Proof-of-concept study exploring the effect of spesolimab in patients with moderate-to-severe hidradenitis suppurativa: A randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease with a considerable disease burden. Existing treatment options are limited and often suboptimal; a high unmet need exists for effective targeted therapies. OBJECTIVE: To explore the effects of spesolimab treatment in patients with HS. METHODS: This randomized, double-blind, placebo-controlled, proof-of-clinical-concept study was conducted at 25 centers across 12 countries from May 3, 2021, to April 21, 2022. Patients had moderate-to-severe HS for ≥1 year before enrollment. Patients were randomized (2:1) to receive a loading dose of 3600 mg intravenous spesolimab (1200 mg at Weeks 0, 1, and 2) or matching placebo, followed by maintenance with either 1200 mg subcutaneous spesolimab every 2 weeks from Week 4-10 or matching placebo. The primary endpoint was the percentage change from baseline in total abscess and inflammatory nodule (AN) count at Week 12. Secondary endpoints were the absolute change from baseline in International Hidradenitis Suppurativa Severity Score System (IHS4), percentage change from baseline in draining tunnel (dT) count, the proportion of patients achieving a dT count of zero, absolute change from baseline in revised Hidradenitis Suppurativa Area and Severity Index (HASI-R), the proportion of patients achieving Hidradenitis Suppurativa Clinical Response (HiSCR50), the proportion of patients with ≥1 flare (all at Week 12), and patient-reported outcomes (PROs). RESULTS: In this completed trial, randomized patients (N=52) received spesolimab (n=35) or placebo (n=17). The difference (95% confidence interval) versus placebo in least squares mean are reported. At Week 12, the percentage change in total AN count was similar between treatment arms: -4.1% (-31.7, 23.4). There was greater numerical improvement in the spesolimab arm, as measured by IHS4: -13.9 (-25.6, -2.3); percentage change from baseline in dT count: -96.6% (-154.5, -38.8); and the proportion of patients achieving a dT count of zero: 18.3% (-7.9, 37.5). Spesolimab treatment also improved HASI-R and HiSCR50 versus placebo. Spesolimab demonstrated a favorable safety profile, similar to that observed in trials in other diseases. CONCLUSIONS: This exploratory proof-of-clinical-concept study supports the development of spesolimab as a new therapeutic option in HS. ClinicalTrials.gov identifier: NCT04762277.

The stromal microenvironment endows pancreatic neuroendocrine tumors with spatially specific invasive and metastatic phenotypes.

Cancer-associated fibroblasts (CAFs) play an important role in a variety of cancers. However, the role of tumor stroma in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs) is often neglected. Profiling the heterogeneity of CAFs can reveal the causes of malignant phenotypes in NF-PanNETs. Here, we found that patients with high stromal proportion had poor prognosis, especially for that with infiltrating stroma (stroma and tumor cells that presented an infiltrative growth pattern and no regular boundary). In addition, myofibroblastic CAFs (myCAFs), characterized by FAP+ and α-SMAhigh, were spatially closer to tumor cells and promoted the EMT and tumor growth. Intriguingly, only tumor cells which were spatially closer to myCAFs underwent EMT. We further elucidated that myCAFs stimulate TGF-ß expression in nearby tumor cells. Then, TGF-ß promoted the EMT in adjacent tumor cells and promoted the expression of myCAFs marker genes in tumor cells, resulting in distant metastasis. Our results indicate that myCAFs cause spatial heterogeneity of EMT, which accounts for liver metastasis of NF-PanNETs. The findings of this study might provide possible targets for the prevention of liver metastasis.

Surufatinib plus toripalimab in patients with advanced neuroendocrine tumours and neuroendocrine carcinomas: An open-label, single-arm, multi-cohort phase II trial.

BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib revealed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumours in a phase I study. PATIENTS AND METHODS: This was an open-label, single-arm, multi-cohort phase II study in China. Patients with advanced neuroendocrine tumours (NETs) or neuroendocrine carcinomas (NECs) or mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) who had failed or were intolerable of standard treatment were given surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every 3 weeks). Primary end-point was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end-points included duration of response (DoR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty patients were enrolled into two cohorts by tumour types (NET, n = 19; NEC-MiNEN, n = 21). ORRs (95% CIs) were 21.1% (6.1-45.6) and 23.8% (8.2-47.2) in the NET and NEC-MiNEN cohorts, respectively. Median DoR was 7.1 months (6.9-not evaluable [NE]) and 4.1 months (3.0-NE), respectively. Median PFS was 9.6 months (4.1-NE) and 4.1 months (1.5-5.5); median OS was 27.3 (15.3-NE) and 10.9 months (9.1-14.6), respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 18 (45.0%) patients. CONCLUSIONS: Surufatinib plus toripalimab showed antitumour activity and a tolerable safety profile in patients with previously treated NETs/NECs/MiNENs. Further study of this combination regimen is ongoing for advanced NECs, for which current therapeutic options remain limited. CLINICALTRIALS: gov: NCT04169672.

MEN1 Degradation Induced by Neddylation and the CUL4B-DCAF7 Axis Promotes Pancreatic Neuroendocrine Tumor Progression.

Pancreatic neuroendocrine tumors (PanNET) are a group of rare sporadic malignant tumors in the pancreas. MEN1 is the most frequently mutated gene in PanNETs. The MEN1-encoded protein is a typical tumor suppressor that forms a complex with epigenetic and transcription factors and is an attractive target for therapeutic interventions for patients with PanNET. A better understanding of the regulation of MEN1 protein expression in PanNETs could identify strategies for targeting MEN1. Here, we found that the neddylation pathway and DCAF7-mediated ubiquitination regulated MEN1 protein expression. Increased expression of members of the neddylation pathway and DCAF7 was found in PanNET tissues compared with paired-adjacent tissues and was associated with poor prognosis in patients with PanNET. Suppression of neddylation using the neddylation inhibitor MLN4924 or RNA interference significantly induced MEN1 accumulation and repressed cancer-related malignant phenotypes. CUL4B and DCAF7 promoted MEN1 degradation by binding and catalyzing its ubiquitination. In PanNET cells resistant to everolimus, a pharmacologic mTOR inhibitor widely used for advanced PanNET patient treatment, the downregulation of DCAF7 expression overcame resistance and synergized with everolimus to suppress mTOR activation and to inhibit cancer cell growth. The effects of DCAF7 loss could be counteracted by the simultaneous knockdown of MEN1 both in vitro and in vivo. The inverse correlation between DCAF7 and MEN1 was further validated in clinical specimens. This study revealed that the posttranslational control of MEN1 expression in PanNET is mediated by neddylation and the CUL4B-DCAF7 axis and identifies potential therapeutic targets in patients with MEN1-associated PanNET. SIGNIFICANCE: Identification of neddylation and ubiquitination pathways that regulate MEN1 protein stability provides an opportunity for therapeutic interventions for treating patients with pancreatic neuroendocrine tumors.

Recent progress of experimental model in pancreatic neuroendocrine tumors: drawbacks and challenges.

The neuroendocrine neoplasm, in general, refers to a heterogeneous group of all tumors originating from peptidergic neurons and neuroendocrine cells. Neuroendocrine neoplasms are divided into two histopathological subtypes: well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Pancreatic neuroendocrine tumors account for more than 80% of pancreatic neuroendocrine neoplasms. Due to the greater proportion of pancreatic neuroendocrine tumors compared to pancreatic neuroendocrine carcinoma, this review will only focus on them. The worldwide incidence of pancreatic neuroendocrine tumors is rising year by year due to sensitive detection with an emphasis on medical examinations and the improvement of testing technology. Although the biological behavior of pancreatic neuroendocrine tumors tends to be inert, distant metastasis is common, often occurring very early. Because of the paucity of basic research on pancreatic neuroendocrine tumors, the mechanism of tumor development, metastasis, and recurrence are still unclear. In this context, the representative preclinical models simulating the tumor development process are becoming ever more widely appreciated to address the clinical problems of pancreatic neuroendocrine tumors. So far, there is no comprehensive report on the experimental model of pancreatic neuroendocrine tumors. This article systematically summarizes the characteristics of preclinical models, such as patient-derived cell lines, patient-derived xenografts, genetically engineered mouse models, and patient-derived organoids, and their advantages and disadvantages, to provide a reference for further studies of neuroendocrine tumors. We also highlight the method of establishment of liver metastasis mouse models.

Semantic Decomposition Network With Contrastive and Structural Constraints for Dental Plaque Segmentation.

Segmenting dental plaque from images of medical reagent staining provides valuable information for diagnosis and the determination of follow-up treatment plan. However, accurate dental plaque segmentation is a challenging task that requires identifying teeth and dental plaque subjected to semantic-blur regions (i.e., confused boundaries in border regions between teeth and dental plaque) and complex variations of instance shapes, which are not fully addressed by existing methods. Therefore, we propose a semantic decomposition network (SDNet) that introduces two single-task branches to separately address the segmentation of teeth and dental plaque and designs additional constraints to learn category-specific features for each branch, thus facilitating the semantic decomposition and improving the performance of dental plaque segmentation. Specifically, SDNet learns two separate segmentation branches for teeth and dental plaque in a divide-and-conquer manner to decouple the entangled relation between them. Each branch that specifies a category tends to yield accurate segmentation. To help these two branches better focus on category-specific features, two constraint modules are further proposed: 1) contrastive constraint module (CCM) to learn discriminative feature representations by maximizing the distance between different category representations, so as to reduce the negative impact of semantic-blur regions on feature extraction; 2) structural constraint module (SCM) to provide complete structural information for dental plaque of various shapes by the supervision of an boundary-aware geometric constraint. Besides, we construct a large-scale open-source Stained Dental Plaque Segmentation dataset (SDPSeg), which provides high-quality annotations for teeth and dental plaque. Experimental results on SDPSeg datasets show SDNet achieves state-of-the-art performance.

Maximum Value on Arterial Phase Computed Tomography Predicts Prognosis and Treatment Efficacy of Sunitinib for Pancreatic Neuroendocrine Tumours.

PURPOSE: This study was designed to assess the computed tomography maximum (CTmax) value on pretherapeutic arterial phase computed tomography (APCT) images to predict pancreatic neuroendocrine tumours (pNETs) recurrence and clarify its role in predicting the outcome of tumour therapy. METHODS: This retrospective study enrolled 250 surgical patients and 24 nonsurgical patients with sunitinib-based treatment in our hospital from 2008 to 2019. CT images were assessed, the maximum value was defined as "CTmax," and recurrence-free survival (RFS) or progression-free survival (PFS) was compared between a high-CTmax group and a low-CTmax group among patients who underwent surgical resection or nonsurgical, sunitinib-based treatment according to the CTmax cutoff value. RESULTS: In ROC curve analysis, a CTmax of 108 Hounsfield units, as the cutoff value, achieved an AUC of 0.796 in predicting recurrence. Compared with the low-CTmax group, the high-CTmax group had a longer RFS (p < 0.001). Low CTmax was identified as an independent factor for RFS (p < 0.001) in multivariate analysis; these results were confirmed using the internal validation set. The CTmax value was significantly correlated with the microvascular density (MVD) value (p < 0.001) and the vascular endothelial growth factor receptor 2 (VEGFR2) score (p < 0.001). Furthermore, the high-CTmax group had a better PFS than the low-CTmax group among the sunitinib treatment group (p = 0.007). CONCLUSIONS: The tumour CTmax on APCT might be a potential and independent indicator for predicting recurrence in patients who have undergone surgical resection and assessing the efficacy of sunitinib for patients with advanced metastatic pNETs.

A real-life treatment cohort of pancreatic neuroendocrine tumors: High-grade increase in metastases confers poor survival.

Background: Tumor grade determined by the Ki67 index is the best prognostic factor for pancreatic neuroendocrine tumors (PanNETs). However, we often observe that the grade of metastases differs from that of their primary tumors. This study aimed to investigate the frequency of grade changes between primary tumors and metastases, explore its association with clinical characteristics, and correlate the findings with the prognosis. Methods: Six hundred forty-eight patients with pancreatic neuroendocrine neoplasms treated at Fudan University Shanghai Cancer Center were screened for inclusion, and 103 patients with PanNETs who had paired primary tumors and metastases with an available Ki67 index were included. Re-evaluation of Ki67 was performed on 98 available samples from 69 patients. Results: Fifty cases (48.5%) had a Ki67 index variation, and 18 cases (17.5%) displayed a grade increase. Metachronous metastases showed significantly higher Ki67 index variation than synchronous metastases (P=0.028). Kaplan-Meier analyses showed that high-grade metastases compared to low-grade primary tumors were significantly associated with decreased progression-free survival (PFS, P=0.012) and overall survival (OS, P=0.027). Multivariable Cox regression analyses demonstrated that a low-grade increase to high-grade was an unfavorable and independent prognostic factor for PFS and OS (P=0.010, and P=0.041, respectively). Conclusions: A high-grade increase in metastases was an unfavorable predictor of PanNETs, which emphasized the importance of accurate pathological grading and could provide a reference for clinical decision-making.

The Interplay of Four Main Pathways Recomposes Immune Landscape in Primary and Metastatic Gastroenteropancreatic Neuroendocrine Tumors.

Background: The four major pathways in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) including chromatin remodeling, DNA damage repair, activation of mTOR signaling, and telomere maintenance were mediated by some critical molecules and constituted critical processes of regulation in cancer-causing processes. However, the interplay and potential role of these pathway-related molecules in the tumor microenvironment of the primary and metastatic site remained unknown. Methods: We systematically evaluated the mRNA expression of 34 molecules associated with the four pathways in 227 GEP-NEN samples from 5 datasets. We assigned the samples into two expression patterns of pathway-related molecules by an unsupervised clustering method. Subsequently, we explored the specific cell-related molecules, especially immune and stromal cells using the WGCNA method, based on differentially expressed genes (DEGs) responsible for the different patterns of pathway-related molecules, which provided a new method to qualify the pathway-related subtypes of individual tumors, then the PC_Score and PI_Score scoring systems were also constructed using obtained specific cell-related molecules. Furthermore, we performed the association of pathway-related subtypes with characteristics of immune landscape in primary and metastatic GEP-NENs. Results: We demonstrated that the specific pathway-related molecules (SMARCA4, MLH1, TSC1, ATRX, and ATR) were associated with cytolytic activity. Then we identified the two distinct patterns of pathway-related molecules, which were characteristic with a significantly distinct immune landscape. Using WGCNA, we also identified the fibroblast-related molecules, including ASPN, COL10A1, COL3A1, EDNRA, MYL9, PRELP, RAB31, SPARC, and THBS2, and immune-related molecules including CASP1, CCL5, CTSS, CYBRD1, PMP22, and TFEC. Based on these specific markers, we identified four distinct pathway-related subtypes, characterized by immune and fibrotic enriched (I/FE), immune enriched (IE), fibrotic enriched (FE), and immune and fibrotic desert (I/FD), of which I/FE was characteristic with the highest PC_Score and PI_Score whereas I/FD presents the opposite trend. I/FE was positively correlated with immune landscape of T-cell activation and immunosuppression. Furthermore, the I/FE marked GEP-NENs with increased immune activation scores (T-cell costimulation, MHC I presentation, and APC costimulation). Importantly, the four distinct pathway-related subtypes were not conserved in different tumor sites, because I/FE was lacking in the liver metastatic site even though IE, FE, and I/FD also could be observed in the metastatic site. Conclusions: This study was the first to perform a comprehensive analysis of the four major pathways in GEP-NENs. We demonstrated the potential function of these pathway-related molecules in immune landscapes. Our findings indicated that the primary and metastatic GEP-NENs had distinct antitumor phenotypes. This work highlighted the interplay and potential clinical utility of these pathway-related molecules in GEP-NENs.

Neoadjuvant chemotherapy endows CD9 with prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer.

BACKGROUND: The selective pressure imposed by chemotherapy creates a barrier to tumor eradication and an opportunity for metastasis and recurrence. As a newly discovered stemness marker of pancreatic ductal adenocarcinoma (PDAC), the impact of CD9 on tumor progression and patient's prognosis remain controversial. METHODS: A total of 179 and 211 PDAC patients who underwent surgical resection with or without neoadjuvant chemotherapy, respectively, were recruited for immunohistochemical analyses of CD9 expression in both tumor and stromal areas prior to statistical analyses to determine the prognostic impact and predictive accuracy of CD9. RESULTS: The relationship between CD9 and prognostic indicators was not significant in the non-neoadjuvant group. Nevertheless, CD9 expression in both tumor (T-CD9) and stromal areas (S-CD9) was significantly correlated with the clinicopathological features in the neoadjuvant group. High levels of T-CD9 were significantly associated with worse OS (p = 0.005) and RFS (p = 0.007), while positive S-CD9 showed the opposite results (OS: p = 0.024; RFS: p = 0.008). Cox regression analyses identified CD9 in both areas as an independent prognostic factor. The T&S-CD9 risk-level system was used to stratify patients with different survival levels. The combination of T&S-CD9 risk level and TNM stage were accurate predictors of OS (C-index: 0.676; AIC: 512.51) and RFS (C-index: 0.680; AIC: 519.53). The calibration curve of the nomogram composed of the combined parameters showed excellent predictive consistency for 1-year RFS. These results were verified using a validation cohort. CONCLUSION: Neoadjuvant chemotherapy endows CD9 with a significant prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer.

Hypoxia-reprogrammed regulatory group 2 innate lymphoid cells promote immunosuppression in pancreatic cancer.

BACKGROUND: Previously, we uncovered a patient subgroup with highly malignant pancreatic cancer with serum markers CEA+/CA125+/CA19-9 ≥ 1000 U/mL (triple-positive, TP). However, the underlying immunosuppressive mechanism in the tumor immune microenvironment (TIME) of this subgroup is still unknown. METHODS: Human tissues were analyzed by flow cytometry, mass cytometry, and immunofluorescence staining. Mouse pancreatic ILC2s were expanded in vivo and used for RNA sequencing, chromatin immunoprecipitation (ChIP), and chemotaxis assays. FINDINGS: Through microarray data, we identified the accumulation of the hypoxia-induced factor-1α (HIF-1α) pathway in these TP patients. Via flow and mass cytometry, we discovered that a special subset of ILC2s were highly infiltrated in TP patients. Under the hypoxia microenvironment, ILC2s were found undergo a transition to a IL10+ regulatory phenotype, we named ILCregs which was correlated with pancreatic ductal adenocarcinoma (PDAC) progression. Further, neoadjuvant chemotherapy could ameliorate hypoxic tumor microenvironments so that significantly reverse the regulatory phenotype of ILCregs. Moreover, most tumor ILC2 were CD103-, which indicated its circulatory origin. The expression of Ccr2 was significantly upregulated on mouse ILCregs, and these cells selectively migrated to CCL2. INTERPRETATION: Our results indicate that the hypoxia microenvironment creates an immunosuppressive TIME by inducing ILCregs from a population of circulating group 2 ILCs in TP PDAC patients. FUNDING: This study was jointly supported by the National Natural Science Foundation of China (U21A20374, 82173091, and 81701630).

Establishment and characterization of the third non-functional human pancreatic neuroendocrine tumor cell line.

The mechanisms of neuroendocrine tumor (NET) were still poorly understood, largely due to the lack of preclinical models of neuroendocrine neoplasms. Herein, we established and characterized SPNE1 cell lines from primary pancreatic NET tissue obtained from a 44-year-old female. Neuroendocrine character of SPNE1 was compared with existing non-functional cell lines BON1 and QGP1, and the results indicated expressions of multiple NET-specific markers in SPNE1 were higher relative to BON1 and QGP1. The growth character measured by Ki67 labeling index, cell cycle analysis, and 3D matrigel spheroid essay indicated that the proliferative rate of SPNE1 was lower than that of BON1 and QGP1. SPNE1 also was characterized with cancer stemness because of the higher proportion of CD44 + and CD117 + subpopulations relative to BON1, whereas it was similar to that of QGP1. Interestingly, SPNE1 highly expressed somatostatin receptors (SSTR2 and SSTR5) and angiogenic factors (VEGF1). SPNE1 had sensitive response to the four clinical treatments including tyrosine kinase inhibitor (TKI), mTOR inhibitors, somatostatin analogs (SSA), chemotherapy, which was similar to the BON1 and QGP1. Subcutaneous transplantations of SPNE1 also present the tumorigenicity, and neuroendocrine marker expression of xenograft tumors resembled the original human NET tissue. Then, we found a total of 8 common mutation in BON1, QGP1 and SPNE1 included CROCC, FAM135A, GPATCH4, CTBP2, FBXL14, HERC2, HYDIN, and PABPC3 using whole-exome sequencing (WES), and more neuroendocrine-related functional processes were enriched based on the private mutation genes in SPNE1, such as neuron migration, insulin secretion, and neuron to neuron synapse. In brief, SPNE1 could be used as a relevant model to study pancreatic NET biology and to develop novel treatment options.

The optimal duration of capecitabine plus temozolomide in patients with well-differentiated pancreatic NETs with or without maintenance therapy.

BACKGROUND: The optimal duration of capecitabine combined with temozolomide (CapTem) for metastatic pancreatic neuroendocrine tumours (PanNETs) remains controversial. The present study aimed to assess the activity and safety of prolonged CapTem and Cap maintenance therapy in patients with metastatic PanNETs. METHODS: Retrospective real-world data of 94 patients with metastatic PanNETs were obtained from one cancer centre. Fifteen patients were treated with Cap maintenance therapy after fixed 12-13 cycles of CapTem (group I), 44 patients were treated with prolonged CapTem until disease progression (group II), and 35 patients were treated with fixed 12-13 cycles of CapTem (group III). RESULTS: The mean ± SE follow-up period was 41.79 ± 26.31 months. The median CapTem treatment duration was 12 months in group I and 14 months in group II. The median time to best partial response was 12 months both in groups I and group II. The objective response rates of groups I and II were significantly higher than those of group III (73.3%, 41.9%, and 20%, respectively, p = .002). The median progression-free survival (mPFS) of group I and group II was significantly higher than that of group III (35 months, 26 months vs. 19 months, p < .001). Safety analysis of the three groups indicated rare events of grade 3-4 toxicities, with nausea, vomiting, fatigue, and anaemia being the most common adverse effects. CONCLUSIONS: Patients with PanNETs who responded well to CapTem treatment may benefit from prolonged CapTem and Cap maintenance therapy after fixed cycles. Prospective studies are encouraged to further explore the prolonged CapTem treatment and maintenance therapy.

Pevonedistat Suppresses Pancreatic Cancer Growth via Inactivation of the Neddylation Pathway.

BACKGROUND: The neddylation pathway is aberrantly overactivated in multiple human cancers and has been indicated as an effective target for anticancer therapy in clinical trials. We aimed to study whether the neddylation pathway is upregulated in pancreatic cancer and whether pevonedistat, a first-in-class anticancer agent specifically targeting this pathway, will suppress cancer tumorigenesis and progression. METHODS: We evaluated the expression pattern of neddylation pathway components in 179 pancreatic adenocarcinoma (PAAD) compared with 171 normal tissues from The Cancer Genome Atlas (TCGA) dataset and further assessed PAAD patient prognosis with high neddylation pathway expression via Gene Expression Profiling Interactive Analysis (GEPIA). We then analyzed malignant cancer phenotypes both in vitro and in vivo, as well as intrinsic molecular mechanisms upon pevonedistat treatment. RESULTS: We found that the neddylation pathway was hyperactivated in pancreatic cancer. Patients with high neddylation pathway expression exhibited worse prognoses. Pevonedistat significantly inhibited the cancer cell cycle, cell growth, and proliferation; increased cell apoptosis; and decreased cancer cell xenografts in a mouse model. Mechanistically, pevonedistat treatment and the siRNA knockdown neddylation pathway were able to remarkably induce the accumulation of Wee1, p27, and p21. Further mechanistic studies revealed that pevonedistat mainly impaired the ubiquitination level and delayed the protein degradation of Wee1, p27, and p21. CONCLUSIONS: Our results showed that pevonedistat targeted the overexpression of the neddylation pathway in pancreatic cancer to induce cell growth suppression by inducing the accumulation of the cell cycle regulators Wee1, p27, and p21, which provides sound evidence for the clinical trial of pevonedistat for pancreatic cancer therapy.

Role of Somatostatin Receptor 2 in Nonfunctional Pancreatic Neuroendocrine Tumors: Clinicopathological Analysis of 223 Cases and Whole Exome Sequencing of a Multifocal Case.

OBJECTIVES: Somatostatin receptors are commonly expressed in most pancreatic neuroendocrine tumors (pNETs), a rare type of pancreatic tumors with high heterogeneity. However, the role of somatostatin receptor 2 (SSTR2) has seldom been investigated separately in pNET. This retrospective study aims to evaluate the role of SSTR2 in the clinicopathological features and genomic background of nonfunctional and well-differentiated pNET. METHODS: A total of 223 cases of nonfunctional well-differentiated pNET were included, and the correlation between SSTR2 status and clinicopathological outcome was evaluated. In addition, we performed whole exome sequencing in SSTR2-positive and SSTR2-negative pNETs and identified that the 2 lesions harbored different mutational landscapes. RESULTS: Negative SSTR2 immunochemistry staining was significantly related to an earlier onset of disease, larger tumor size, advanced stage of American Joint Committee on Cancer, and tumor metastasis in lymph nodes and liver. Under pathological assessment, positive peripheral aggression, vascular invasion, and perineural invasion were markedly increased in SSTR2-negative cases. Moreover, SSTR2-negative patients exhibited significantly worse progression-free survival than SSTR2-positive patients (hazard ratio, 0.23; 95% confidence interval, 0.10-0.53; P = 0.001). CONCLUSIONS: Somatostatin receptor 2-negative nonfunctional pNET might represent a subtype of pNET with poor outcomes and evolve from a different genomic background.

Sequential Capecitabine/Temozolomide and Sunitinib Treatment in Patients With Metastatic Well-Differentiated Grade 1/Grade 2 Pancreatic Neuroendocrine Tumors.

OBJECTIVE: The role of alternate sequential administration of sunitinib and capecitabine/temozolomide (CAPTEM) in metastatic pancreatic neuroendocrine tumors (PanNETs) remains unexplored. We thus aimed to analyze the efficacy and tolerability of this strategy in advanced grade 1/grade 2 PanNETs. METHODS: In total, data of 43 patients with metastatic PanNET were collected from a real-world database of a cancer center. Twenty-four patients were treated with sunitinib followed by CAPTEM (group 1), and 19 patients were treated with CAPTEM followed by sunitinib (group 2). RESULTS: Twenty-three patients were treated with first-line sunitinib or CAPTEM, and 20 patients were pretreated with somatostatin analog (SSA) or SSA in combination with transcatheter arterial chemoembolization. The objective response rate with first-line treatment was similar in both groups, whereas that with second-line treatment was higher in group 1 than in group 2, albeit with no significant differences (21.1% vs 5.3%, respectively; P = .205). Median progression-free survival (mPFS) for first-line and second-line treatments did not differ between the 2 groups (11 and 12 months vs 12 and 8 months, respectively). Following subgroup analyses, treatment with first-line sunitinib and sunitinib after pretreated SSA had a longer mPFS than that with second-line sunitinib after CAPTEM (11 months vs 8 months, respectively; P = .046), whereas treatment with first-line CAPTEM and CAPTEM after pretreated SSA had an mPFS similar to that of second-line CAPTEM after sunitinib treatment. CAPTEM and sunitinib had similar tolerability. CONCLUSION: Alternating sunitinib and CAPTEM were well tolerated and associated with similar mPFS in grade 1/grade 2 PanNETs. However, larger prospective studies are required to investigate the efficacy of alternate sequential therapies for metastatic PanNET.

MEN1 promotes ferroptosis by inhibiting mTOR-SCD1 axis in pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumor (pNET) is the second most common malignant tumors of the pancreas. Multiple endocrine neoplasia 1 ( MEN1) is the most frequently mutated gene in pNETs and MEN1-encoded protein, menin, is a scaffold protein that interacts with transcription factors and chromatin-modifying proteins to regulate various signaling pathways. However, the role of MEN1 in lipid metabolism has not been studied in pNETs. In this study, we perform targeted metabolomics analysis and find that MEN1 promotes the generation and oxidation of polyunsaturated fat acids (PUFAs). Meanwhile lipid peroxidation is a hallmark of ferroptosis, and we confirm that MEN1 promotes ferroptosis by inhibiting the activation of mTOR signaling which is the central hub of metabolism. We show that stearoyl-coA desaturase (SCD1) is the downstream of MEN1-mTOR signaling and oleic acid (OA), a metabolite of SCD1, recues the lipid peroxidation caused by MEN1 overexpression. The negative correlation between MEN1 and SCD1 is further verified in clinical specimens. Furthermore, we find that BON-1 and QGP-1 cells with MEN1 overexpression are more sensitive to everolimus, a widely used drug in pNETs that targets mTOR signaling. In addition, combined use everolimus with ferroptosis inducer, RSL3, possesses a more powerful ability to kill cells, which may provide a new strategy for the comprehensive therapy of pNETs.

Patterns and predictors of pancreatic neuroendocrine tumor prognosis: Are no two leaves alike?

Pancreatic neuroendocrine tumors (PanNETs) are heterogeneous; thus, individual prognostic prediction is important. Clinicopathological features, like TNM stage, grade, and differentiation, are independent clinical predictors. However, single predictors are insufficient, as patients sharing similar clinicopathological features usually show distinct prognoses. Accordingly, novel nomograms and risk stratifications have been developed for more accurate PanNET prognostic prediction. Moreover, the exploration of molecular mechanisms has identified novel prognostic predictors for PanNET. Multi-analyte assays of molecular biomarkers provide a deeper understanding of PanNET features; however, the priority, and the optimal combination of classic and novel predictors for PanNET prognosis prediction remain unclear. In this review, we summarized the patterns and predictors of PanNET prognosis and discussed their clinical utility; we emphasized that PanNET at different stages have different superior predictor, and that multi-analyte assays are more sensitive than mono-analyte biomarkers. Therefore, combined biomarkers improve the accuracy of surveillance and optimize decision-making in clinical practice.

Follicular Helper T Cells Remodel the Immune Microenvironment of Pancreatic Cancer via Secreting CXCL13 and IL-21.

Immunosuppression is an important factor for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Follicular helper T cells (Tfh cells) play an anti-tumor role in various malignant solid tumors and predict better patient prognosis. In the present study, we aimed to determine the immunosuppressive mechanism associated with Tfh cells and explore a new strategy to improve the tumor microenvironment of PDAC. Flow cytometry was used to detect the infiltration and proportion of Tfh cells in tumor tissues and peripheral blood from patients with PDAC. The spatial correlations of Tfh cells with related immune cells were evaluated using immunofluorescence. The function of Tfh cells was examined using in vitro and in vivo model systems. The high infiltration of Tfh cells predicted better prognosis in patients with PDAC. Tfh cells recruited CD8+ T cells and B cells by secreting C-X-C motif chemokine ligand 13 (CXCL13), and promoted the maturation of B cells into antibody-producing plasma cells by secreting interleukin 21 (IL-21), thereby promoting the formation of an immunoactive tumor microenvironment. The function of Tfh cells was inhibited by the programmed cell death 1 ligand 1 (PD-L1)/programmed cell death 1 (PD-1) signaling pathway in PDAC, which could be reversed using neoadjuvant chemotherapy. Treatment with recombinant CXCL13, IL-21 and Tfh cells alleviated tumor growth and enhanced the infiltration of CD8+ T cells and B cells, as well as B cell maturation in a PDAC mouse model. Our results revealed the important role of Tfh cells in mediating anti-tumor cellular immunity and humoral immunity in PDAC via secreting CXCL13 and IL-21 and determined a novel mechanism of immunosuppression in PDAC.