Special issue "The advance of solid tumor research in China": Prediction of Sunitinib efficacy using computed tomography in patients with pancreatic neuroendocrine tumors.

Clinically effective methods to predict the efficacy of sunitinib, for patients with metastatic or locally advanced pancreatic neuroendocrine tumors (panNET) are scarce, making precision treatment difficult. This study aimed to develop and validate a computed tomography (CT)-based method to predict the efficacy of sunitinib in patients with panNET. Pretreatment CT images of 171 lesions from 38 patients with panNET were included. CT value ratio (CT value of tumor/CT value of abdominal aorta from the same patient) and radiomics features were extracted for model development. Receiver operating curve (ROC) with area under the curve (AUC) and decision curve analysis (DCA) were used to evaluate the proposed model. Tumor shrinkage of >10% at first follow-up after sunitinib treatment was significantly associated with longer progression-free survival (PFS; P < .001) and was used as the major treatment outcome. The CT value ratio could predict tumor shrinkage with AUC of 0.759 (95% confidence interval [CI], 0.685-0.833). We then developed a radiomics signature, which showed significantly higher AUC in training (0.915; 95% CI, 0.866-0.964) and validation (0.770; 95% CI, 0.584-0.956) sets than CT value ratio. DCA also confirmed the clinical utility of the model. Subgroup analysis showed that this radiomics signature had a high accuracy in predicting tumor shrinkage both for primary and metastatic tumors, and for treatment-naive and pretreated tumors. Survival analysis showed that radiomics signature correlated with PFS (P = .020). The proposed radiomics-based model accurately predicted tumor shrinkage and PFS in patients with panNET receiving sunitinib and may help select patients suitable for sunitinib treatment.

Molecular and Functional Heterogeneity of Primary Pancreatic Neuroendocrine Tumors and Metastases.

INTRODUCTION: Treatment response to the standard therapy is low for metastatic pancreatic neuroendocrine tumors (PanNETs) mainly due to the tumor heterogeneity. We investigated the heterogeneity between primary PanNETs and metastases to improve the precise treatment. METHODS: The genomic and transcriptomic data of PanNETs were retrieved from the Genomics, Evidence, Neoplasia, Information, Exchange (GENIE), and Gene Expression Omnibus (GEO) database, respectively. Potential prognostic effects of gene mutations enriched in metastases were investigated. Gene set enrichment analysis was performed to investigate the functional difference. Oncology Knowledge Base was interrogated for identifying the targetable gene alterations. RESULTS: Twenty-one genes had significantly higher mutation rates in metastases which included TP53 (10.3% vs. 16.9%, p = 0.035) and KRAS (3.7% vs. 9.1%, p = 0.016). Signaling pathways related to cell proliferation and metabolism were enriched in metastases, whereas epithelial-mesenchymal transition (EMT) and TGF-ß signaling were enriched in primaries. Gene mutations were highly enriched in metastases that had significant unfavorable prognostic effects included mutation of TP53 (p < 0.001), KRAS (p = 0.001), ATM (p = 0.032), KMT2D (p = 0.001), RB1 (p < 0.001), and FAT1 (p < 0.001). Targetable alterations enriched in metastases included mutation of TSC2 (15.5%), ARID1A (9.7%), KRAS (9.1%), PTEN (8.7%), ATM (6.4%), amplification of EGFR (6.0%), MET (5.5%), CDK4 (5.5%), MDM2 (5.0%), and deletion of SMARCB1 (5.0%). CONCLUSION: Metastases exhibited a certain extent of genomic and transcriptomic diversity from primary PanNETs. TP53 and KRAS mutation in primary samples might associate with metastasis and contribute to a poorer prognosis. A high fraction of novel targetable alterations enriched in metastases deserves to be validated in advanced PanNETs.

Management of type 1 gastric neuroendocrine tumors: an 11-year retrospective single-center study.

BACKGROUND: Type 1 gastric neuroendocrine tumors (NETs) are relatively rare to the extent that some physicians have little experience in diagnosing and treating them. The purpose of this study was to increase the understanding of the disease by analyzing and summarizing the management and prognoses of patients with type 1 gastric NETs at our center. METHODS: The data of 229 patients (59.4% female) with type 1 gastric NETs who were treated at our center during 2011-2022 were retrospectively analyzed. RESULTS: The average patient age was 50.5 ± 10.8 years. Multiple tumors affected 72.5% of the patients; 66.4% of the tumors were < 1 cm, 69.4% were NET G1, and 2.2% were stage III-IV. A total of 76.9% of the patients had received endoscopic management, 60.7% had received traditional Chinese medicine treatment, 10.5% received somatostatin analogues treatment, and 6.6% underwent surgical resection. Seventy patients (41.2%) experienced the first recurrence after a median follow-up of 31 months (range: 2-122 months), and the median recurrence-free time was 43 months. The 1-, 2-, and 3-year cumulative recurrence-free survival rates were 71.8%, 56.8%, and 50.3%, respectively. During a median follow-up of 39 months (range: 2-132 months), one patient had bilateral pulmonary metastasis, and no disease-related deaths were observed. CONCLUSION: Type 1 gastric NETs have a high recurrence rate and a long disease course, underscoring the importance of long-term and comprehensive management.

Meta-Analysis of Prognostic Factors for Recurrence of Resected Well-Differentiated Pancreatic Neuroendocrine Tumors.

INTRODUCTION: Well-differentiated pancreatic neuroendocrine tumors (WDPNETs) are a group of rare and heterogeneous tumors. However, the prognostic factors for recurrence after curative resection still remain controversial. We aim to illustrate the prognostic factors for recurrence of resected WDPNETs. METHODS: All relevant articles published through June 2020 were identified via PubMed, Embase, Web of Science, and Cochrane Library. Articles that examined the prognostic factors of WDPNETs were enrolled. RESULTS: Ten articles were finally included in this study. From 1993 to 2018, 2,863 patients underwent curative resection and 358 patients had recurrence, and the combined recurrence rate was 13%. Furthermore, the pooled data indicated that patients with G2, positive lymph node and surgical resection margin, vascular invasion, and perineural invasion had a decreased disease-free survival for WDPNETs. However, gender, function, and tumor size had no significant relationship with WDPNETs recurrence. CONCLUSION: These findings demonstrated that G2, positive lymph node and surgical resection margin, vascular invasion, and perineural invasion could be prognostic factors for recurrence of resected WDPNETs, indicating that patients with these high-risk factors need closer postoperative follow-up and may benefit from adjuvant therapy.

A Ki-67 Index to Predict Treatment Response to the Capecitabine/Temozolomide Regimen in Neuroendocrine Neoplasms: A Retrospective Multicenter Study.

OBJECTIVE: The efficacy of the capecitabine/temozolomide (CAPTEM) regimen has been demonstrated in metastatic neuroendocrine neoplasms (NENs), but because of varying response rates among the patients, biomarkers to predict its response are greatly needed. Here, we investigated the clinical utility of a Ki-67 index to predict the CAPTEM regimen objective responses and select patients who could benefit from this regimen. METHODS: Metastatic NENs patients treated with the CAPTEM regimen from 4 high-volume medical centers were selected and grouped in a training and validation cohort. The classification and regression tree (CART) was generated to identify the optimal threshold of Ki-67 for stratifying the patients into different Ki-67 range groups based on their response to the CAPTEM regimen. RESULTS AND CONCLUSIONS: The overall response rate (ORR) and disease control rate of the entire cohort (N = 151) were 26.5 and 76.2%, respectively, with a median progression-free survival (PFS) of 12.0 months. CART analysis showed that patients in the Ki-67 range group 10-40% demonstrated a significantly higher ORR than those in Ki-67 >40 and <10% groups (p < 0.001 in the training cohort and p = 0.036 in the validation cohort). Response to the CAPTEM regimen was not influenced by the expression of O6-methylguanine-DNA methyltransferase or primary tumor location. Multivariate analysis identified the Ki-67 index as the only independent prognostic factor for overall survival (p = 0.031) and PFS (p = 0.006). The proposed Ki-67 index was externally validated and could be used to clinically identify suitable metastatic NENs patients who could achieve an optimal cytoreduction using the CAPTEM regimen.

Circulating miRNA-202-3p is a potential novel biomarker for diagnosis of type 1 gastric neuroendocrine neoplasms.

BACKGROUND: Currently, there are no circulating diagnostic biomarkers for gastric neuroendocrine neoplasms (g-NENs). In previous studies, we found that miRNA-202-3p is overexpressed in the tumour tissue of type 1 g-NEN. We speculated that miRNA-202-3p is also likely to be highly expressed in circulating blood. METHODS: A total of 27 patients with type 1 g-NEN and 27 age- and sex-matched control participants were enrolled in this study. The miRNA-202-3p levels in serum obtained from the participants were measured by qRT-PCR. The expression level of miRNA-202-3p in the samples was calculated by comparison with a standard curve. RESULTS: The clinical characteristics of the patients were similar to those of the patient samples in previous reports. Expression of miRNA-202-3p was significantly higher in the patient group (3.84 × 107 copies/nl) than in the control group (0.635 × 107 copies/nl). The area under the ROC curve (AUC) was 0.878 (95% CI: 0.788-0.968), and the optimal cut-off point was approximately 1.12 × 107 copies/nl. The sensitivity and specificity were 88.9% and 77.8%, respectively. CONCLUSION: This study suggests that miRNA-202-3p is potentially useful as a biomarker of type 1 g-NEN; further investigation and verification should be performed in future research.

Ki-67 index of 5% could better predict the clinical prognosis of well-differentiated pancreatic neuroendocrine tumours.

BACKGROUND: The pathological classification of well-differentiated pancreatic neuroendocrine tumour (pNET) is based largely upon Ki-67 index. However, current controversies abound about the classification of pNETG1/pNETG2. PATIENTS AND METHODS: Clinicopathological data were retrospectively analysed for 153 pNETG1/pNETG2 patients hospitalized at China-Japan Friendship Hospital. The critical values of pNETG1/pNETG2 were examined by using the area under the receiver operating characteristic curve and survival analysis was used to compare the clinical prognosis of pNETG1/G2. RESULTS: Among them, 52.3% were males. The median age was 49 (18-81) years and the clinical types were pNETG1 (n = 38) and pNETG2 (n = 115). According to the receiver operating characteristic curve, the optimal cut-off value was 5.5% for classifying pNETG1/pNETG2. Significant differences between pNETG1 (n = 101) and pNETG2 (n = 52) existed in overall survival (P = 0.001) and disease-free survival (P = 0.013) when Ki-67 index was 5%. Yet no significant differences existed in overall survival (P = 0.378) or disease-free survival (P = 0.091) between pNETG1 and pNETG2 when Ki-67 index was 3%. Furthermore, multivariate analysis indicated that the revised pathological grade was an independent risk factor for mortality and post-operative recurrence of pNET patients (P = 0.003 and 0.014; hazard ratio (HR) = 4.005 and 2.553). CONCLUSION: Thus, differentiating pNETG1/pNETG2 with Ki-67 index (5%) is proposed as the cut-off value and a new Ki-67 index (5%) is a better predictor of pNET mortality and post-operative recurrence than Ki-67 index (3%).

Capecitabine and Temozolomide as a Promising Therapy for Advanced Thymic Atypical Carcinoid.

BACKGROUND: Thymic atypical carcinoid (TAC) is a rare thymic neuroendocrine tumor that originates in the neuroendocrine system and lacks a standardized treatment. The combination of capecitabine (CAP) and temozolomide (TEM) is associated with an extremely high and long-lasting response rate in patients with metastatic pancreatic neuroendocrine tumors. However, there is little evidence showing that the CAPTEM regimen is effective for TAC. For patients with unresectable or metastatic atypical carcinoid of the thymus, few treatment options are available, and the treatment efficacy is not satisfactory. To explore the efficacy and safety of the CAPTEM regimen against TAC, we conducted a retrospective review. PATIENTS AND METHODS: A total of nine patients with advanced atypical carcinoid of the thymus in the China-Japan Friendship Hospital were treated with capecitabine (750 mg/m2 twice daily, days 1-14) and temozolomide (200 mg/m2 once daily, days 10-14) every 28 days between 2014 and 2018. The disease control rate (DCR), progression-free survival (PFS), and adverse effects after treatment were analyzed. The DCR was calculated by RECIST version 1.1. Progression-free survival was calculated by the Kaplan-Meier survival method. RESULTS: A total of nine patients (six male and three female) were included. The median age at CAPTEM initiation was 50 years (range, 26-58). The median number of CAPTEM cycles was 8 (range, 3-23). The DCR was 89% (8/9), with eight patients achieving stable disease. Only one patient (11%) showed progressive disease. The median PFS was 8 months. Because we applied vitamin B6 and ondansetron before administering the drugs, the side effects of this regimen were very small. Adverse reactions were all below grade 3 and included myelosuppression and digestive tract reaction. CONCLUSION: Our results suggest that the CAPTEM regimen may be effective and well tolerated for the treatment of TAC. More evidence is needed to validate the effectiveness of this regimen. IMPLICATIONS FOR PRACTICE: Capecitabine and temozolomide regimen is effective and well tolerated in patients with advanced thymic atypical carcinoid.

Clinicopathological characteristics and risk factors for recurrence of well-differentiated pancreatic neuroendocrine tumors after radical surgery: a case-control study.

BACKGROUND: Well-differentiated pancreatic neuroendocrine tumors (PanNETs) usually have a good prognosis; however, there are patients that experience recurrence after curative resection. AIM: To explore recurrence-related risk factors by analyzing clinicopathological data of PanNETs after radical surgery. METHODS: Clinical and pathological data from 47 patients with well-differentiated PanNETs at China-Japan Friendship Hospital from January 2012 to March 2016 were analyzed retrospectively. Univariate and multivariate analyses of the risk factors of PanNETs for postoperative recurrence were conducted. RESULTS: Among the 47 patients with well-differentiated PanNETs, there were 38 cases with non-functioning tumors, 9 cases with functional tumors (6 insulinomas, 1 gastrinoma, 1 glucagonoma, and 1 VIPomas). There are 17 cases (36.2%) in the pancreatic head, 17 (36.2%) in the body and tail, 9 (19.1%) in the tail, and 4 (8.5%) in the body. The median tumor size was 3.65 (IQR 2-5.5) cm. Fourteen cases (29.8%) were NET G1, and 33 cases (70.2%) were NET G2. In regard to the clinical stage, 9 (19.1%) cases were IA, 14 (29.8%) cases were IB, 7 (14.9%) cases were IIA, 14 (29.8%) cases were IIB, and 3 cases unknown. There were 17 patients who presented with postoperative recurrence. Univariate analysis showed that AJCC TNM staging, Ki67 index, vascular invasion, margin status, and the regional stage of the tumors are related to the recurrence of patients with PanNETs (p < 0.05). The results of multivariate analysis showed that Ki67 index ≥ 10% is an independent risk factor for the postoperative recurrence of PanNETs (p < 0.05). CONCLUSION: The Ki67 index ≥ 10% is an independent risk factor for recurrence in well-differentiated PanNETs after radical surgery, and close surveillance for these patients may be needed.

Clinicopathological features and prognostic validity of WHO grading classification of SI-NENs.

BACKGROUND: The clinicopathological characteristics of small intestinal neuroendocrine neoplasms (SI-NENs) and the prognostic validity of WHO grading classification for SI-NENs are still unknown in Asian patients. METHODS: 277 patients and 8315 patients with SI-NENs were retrieved respectively from eleven Chinese hospitals and Surveillance, Epidemiology, and End Results (SEER) cancer registry. Overall survival was used as the major study outcome. Survival analysis using Kaplan-Meier analysis with log-rank test and cox regression analysis were applied. RESULTS: Clinicopathological characteristics of SI-NENs were quite different among different races. Duodenum was the predominant tumor site in Chinese patients and Asian/Pacific Islander patients but not in white patients from SEER database. Patients with duodenal NENs tended to have more localized disease than patients with jejunal/ileal NENs which were confirmed by patients from SEER database. Grade 3 or poorly differentiated/undifferentiated tumor were more common and tumor size was significantly larger in ampullary NENs compared with that in non-ampullary duodenal NENs. As for the prognostic validity of WHO grading classification, survival between patients with grade 1 and grade 2 disease was not significantly different. Ki-67 index of 5% might be a better threshold between grade 1 and grade 2 than Ki-67 index of 2% in SI-NENs. CONCLUSIONS: Our study revealed that the clinicopathological characteristics of SI-NENs among different races were quite different. This might because duodenal NENs was much more common in Chinese patients and Asian/Pacific Islander patients. Duodenal NENs and jejunal/ileal NENs, ampullary and non-ampullary duodenal NENs shared different characteristics. Ki-67 index of 5% might be a better threshold between grade 1 and grade 2 in SI-NENs.

Effects of Shengjiangxiexin decoction on irinotecan-induced toxicity in patients with UGT1A1*28 and UGT1A1*6 polymorphisms.

OBJECTIVE: To evaluate the efficacy of Shengjiangxiexin decoction (SXD), prepared with a formula from Traditional Chinese Medicine (TCM), in reducing irinotecan-induced hematological and gastrointestinal toxicities in patients with UDP-glucuronosyltransferase (UGT)1A1*28 and UGT1A1*6 polymorphisms. METHODS: This clinical trial included 115 patients receiving irinotecan combined with 5-fluorouracil plus l-leucovorin (FOLFIRI) treatment. All patients consented to UGT1A1*28 and *6 gene polymorphism detection prior to chemotherapy. SXD were administered from 1 day prior to chemotherapy to 6 day post chemotherapy. Chemotherapy induced adverse reactions (neutropenia, diarrhea, nausea, vomiting, anorexia and infection) were recorded, and short-term effect of chemotherapy was evaluated regularly. RESULTS: A total of 50 patients had *1/*1 wild genotype, 58 patients had single allele variants with genotype *1/*6 or *1/*28 , and 7 patients had two alleles variants with genotype *6/*6, *28/*28 or *6/* 28. In *1/*6 or *1/*28 patients (high risk group), 9 patients (15.5% ) developed Ⅰ-Ⅱ grade diarrhea and no patient developed severe diarrhea; neutropenia occurred in 19 patients (32.8%) and only 3 patients (8.6% ) developed sever neutropenia. There were no significant differences in any toxic effects (neutropenia, diarrhea, nausea, vomiting, anorexia or infection) between *6 or *28 variant patients (high risk group) and wild type patients. No sever toxicity was found in high risk two alleles variants patients (*6/*6, *6/*28 or *28/*28). No significant differences were observed between UGT1A1*6/*28 polymorphisms and clinical response of chemotherapy. CONCLUSION: SXD could significantly reduce irinotecan-induced hematological and gastrointestinal toxicities in UGT1A1*28 or *6 variant patients (high risk group), while this treatment didn't affect clinical response of chemotherapy.

Safety and efficacy of Tongkuaixiao ointment in reliving cancer-induced pain: a multicenter double-blind placebo-controlled randomized trial.

OBJECTIVE: To evaluate the safety and efficacy of Tongkuaixiao ointment (TKXO) in treating moderate-to-severe cancer induced somatalgia. METHODS: Totally 130 patients with moderateto-severe cancer induced somatalgia were randomly divided into a TKXO group and a control group. The patients were treated with either TKXO applied externally or placebo, with opioid analgesics orally at the same time. Observation parameters were included numerical rating scale (NRS) scores, analgesic efficacy, initiation effective time, persistent analgesic time, equivalent morphine dose, National Comprehensive Cancer Network (NCCN) grade in Impact of Pain Measurement Scores, and safety and satisfaction extent investigation. RESULTS: NRS scores and NCCN grade in Impact of Pain Measurement Scores decreased significantly after 5-days' treatment in the two groups (P < 0.0001). Compared to the control group, initiation effective time was significantly shorter (P < 0.05) and persistent analgesic time was significantly longer (P < 0.01), equivalent oral morphine doses of the first day and the whole treatment course were significantly decreased in the TKXO treatment group (P < 0.01 or P < 0.05). No obvious adverse effects were found in the TKXO group. CONCLUSION: TKXO combined with opioid analgesics possesses the advantages of high efficacy, fast action, long persistent action, safety and convenience in use, and it can reduce the dose of opioid.

[Effect of Shengjiang Xiexin Decoction on the Repair of Damaged Rat Intestinal Mucosa after Irinotecan Chemotherapy].

OBJECTIVE: To explore the effect of Shengjiang Xiexin Decoction (SXD) on the intestinal mucosal and functional cells of rats after irinotecan (CPT-11) chemotherapy. METHODS: Totally 24 healthy Sprague-Dawley (SD) male rats were divided into three groups, the normal control group, the CPT-11 group, the SXD combined CPT-11 group according to random digit table, 8 in each group. CPT-11 was injected at the daily dose of 150 mg/kg to rats in the CPT-11 group and the SXD combined CPT-11 group from the caudal vein on the 4th day, once daily for 2 successive days to duplicate delayed diarrhea model. Equal volume of normal saline was injected to rats in the normal control group from the caudal vein. SXD at 2 g/mL (10 g/kg body weight) was administered to rats in the SXD combined CPT-11 group by gastrogavage for 9 successive days. Deionized water was administered to rats in the CPT-11 group and the normal control group. Diarrhea was observed at 48, 60, 72, 84, 96, and 108 h to calculate the incidence rate of diarrhea. Meanwhile, scoring for diarrhea was performed by referring methods of Akinobu Kurita. Rats were killed on day 10, ileum, cecum, and colon tissues were collected and fixed in 10% formalin solution. HE staining was performed. Intestinal mucosa injuries were graded under light microscope according to the criterion of Chiu's score. The expressions of goblet cells and Paneth cells were observed by PAS stain. Enteroendocrine cells were observed by immunohistochemical CgA staining. Positive cells were counted and cumulative optical density (IOD) analyzed by Image-Pro-Plus 6.0. RESULTS: No diarrhea occurred in rats of the normal control group at each time point. The incidence rate of diarrhea was 75.0% (6/8) at 48 h, 100.0% (8/8) at 60 h, 100.0% (8/8) at 72 h, 87.5% (7/8) at 84 h, 75.0% (6/8) at 96 h, and 75.0% (6/8) at 108 h in the CPT-11 group. The incidence rate of diarrhea was 25.0% (2/8) at 48 h, 50.0% (4/8) at 60 h, 12.5% (1/8) at 72 h, 0.0% (0/8) at 84 h in the SXD combined CPT-11 group. Compared with the same group at 60 h, scores for diarrhea at 48, 84, 96, and 108 h obviously decreased in the CPT-11 group, and scores for diarrhea at 48, 72, 84, 96, and 108 h obviously decreased in the SXD combined CPT-11 group (P < 0.05, P < 0.01). Compared with the same group at 72 h, scores for diarrhea at 84, 96, and 108 h obviously decreased in the CPT-11 group (P < 0.05, P < 0.01). Compared with the normal control group, scores for diarrhea increased in the CPT-11 group at each time point (P < 0.01); grading of ileum, cecum, and colon mucosal tissues increased (P < 0.05, P < 0.01); expressions of ileum and cecum mucosal epithelial goblet cells obviously decreased (P < 0.05); the number and expressions of ileum and cecum mucosal epithelial Paneth cells increased (P < 0.01). Expressions of ilium endocrine cells increased, while those of cecum and colon endocrine cells decreased in the CPT-11 group (P < 0.01). Compared with the CPT-11 group, scores for diarrhea were obviously lowered (P < 0.05, P < 0.01), grading of ileum, and cecum mucosal tissues decreased (P < 0.05, P < 0.01); expressions of ileum, cecum, and colon mucosal epithelial goblet cells obviously increased (P < 0.05, P < 0.01); the number and expressions of ileum cecum mucosal epithelial Paneth cells increased (P < 0.05); expressions of cecum and colon endocrine cells increased (P < 0.05, P < 0.01) in the SXD combined CPT-11 group. CONCLUSION: SXD played roles in preventing and treating CPT-11 induced delayed diarrhea by improving CPT-11 chemotherapy induced apoptosis and necrosis of intestinal mucosal and functional cells.

[Treatment of Epidermal Growth Factor Receptor Inhibitors Associated Adverse Skin Reactions by Zhiyang Pingfu Liquid: a Clinical Study].

OBJECTIVE: To study the curative effect of Zhiyang Pingfu Liquid (ZPL) in treating epidermal growth factor receptor inhibitors (EGFRIs) associated adverse reactions of the skin. METHODS: All 54 patients with pathologically confirmed malignant tumor had EGFRIs induced adverse reactions of the skin to various degrees. ZPL was externally applied for them all, once or twice per day, 14 days consisting of one therapeutic course. Changes of adverse skin reactions, time for symptoms relief, adverse skin reaction types suitable for ZPL were observed before and after treatment. RESULTS: EGFRIs associated skin adverse reactions were improved to various degrees after they used ZPL. The shortest symptoms relief time was 1 day while the longest was 12 days, with an average of 6.93 days and the median time 7 days. Compared with before treatment, itching, rash/scaling, acne/acneform eruptions were obviously improved (P < 0.05). CONCLUSION: ZPL could alleviate EGFRls associated adverse skin reactions, especially showed better effect on itching, rash/scaling, acne/acneform eruptions.

Treatment, Prognostic Markers, and Survival in Thymic Neuroendocrine Tumors, with Special Reference to Temozolomide-Based Chemotherapy.

BACKGROUND: Thymic neuroendocrine tumors (Th-NETs) are rare and aggressive, with a scarcity of research on predicting patient prognosis. Our study aimed to assess the impact of prognostic markers and temozolomide (TMZ)-based chemotherapy on survival in Th-NETs. METHODS: We retrospectively reviewed the medical records of patients diagnosed with Th-NETs between 2013 and 2023 at our institution. We collected clinicopathological data, including tumor pathological grading, staging, serum concentrations of neuron-specific enolase (NSE) and pro-gastrin-releasing peptide, levels of inflammatory factors, and expression of oxygen 6-methylguanine-DNA methyltransferase (MGMT). Treatment details (such as surgery and chemotherapy) and survival outcomes were also documented. RESULTS: A total of 32 patients were included in our study after excluding those without complete available information. The median progression-free survival (PFS) was 12.5 months (95%CI, 8-16 months) for 19 patients who received TMZ-based chemotherapy. Twenty-one patients underwent surgery as the primary treatment, demonstrating a median disease-free survival (DFS) of 51.0 months. The inflammatory factor neutrophil-to-lymphocyte ratio (NLR) was an independent prognostic indicator of DFS in postoperative patients and PFS in TMZ-treated patients. The overall 3-, 5-, and 10-year survival rates were 86.6%, 69.5%, and 33.8%, respectively. Ki67 level exceeding 10% (p = 0.048) and absence of surgical resection (p = 0.003) were significantly associated with worse overall survival (OS). CONCLUSION: Surgical treatment was currently the primary method for treating Th-NETs, and postoperative adjuvant therapy was an essential consideration for specific patient cohorts. Despite widespread positive MGMT expression, TMZ-based chemotherapy showed promise. Some potential prognostic biomarkers such as NLR and NSE need more attention.

Prognostic value of inflammation-related biomarkers in patients with gastroenteropancreatic neuroendocrine neoplasms: A systematic review and meta-analysis.

Hematological indicators of chronic systemic inflammation are significant biomarkers for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). We performed a systematic review and meta-analysis to assess the impact of certain factors on the overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) of patients with GEP-NENs. These factors include the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and C-reactive protein (CRP) levels. After searching the Medline, Embase, and Cochrane Library databases from January 1, 2000 to October 20, 2022 and the American Society of Clinical Oncology conference proceedings from January 1, 2017, hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted. Subgroup analyses were conducted to identify the origins of heterogeneity and examine the impact of factor grouping. The effects of the cut-off values and sample size were assessed by meta-regression. The results revealed that higher NLRs, PLRs, and CRP levels were associated with shorter OS (HR = 2.09, 95% CI = 1.55-2.8; HR = 1.79, 95% CI = 1.40-2.28; and HR = 2.88, 95% CI = 2.09-3.95, respectively; all p < 0.001). Higher NLRs and lower LMRs were associated with shorter DFS (HR = 3.34, 95% CI = 2.11-5.29 and HR = 2.71, 95% CI = 2.27-3.24, respectively; both p < 0.001). Higher PLRs and CRP levels were correlated with shorter PFS (HR = 3.48, 95% CI = 1.34-9.03, p = 0.01 and HR = 3.14, 95% CI = 1.63-6.08, p = 0.001). As demonstrated in the research, hematological indicators of systemic inflammation are promising biomarkers for GEP-NEN assessment.

Effect of mitotane in patients with ectopic adrenocorticotropic hormone syndrome caused by advanced pancreatic neuroendocrine tumors: a case series and review of the literature.

Ectopic adrenocorticotropic hormone syndrome (EAS) is a rare condition caused by pancreatic neuroendocrine tumors (p-NETs). The severe hypercortisolemia that characterizes EAS is associated with a poor prognosis and survival. Mitotane is the only adrenolytic drug approved by the Food and Drug Administration and is often used to treat adrenocortical carcinoma. Combination therapy with mitotane and other adrenal steroidogenesis inhibitors is common for patients with Cushing's syndrome (CS). Here, we describe three patients who developed EAS secondary to the liver metastasis of p-NETs. All three rapidly developed hypercortisolemia but no typical features of CS. They underwent anti-tumor and mitotane therapy, which rapidly reduced their blood cortisol concentrations and ameliorated their symptoms. Their hypercortisolemia was controlled long term using a low dose of mitotane. The principal adverse effects were a slight loss of appetite and occasional dizziness, and there were no severe adverse effects. Importantly, even when the tumor progressed, the patients' circulating cortisol concentrations remained within the normal range. In summary, the present case series suggests that mitotane could be used to treat hypercortisolemia in patients with EAS caused by advanced p-NETs, in the absence of significant adverse effects.

Whole-exome sequencing of rectal neuroendocrine tumors.

The genetic characteristics of rectal neuroendocrine tumors (R-NETs) were poorly understood. Depicting the genetic characteristics may provide a biological basis for prognosis prediction and novel treatment development. Tissues of 18 R-NET patients were analyzed using whole-exome sequencing. The median tumor mutation burden (TMB) and microsatellite instability (MSI) were 1.15 Muts/MB (range, 0.03-23.28) and 0.36 (range, 0.00-10.97), respectively. Genes involved in P53 signaling, PI3K-AKT signaling, DNA damage repair, WNT signaling, etc. were frequently altered. Higher TMB (P = 0.078), higher CNV (P = 0.110), somatic mutation of CCDC168 (P = 0.049), HMCN1 (P = 0.040), MYO10 (P = 0.007), and amplification of ZC3H13 (P < 0.001) were associated with shorter OS. Potentially targetable gene alterations (PTGAs) were seen in 72% of the patients. FGFR1 amplification (22%) was the most common PTGA followed by BARD1 and BRCA2 mutation (each 17%). As for gene variations associated with the efficacy of immune checkpoint blockade (ICB), FAT1 alteration (39%) and PTEN depletion (28%) were commonly observed. In conclusion, frequently altered oncogenic pathways might contribute to the development and progression of R-NETs. Gene alterations significantly associated with prognosis might be potential novel targets. Targeted therapy might be a promising strategy as targetable alterations were prevalent in R-NETs. FAT1 alteration and PTEN depletion might be the main genetic alterations influencing the response to ICB besides overall low TMB and MSI in R-NETs.

Effects of sangu decoction on osteoclast activity in a rat model of breast cancer bone metastasis.

Bone metastasis (BM) is a major clinical problem for which current treatments lack full efficacy. The Traditional Chinese Medicine (TCM) Sangu Decoction (SGD) has been widely used to treat BM in China. However, no in vivo experiments to date have investigated the effects of TCM on osteoclast activity in BM. In this study, the protective effect and probable mechanism of SGD were evaluated. The model was established using the breast cancer MRMT-1 cells injected into the tibia of rat. SGD was administrated, compared with Zoledronic acid as a positive control. The development of the bone tumor and osteoclast activity was monitored by radiological analysis. TRAP stain was used to identify osteoclasts quantity and activity. TRAP-5b in serum or bone tumor and TRAP mRNA were also quantified. Radiological examination showed that SGD inhibited tumor proliferation and preserved the cortical and trabecular bone structure. In addition, a dramatic reduction of TRAP positive osteoclasts was observed and TRAP-5b levels in serum and bone tumor decreased significantly. It also reduced the mRNA expression of TRAP. The results indicated that SGD exerted potent antiosteoclast property that could be directly related to its TRAP inhibited activity. In addition it prevented bone tumor proliferation in BM model.

Advances in medical treatment for pancreatic neuroendocrine neoplasms.

Pancreatic neuroendocrine neoplasms (PanNENs) are rare neoplasms with strong heterogeneity that have experienced an increasing incidence rate in recent years. For patients with locally advanced or distant metastatic PanNENs, systemic treatment options vary due to the different differentiations, grades and stages. The available options for systemic therapy include somatostatin analogs, mole-cularly targeted agents, cytotoxic chemotherapeutic agents, immune checkpoint inhibitors, and peptide receptor radionuclide therapy. In addition, the development of novel molecularly targeted agents is currently in progress. The sequence of selection between different chemotherapy regimens has been of great interest, and resistance to chemotherapeutic agents is the major limitation in their clinical application. Novel agents and high-level clinical evidence continue to emerge in the field of antiangiogenic agents. Peptide receptor radionuclide therapy is increasingly employed for the treatment of advanced neuroendocrine tumors, and greater therapeutic efficacy may be achieved by emerging radio-labeled peptides. Since immune checkpoint inhibitor monotherapies for PanNENs appear to have limited antitumor activity, dual immune checkpoint inhibitor therapies or combinations of antiangiogenic therapies and immune checkpoint inhibitors have been applied in the clinic to improve clinical efficacy. Combining the use of a variety of agents with different mechanisms of action provides new possibilities for clinical treatments. In the future, the study of systemic therapies will continue to focus on the screening of the optimal benefit population and the selection of the best treatment sequence strategy with the aim of truly achieving individualized precise treatment of PanNENs.