Subject(s)
Pancreatic Neoplasms , Sarcoma, Ewing , Humans , Sarcoma, Ewing/diagnostic imaging , Sarcoma, Ewing/pathology , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/diagnostic imaging , Neuroectodermal Tumors, Primitive/pathology , Neuroectodermal Tumors, Primitive/diagnostic imaging , Neuroectodermal Tumors, Primitive/diagnosis , Male , FemaleABSTRACT
This case report describes a patient with medulloepithelioma of the ciliary body that was subsequently diagnosed as DICER1 syndrome.
Subject(s)
DEAD-box RNA Helicases , Eye Neoplasms , Neuroectodermal Tumors, Primitive , Thyroid Neoplasms , Female , Humans , Male , DEAD-box RNA Helicases/genetics , Eye Neoplasms/diagnosis , Eye Neoplasms/pathology , Ribonuclease III/genetics , Neuroectodermal Tumors, Primitive/diagnosis , Neuroectodermal Tumors, Primitive/pathology , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/pathologyABSTRACT
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.
Subject(s)
Neuroectodermal Tumors, Primitive , Sarcoma, Ewing , Thoracic Wall , Humans , Sarcoma, Ewing/radiotherapy , Sarcoma, Ewing/pathology , Sarcoma, Ewing/mortality , Male , Female , Child , Adolescent , Thoracic Wall/pathology , Thoracic Wall/radiation effects , Child, Preschool , Retrospective Studies , Infant , Neuroectodermal Tumors, Primitive/radiotherapy , Neuroectodermal Tumors, Primitive/pathology , Neuroectodermal Tumors, Primitive/mortality , Neuroectodermal Tumors, Primitive/therapy , Survival Rate , Prognosis , Thoracic Neoplasms/radiotherapy , Thoracic Neoplasms/pathology , Thoracic Neoplasms/mortality , Follow-Up Studies , Bone Neoplasms/radiotherapy , Bone Neoplasms/pathology , Bone Neoplasms/mortalitySubject(s)
Lung Neoplasms , Neuroectodermal Tumors, Primitive , Humans , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/diagnosis , Lung Neoplasms/pathology , Neuroectodermal Tumors, Primitive/diagnosis , Neuroectodermal Tumors, Primitive/diagnostic imaging , Neuroectodermal Tumors, Primitive/pathology , Tomography, X-Ray ComputedABSTRACT
PURPOSE: The purpose of our study was to investigate the clinical significance and prognostic role of the systemic immune-inflammation index (SII) in patients who underwent surgical resection for nonfunctioning pancreatic neuroendocrine tumors (pNETs). METHODS: We conducted a retrospective analysis of 364 patients with nonfunctioning pNETs. The association between the SII level and clinical parameters was investigated. The receiver operating characteristic (ROC) curve was used to calculate the optimal SII value. Cox proportional hazard analysis was performed to evaluate the prognostic factors. RESULTS: Our study included 364 patients with nonfunctioning pNETs who underwent surgery. The median age was 51.0 (43.0, 59.3), and 164 (45.1%) were male. The optimal threshold of SII determined by ROC analysis was 523.95. Higher SII levels were significantly associated with older age (p = 0.001), sex (p = 0.011), tumor size (p = 0.032), and tumor grade (p = 0.002). Recurrence was observed in 70 (19.2%) patients following a median follow-up of 98 months. Univariate analysis showed that higher SII (p < 0.0001), tumor size >4 cm (p = 0.015), and G2/G3 grade (p = 0.002) were significantly associated with disease-free survival (DFS). Multivariate analysis revealed that higher SII (HR: 7.35; 95% CI: 3.44, 15.70; p < 0.0001) and G2/G3 grade (HR: 3.11; 95% CI: 1.42, 6.82; p = 0.005) remained significantly associated with tumor recurrence. Furthermore, 46 (12.6%) patients died during the follow-up. Higher SII (HR: 8.43; 95% CI: 3.19, 22.72; p < 0.0001) and G2/G3 grade (HR: 3.16; 95% CI: 1.01, 9.86; p = 0.048) were independent predictors of overall survival (OS) by multivariate analysis. CONCLUSION: In conclusion, our study revealed that a higher SII level was associated with tumor-related features (larger tumor size and advanced grade) and subsequent shorter DFS and OS in patients with nonfunctioning pNETs. These results indicated that the SII could serve as an efficient prognostic biomarker for nonfunctioning pNETs.
Subject(s)
Neuroectodermal Tumors, Primitive , Neuroendocrine Tumors , Pancreatic Neoplasms , Humans , Male , Middle Aged , Female , Prognosis , Neuroendocrine Tumors/surgery , Retrospective Studies , Neoplasm Recurrence, Local , Inflammation/pathology , Pancreatic Neoplasms/surgery , Pancreatic Neoplasms/pathologyABSTRACT
BACKGROUND: Pulmonary primitive neuroectodermal tumor (PNET), a member of the Ewing sarcoma family of tumors, is a rare malignancy that is associated with a grim prognosis. To date, fewer than 30 cases of pulmonary PNET have been reported. In this case report, we present the clinical details of a 12-year-old girl with pulmonary PNET who underwent surgical treatment. We also conducted an analysis and summary of other relevant studies and the surgical outcomes. CASE PRESENTATION: In May 2018, a 12-year-old girl was admitted with symptoms of cough and blood-tinged phlegm. A computed tomography scan revealed a large mass, measuring 12.9 cm × 8.1 cm, in the right middle and lower lungs. A percutaneous lung biopsy confirmed poorly differentiated tumor cells with a nested growth pattern. Immunohistochemical staining demonstrated positive expression of CD99, CD56, Vimentin, and Synaptophysin. The patient was diagnosed with pulmonary PNET. Following three cycles of neoadjuvant chemotherapy, a substantial reduction in tumor volume was observed. Subsequently, the patient underwent a surgical procedure involving pneumonectomy and partial resection of the left atrium with the assistance of cardiopulmonary bypass. The patient was discharged 37 days after surgery. During a three-year follow-up period, she exhibited no signs of tumor recurrence and has successfully returned to school. CONCLUSIONS: This case highlights the successful management of an advanced PNET with neoadjuvant chemotherapy, pneumonectomy, and partial resection of the left atrium employing cardiopulmonary bypass. The patient remained disease-free after three years. Our analysis of surgically treated cases indicates that neoadjuvant chemotherapy can contribute to improved prognoses for PNET patients. It is crucial to emphasize that complete surgical excision remains the cornerstone of treatment, underscoring the importance of surgeons considering radical surgical approaches whenever feasible for patients with pulmonary PNETs.
Subject(s)
Neoplasm Recurrence, Local , Neuroectodermal Tumors, Primitive , Female , Humans , Child , Pneumonectomy , Neoadjuvant Therapy , Lung , Neuroectodermal Tumors, Primitive/diagnosis , Neuroectodermal Tumors, Primitive/surgeryABSTRACT
BACKGROUND: Most patients with advanced pancreatic neuroendocrine tumors (pNETs) die due to tumor progression. Therefore, identifying new therapies with low toxicity and good tolerability to use concomitantly with the established pNET treatment is relevant. In this perspective, metformin is emerging as a molecule of interest. Retrospective studies have described metformin, a widely used agent for the treatment of patients with type 2 diabetes mellitus (T2DM), to be effective in modulating different tumor-related events, including cancer incidence, recurrence and survival by inhibiting mTOR phosphorylation. This systematic review evaluates the role of T2DM and metformin in the insurgence and post-treatment outcomes in patients with pNET. AIM: To systematically analyze and summarize evidence related to the diagnostic and prognostic value of T2DM and metformin for predicting the insurgence and post-treatment outcomes of pNET. METHODS: A systematic review of the published literature was undertaken, focusing on the role of T2DM and metformin in insurgence and prognosis of pNET, measured through outcomes of tumor-free survival (TFS), overall survival and progression-free survival. RESULTS: A total of 13 studies (5674 patients) were included in this review. Analysis of 809 pNET cases from five retrospective studies (low study heterogeneity with I² = 0%) confirms the correlation between T2DM and insurgence of pNET (OR = 2.13, 95%CI = 1.56-4.55; P < 0.001). The pooled data from 1174 pNET patients showed the correlation between T2DM and post-treatment TFS in pNET patients (hazard ratio = 1.84, 95%CI = 0.78-2.90; P < 0.001). The study heterogeneity was intermediate, with I² = 51%. A few studies limited the possibility of performing pooled analysis in the setting of metformin; therefore, results were heterogeneous, with no statistical relevance to the use of this drug in the diagnosis and prognosis of pNET. CONCLUSION: T2DM represents a risk factor for the insurgence of pNET and is a significant predictor of poor post-treatment TFS of pNET patients. Unfortunately, a few studies with heterogeneous results limited the possibility of exploring the effect of metformin in the diagnosis and prognosis of pNET.
Subject(s)
Diabetes Mellitus, Type 2 , Metformin , Neuroectodermal Tumors, Primitive , Neuroendocrine Tumors , Pancreatic Neoplasms , Humans , Metformin/adverse effects , Diabetes Mellitus, Type 2/drug therapy , Neuroendocrine Tumors/pathology , Retrospective Studies , Pancreatic Neoplasms/pathology , Neuroectodermal Tumors, Primitive/drug therapyABSTRACT
BACKGROUND: Small round cell tumors (SRCTs) are a group of malignant neoplasms with minimal or no differentiation, characterized by the presence of round cells with high nuclear-cytoplasmic ratio. Although SRCTs can occur in any part of the body, involvement of central nervous system (CNS) is uncommon. AIM: We aimed to study the clinicopathological spectrum of cranial SRCT diagnosed in our institute over a period of four years (2016-2019). MATERIAL AND METHODS: A retrospective review of medical records (2016-2019) with a morphological diagnosis of cranial SRCT was made. Both intra-axial and extra-axial tumors were included. A total of 60 cases were retrieved, and the clinical and histopathological features were studied. Special cytochemical staining and immunohistochemistry were performed, where needed. RESULTS: The mean age at presentation was 18.4 years (range, 1-60 years), with a male-to-female ratio of 2.5:1. The most common site was posterior fossa of brain (n = 28, 47%), followed by dorso-lumbar spine (n = 9, 15%). The most common type of tumor was medulloblastoma (n = 29, 48.3%), followed by Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumor (pPNET) (n = 11, 18.3%), non-Hodgkin lymphoma (NHL) (n = 9, 15%), neuroblastoma (n = 3, 5%), and CNS embryonal tumor, NOS (n = 2, 3.3%). One case each of atypical teratoid rhabdoid tumor (ATRT), rhabdomyosarcoma, pineoblastoma, melanoma, rhabdomyosarcoma, and undifferentiated pleomorphic sarcoma was also documented. CONCLUSIONS: SRCTs have a variable age of presentation. Their incidence in CNS is low as compared to other organ systems. On light microscopy, the histopathology of these lesions is overlapping, posing a great diagnostic dilemma for the pathologist. The use of ancillary techniques like immunohistochemistry helps in arriving at the correct diagnosis. Treatment strategy and tumor prognosis also vary along the entire spectrum of SRCT, thus making exact characterization essential for proper management.
Subject(s)
Central Nervous System Neoplasms , Cerebellar Neoplasms , Neoplasms, Germ Cell and Embryonal , Neuroectodermal Tumors, Primitive , Rhabdomyosarcoma , Sarcoma , Humans , Male , Female , Infant , Child, Preschool , Child , Adolescent , Young Adult , Adult , Middle Aged , Tertiary Care Centers , Sarcoma/pathology , Rhabdomyosarcoma/pathology , Neuroectodermal Tumors, Primitive/pathology , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/epidemiologyABSTRACT
Primitive neuroectodermal tumor (PNET) is a general term used in scientific literature for a heterogeneous group of small round-cell malignant tumors primarily arising from neural crest cells. These are extremely aggressive neoplasms which usually occur within soft tissue or bone of young adults. Ovarian tumors composed of primitive neuroectodermal elements are extremely rare, with only few case reports in scientific literature. Due to being so exceedingly rare, PNETs are frequently misdiagnosed and there are no standard therapeutic guidelines. Young patients seem to have better prognoses and individualized strategy is recommended. Limited data suggests that various gene deletions as well as amplifications may be crucial factors for tumorigenesis and the aggressive behavior of PNET. In this paper, we performed a brief review of all cases of primary ovarian PNETs published in the scientific literature to date, in regard to their clinical, histopathological, and therapeutic aspects, with the aim to provide a more comprehensive understanding of this exceedingly rare pathology.
Subject(s)
Neuroectodermal Tumors, Primitive , Ovarian Neoplasms , Female , Humans , Young Adult , Neuroectodermal Tumors, Primitive/drug therapy , Neuroectodermal Tumors, Primitive/pathology , Ovarian Neoplasms/geneticsSubject(s)
Central Nervous System Neoplasms , Neuroectodermal Tumors, Primitive , Humans , Transcription Factors/genetics , Nuclear Proteins/genetics , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/pathology , Repressor Proteins , Proto-Oncogene Proteins/genetics , Bromodomain Containing Proteins , Cell Cycle Proteins/geneticsABSTRACT
Background: Non-invasive prognostic predictors for rare pancreatic neuroendocrine tumors (PNETs) are lacking. We aimed to approach the prognostic value of preoperative systemic inflammatory markers in patients with PNETs. Methods: The clinical data of 174 patients with PNETs undergoing surgical treatment were retrospectively analyzed to explore the correlation of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and platelet to white blood cell ratio (PWR) with clinicopathological parameters and the progression of tumor after the operation. The optimal cutoff values for predictors and the area under the curve (AUC) of the receiver operating characteristic (ROC) were estimated. Univariate and multivariate Cox proportional hazards models were used to assess the relation between NLR, LMR, PLR, and progression-free survival (PFS), examined by the Kaplan-Meier and log-rank tests. Results: The scores of the NLR (P = 0.039) and PLR (P = 0.011) in the progression group were significantly higher than those in the progression-free group, and the LMR was significantly lower than those in the progression-free group (P = 0.001). The best cutoff values of NLR, LMR, and PLR before operation were 2.28, 4.36, and 120.91. The proportions of tumor progression in the high NLR group (P = 0.007) and high PLR group (P = 0.013) obviously increased, and the proportion of tumor development in the low LMR group was higher than that in the high LMR group (P < 0.001). The K-M survival curve showed that the progression-free survival rate was lower in the high NLR group (P = 0.004), the low LMR group (P < 0.001), and the high PLR group (P = 0.018). The results of the multivariate Cox proportional hazards model suggested that preoperative LMR (HR = 3.128, 95% CI: 1.107~8.836, P = 0.031) was an independent predictor of PFS. Conclusion: The markers of systemic inflammation, especially LMR, can predict the postoperative progression of PNETs.
Subject(s)
Neuroectodermal Tumors, Primitive , Neuroendocrine Tumors , Pancreatic Neoplasms , Humans , Retrospective Studies , Neuroendocrine Tumors/diagnosis , Neuroendocrine Tumors/surgery , Inflammation/diagnosis , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/surgeryABSTRACT
INTRODUCTION: Insulinomas are the most common functional pancreatic neuroendocrine tumors (PNETs) that lead to incapacitating hypoglycemia. Guidelines recommend surgical resection as the mainstay of management. However, surgery is fraught with complications, causing significant peri/post-operative morbidity. Since insulinomas are usually benign, solitary, small (<2 cm), and do not need lymphadenectomy, hence, in this regard, endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is now being increasingly performed, to circumvent these adverse events and impairment of pancreatic function. AREAS COVERED: A comprehensive literature search was undertaken across various databases (PubMed/MEDLINE, Embase, Scopus), with no language restriction, for relevant articles (case series, reviews, case reports) pertaining to EUS-RFA for insulinoma and PNETs, till October 2023. In this review, we have explicated the role of EUS-RFA for insulinoma management, detailing thoroughly its mechanism of action, EUS-RFA devices with data on its safety and efficacy, and an algorithmic approach for its management. EXPERT OPINION: EUS-RFA is being advocated as a 'mini-invasive' option with the potential to replace surgery as a first-line approach for benign, sporadic, solitary, and small (<2 cm) insulinomas. Under real-time guidance, EUS-RFA has immense precision, is safe, predictable, with acceptable safety profile. Presently, it is being frequently performed for high-risk or inoperable candidates. Current need-of-the-hour is a randomized controlled trial to substantiate its role in the therapeutic algorithm for insulinoma management.
Subject(s)
Insulinoma , Neuroectodermal Tumors, Primitive , Pancreatic Neoplasms , Radiofrequency Ablation , Humans , Insulinoma/diagnostic imaging , Insulinoma/surgery , Insulinoma/complications , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/surgery , Pancreatic Neoplasms/complications , Treatment Outcome , Endosonography , Ultrasonography, Interventional/adverse effects , Neuroectodermal Tumors, Primitive/complicationsABSTRACT
BACKGROUND: To date, real-world evidence around the clinical and economic burden related to von Hippel-Lindau (VHL) disease is limited. Therefore, this study characterized the prevalence, healthcare resource utilization (HRU), and economic burden of von Hippel-Lindau-associated central nervous system hemangioblastoma (VHL-CNS-Hb) and pancreatic neuroendocrine tumors (VHL-pNET) in the United States (US). METHODS: Patients with VHL-CNS-Hb or VHL-pNET were identified from Optum's de-identified Clinformatics® Data Mart Database (2007-2020) and matched 1:5 to control patients without VHL disease or CNS-Hb/pNET. Prevalence rates of VHL-CNS-Hb and VHL-pNET (standardized by age and sex) in 2019 were estimated. HRU and healthcare costs (2020 US dollars) were compared between the VHL-CNS-Hb/VHL-pNET and control cohorts. RESULTS: In 2019, US prevalence rates of VHL-CNS-Hb and VHL-pNET were estimated to be 1.12 cases per 100,000 (3,678 patients) and 0.12 cases per 100,000 (389 patients), respectively. Patients with VHL-CNS-Hb (N = 220) had more inpatient, outpatient, and emergency department visits and $49,645 higher annual healthcare costs than controls (N = 1,100). Patients with VHL-pNET (N = 20) had more inpatient and outpatient visits and $56,580 higher annual healthcare costs than controls (N = 100). Costs associated with surgical removal of CNS-Hb and pNET were particularly high. CONCLUSIONS: In this retrospective, claims-based study, both VHL-CNS-Hb and VHL-pNET were associated with substantial HRU and healthcare costs, particularly tumor reduction surgery-related costs. These findings provide important insight for healthcare payers regarding the expected real-world costs that enrollees with VHL-CNS-Hb and VHL-pNET may incur over the course of their disease.
Subject(s)
Hemangioblastoma , Neuroectodermal Tumors, Primitive , Neuroendocrine Tumors , Pancreatic Neoplasms , von Hippel-Lindau Disease , Humans , von Hippel-Lindau Disease/complications , Neuroendocrine Tumors/epidemiology , Neuroendocrine Tumors/pathology , Hemangioblastoma/epidemiology , Financial Stress , Retrospective Studies , Central Nervous System/pathology , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/pathologyABSTRACT
Because of its rarity, the diagnosis of optic nerve medulloepithelioma poses a real diagnostic challenge. Medulloepithelioma is a congenital tumor that derives from the primitive medullary epithelium present in the neural tube and the optic vesicle. Its classical location is the ciliary body. Cases of retinal or optic nerve locations have been rarely reported in the literature. Only 11 cases have been published in the English literature. Herein, we report the case of a 2-year-old boy who underwent enucleation of the right eye for a presumed diagnosis of right-eye retinoblastoma, based on the presence of leukocoria on ophthalmological examination. Pathological examination showed an optic nerve medulloepithelioma. A review of the literature is also discussed in our work.
Subject(s)
Neuroectodermal Tumors, Primitive , Retinal Neoplasms , Retinoblastoma , Male , Humans , Child, Preschool , Neuroectodermal Tumors, Primitive/pathology , Optic Nerve/pathology , Retinoblastoma/pathology , Ciliary Body/pathology , Retinal Neoplasms/pathology , Eye EnucleationABSTRACT
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).
Subject(s)
Neuroectodermal Tumors, Primitive , Neuroendocrine Tumors , Pancreatic Neoplasms , Humans , Temozolomide/adverse effects , Neuroendocrine Tumors/drug therapy , Neuroendocrine Tumors/pathology , Response Evaluation Criteria in Solid Tumors , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathologyABSTRACT
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.
Subject(s)
Cancer-Associated Fibroblasts , Neuroectodermal Tumors, Primitive , Neuroendocrine Tumors , Pancreatic Neoplasms , Humans , Cancer-Associated Fibroblasts/metabolism , Neuroendocrine Tumors/pathology , Cell Line, Tumor , Pancreatic Neoplasms/pathology , Neuroectodermal Tumors, Primitive/metabolism , Neuroectodermal Tumors, Primitive/pathology , Tumor Microenvironment , Fibroblasts/metabolism , Mucoproteins/metabolism , Mucoproteins/therapeutic use , Oncogene Proteins/metabolismABSTRACT
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.
Subject(s)
Neuroectodermal Tumors, Primitive , Neuroendocrine Tumors , Pancreatic Neoplasms , Humans , Pancreatic Neoplasms/pathology , Neuroendocrine Tumors/pathology , Epigenesis, Genetic , Signal TransductionABSTRACT
OBJECTIVES: To develop a nomogram to predict the aggressiveness of non-functional pancreatic neuroendocrine tumors (NF-pNETs) based on preoperative computed tomography (CT) features. METHODS: This study included 176 patients undergoing radical resection for NF-pNETs. These patients were randomly divided into the training (n = 123) and validation sets (n = 53). A nomogram was developed based on preoperative predictors of aggressiveness of the NF-pNETs which were identified by univariable and multivariable logistic regression analysis. The aggressiveness of NF-pNETs was defined as a composite measure including G3 grading, N+, distant metastases, and/ or disease recurrence. RESULTS: Altogether, the number of patients with highly aggressive NF-pNETs was 37 (30.08 %) and 15 (28.30 %) in the training and validation sets, respectively. Multivariable logistic regression analysis identified that tumor size, biliopancreatic duct dilatation, lymphadenopathy, and enhancement pattern were preoperative predictors of aggressiveness. Those variables were used to develop a nomogram with good concordance statistics of 0.89 and 0.86 for predicting aggressiveness in the training and validation sets, respectively. With a nomogram score of 59, patients with NF-pNETs were divided into low-aggressive and high-aggressive groups. The high-aggressive group had decreased overall survival (OS) and disease-free survival (DFS). Moreover, the nomogram showed good performance in predicting OS and DFS at 3, 5, and 10 years. CONCLUSION: The nomogram integrating CT features helped preoperatively predict the aggressiveness of NF-pNETs and could potentially facilitate clinical decision-making.
Subject(s)
Neuroectodermal Tumors, Primitive , Neuroendocrine Tumors , Pancreatic Neoplasms , Humans , Nomograms , Neuroendocrine Tumors/diagnostic imaging , Neuroendocrine Tumors/surgery , Neuroendocrine Tumors/pathology , Retrospective Studies , Neoplasm Recurrence, Local/diagnostic imaging , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/surgery , Pancreatic Neoplasms/pathology , Tomography, X-Ray Computed/methodsABSTRACT
Purpose To minimize the various errors introduced by image-guided radiotherapy (IGRT) in the application of esophageal cancer treatment, this study proposes a novel technique based on the 'CBCT-only' mode of pseudo-medical image guidance. Methods The framework of this technology consists of two pseudo-medical image synthesis models in the CBCTâCT and the CTâPET direction. The former utilizes a dual-domain parallel deep learning model called AWM-PNet, which incorporates attention waning mechanisms. This model effectively suppresses artifacts in CBCT images in both the sinogram and spatial domains while efficiently capturing important image features and contextual information. The latter leverages tumor location and shape information provided by clinical experts. It introduces a PRAM-GAN model based on a prior region aware mechanism to establish a non-linear mapping relationship between CT and PET image domains. As a result, it enables the generation of pseudo-PET images that meet the clinical requirements for radiotherapy. Results The NRMSE and multi-scale SSIM (MS-SSIM) were utilized to evaluate the test set, and the results were presented as median values with lower quartile and upper quartile ranges. For the AWM-PNet model, the NRMSE and MS-SSIM values were 0.0218 (0.0143, 0.0255) and 0.9325 (0.9141, 0.9410), respectively. The PRAM-GAN model produced NRMSE and MS-SSIM values of 0.0404 (0.0356, 0.0476) and 0.9154 (0.8971, 0.9294), respectively. Statistical analysis revealed significant differences (p < 0.05) between these models and others. The numerical results of dose metrics, including D98 %, Dmean, and D2 %, validated the accuracy of HU values in the pseudo-CT images synthesized by the AWM-PNet. Furthermore, the Dice coefficient results confirmed statistically significant differences (p < 0.05) in GTV delineation between the pseudo-PET images synthesized using the PRAM-GAN model and other compared methods. Conclusion The AWM-PNet and PRAM-GAN models have the capability to generate accurate pseudo-CT and pseudo-PET images, respectively. The pseudo-image-guided technique based on the 'CBCT-only' mode shows promising prospects for application in esophageal cancer radiotherapy.