Comparative analysis of nascent RNA sequencing methods and their applications in studies of cotranscriptional splicing dynamics.

High-throughput detection of nascent RNA is critical for studies of transcription and much more challenging than that of mRNA. Recently, several massively parallel nascent RNA sequencing methods were established in eukaryotic cells. Here, we systematically compared 3 classes of methods on the same pure or crude nuclei preparations: GRO-seq for sequence nuclear run-on RNAs, pNET-seq for sequence RNA polymerase II-associated RNAs, and CB RNA-seq for sequence chromatin-bound (CB) RNAs in Arabidopsis (Arabidopsis thaliana). To improve the resolution of CB RNAs, 3'CB RNA-seq was established to sequence the 3' ends of CB RNAs. In addition, we modified pNET-seq to establish the Chromatin Native Elongation Transcript sequencing (ChrNET) method using chromatin as the starting material for RNA immunoprecipitation. Reproducibility, sensitivity and accuracy in detecting nascent transcripts, experimental procedures, and costs were analyzed, which revealed the strengths and weaknesses of each method. We found that pNET and GRO methods best detected active RNA polymerase II. CB RNA-seq is a simple and cost-effective alternative for nascent RNA studies, due to its high correlation with pNET-seq and GRO-seq. Compared with pNET, ChrNET has higher specificity for nascent RNA capture and lower sequencing cost. 3'CB is sensitive to transcription-coupled splicing. Using these methods, we identified 1,404 unknown transcripts, 4,482 unannotated splicing events, and 60 potential recursive splicing events. This comprehensive comparison of different nascent/chromatin RNA sequencing methods highlights the strengths of each method and serves as a guide for researchers aiming to select a method that best meets their study goals.

Unraveling the impact of cancer-associated fibroblasts on hypovascular pancreatic neuroendocrine tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) with low microvessel density and fibrosis often exhibit clinical aggressiveness. Given the contribution of cancer-associated fibroblasts (CAFs) to the hypovascular fibrotic stroma in pancreatic ductal adenocarcinoma, investigating whether CAFs play a similar role in PNETs becomes imperative. In this study, we investigated the involvement of CAFs in PNETs and their effects on clinical outcomes. METHODS: We examined 79 clinical PNET specimens to evaluate the number and spatial distribution of α-smooth muscle actin (SMA)-positive cells, which are indicative of CAFs. Then, the findings were correlated with clinical outcomes. In vitro and in vivo experiments were conducted to assess the effects of CAFs (isolated from clinical specimens) on PNET metastasis and growth. Additionally, the role of the stromal-cell-derived factor 1 (SDF1)-AGR2 axis in mediating communication between CAFs and PNET cells was investigated. RESULTS: αSMA-positive and platelet-derived growth factor-α-positive CAFs were detected in the hypovascular stroma of PNET specimens. A higher abundance of α-SMA-positive CAFs within the PNET stroma was significantly associated with a higher level of clinical aggressiveness. Notably, conditioned medium from PNET cells induced an inflammatory phenotype in isolated CAFs. These CAFs promoted PNET growth and metastasis. Mechanistically, PNET cells secreted interleukin-1, which induced the secretion of SDF1 from CAFs. This cascade subsequently elevated AGR2 expression in PNETs, thereby promoting tumor growth and metastasis. The downregulation of AGR2 in PNET cells effectively suppressed the CAF-mediated promotion of PNET growth and metastasis. CONCLUSION: CAFs drive the growth and metastasis of aggressive PNETs. The CXCR4-SDF1 axis may be a target for antistromal therapy in the treatment of PNET. This study clarifies mechanisms underlying PNET aggressiveness and may guide future therapeutic interventions targeting the tumor microenvironment.

Patient Priorities Concerning Treatment Decisions for Advanced Neuroendocrine Tumors Identified by Discrete Choice Experiments.

BACKGROUND: Patients with advanced neuroendocrine tumors (NETs) have multiple treatment options. Ideally, treatment decisions are shared between physician and patient; however, previous studies suggest that oncologists and patients place different value on treatment attributes such as adverse event (AE) rates. High-quality information on NET patient treatment preferences may facilitate patient-centered decision making by helping clinicians understand patient priorities. METHODS: This study used 2 discrete choice experiments (DCE) to elicit preferences of NET patients regarding advanced midgut and pancreatic NET (pNET) treatments. The DCEs used the "potentially all pairwise rankings of all possible alternatives" (PAPRIKA) method. The primary objective was to determine relative utility rankings for treatment attributes, including progression-free survival (PFS), treatment modality, and AE rates. Ranking of attribute profiles matching specific treatments was also determined. Levels for treatment attributes were obtained from randomized clinical trial data of NET treatments. RESULTS: One hundred and 10 participants completed the midgut NET DCE, and 132 completed the pNET DCE. Longer PFS was the highest ranked treatment attribute in 64.5% of participants in the midgut NET DCE, and in 59% in the pNET DCE. Approximately, 40% of participants in both scenarios prioritized lower AE rates or less invasive treatment modalities over PFS. Ranking of treatment profiles in the midgut NET scenario identified 60.9% of participants favoring peptide receptor radionuclide therapy (PRRT), and 30.0% somatostatin analogue dose escalation. CONCLUSION: NET patients have heterogeneous priorities when choosing between treatment options based on the results of 2 independent DCEs. These results highlight the importance of shared decision making for NET patients.

Accuracy and Prognostic Impact of Nodal Status on Preoperative Imaging for Management of Pancreatic Neuroendocrine Tumors: A Multi-Institutional Study.

BACKGROUND: We sought to define the accuracy of preoperative imaging to detect lymph node metastasis (LNM) among patients with pancreatic neuroendocrine tumors (pNETs), as well as characterize the impact of preoperative imaging nodal status on survival. METHODS: Patients who underwent curative-intent resection for pNETs between 2000 and 2020 were identified from eight centers. Sensitivity and specificity of computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET)-CT, and OctreoScan for LNM were evaluated. The impact of preoperative lymph node status on lymphadenectomy (LND), as well as overall and recurrence-free survival was defined. RESULTS: Among 852 patients, 235 (27.6%) individuals had LNM on final histologic examination (hN1). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 12.4%, 98.1%, 71.8%, and 74.4% for CT, 6.3%, 100%, 100%, and 80.1% for MRI, 9.5%, 100%, 100%, and 58.7% for PET, 11.3%, 97.5%, 66.7%, and 70.8% for OctreoScan, respectively. Among patients with any combination of these imaging modalities, overall sensitivity, specificity, PPV, and NPV was 14.9%, 97.9%, 72.9%, and 75.1%, respectively. Preoperative N1 on imaging (iN1) was associated with a higher number of LND (iN1 13 vs. iN0 9, p = 0.003) and a higher frequency of final hN1 versus preoperative iN0 (iN1 72.9% vs. iN0 24.9%, p < 0.001). Preoperative iN1 was associated with a higher risk of recurrence versus preoperative iN0 (median recurrence-free survival, iN1→hN1 47.5 vs. iN0→hN1 92.7 months, p = 0.05). CONCLUSIONS: Only 4% of patients with LNM on final pathologic examine had preoperative imaging that was suspicious for LNM. Traditional imaging modalities had low sensitivity to determine nodal status among patients with pNETs.

Efficacy and safety of temozolomide-based regimens in advanced pancreatic neuroendocrine tumors: a systematic review and meta-analysis.

BACKGROUND: Recent advances in the management of pancreatic neuroendocrine tumors (pNETs) highlight the potential benefits of temozolomide, an alkylating agent, for these patients. In this meta-analysis, we aimed to assess the outcome of temozolomide, alone or in combination with other anticancer medications in patients with advanced pNET. METHODS: Online databases of PubMed, Web of Science, Embase, the Cochrane Library, and ClinicalTrials.gov were searched systematically for clinical trials that reported the efficacy and safety of temozolomide in patients with advanced pNET. Random-effect model was utilized to estimate pooled rates of outcomes based on Response Evaluation Criteria in Solid Tumors criteria, biochemical response, and adverse events (AEs). RESULTS: A total of 14 studies, providing details of 441 individuals with advanced pNET, were included. The quantitative analyses showed a pooled objective response rate (ORR) of 41.2% (95% confidence interval, CI, of 32.4%-50.6%), disease control rate (DCR) of 85.3% (95% CI of 74.9%-91.9%), and a more than 50% decrease from baseline chromogranin A levels of 44.9% (95% CI of 31.6%-49.0%). Regarding safety, the results showed that the pooled rates of nonserious AEs and serious AEs were 93.8% (95% CI of 88.3%-96.8%) and 23.7% (95% CI of 12.0%-41.5%), respectively. The main severe AEs encompassed hematological toxicities. CONCLUSIONS: In conclusion, our meta-analysis suggests that treatment with temozolomide, either as a monotherapy or in combination with other anticancer treatments might be an effective and relatively safe option for patients with advanced locally unresectable and metastatic pNET. However, additional clinical trials are required to further strengthen these findings. This study has been registered in PROSPERO (CRD42023409280).

A radiomics-based interpretable model to predict the pathological grade of pancreatic neuroendocrine tumors.

OBJECTIVES: To develop a computed tomography (CT) radiomics-based interpretable machine learning (ML) model to predict the pathological grade of pancreatic neuroendocrine tumors (pNETs) in a non-invasive manner. METHODS: Patients with pNETs who underwent contrast-enhanced abdominal CT between 2010 and 2022 were included in this retrospective study. Radiomics features were extracted, and five radiomics-based ML models, namely logistic regression (LR), random forest (RF), support vector machine (SVM), XGBoost, and GaussianNB, were developed. The performance of these models was evaluated using a time-independent testing set, and metrics such as sensitivity, specificity, accuracy, and the area under the receiver operating characteristic curve (AUC) were calculated. The accuracy of the radiomics model was compared to that of needle biopsy. The Shapley Additive Explanation (SHAP) tool and the correlation between radiomics and biological features were employed to explore the interpretability of the model. RESULTS: A total of 122 patients (mean age: 50 ± 14 years; 53 male) were included in the training set, whereas 100 patients (mean age: 48 ± 13 years; 50 male) were included in the testing set. The AUCs for LR, SVM, RF, XGBoost, and GaussianNB were 0.758, 0.742, 0.779, 0.744, and 0.745, respectively, with corresponding accuracies of 73.0%, 70.0%, 77.0%, 71.9%, and 72.9%. The SHAP tool identified two features of the venous phase as the most significant, which showed significant differences among the Ki-67 index or mitotic count subgroups (p < 0.001). CONCLUSIONS: An interpretable radiomics-based RF model can effectively differentiate between G1 and G2/3 of pNETs, demonstrating favorable interpretability. CLINICAL RELEVANCE STATEMENT: The radiomics-based interpretable model developed in this study has significant clinical relevance as it offers a non-invasive method for assessing the pathological grade of pancreatic neuroendocrine tumors and holds promise as an important complementary tool to traditional tissue biopsy. KEY POINTS: • A radiomics-based interpretable model was developed to predict the pathological grade of pNETs and compared with preoperative needle biopsy in terms of accuracy. • The model, based on CT radiomics, demonstrated favorable interpretability. • The radiomics model holds potential as a valuable complementary technique to preoperative needle biopsy; however, it should not be considered a replacement for biopsy.

Radiomics analysis from magnetic resonance imaging in predicting the grade of nonfunctioning pancreatic neuroendocrine tumors: a multicenter study.

OBJECTIVES: To explore the potential of radiomics features to predict the histologic grade of nonfunctioning pancreatic neuroendocrine tumor (NF-PNET) patients using non-contrast sequence based on MRI. METHODS: Two hundred twenty-eight patients with NF-PNETs undergoing MRI at 5 centers were retrospectively analyzed. Data from center 1 (n = 115) constituted the training cohort, and data from centers 2-5 (n = 113) constituted the testing cohort. Radiomics features were extracted from T2-weighted images and the apparent diffusion coefficient. The least absolute shrinkage and selection operator was applied to select the most important features and to develop radiomics signatures. The area under receiver operating characteristic curve (AUC) was performed to assess models. RESULTS: Tumor boundary, enhancement homogeneity, and vascular invasion were used to construct the radiological model to stratify NF-PNET patients into grade 1 and 2/3 groups, which yielded AUC of 0.884 and 0.684 in the training and testing groups. A radiomics model including 4 features was constructed, with an AUC of 0.941 and 0.871 in the training and testing cohorts. The fusion model combining the radiomics signature and radiological characteristics showed good performance in the training set (AUC = 0.956) and in the testing set (AUC = 0.864), respectively. CONCLUSION: The developed model that integrates radiomics features with radiological characteristics could be used as a non-invasive, dependable, and accurate tool for the preoperative prediction of grade in NF-PNETs. CLINICAL RELEVANCE STATEMENT: Our study revealed that the fusion model based on a non-contrast MR sequence can be used to predict the histologic grade before operation. The radiomics model may be a new and effective biological marker in NF-PNETs. KEY POINTS: The diagnostic performance of the radiomics model and fusion model was better than that of the model based on clinical information and radiological features in predicting grade 1 and 2/3 of nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs). Good performance of the model in the four external testing cohorts indicated that the radiomics model and fusion model for predicting the grades of NF-PNETs were robust and reliable, indicating the two models could be used in the clinical setting and facilitate the surgeons' decision on risk stratification. The radiomics features were selected from non-contrast T2-weighted images (T2WI) and diffusion-weighted imaging (DWI) sequence, which means that the administration of contrast agent was not needed in grading the NF-PNETs.

A Single-center Experience of Radiotherapy in Pediatric Ewing Sarcoma/Primitive Neuroectodermal Tumor of the Chest Wall.

AIM: To evaluate the treatment results, prognostic parameters, and treatment-related toxicity in patients with Ewing sarcoma (ES)/primitive neuroectodermal tumor (PNET) of the chest wall who underwent surgery, chemotherapy, and radiotherapy (RT) in a tertiary referral center. METHODS: The data of 24 patients under 18 years of age with a histologic diagnosis of ES/PNET in the chest wall that received RT in our department between February 2003 and July 2020 were retrospectively evaluated. RT was applied to the primary site±whole involved chest wall and to the whole lung in patients with lung metastasis. RESULTS: The median age was 8.5 years (range: 1.5 to 17 y), 15 (63%) patients were female and 9 were male (37%). The tumor localization was extrathoracic in 18 (75%) and intrathoracic in 6 (25%) patients. Mediastinal lymph node and distant metastasis (DM) was present in 5 (21%) and 4 (16%) cases at diagnosis, respectively. The median follow-up after RT was 47 months (range: 11 to 162 mo). The 2-year and 5-year overall survival, event-free survival, local recurrence-free survival, and pleural recurrence-free survival were 83% and 48%, 48% and 42%, 74% and 48%, and 61% and 52%, respectively. The overall local control rate was 83% and the pleural control rate was 67%. RT was well tolerated, with 1 case of grade 3 acute dermatitis and 1 case of grade 3 subacute radiation pneumonitis. Late toxicity was observed in 3 (13%) cases. CONCLUSION: Long-term survival can be achieved with extended-field RT even in patients with ES/PNET of the chest wall with DM. The low toxicity rates allow us to draw the conclusion that RT with modern techniques is an effective and safe treatment modality for these patients.

Primary diffuse leptomeningeal primitive neuroectodermal tumor presenting as chronic meningitis.

Primary diffuse leptomeningeal primitive neuroectodermal tumor is a rare meningeal neoplasm which can masquerade as chronic meningitis. While the clinical presentation and radiological features may provide a clue to this condition, meningeal biopsy is essential to clinch the diagnosis. A high index of suspicion and a low threshold for re-evaluating cases of neuroinfection that do not respond to empirical therapy are essential in this scenario. We present the case of a nine year old boy who was initiated on antituberculous treatment for chronic meningitis with hydrocephalus. Meningeal biopsy revealed a primary diffuse leptomeningeal primitive neuroectodermal tumor.

Pancreatic Neuroendocrine Tumors: Signaling Pathways and Epigenetic Regulation.

Pancreatic neuroendocrine tumors (PNETs) are characterized by dysregulated signaling pathways that are crucial for tumor formation and progression. The efficacy of traditional therapies is limited, particularly in the treatment of PNETs at an advanced stage. Epigenetic alterations profoundly impact the activity of signaling pathways in cancer development, offering potential opportunities for drug development. There is currently a lack of extensive research on epigenetic regulation in PNETs. To fill this gap, we first summarize major signaling events that are involved in PNET development. Then, we discuss the epigenetic regulation of these signaling pathways in the context of both PNETs and commonly occurring-and therefore more extensively studied-malignancies. Finally, we will offer a perspective on the future research direction of the PNET epigenome and its potential applications in patient care.

Is long-term follow-up solely by imaging tests safe in non-operated pancreatic neuroendocrine tumors?

INTRODUCTION: the diagnosis of asymptomatic sporadic nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) has increased significantly due to the widespread use of high-resolution imaging tests, which is why the most appropriate management at the time of diagnosis is the subject of debate, as is how to follow-up patients. AIMS: the objective of this study was to analyze the frequency of imaging and endoscopic studies performed during long-term follow-up. METHODS: a retrospective review was performed of a database collected between January 2008 and December 2020 of patients with an incidental diagnosis of small NF-PNETs; follow-up was closed in March 2023. The imaging tests performed at the time of diagnosis and long-term follow-up were recorded. Growing less than 1 mm per year has not been considered as a worrisome feature. Follow-up was performed through imaging tests, considering endoscopic cytology for lesions with a faster grow rate. RESULTS: fifty-eight patients were included; the median age was 69 years. The initial mean size of the lesions studied was 12.79 mm (5-27). Follow-up was carried out only with computed tomography (CT) or magnetic resonance imaging (MRI). The initial size did not influence the behavior of the lesion in a statistically significant manner. Twenty-eight tumors (45 %) increased in size, with a growth equal to or less than 4 mm in 24 cases. The mean follow-up time was 82.41 months (12-164). No patient developed metastasis or died from PNET progression. CONCLUSIONS: the follow-up of neuroendocrine tumors of small size can be performed safely with only imaging tests.

Anti-angiogenic therapy using the multi-tyrosine kinase inhibitor Regorafenib enhances tumor progression in a transgenic mouse model of ß-cell carcinogenesis.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) represent a distinct hypervascularized tumor entity, often diagnosed at metastatic stage. Therapeutic efficacy of anti-angiogenic multi-kinase inhibitors is frequently limited by primary or acquired resistance in vivo. This study aimed to characterize the molecular mode of action as well as resistance mechanisms to the anti-angiogenic multi-tyrosine kinase inhibitor (TKI) Regorafenib in vitro and in vivo. METHODS: In vitro, human and murine pancreatic neuroendocrine cell lines were comparatively treated with Regorafenib and other TKIs clinically used in PNETs. Effects on cell viability and proliferation were analyzed. In vivo, transgenic RIP1Tag2 mice were treated with Regorafenib at two different time periods during carcinogenesis and its impact on angiogenesis and tumor progression was evaluated. RESULTS: Compared to the established TKI therapies with Sunitinib and Everolimus, Regorafenib showed the strongest effects on cell viability and proliferation in vitro, but was unable to induce apoptosis. Unexpectedly and in contrast to these in vitro findings, Regorafenib enhanced proliferation during early tumor development in RIP1Tag2 mice and had no significant effect in late tumor progression. In addition, invasiveness was increased at both time points. Mechanistically, we could identify an upregulation of the pro-survival protein Bcl-2, the induction of the COX2-PGE2-pathway as well as the infiltration of CSF1R positive immune cells into the tumors as potential resistance mechanisms following Regorafenib treatment. DISCUSSION: Our data identify important tumor cell-autonomous and stroma-dependent mechanisms of resistance to antiangiogenic therapies.

Breastfeeding and risk of childhood brain tumors: a report from the Childhood Cancer and Leukemia International Consortium.

PURPOSE: Studies report mixed findings regarding the association of breastfeeding with childhood brain tumors (CBT), the leading causes of cancer-related mortality in young people. Our objective was to determine whether breastfeeding is associated with CBT incidence. METHODS: We pooled data on N = 2610 cases with CBT (including 697 cases with astrocytoma, 447 cases with medulloblastoma/primitive neuroectodermal tumor [PNET], 167 cases with ependymoma) and N = 8128 age- and sex-matched controls in the Childhood Cancer and Leukemia International Consortium. We computed unconditional logistic regression models to estimate the odds ratio (OR) and 95% confidence interval (CI) of CBT, astrocytoma, medulloblastoma/PNET, and ependymoma according to breastfeeding status, adjusting for study, sex, mode of delivery, birthweight, age at diagnosis/interview, maternal age at delivery, maternal educational attainment, and maternal race/ethnicity. We evaluated any breastfeeding versus none and breastfeeding ≥ 6 months versus none. We subsequently performed random effects meta-analysis to confirm our findings, identify potential sources of heterogeneity, and evaluate for outliers or influential studies. RESULTS: Breastfeeding was reported by 64.8% of control mothers and 64.5% of case mothers and was not associated with CBT (OR 1.04, 95% CI 0.94-1.15), astrocytoma (OR 1.01, 95% CI 0.87-1.17), medulloblastoma/PNET (OR 1.11, 95% CI 0.93-1.32), or ependymoma (OR 1.06, 95% CI 0.81-1.40). Results were similar when we restricted to breastfeeding ≥ 6 months and in meta-analyses. CONCLUSION: Our data suggest that breastfeeding does not protect against CBT.

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.

Calcifications and Cystic Morphology on Preoperative Imaging Predict Survival After Resection of Pancreatic Neuroendocrine Tumors.

BACKGROUND: Radiographic calcifications and cystic morphology are associated with higher and lower tumor grade, respectively, in pancreatic neuroendocrine tumors (PNETs). Whether calcifications and/or cystic morphology could be used preoperatively to predict post-resection survival in patients with PNETs remains elusive. METHODS: Patients undergoing curative-intent resection of well-differentiated PNETs from 2000 to 2017 at eight academic institutions participating in the US Neuroendocrine Tumor Study Group were identified. Preoperative cross-sectional imaging reports were reviewed to identify the presence of calcifications and of a cystic component occupying >50% of the total tumor area. Clinicopathologic characteristics and recurrence-free survival (RFS) were compared. RESULTS: Of 981 patients studied, 18% had calcifications and 17% had cystic tumors. Tumors with calcifications were more commonly associated with Ki-67 ≥3% (47% vs. 33%; p = 0.029), lymph node metastasis (36% vs. 24%; p = 0.011), and distant metastasis (13% vs. 4%; p < 0.001). In contrast, cystic tumors were less commonly associated with lymph node metastasis (12% vs. 30%; p < 0.001). Five-year RFS after resection was most favorable for cystic tumors without calcifications (91%), intermediate for solid tumors without calcifications (77%), and least favorable for any calcified PNET (solid 69%, cystic 67%; p = 0.043). Calcifications remained an independent predictor of RFS on multivariable analysis (p = 0.043) controlling for nodal (p < 0.001) and distant metastasis (p = 0.001). CONCLUSIONS: Easily detectable radiographic features, such as calcifications and cystic morphology, can be used preoperatively to stratify prognosis in patients with PNETs and possibly inform the decision to operate or not, as well as guide the extent of resection and potential use of neoadjuvant therapy.

A dose escalation/expansion study evaluating dose, safety, and efficacy of the novel tyrosine kinase inhibitor surufatinib, which inhibits VEGFR 1, 2, & 3, FGFR 1, and CSF1R, in US patients with neuroendocrine tumors.

Surufatinib, is a potent inhibitor of vascular endothelial growth factor receptors 1-3; fibroblast growth factor receptor-1; colony-stimulating factor 1 receptor. This Phase 1/1b escalation/expansion study in US patients with solid tumors evaluated 5 once daily (QD) surufatinib doses (3 + 3 design) to identify maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and evaluate safety and efficacy at the RP2D in 4 disease-specific expansion cohorts including pancreatic neuroendocrine tumors [pNET] and extrapancreatic NETs [epNET]. MTD and RP2D were 300 mg QD (escalation [n = 35]); 5 patients (15.6%) (Dose Limiting Toxicity [DLT] Evaluable Set [n = 32]) had DLTs. Pharmacokinetics were dose proportional. Estimated progression-free survival (PFS) rates at 11 months were 57.4% (95% confidence interval [CI]: 28.7, 78.2) and 51.1% (95% CI: 12.8, 80.3) for pNET and epNET expansion cohorts, respectively. Median PFS was 15.2 (95% CI: 5.2, not evaluable) and 11.5 (95% CI: 6.5,11.5) months. Response rates were 18.8% and 6.3%. The most frequent treatment-emergent adverse events (both cohorts) were fatigue (46.9%), hypertension (43.8%), proteinuria (37.5%), diarrhea (34.4%). Pharmacokinetics, safety, and antitumor efficacy of 300 mg QD oral surufatinib in US patients with pNETs and epNETs are consistent with previously reported studies in China and may support applicability of earlier surufatinib studies in US patients. Clinical trial registration: Clinicaltrials.gov NCT02549937.

Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification.

Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/ß-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.

Bibliometric analysis of Ewing sarcoma from 1993 to 2022.

BACKGROUND: Ewing sarcoma has attracted more attention in recent years but has yet to be bibliometrically analyzed. Hence, this study investigated the trend of Ewing sarcoma over the past 30 years with bibliometric analysis. METHODS: Original publications related to Ewing sarcoma were obtained from the Science Citation Index Extension (SCI-E), Social Sciences Citation Index (SSCI), and Web of Science Core Collection (WoSCC) between 1993 and 2022. CiteSpace and VOSviewer were used to extract the countries/regions, institutions, authors, journals, references, and keywords involved in this topic to identify and analyze the research hotspots and trends in this field. RESULTS: Over the past 30 years (especially in the past five years), the number of articles published on Ewing sarcoma continued to increase, and the most published country was the United States of America (USA). High-frequency keywords included "Ewing sarcoma", "tumor", "family", "bone", "chemotherapy", "expression", "primitive neuroectodermal tumor", "prognostic factors", "children", and "survival rate". According to the analysis of keyword saliency of Ewing sarcoma, we found that "chromosome translocation", "intergroup", "sarcoma", "genomic landscape", and "children oncology group" were emerging research hotspots. The timeline of the cluster map of co-cited literature indicated that the treatment of Ewing sarcoma emerged as a research hotspot. CONCLUSION: Researchers' understanding of Ewing sarcoma has improved dramatically over the past 30 years. At present, the research hotspots of Ewing sarcoma mainly focus on the aspects of "chromosome translocation", "intergroup", and "sarcoma". In addition, the timeline of the cluster map of co-cited literature indicated the emergence of the treatment of Ewing sarcoma as a research hotspot.

Two machine learning-based nomogram to predict risk and prognostic factors for liver metastasis from pancreatic neuroendocrine tumors: a multicenter study.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are one of the most common endocrine tumors, and liver metastasis (LMs) are the most common location of metastasis from PNETS; However, there is no valid nomogram to predict the diagnosis and prognosis of liver metastasis (LMs) from PNETs. Therefore, we aimed to develop a valid predictive model to aid physicians in making better clinical decisions. METHODS: We screened patients in the Surveillance, Epidemiology, and End Results (SEER) database from 2010-2016. Feature selection was performed by machine learning algorithms and then models were constructed. Two nomograms were constructed based on the feature selection algorithm to predict the prognosis and risk of LMs from PNETs. We then used the area under the curve (AUC), receiver operating characteristic (ROC) curve, calibration plot and consistency index (C-index) to evaluate the discrimination and accuracy of the nomograms. Kaplan-Meier (K-M) survival curves and decision curve analysis (DCA) were also used further to validate the clinical efficacy of the nomograms. In the external validation set, the same validation is performed. RESULTS: Of the 1998 patients screened from the SEER database with a pathological diagnosis of PNET, 343 (17.2%) had LMs at the time of diagnosis. The independent risk factors for the occurrence of LMs in PNET patients included histological grade, N stage, surgery, chemotherapy, tumor size and bone metastasis. According to Cox regression analysis, we found that histological subtype, histological grade, surgery, age, and brain metastasis were independent prognostic factors for PNET patients with LMs. Based on these factors, the two nomograms demonstrated good performance in model evaluation. CONCLUSION: We developed two clinically significant predictive models to aid physicians in personalized clinical decision-makings.

Comparison of EUS-guided ablation and surgical resection for nonfunctioning small pancreatic neuroendocrine tumors: a propensity score-matching study.

BACKGROUND AND AIMS: Treatment strategies for small pancreatic neuroendocrine tumors (PNETs) <2 cm in size are still under debate. The feasibility and safety of EUS-guided ethanol ablation (EUS-EA) have been demonstrated. However, sample sizes in previous studies were small with no comparative studies on surgery. Therefore, we aimed to compare the safety and long-term outcomes of EUS-EA with those of surgery for the management of nonfunctioning small PNETs. METHODS: We retrospectively reviewed patients with PNETs who were managed by EUS-EA (from 2011 to 2018) and surgery (from 2000 to 2018) at Asan Medical Center. Propensity score matching (PSM) was performed to increase comparability. The primary outcome was early and late major adverse events (Clavien-Dindo grade ≥III) after treatment. Secondary outcomes were 10-year overall (OS) and disease-specific survival (DSS) rates, length of hospital stay, and development of endocrine pancreatic insufficiency. RESULTS: Of all patients, 97 and 188 patients were included in the EUS-EA and surgery groups, respectively. PSM created 89 matched pairs. EUS-EA was associated with a significantly lower rate of early major adverse events (0% vs 11.2%, P = .003). Late major adverse events occurred more frequently after surgery, with no significant difference between groups (3.4% vs 10.1%, P = .07). Both treatment modalities showed comparable 10-year OS and DSS rates. The length of hospital stay was significantly shorter in the EUS-EA group (4 days vs 14.1 days, P < .001), and endocrine pancreatic insufficiency was less common after EUS-EA than after surgery (33.3% vs 48.6%, P = .121). CONCLUSIONS: EUS-EA had fewer adverse events and a shorter hospital stay with similar OS and DSS rates compared with surgery, suggesting that EUS-EA may be a preferred alternative to surgical resection in selected patients with nonfunctioning small PNETs.