MicroRNAs in thyroid cancer with focus on medullary thyroid carcinoma: potential therapeutic targets and diagnostic/prognostic markers and web based tools.

This review aimed to describe the inculpation of microRNAs (miRNAs) in thyroid cancer (TC) and its subtypes, mainly medullary thyroid carcinoma (MTC), and to outline web-based tools and databases for bioinformatics analysis of miRNAs in TC. Additionally, the capacity of miRNAs to serve as therapeutic targets and biomarkers in TC management will be discussed. This review is based on a literature search of relevant articles on the role of miRNAs in TC and its subtypes, mainly MTC. Additionally, web-based tools and databases for bioinformatics analysis of miRNAs in TC were identified and described. MiRNAs can perform as oncomiRs or antioncoges, relying on the target mRNAs they regulate. MiRNA replacement therapy using miRNA mimics or antimiRs that aim to suppress the function of certain miRNAs can be applied to correct miRNAs aberrantly expressed in diseases, particularly in cancer. MiRNAs are involved in the modulation of fundamental pathways related to cancer, resembling cell cycle checkpoints and DNA repair pathways. MiRNAs are also rather stable and can reliably be detected in different types of biological materials, rendering them favorable diagnosis and prognosis biomarkers as well. MiRNAs have emerged as promising tools for evaluating medical outcomes in TC and as possible therapeutic targets. The contribution of miRNAs in thyroid cancer, particularly MTC, is an active area of research, and the utility of web applications and databases for the biological data analysis of miRNAs in TC is becoming increasingly important.

[Imaging characteristics and diagnosis of primary middle mediastinal tumors].

Objectives: To investigate the proportion of different histological types and CT enhanced imaging features of primary middle mediastinal lesions in order to improve the understanding of these tumors and the accuracy of preoperative diagnosis. Methods: Retrospective analysis was conducted on 84 patients with primary middle mediastinal lesions and clear histological classifications diagnosed and treated at the Cancer Hospital, Chinese Academy of Medical Sciences from January 2012 to December 2022. Clinical, imaging, and pathological data were collected and classified according to tumor histological classifications. CT imaging manifestations such as tumor location, size, morphology, edge, boundary, internal components, enhancement characteristics, and surrounding tissue invasion were evaluated and recorded. Results: The histological types of the primary middle mediastinal lesions from the 84 patients included mesenchymal tumors, anterior intestinal cysts, giant lymph node hyperplasia, substernal goiter, neuroendocrine carcinoma, lymphohematopoietic system tumors, and mesothelioma, accounting for 28.6%, 27.4%, 14.3%, 3.6%, 11.9%, 9.5%, and 4.8%, respectively. Mesenchymal tumors included peripheral nerve sheath tumors, vascular tumors, adipogenic tumors, solitary fibrous tumors, and synovial sarcoma, accounting for 54.2%, 20.8%, 12.5%, 8.3%, and 4.2%, respectively. The above tumors had diverse imaging manifestations and specific imaging features. Mature fat were found in 3 cases of liposarcoma; Calcification was observed in 2 cases of thyroid nodules and 7 cases of giant lymph node hyperplasia; Enhanced scanning showed significant enhancement in 2 cases of solitary fibrous tumors, 3 cases of thyroid nodules, and 11 cases of giant lymph node hyperplasia; Mediastinal large lymph nodes was observed in 6 cases of lymphoma and 3 cases of mesothelioma; High invasiveness was observed in 4 cases of mesothelioma and 9 cases of neuroendocrine carcinoma. Conclusion: Mediastinal tumors have low incidence rate and rich histological types, and their imaging manifestations are diverse. Preoperative differential diagnosis can be made according to their specific imaging characteristics.

Total hysterectomy versus radical hysterectomy in neuroendocrine cervical cancer: a SEER-database analysis.

PURPOSE: We conducted this study to evaluate the efficacy of total hysterectomy versus radical hysterectomy in the treatment of neuroendocrine cervical cancer (NECC). METHODS: Eligible NECC patients were identified from the Surveillance, Epidemiology and End Results (SEER) database. Demographic characteristics, clinical treatment and survival of the patients were collected. The overall survival (OS) and cancer-specific survival (CSS) were estimated by Kaplan-Meier analysis with log-rank test. RESULTS: A total of 286 patients were included, with 104 patients undergoing total hysterectomy and 182 patients undergoing radical hysterectomy. The 5-year OS were 50.8% in the total hysterectomy group and 47.5% in the radical hysterectomy group (p = 0.450); and the corresponding 5-year CSS were 51.6% and 49.1% (p = 0.494), respectively. Along with surgery, radiotherapy was given to 49.0% of patients in the total hysterectomy group and 50.5% in the radical hysterectomy group; and chemotherapy was administered to 77.9% of patients in the total hysterectomy group and 85.7% in the radical hysterectomy group. Unexpectedly, in patients who received adjuvant radiotherapy with or without chemotherapy, the OS was superior in the total hysterectomy group compared with the radical hysterectomy group (p = 0.034). While in patients who received chemotherapy alone and those who received neither radiotherapy nor chemotherapy, the OS still remained comparable between the total hysterectomy and radical hysterectomy group. CONCLUSION: Compared with radical hysterectomy, total hysterectomy was not associated with compromised survival prognosis in patients with NECC. Total hysterectomy has the potential to be a surgical alternative in the multimodal management of NECC.

LINC00887 Acts as an Enhancer RNA to Promote Medullary Thyroid Carcinoma Progression by Binding with FOXQ1.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a rare but aggressive endocrine malignancy that originates from the parafollicular C cells of the thyroid gland. Enhancer RNAs (eRNAs) are non-coding RNAs transcribed from enhancer regions, which are critical regulators of tumorigenesis. However, the roles and regulatory mechanisms of eRNAs in MTC remain poorly understood. This study aims to identify key eRNAs regulating the malignant phenotype of MTC and to uncover transcription factors involved in the regulation of key eRNAs. METHODS: GSE32662 and GSE114068 were used for the identification of differentially expressed genes, eRNAs, enhancers and enhancer-regulated genes in MTC. Metascape and the transcription factor affinity prediction method were used for gene function enrichment and transcription factor prediction, respectively. qRT-PCR was used to detect gene transcription levels. ChIP-qPCR was used to assess the binding of histone H3 lysine 27 acetylation (H3K27ac)-enriched regions to anti- H3K27ac. RIP-qPCR was used to detect the binding between FOXQ1 and LINC00887. CCK8 and Transwell were performed to measure the proliferation and invasion of MTC cells, respectively. Intracellular reactive oxygen species (ROS) levels were quantified using a ROS assay kit. RESULTS: Four eRNAs (H1FX-AS1, LINC00887, MCM3AP-AS1 and A1BG-AS1) were screened, among which LINC00887 was the key eRNA promoting the proliferation and invasion of MTC cells. A total of 135 genes controlled by LINC00887-regulated enhancers were identified; among them, BCL2, PRDX1, SFTPD, TPO, GSS, RAD52, ZNF580, and ZFP36L1 were significantly enriched in the "ROS metabolic process" term. As a transcription factor regulating genes enriched in the "ROS metabolic process" term, FOXQ1 could recruit LINC00887. Overexpression of FOXQ1 restored LINC00887 knockdown-induced downregulation of GSS and ZFP36L1 transcription in MTC cells. Additionally, FOXQ1 overexpression counteracted the inhibitory effects of LINC00887 knockdown on the proliferation and invasion of MTC cells and the promotion of intracellular ROS accumulation induced by LINC00887 knockdown. CONCLUSION: LINC00887 was identified as a key eRNA promoting the malignant phenotype of MTC cells. The involvement of FOXQ1 was essential for LINC00887 to play a pro-tumorigenic role in MTC. Our findings suggest that the FOXQ1/LINC00887 axis is a potential therapeutic target for MTC.

Neuroendocrine carcinoma of the endometrium: a retrospective analysis of data from a single center.

BACKGROUND: Neuroendocrine carcinoma (NEC) originating from the endometrium is rare, and there is limited knowledge regarding its diagnosis and optimal management. In this study, we present our experience with 11 patients with endometrial NEC, aiming to provide guidance for clinical practice. METHODS: We retrospectively collected the clinical, pathological, and treatment data of 11 patients with endometrial NEC who were treated at the First Affiliated Hospital of Zhengzhou University from January 2011 to July 2023. The clinicopathological characteristics, treatment and prognosis of these patients were analyzed. RESULTS: The median age of the patients was 55.0 (39.0-64.0) years, and the median tumor size was 40.0 (33.0-60.0) mm. Irregular vaginal bleeding was the most common symptom observed in 10 out of 11 patients, while metabolic syndrome occurred in only 2 out of 11 patients. Six out of the 11 patients were diagnosed at an early stage. Among the patients, 6 were diagnosed with endometrial NECs, while the remaining patients had a combination of endometrial NEC and other non-NEC endometrial carcinomas. All patients underwent surgery, except for one who received only chemotherapy due to multiple metastases. After surgery, adjuvant chemotherapy was administered to 5 patients, chemotherapy combined with radiotherapy was given to 3 patients, and 2 patients did not receive any adjuvant therapy. A total of 10 patients completed the follow-up, with a median follow-up time of 51.0 (14.3-81.0) months. Unfortunately, 2 patients died from the disease. CONCLUSION: NECs originating from the endometrium might not be affected by metabolic disorders. Preoperative diagnosis of these tumors was challenging. The primary approach for managing endometrial NEC can be multimodal treatment centered around surgery.

[The pathological characteristics and prognostic analysis of medullary thyroid microcarcinoma].

Objectives: To analyze the clinical characteristics and prognosis of medullary thyroid microcarcinoma (MTMC). Methods: A case series studies. The clinical data of patients with medullary thyroid carcinoma (MTC) diagnosed by postoperative pathology and with complete follow-up data who were initially treated in Tianjin Medical University Cancer Hospital from January 2013 to December 2019 were retrospectively analyzed. There were a total of 170 cases, including 70 males and 100 females, aged (49.7±12.3) years old. Among them, there were 61 patients with MTMC. They were divided into group A (with a maximum tumor idameter of ≤0.5 cm, n=13) and group B (with a maximum tumor diameter >0.5~≤1.0 cm, n=48) based on whether the maximum diameter of the tumor was >0.5 cm. Analysis was conducted on their pathological results and prognosis. Results: Among the MTC, MTMC accounted for 26.4% (61/231) with 26 males and 35 females aged Mï¼»Q1，Q3ï¼½51.0 (41.0, 59.0) years. Among the MTMC patients, 57.4% (35/61) were in stage Ⅰ, 16.4% (10/61) were in stage Ⅲ, and 26.2% (16/61) were in stage Ⅳ. For MTMC with a maximum diameter of≤0.5 cm and a maximum diameter of >0.5-≤1.0 cm, there was no statistically significant difference between the two groups in terms of gender, age, mixed cancer, invasion of glandular lobes, multifocal, central lymph node metastasis, lateral neck lymph node metastasis rate and other pathological characteristics(both P>0.05). In terms of prognosis, the recurrence free survival time of MTMC patients was 83.1 (68.0, 97.0) months. Among them, structural tumor recurrence occurred in 5 patients (8.2%) after surgery, and 1 patient (1.6%) died. The expected 5-year and 10-year survival rates were 93.4% and 89.0%, respectively. There was no statistically significant difference in recurrence free survival time among MTMC patients, MTC patients with a maximum diameter of >1.0-≤2.0 cm, and MTC patients with a maximum diameter of >2.0 cm (all P>0.05). Conclusion: MTMC has strong invasiveness, and although the prognosis of most MTMCs is relatively good, the risk of long-term recurrence and death is still high.

Time Kinetics and prognosis roles of calcitonin after surgery for medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a malignant tumor with low incidence. Currently, most studies have focused on the prognostic risk factors of MTC, whatever, time kinetic and risk factors related to calcitonin normalization (CN) and biochemical persistence/recurrence (BP) are yet to be elucidated. METHODS: A retrospective study was conducted for 190 MTC patients. Risk factors related to calcitonin normalization (CN) and biochemical persistence/recurrence (BP) were analyzed. The predictors of calcitonin normalization time (CNT) and biochemical persistent/recurrent time (BPT) were identified. Further, the prognostic roles of CNT and BPT were also demonstrated. RESULTS: The 5- and 10-year DFS were 86.7% and 70.2%, respectively. The 5- and 10-year OS were 97.6% and 78.8%, respectively. CN was achieved in 120 (63.2%) patients, whereas BP was presented in 76 (40.0%) patients at the last follow up. After curative surgery, 39 (32.5%) and 106 (88.3%) patients achieved CN within 1 week and 1 month. All patients who failed to achieve CN turned to BP over time and 32/70 of them developed structural recurrence. The median time of CNT and BPT was 1 month (1 day to 84 months) and 6 month (3 day to 63months), respectively. LNR > 0.23 and male gender were independent predictors for CN and BP. LNR > 0.23 (Hazard ratio (HR), 0.24; 95% CI,0.13-0.46; P < 0.01) and male gender (HR, 0.65; 95% CI, 0.42-0.99; P = 0.045) were independent predictors for longer CNT. LNR > 0.23 (HR,5.10; 95% CI,2.15-12.11; P < 0.01) was still the strongest independent predictor followed by preoperative serum Ctn > 1400ng/L (HR,2.34; 95% CI,1.29-4.25; P = 0.005) for shorter BPT. In survival analysis, primary tumor size > 2 cm (HR, 5.81; 95% CI,2.20-15.38; P < 0.01), CNT > 1 month (HR, 5.69; 95% CI, 1.17-27.61; P = 0.031) and multifocality (HR, 3.10; 95% CI, 1.45-6.65; P = 0.004) were independent predictor of DFS. CONCLUSION: Early changes of Ctn after curative surgery can predict the long-term risks of biochemical and structural recurrence, which provide a useful real-time prognostic information. LNR significantly affect the time kinetic of biochemical prognosis. Tumor burden and CNT play a crucial role in MTC survival, the intensity of follow-up must be tailored accordingly.

Advances in combined neuroendocrine carcinoma of lung cancer.

Lung cancer incidence and mortality rates are increasing worldwide, posing a significant public health challenge and an immense burden to affected families. Lung cancer encompasses distinct subtypes, namely, non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). In clinical investigations, researchers have observed that neuroendocrine tumors can be classified into four types: typical carcinoid, atypical carcinoid, small-cell carcinoma, and large-cell neuroendocrine carcinoma based on their unique features. However, there exist combined forms of neuroendocrine cancer. This study focuses specifically on combined pulmonary carcinomas with a neuroendocrine component. In this comprehensive review article, the authors provide an overview of combined lung cancers and present two pathological images to visually depict these distinctive subtypes.

The machine learning-based model for lateral lymph node metastasis of thyroid medullary carcinoma improved the prediction ability of occult metastasis.

BACKGROUND: For medullary thyroid carcinoma (MTC) with no positive findings in the lateral neck before surgery, whether prophylactic lateral neck dissection (LND) is needed remains controversial. A better way to predict occult metastasis in the lateral neck is needed. METHODS: From January 2010 to January 2022, patients who were diagnosed with MTC and underwent primary surgery at our hospital were retrospectively reviewed. We collected the patients' baseline characteristics, surgical procedure, and rescored the ultrasound images of the primary lesions using American College of Radiology (ACR) Thyroid Imaging, Reporting and Data System (TI-RADS). Regularized logistic regression, 5-fold cross-validation and decision curve analysis was applied for lateral lymph node metastasis (LLNM) model's development and validation. Then, we tested the predictive ability of the LLNM model for occult LLNM in cN0-1a patients. RESULTS: A total of 218 patients were enrolled. Five baseline characteristics and two TI-RADS features were identified as high-risk factors for LLNM: gender, baseline calcitonin (Ctn), tumor size, multifocality, and central lymph node (CLN) status, as well as TI-RADS margin and level. A LLNM model was developed and showed a good discrimination with 5-fold cross-validation mean area under curve (AUC) = 0.92 ± 0.03 in the test dataset. Among cN0-1a patients, our LLNM model achieved an AUC of 0.91 (95% CI, 0.88-0.94) for predicting occult LLNM, which was significantly higher than the AUCs of baseline Ctn (0.83) and CLN status (0.64). CONCLUSIONS: We developed a LLNM prediction model for MTC using machine learning based on clinical baseline characteristics and TI-RADS. Our model can predict occult LLNM for cN0-1a patients more accurately, then benefit the decision of prophylactic LND.

Efficacy of second-line chemotherapy in patients with pulmonary large cell neuroendocrine carcinoma.

The efficacy of second-line chemotherapy in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) is unclear. This study aimed to evaluate the efficacy of second-line chemotherapy in patients with pulmonary LCNEC. We retrospectively reviewed patients with pulmonary LCNEC or possible LCNEC (pLCNEC) who received platinum-based chemotherapy as the first-line treatment. Among these patients, we evaluated the efficacy of second-line treatment by comparing patients with small cell lung cancer (SCLC group). Of the 61 patients with LCNEC or pLCNEC (LCNEC group) who received first-line chemotherapy, 39 patients were treated with second-line chemotherapy. Among the 39 patients, 61.5% received amrubicin monotherapy. The median progression-free survival (PFS) and overall survival (OS) in the LCNEC groups were 3.3 and 8.3 months, respectively. No significant differences in the PFS (hazard ratio [HR]: 0.924, 95% confidence interval [CI] 0.647-1.320; P = 0.664) and OS (HR: 0.926; 95% CI 0.648-1.321; P = 0.670) were observed between the LCNEC and SCLC groups. In patients treated with amrubicin, the PFS (P = 0.964) and OS (P = 0.544) were not different between both the groups. Second-line chemotherapy, including amrubicin, may be considered as a treatment option for patients with pulmonary LCNEC.

Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix.

High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D/MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36.21/5q31.3/6p22.2/9q21.11/11p15.5). Also, gene fusions affecting the ACLY-CRHR1 and PVT1-MYC genes were identified in one of the eight samples subjected to RNA sequencing. To resolve evolutionary history, multiregion WES in NETc admixed with adenocarcinoma cells was performed (i.e., mixed-NETc). Phylogenetic analysis of mixed-NETc demonstrated that adenocarcinoma and neuroendocrine elements derive from a common precursor with mutations typical of adenocarcinomas. Over one-third (22/64) of NETc demonstrated a mutator phenotype of C > T at CpG consistent with deficiencies in MBD4, a member of the base excision repair (BER) pathway. Mutations in the PI3K/AMPK pathways were identified in 49/64 samples. We used two patient-derived-xenografts (PDX) (i.e., NET19 and NET21) to evaluate the activity of pan-HER (afatinib), PIK3CA (copanlisib), and ATR (elimusertib) inhibitors, alone and in combination. PDXs harboring alterations in the ERBB2/PI3K/AKT/mTOR/ATR pathway were sensitive to afatinib, copanlisib, and elimusertib (P < 0.001 vs. controls). However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies.

An orthotopic prostate cancer model for new treatment development using syngeneic or patient-derived tumors.

BACKGROUND: There are limited preclinical orthotopic prostate cancer models due to the technical complexity of surgical engraftment and tracking the tumor growth in the mouse prostate gland. Orthotopic xenografts recapitulate the tumor microenvironment, tumor stromal interactions, and clinical behavior to a greater extent than xenografts grown at subcutaneous or intramuscular sites. METHODS: This study describes a novel micro-surgical technique for orthotopically implanting intact tumors pieces from cell line derived (transgenic adenocarcinoma mouse prostate [TRAMP]-C2) or patient derived (neuroendocrine prostate cancer [NEPC]) tumors in the mouse prostate gland and monitoring tumor growth using magnetic resonance (MR) imaging. RESULTS: The TRAMP-C2 tumors grew rapidly to a predetermined endpoint size of 10 mm within 3 weeks, whereas the NEPC tumors grew at a slower rate over 7 weeks. The tumors were readily detected by MR and confidently identified when they were approximately 2-3 mm in size. The tumors were less well-defined on CT. The TRAMP-C2 tumors were characterized by amorphous sheets of poorly differentiated cells similar to a high-grade prostatic adenocarcinoma and frequent macroscopic peritoneal and lymph node metastases. In contrast, the NEPC's displayed a neuroendocrine morphology with polygonal cells arranged in nests and solid sheets and high count. There was a local invasion of the bladder and other adjacent tissues but no identifiable metastases. The TRAMP-C2 tumors were more hypoxic than the NEPC tumors. CONCLUSIONS: This novel preclinical orthotopic prostate cancer mouse model is suitable for either syngeneic or patient derived tumors and will be effective in developing and advancing the current selection of treatments for patients with prostate cancer.

CytoLyt fixation impedes insulinoma-associated protein 1 (INSM1) immunoreactivity compared to formalin fixation.

INTRODUCTION: Insulinoma-associated protein 1 (INSM1) is an immunohistochemical marker commonly used to confirm cytomorphological concordant neuroendocrine tumors/carcinomas (NETs/NECs), demonstrating high utility in small samples. Previous reports have suggested comparable INSM1 staining in CytoLyt-fixed cell blocks and formalin-fixed surgical pathology specimens. This study aimed to assess INSM1 immunoreactivity using both fixation methods and investigate potential factors contributing to its variable expression. MATERIALS AND METHODS: A retrospective query was performed (03/31/21-05/31/22) for NET/NEC cases that had both formalin- and CytoLyt-fixed cell blocks. We collected clinical data and reporting of immunostains for each case. INSM1 staining was evaluated in both fixation methods, and reported as positive, negative, or equivocal. Equivocal INSM1 staining was further scored as a percentage of 1%-100% and intensity of weak (faint staining), moderate (darker staining), and strong (dense staining). RESULTS: Our search identified 20 cases from diverse body sites, including mediastinal lymph nodes (40%), pancreas (35%), lung (20%), and porta hepatis lymph nodes (5%). All cases exhibited a widespread positivity (over 90%) in formalin-fixed cell blocks. In contrast, CytoLyt fixed cells showed a negative stain in 65% of cases and 30% exhibited an equivocal positivity. CONCLUSIONS: While INSM1 is previously reported as a sensitive (75%-100%) and specific (82.7%-100%) marker for NET/NECs, our study found a reduced immunohistochemical staining in CytoLyt-fixed cell blocks. Consequently, false negative INSM1 immunohistochemical results in CytoLyt-fixed cell block material may pose a pitfall in the diagnosis of NET/NEC.

Small-cell neuroendocrine carcinoma of the female genital tract: A comprehensive overview.

Small-cell neuroendocrine carcinomas (SCNECs) of the female genital tract are rare and aggressive tumors that are characterized by a high rate of recurrence and poor prognosis. They can arise from various sites within the female genital tract, including the cervix, endometrium, ovary, fallopian tube, vagina, and vulva. They are composed of cells with neuroendocrine features, such as the ability to produce and secrete hormones and peptides, and a high mitotic rate. Immunohistochemical staining for neuroendocrine markers, such as chromogranin A, synaptophysin, and CD56, can aid in the diagnosis of these tumors. This article provides an overview of the epidemiology, etiology, and risk factors associated with these tumors, as well as their clinical presentation, cellular characteristics, diagnosis, and finally the current treatment options for SCNECs, including surgery, chemotherapy, and radiation therapy, alone or in combination.

Initial surgical management of sporadic medullary thyroid cancer: Guidelines based optimal care - A systematic review.

INTRODUCTION: Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor from parafollicular cells that produce calcitonin (Ct). Despite several existing guidelines for the surgical management of sporadic MTC (sMTC), optimal initial surgical management of the thyroid, the central and the lateral neck remains a matter of debate. METHODS: A systematic review in PubMed and Scopus for current guidelines addressing the surgical management of sMTC and its referenced citations was conducted as per the PRISMA guidelines. RESULTS: Two-hundred and one articles were identified, of which 7 met the inclusion criteria. Overall, guidelines vary significantly in their recommendations for the surgical management of sMTC. Only one guideline recommended partial thyroidectomy for limited disease, but the possibility to avoid completion thyroidectomy in selected cases is acknowledged in 42% (3/7) of the remaining guidelines. The majority of guidelines (71.4%; 5/7) recommended prophylactic central neck dissection (CND) for all patients while the remaining two guidelines recommended CND based on Ct level and tumor size. The role of prophylactic lateral neck dissection based on preoperative Ct levels was recommended by 42% (3/7) of guidelines. Overall, these guidelines are based on low-quality evidence, mostly single-center retrospective series, some of which are over 20 years old. CONCLUSION: Current surgical management guidelines of sMTC should be revised, and ought to be based on updated data challenging current recommendations, which are based on historic, low-quality evidence. Partial thyroidectomy may become a viable option for small, limited tumors. Prospective, multi-center studies may be useful to conclude whether prophylactic ND is necessary in all sMTC patients.

Expression and clinical value of CXCR4 in high grade gastroenteropancreatic neuroendocrine neoplasms.

Background: CXC chemokine receptor 4 (CXCR4) is associated with the progression and metastasis of numerous malignant tumors. However, its relationship with Gastroenteropancreatic Neuroendocrine Neoplasms Grade 3 (GEP-NENs G3) is unclear. The aim of this study was to characterize the expression of CXCR4 in GEP-NENS and to explore the clinical and prognostic value of CXCR4. Methods: This study retrospectively collected clinical and pathological data from patients with GEP-NENs who receiving surgery in Qilu Hospital of Shandong University from January 2013 to April 2021, and obtained the overall survival of the patients based on follow-up. Immunohistochemistry (IHC) was performed on pathological paraffin sections to observe CXCR4 staining. Groups were made according to pathological findings. Kaplan-Meier (K-M) curve was used to evaluate prognosis. SPSS 26.0 was used for statistical analysis. Results: 100 GEP-NENs G3 patients were enrolled in this study. There was a significant difference in primary sites (P=0.002), Ki-67 index (P<0.001), and Carcinoembryonic Antigen (CEA) elevation (P=0.008) between neuroendocrine tumor (NET) G3 and neuroendocrine carcinoma (NEC). CXCR4 was highly expressed only in tumors, low or no expressed in adjacent tissues (P<0.001). The expression level of CXCR4 in NEC was significantly higher than that in NET G3 (P=0.038). The K-M curves showed that there was no significant difference in overall survival between patients with high CXCR4 expression and patients with low CXCR4 expression, either in GEP-NEN G3 or NEC (P=0.920, P=0.842. respectively). Conclusion: Differential expression of CXCR4 was found between tumor and adjacent tissues and between NET G3 and NEC. Our results demonstrated that CXCR4 can be served as a new IHC diagnostic indicator in the diagnosis and differential diagnosis of GEP-NENs G3. Further studies with multi-center, large sample size and longer follow-up are needed to confirm the correlation between CXCR4 expression level and prognosis.