Real-world study of antiresorptive-related osteonecrosis of jaw based on the US food and drug administration adverse event reporting system database.

Objective: This study aims to explore the risk signals of osteonecrosis of the jaw induced by antiresorptive drugs and provide references for the clinical safety application. Method: According to the FDA's Adverse Event Reporting System (FAERS), from January 2004 to September 2021, we chose "Osteonecrosis of the jaw (10064658)" and "Exposed bone in jaw (10071014)" as preferred terms, "antiresorptive drugs" as the target drugs, and primary suspect drug as the drug role code in the dataset. We evaluated the association between drugs and adverse events by using reporting odds ratio (ROR) based on disproportionality analysis. We took the High-Level Terms (HLT) of MedDRA® as the classification level of indications to calculate ROR to compare the signal difference of ONJ in different indications. In addition, patients with antiresorptive-induced osteonecrosis of the jaw and the time of onset of the condition following different antiresorptive medications were collected for the study. Results: The FAERS contained 18,421 reports relating to jaw osteonecrosis from January 2004 to September 2021. A total of eight antiresorptive agents were included in the analysis. From high to low, the ROR of ONJ induced by antiresorptive agents (regardless of indication) is pamidronate (ROR = 494.8), zoledronic acid (ROR = 431.9), denosumab (ROR = 194.8), alendronate (ROR = 151.2), risedronate (ROR = 140.2), etidronic acid (ROR = 64.5), ibandronate (ROR = 40.8), and romosozumab (ROR = 6.4). HLT ROR values for "metabolic bone disorders" were the lowest for each drug, while HLT ROR values were high for "tumor-related indications," including breast and nipple neoplasms malignant, plasma cell myelomas, and prostatic neoplasms malignant. The onset time for osteonecrosis of the jaw as median (Q1, Q3), osteoporosis-related indications, and the onset time for ONJ were 730 (368, 1268), 489.5 (236.3, 909.8), 722.5 (314, 1055), 761 (368, 1720), and 153 (50, 346) for zoledronic acid, denosumab, ibandronate, risedronate, and romosozumab, respectively. Cancer-related indications: the onset time for ONJ were 680.5 (255.3, 1283), 488 (245, 851), and 696.5 (347, 1087) for zoledronic acid, denosumab, and pamidronate, respectively. Conclusion: When antiresorptive drugs are used for metastasis, they have the largest risk signal, followed by malignancy, and the smallest is osteoporosis. The onset time of ONJ may not be related to the indications. The onset time of ONJ for BPs was about 2 years, denosumab about 1.3 years, and romosozumab less than 1 year, which may be related to sequential treatment. When used according to the instructions, the risk of ONJ caused by denosumab was higher than that of zoledronic acid, regardless of the indication. Based on these findings, researchers will continue to monitor and identify risk factors.

Endoscopic diagnosis of early-stage primary esophageal small cell carcinoma: Report of two cases.

BACKGROUND: Primary esophageal small cell carcinoma (PESCC) is a highly aggressive malignancy, and its detailed clinical behaviors have remained virtually unknown. Because of the rapid tumor progression, the diagnosis of esophageal small cell carcinoma at early stage is extremely difficult in clinical practice. Currently, only a handful of PESCC cases have been reported. CASE SUMMARY: Case 1: A 62-year-old man was diagnosed with an esophageal submucosal tumor by endoscopy. Endoscopic ultrasonography showed a 0.8 cm low echo nodule in the muscularis mucosa. As the patient refused to undergo endoscopic resection, neoplasia was detected by endoscopy 1 year later. Case 2: A 68-year-old woman was diagnosed as having an esophageal submucosal tumor by endoscopy at a local hospital. About 2 wk later, we performed endoscopic ultrasonography and found a 1 cm low echo nodule in the muscularis mucosa; the submucosal was thinner than normal but still continuous; mucosal hyperemia and erosion were found on the surface of the tumor. Endoscopic submucosal dissection (ESD) was performed and the histopathological finding showed a small cell carcinoma invading the submucosal layer. CONCLUSION: Early esophageal small cell carcinoma shows submucosal infiltrating growth with a hypoechoic mass in the muscularis mucosa as diagnosed by endoscopic ultrasonography. It is easily misdiagnosed as submucosal masses. Endoscopic manifestations should be identified and pathological biopsies should be employed. ESD may be performed to provide an opportunity for early treatment of PESCC.

Expression of IMP3 as a marker for predicting poor outcome in gastroenteropancreatic neuroendocrine neoplasms.

The aim of the present study was to investigate the expression and clinical significance of oncofetal protein insulin-like growth factor (IGF) II mRNA-binding protein 3 (IMP3) in the differentiation of gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN). A total of 162 patients who were diagnosed with GEP-NEN, and who underwent surgical or endoscopic resection from January 2006 to March 2013, were enrolled in the study, including 85 cases of grade (G)1 neuroendocrine tumors, 40 cases of G2 neuroendocrine tumors, 28 cases of G3 neuroendocrine carcinomas and 9 cases of mixed stage adenoneuroendocrine carcinomas. The clinical and pathological data were recorded for analysis. The expression of IMP3, cluster of differentiation (CD)44, IGF1 receptor (IGF1R) and matrix metalloproteinase (MMP)2 was determined by immunohistochemistry. SPSS 13.0 software was used for data processing and analyses, and P<0.05 was used to determine significance. Oncofetal protein IMP3 exhibited a high expression rate (74.69%) in GEP-NEN. IMP3-positive cases demonstrated significantly decreased overall and disease-free survival times, as compared with IMP3-negative cases (P=0.012). Overexpression of IMP3 was correlated with tumor grade, clinical stage, tumor size and poor prognosis (all P<0.05). Therefore, patients with overexpressed IMP3 had a poorer prognosis (P<0.01); COX regression analysis revealed that the overexpression of IMP3, the tumor grade, tumor size and metastasis of GEP-NEN were each associated with the clinical outcomes. The results also indicated that the expression rates of CD44, IGF1R and MMP2 in GEP-NEN were 19.75, 53.7 and 55.56%, respectively. While it was negatively associated with the expression of CD44 (r=-0.131; P=0.096), the expression of IMP3 was positively correlated with the expression of IGF1R and MMP2 (r=0.288, P<0.01; r=0.208, P=0.008). In addition, the expression levels of IGF1R and MMP2 were positively associated (r=0.687; P<0.01). In conclusion, high IMP3 expression levels were determined to be associated with a high disease stage in patients with GEP-NEN, thus it may serve as a predictor for metastasis and poor clinical outcomes in GEP-NEN.

Insulin-like growth factor II mRNA binding protein 3 regulates proliferation, invasion and migration of neuroendocrine cancer cells.

This study aimed to investigate the role of insulin-like growth factor II mRNA binding protein 3 (IMP3) in neuroendocrine tumor (NET). Mouse NET STC-1 cell line was chosen as the experimental model and three IMP3-targeting siRNAs and a non-specific scramble siRNA were transfected into STC-1 cells. The efficiency of IMP3 siRNA to knockdown IMP3 was evaluated by immunocytochemical staining. Cell proliferation was detected by MTT assay. Cell migration and invasion was analyzed with Transwell chamber assay. Protein expression was detected by Western blot analysis. We found that IMP3 silencing inhibited the proliferation of STC-1 cells potentially by downregulating the expression of cell proliferation associated proteins EGFR and Ki67. Furthermore, IMP3 silencing inhibited the migration and invasion of STC-1 cells potentially by downregulating the expression of metastasis associated proteins IGF1R, MMP2 and MMP9. In conclusion, this study provides the first evidence that IMP3 plays an oncogenic role in Net and is a promising therapeutic target for NET.

Identification of sequence polymorphisms in the displacement loop region of mitochondrial DNA as a risk factor for gastroenteropancreatic neuroendocrine neoplasm.

BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are relatively rare tumors that arise from the diffuse neuroendocrine system, and the biggest advances in molecular biology have helped in understanding these biological diversity of tumors over the past decades. It is important to determine the carcinogenesis of GEP-NEN from the perspective of genetic backgrounds. METHODS: Mitochondrial DNA (mtDNA) of peripheral blood from 66 GEP-NEN patients and from 75 healthy controls without history of any cancer were examined for single nucleotide polymorphisms (SNPs) and mutations in the displacement loop (D-loop) region. RESULTS: Single nucleotide polymorphisms were detected in 148 sites within the 982 bp mitochondria D-loop region from blood samples of healthy controls and GEP-NEN patients. SNPs with a rare allele frequency >5% in either controls or GEP-NEN patients were used for cancer risk analysis; a total of 23 SNPs were selected. When individual SNPs of GEP-NEN patients compared with healthy controls were analyzed, a statistically significant increase in the SNP frequency was observed for 73G, 150T, 151T, 492C, 16257A, 16261T, and 16399G in GEP-NEN patients (P<.05). It was also observed that the SNP frequency for 489C and 16519C significantly decreased in GEP-NEN patients compared with controls (P<.05). CONCLUSION: In summary, SNPs in the mutations of the mitochondrial D-loop may be valuable markers for GEP-NEN risk evaluation. Analysis of the genetic polymorphisms in the D-loop may be useful for diagnosis of high-risk individuals.

The anomeric mixture of some O-galactolipid derivatives is more toxic against cancer cells than either anomer alone.

The anomeric mixture of a series of O-galactolipid derivatives is revealed to be more toxic against several cancer cell lines than their either single component with the pure α- or ß-configuration. This interesting phenomenon has been confirmed on pairs of synthesized O-galactosyl anomers bearing length-varied alkyl chains at the lipid end. Furthermore, the most potent mixture was determined inoffensive to a normal cell line tested.

[The value of endoscopic mucosal resection for dysplasia and early-stage cancer of the esophagus and gastric cardia].

OBJECTIVE: To evaluate the long-term effect and clinical value of endoscopic mucosal resection (EMR) with transparent cap for dysplasia and early-stage cancer of the esophagus and gastric cardia. METHODS: From September 1996 to June 2007, 154 lesions in the esophagus or gastric cardia of 147 patients were treated using EMR with transparent cap. Among the lesions, there were 69 early-stage squamous-cell carcinomas in 64 patients and 47 squamous cell precancerous lesions of the esophagus in 45 patients, with an average lesion size of (14.8 +/- 6.1) mm (range, 3-40 mm), furthermore, there were 23 early-stage adenocarcinomas in 23 patients and 15 precancerous lesions in the gastric cardia in 15 patients, with an average lesion size of (8.2 +/- 4.3) mm (rang, 5-25 mm). All lesions were finally confirmed histopathologically. RESULTS: Of the 154 lesions, 139 (90.3%) were resected completely through EMR procedure. A close relationship between the complete resection rate and the lesion size was observed. The bigger the lesion size, the lower the complete resection rate. Endoscopic follow-up was carried out in 7 patients for more than 10 years, in 43 for 5 - 10 years, in 31 for 3 - 5 years and in 66 for less than 3 years. Of 11 dead patients during following-up, 10 died of other diseases, only 1 of recurrence. The 5-year survival rate was 96.2% for early-stage esophageal cancer, and 100% for early cancer of the gastric cardia. Perioperative complications included oozing bleeding in 5 patients (3.4%) and stricture in 1 (0.7%), no perforation occurred in this series. CONCLUSION: Endoscopic mucosal resection is suitable to treat precancerous lesions or early-stage esophageal cancers without invasion into submucosa. Compared with conventional resection through open thoracotomy, similar long-term survival and curative effect can be achieved by this EMR treatment, preserving a good quality of life.

[Clinical value of esophageal mucosal iodine stain during esophagoscopy for patients without swallowing symptoms].

OBJECTIVE: To investigate the clinical value of esophageal mucosal iodine stain during esophagoscopy for patients with early esophageal carcinoma or precancerous lesions without swallowing symptoms, through analyzing the correlation between endoscopic findings and pathological results of biopsy on the suspicious spots. METHODS: For 366 patients examined by iodine stain during esophagoscopy, the position, size, shape and boundary of all visible unstained lesions were recorded and multiple biopsies were taken on the unstained spots. RESULTS: Before iodine stain, 462 lesions had been discovered in 366 patients. However, 478 abnormal lesions stained in 341 patients were detected after iodine stain, the remaining 25 gave no abnormal findings. More than 1/3 of patients were found to have more than 2 abnormally stained lesions. 28.4% of them (104 cases) had moderate or severe dysplasia or early esophageal cancer. The sensitivity of iodine stain in this series was 89.8%. CONCLUSION: Iodine stain is very useful in detecting occult early esophageal carcinoma and precancerous lesions. The degree of coloration and the margin of suspicious spots are closely correlated with the pathological results.

[The NAD(P)H: quinone oxidoreductase 1 C609T polymorphism and susceptibility to esophageal cancer].

OBJECTIVE: To investigate the association of the NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T polymorphism with susceptibility to esophageal squamous cell carcinoma (ESCC) in a northern Chinese population. METHODS: The NQO1 C609T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) analysis in 193 patients with ESCC and 141 unrelated healthy controls. RESULTS: The frequency of the T allele (null) among ESCC patients was significantly higher than that among healthy controls (Chi-square=4.86, P=0.028). The NQO1 C/C and C/T genotype distribution among ESCC patients was not significantly different from that among healthy controls (Chi-square= 2.27 and 0.127; P=0.132 and 0.721, respectively). However, the T/T genotype frequency among ESCC patients was significantly higher than that among healthy controls (Chi-square=4.39, P=0.036). The NQO1 T/T genotype significantly increased the risk for developing ESCC, compared to the combination of C/C and C/T genotypes, with the adjusted odds ratio (OR) of 1.81 (95%CI: 1.04-3.15). This increased susceptibility exhibited pronouncedly in patients with family history of upper gastrointestinal cancers (adjusted OR=2.22, 95%CI 1.18-4.17). CONCLUSION: Determination of the NQO1 C609T genotype may be used as a stratification marker to predicate high-risk individuals for ESCC.

[p53 gene polymorphism with susceptibility to esophageal cancer and lung cancer in Chinese population].

OBJECTIVE: To investigate the association of p53 codon 72 polymorphism with susceptibility to esophageal cancer and lung cancer in the northern Chinese population. METHODS: p53 codon 72 genotyping was performed by amplifying DNA fragments with sequence specific primers among 173 patients with esophageal squamous cell carcinoma, 98 with non-small cell lung carcinoma as well as 136 healthy controls. RESULTS: No significant difference of p53 allelotype and genotype distribution was observed between esophageal cancer and lung cancer patients. The Pro allele frequency was significantly higher among esophageal cancer and lung cancer patients than among healthy controls (P value was 0.024 and 0.027 respectively). There were no significant differences in Pro/Arg and Arg/Arg genotype frequency among cancer patients and healthy controls (P > 0.05). However, the Pro/Pro genotype frequency was significantly higher among esophageal cancer and lung cancer patients than among healthy controls (P value was 0.041 and 0.026 respectively). The risk of Pro homozygotes for both esophageal cancer and lung cancer was about 2 times against Arg homozygotes with adjusted odds ratio of 2.12 (95% CI = 1.13 - 4.01) and 2.30 (95% CI = 1.13 - 4.93), respectively. There was no interaction between p53 Pro/Pro genotype and smoking status to the risk for esophageal cancer and lung cancer. CONCLUSION: In the northern Chinese population, p53 Pro/Pro genotype is an independent risk factor for both esophageal cancer and lung cancer. The possible common genetic basis of the development of these two cancers is suggested by this study.

NQO1 C609T polymorphism associated with esophageal cancer and gastric cardiac carcinoma in North China.

AIM: To investigate the association of the NQO1 (C609T) polymorphism with susceptibility to esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA) in North China. METHODS: The NQO1 C609T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 317 cancer patients (193 ESCC and 124 GCA) and 165 unrelated healthy controls. RESULTS: The NQO1 C609T C/C, C/T and T/T genotype frequency among healthy controls was 31.5 %, 52.1 % and 16.4 % respectively. The NQO1 T/T genotype frequency among ESCC patients (25.9 %) was significantly higher than that among healthy controls (chi(2)=4.79, P=0.028). The NQO1 T/T genotype significantly increased the risk for developing ESCC compared with the combination of C/C and C/T genotypes, with an age, sex and smoking status adjusted odds ratio (OR) of 1.78 (1.04-2.98). This increased susceptibility was pronounced in ESCC patients with family histories of upper gastrointestinal cancers (UGIC) (adjusted OR=2.20, 95 % CI=1.18-3.98). Similarly, the susceptibility of the NQO1 T/T genotype to GCA development was also observed among patients with family histories of UGIC, with an adjusted odds ratio of 2.55 (95 % CI=1.21-5.23), whereas no difference in NQO1 genotype distribution was shown among patients without family histories of UGIC. CONCLUSION: Determination of the NQO1 C609T genotype may be used as a stratification marker to predicate the individuals at high risk for developing ESCC and GCA in North China.