-ZES patients is reviewed, primarily concentrating on data from the prospective long-term studies of ZES patients at NIH.

Efficacy and Safety of Sunitinib in Patients with Well-Differentiated Pancreatic Neuroendocrine Tumours.

BACKGROUND: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data. METHODS: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9-16.7): 13.2 (7.4-16.8) and 13.0 (9.2-20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7-33.8) in the total population: 21.3% (11.9-33.7) in treatment-naive and 28.9% (16.4-44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0-not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%). CONCLUSIONS: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib.