AIM: To clarify the biological role of stem cell factor (SCF)-mediated wild-type KIT receptor activation in gastrointestinal stromal tumor (GIST) growth. METHODS: The co-expression of wild-type KIT receptor and SCF wa...AIM: To clarify the biological role of stem cell factor (SCF)-mediated wild-type KIT receptor activation in gastrointestinal stromal tumor (GIST) growth. METHODS: The co-expression of wild-type KIT receptor and SCF was evaluated in 51 GIST samples using mutation analysis and immunohistochemistry, and the results were correlated with clinicopathological param- eters, including the mitotic count, proliferative index (Ki-67 immunohistochemical staining), mitotic index (phospho-histone H3 immunohistochemical staining) and apoptotic index (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling). Using primary cultured GIST cells, the effect of SCF-mediated wild-type KIT receptor activation was determined by western blotting, methyl thiazolyl tetrazolium (MTT), and apoptosis assays. RESULTS: We found that wild-type KIT receptor and SCF protein were expressed in 100% and 76.5% of the 51 GIST samples, respectively, and the co-expression of wild-type KIT receptor and SCF was associated with known indicators of poor prognosis, including larger tumor size (P = 0.0118), higher mitotic count (P = 0.0058), higher proliferative index (P = 0.0012), higher mitotic index (P = 0.0282), lower apoptosis index (P = 0.0484), and increased National Institutes of Health risk level (P = 0.0012). We also found that the introduction of exogenous SCF potently increased KIT kinase activity, stimulated cell proliferation (P < 0.01) and inhibited apoptosis (P < 0.01) induced by serum starvation, while a KIT immunoblocking antibody suppressed proliferation (P = 0.01) and promoted apoptosis (P < 0.01) in cultured GIST cells. CONCLUSION: SCF-mediated wild-type KIT receptor activation plays an important role in GIST cell growth. The inhibition of SCF-mediated wild-type KIT receptor activation may prove to be particularly important for GIST therapy.展开更多
For over one hundred years, viruses have been recognized as capable of killing tumor cells. At present, people are still researching and constructing more suitable oncolytic viruses for treating different malignant tu...For over one hundred years, viruses have been recognized as capable of killing tumor cells. At present, people are still researching and constructing more suitable oncolytic viruses for treating different malignant tumors. Although extensive studies have demonstrated that herpes simplex virus type 1 (HSV-1) is the most potential oncolytic virus, therapies based on herpes simplex virus type 1 vectors still arouse bio-safety and risk management issues. Researchers have therefore introduced the new idea of treating cancer with HSV-1 mutants labeled with radionuclides, combining radionuclide and oncolytic virus therapies. This overview briefly summarizes the status and mechanisms by which oncolytic viruses kill tumor cells, discusses the application of HSV-1 and HSV-1 derived vectors for tumor therapy, and demonstrates the feasibility and prospect of HSV-1 mutants labeled with radionuclides for treating tumors.展开更多
Neurofibromatosis type 1(NF-1) is commonly associated with benign or malignant tumors in both the central and peripheral nervous systems. However, rare cases of NF-1-associated multiplerectal neuroendocrine tumors hav...Neurofibromatosis type 1(NF-1) is commonly associated with benign or malignant tumors in both the central and peripheral nervous systems. However, rare cases of NF-1-associated multiplerectal neuroendocrine tumors have been reported. This report describes a case of a 39 year old female with NF-1 and intermittent hematochezia as a primary symptom. Physical examination showed multiple subcutaneous nodules and café au lait spots with obvious scoliosis of the back. Imaging examinations and colonoscopy found malformation of the left external iliac vein and multiple gray-yellow nodules with varying sizes and shapes in the rectal submucosal layer. Histological and immunohistochemical results suggested multiple rectal neuroendocrine tumors, a rare disease with few appreciable symptoms and a particularly poor prognosis. The patient with NF-1 presented here had not only multiple rectal neuroendocrine neoplasms but also vascular malformations, scoliosis and other multiple system lesions. This case therefore contributes to improving clinical understanding, diagnosis and treatment of related complications for patients with NF-1 who present with associated medical conditions.展开更多
AIM: To investigate the accuracy of preoperative examinations in follicular type tumors, we re-evaluate results of our operative cases.METHODS: Cases are follicular neoplasms in 36 patients, which are more than 30 mm ...AIM: To investigate the accuracy of preoperative examinations in follicular type tumors, we re-evaluate results of our operative cases.METHODS: Cases are follicular neoplasms in 36 patients, which are more than 30 mm in diameter and underwent surgery in our hospital in 2005-2006. These cases had been suspected of malignancy on one or more of the preoperative examinations, including ultrasound(US), thallium-technecium(Tl-Tc) scinitigram,computed tomography(CT), or fine needle aspiration biopsy(FNA) examinations. Concern about operative procedure, lobectomy plus sentinel lymph node biopsy(SNB) was performed in all 36 follicular tumors at the first surgery. Because we can diagnose a suspected follicular tumor as carcinoma and can change the operative procedure intra-operatively, when the metastasis of lymph nodes, outside of the thyroid, is found. The operative procedure was changed from lobectomy to total thyroidectomy plus lymph nodes dissection(centralcomponent), when the SNB has metastasis. All thirty six cases were obtained to track the prognosis until 2012, for 6-7 years follow up periods.RESULTS: The final pathological results are 3 cases of follicular carcinoma, 6 cases of papillary carcinoma, 1 case of papillary carcinoma follicular type, 1 case of malignant lymphoma, 16 cases of follicular adenoma, and 9 cases of adenomatous goiter. The malignant tumor were observed in 11/36(30.6%) cases. All six papillary carcinomas were less than 20 mm, and present with follicular adenoma and adenomatous goiter, which have more than 40 mm diameter. In physical examination, tumor size of 36 cases of follicular neoplasm is more than 30 mm all at the time of surgery. The tumors were palpable somewhat stiff, such as no cystic component in 34 cases. Occasional dyspnea, dysphagia, and cough was accompanied in all 36 cases. The true ratio of correct diagnosis of preoperative US, Tl-Tc scinitigram, CT, and FNA were 17/36(47.2%), 16/36(44.4%), 24/36(66.7%), 21/36(58.3%), respectively. In 11 malignant cases, there was one SNB positive case(one lymph node metastasis in 3 SNB: 1/3). This case was changed the operative procedure from lobectomy to total thyroidectomy plus lymph node dissection(central component). There is other lymph nodes metastasis in dissected lymph nodes(4/15). For the remaining malignant 10 cases, the observations were selected without additional resection, because surgical margins and SN were negative in postoperative pathology results at the first operation. No recurrence and metastasis are allowed in 11 malignant cases, up to 7 years after post-operation. Over all, the more than 30 mm in diameter follicular neoplasms, which were suspected the malignancy in the one and more preoperative examinations, are present the malignancy by pathological diagnosis in 11/36(30.6%) cases after surgery. The non SNB metastasis cases had no symptoms of lymph nodes metastasis up to 7 years after post-operation.CONCLUSION: We think that more than 30 mm in diameter follicular neoplasms are considered as candidates of surgery from our results.展开更多
BACKGROUND The molecular changes present in gastric neuroendocrine tumors(NETs)include a loss of heterozygosity or mutation of MEN1,CDKN1B gene mutation,P27 heterozygous mutation,and ATP4A gene missense mutation.We id...BACKGROUND The molecular changes present in gastric neuroendocrine tumors(NETs)include a loss of heterozygosity or mutation of MEN1,CDKN1B gene mutation,P27 heterozygous mutation,and ATP4A gene missense mutation.We identified and are the first to report a case of type 1 histamine-producing enterochromaffin-like cell NETs(ECL-cell NETs)with a BRCA2 gene germline mutation.CASE SUMMARY The patient had a history of iron-deficient anemia for 5 years,and gastroscopic examination indicated multiple gastric tumors.Then,the patient underwent distal gastrectomy.Microscopically,multifocal tumor cells were found in the mucosa and submucosa;tumor cells were organoid and arranged in nests and cords,and the stroma was rich in sinusoids.The surrounding gastric mucosa showed atrophy with mild intestinal metaplasia or pseudopyloric gland metaplasia.Neuroendocrine cells could be seen with diffuse linear,nodular,and adenomatous hyperplasia.Immunohistochemically,the tumor cells diffusely expressed cytokeratin,chromogranin,synaptophysin,and CD56.Whole-genome highthroughput molecular sequencing revealed a pathogenic germline mutation in the BRCA2 gene,a heterozygous germline frameshift mutation in exon 11,c.6443_6444del(p.S2148Yfs*2).The final diagnosis was gastric type 1 ECL-cell NETs with a BRCA2 gene germline mutation,accompanied by autoimmune gastritis.CONCLUSION This is the first report of a case of type 1 gastric ECL-cell NETs with a pathogenic germline mutation of the BRCA2 gene.The findings of this report will expand the germline mutation spectrum of gastric NETs and increase the understanding of the molecular changes present in these tumors for their improved diagnosis in the future.展开更多
Ⅰ型神经纤维瘤病(neurofibromatosis type 1,NF1)是一种由NF1基因突变导致的常染色体显性遗传病,以多发皮肤咖啡斑和神经纤维瘤为主要特征,国际上针对NF1尚无规范治疗策略。NF 1基因庞大,其编码的神经纤维蛋白(neurofibromin,NF)参与...Ⅰ型神经纤维瘤病(neurofibromatosis type 1,NF1)是一种由NF1基因突变导致的常染色体显性遗传病,以多发皮肤咖啡斑和神经纤维瘤为主要特征,国际上针对NF1尚无规范治疗策略。NF 1基因庞大,其编码的神经纤维蛋白(neurofibromin,NF)参与细胞增殖调控,该病发病机制复杂,为药物研发带来较大挑战。在NF1信号通路方面,丝裂原活化蛋白激酶的激酶的激酶/丝裂原活化蛋白激酶的激酶/丝裂原活化蛋白激酶通路(RAF/MEK/ERK)、磷脂酰肌醇3激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白通路(PI3K/AKT/mTOR)、无翅蛋白/β联蛋白通路(WNT/β-catenin)、河马蛋白/转录共激活子/YES相关蛋白通路(HIPPO/TAZ/YAP)等均有研究,其中针对RAF/MEK/ERK通路的MEK1/2抑制剂药物已上市,即司美替尼(selumetinib),用于治疗NF1和不能手术的丛状神经纤维瘤(plexiform neurofibroma,PNF)患者。近年研究发现,NF1肿瘤微环境包括施万细胞(Schwann cells,SCs)及其前体、肥大细胞、巨噬细胞、T细胞、树突状细胞、细胞外基质和周围血管等,对NF1的发生发展发挥不可忽视的作用。现今NF1的治疗方法包括手术切除肿瘤、放射治疗和药物治疗,这些方法均有缺陷,迫切需要从NF1信号通路及肿瘤微环境等方面继续深入探索新的治疗药物。本文主要综述了NF1相关信号通路及肿瘤微环境的研究现状,重点讨论了NF1基因突变引起的信号通路改变以及肿瘤微环境的组分异常,并剖析了NF1疾病可能的发病机制,以期为临床NF1早期诊断、治疗、预防和药物研发提供新的思路。展开更多
基金Supported by The National Natural Science Foundation of China, No.30700809 and No.30972876
文摘AIM: To clarify the biological role of stem cell factor (SCF)-mediated wild-type KIT receptor activation in gastrointestinal stromal tumor (GIST) growth. METHODS: The co-expression of wild-type KIT receptor and SCF was evaluated in 51 GIST samples using mutation analysis and immunohistochemistry, and the results were correlated with clinicopathological param- eters, including the mitotic count, proliferative index (Ki-67 immunohistochemical staining), mitotic index (phospho-histone H3 immunohistochemical staining) and apoptotic index (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling). Using primary cultured GIST cells, the effect of SCF-mediated wild-type KIT receptor activation was determined by western blotting, methyl thiazolyl tetrazolium (MTT), and apoptosis assays. RESULTS: We found that wild-type KIT receptor and SCF protein were expressed in 100% and 76.5% of the 51 GIST samples, respectively, and the co-expression of wild-type KIT receptor and SCF was associated with known indicators of poor prognosis, including larger tumor size (P = 0.0118), higher mitotic count (P = 0.0058), higher proliferative index (P = 0.0012), higher mitotic index (P = 0.0282), lower apoptosis index (P = 0.0484), and increased National Institutes of Health risk level (P = 0.0012). We also found that the introduction of exogenous SCF potently increased KIT kinase activity, stimulated cell proliferation (P < 0.01) and inhibited apoptosis (P < 0.01) induced by serum starvation, while a KIT immunoblocking antibody suppressed proliferation (P = 0.01) and promoted apoptosis (P < 0.01) in cultured GIST cells. CONCLUSION: SCF-mediated wild-type KIT receptor activation plays an important role in GIST cell growth. The inhibition of SCF-mediated wild-type KIT receptor activation may prove to be particularly important for GIST therapy.
基金National Natural Science Foundation of China, No. 30770604
文摘For over one hundred years, viruses have been recognized as capable of killing tumor cells. At present, people are still researching and constructing more suitable oncolytic viruses for treating different malignant tumors. Although extensive studies have demonstrated that herpes simplex virus type 1 (HSV-1) is the most potential oncolytic virus, therapies based on herpes simplex virus type 1 vectors still arouse bio-safety and risk management issues. Researchers have therefore introduced the new idea of treating cancer with HSV-1 mutants labeled with radionuclides, combining radionuclide and oncolytic virus therapies. This overview briefly summarizes the status and mechanisms by which oncolytic viruses kill tumor cells, discusses the application of HSV-1 and HSV-1 derived vectors for tumor therapy, and demonstrates the feasibility and prospect of HSV-1 mutants labeled with radionuclides for treating tumors.
文摘Neurofibromatosis type 1(NF-1) is commonly associated with benign or malignant tumors in both the central and peripheral nervous systems. However, rare cases of NF-1-associated multiplerectal neuroendocrine tumors have been reported. This report describes a case of a 39 year old female with NF-1 and intermittent hematochezia as a primary symptom. Physical examination showed multiple subcutaneous nodules and café au lait spots with obvious scoliosis of the back. Imaging examinations and colonoscopy found malformation of the left external iliac vein and multiple gray-yellow nodules with varying sizes and shapes in the rectal submucosal layer. Histological and immunohistochemical results suggested multiple rectal neuroendocrine tumors, a rare disease with few appreciable symptoms and a particularly poor prognosis. The patient with NF-1 presented here had not only multiple rectal neuroendocrine neoplasms but also vascular malformations, scoliosis and other multiple system lesions. This case therefore contributes to improving clinical understanding, diagnosis and treatment of related complications for patients with NF-1 who present with associated medical conditions.
文摘AIM: To investigate the accuracy of preoperative examinations in follicular type tumors, we re-evaluate results of our operative cases.METHODS: Cases are follicular neoplasms in 36 patients, which are more than 30 mm in diameter and underwent surgery in our hospital in 2005-2006. These cases had been suspected of malignancy on one or more of the preoperative examinations, including ultrasound(US), thallium-technecium(Tl-Tc) scinitigram,computed tomography(CT), or fine needle aspiration biopsy(FNA) examinations. Concern about operative procedure, lobectomy plus sentinel lymph node biopsy(SNB) was performed in all 36 follicular tumors at the first surgery. Because we can diagnose a suspected follicular tumor as carcinoma and can change the operative procedure intra-operatively, when the metastasis of lymph nodes, outside of the thyroid, is found. The operative procedure was changed from lobectomy to total thyroidectomy plus lymph nodes dissection(centralcomponent), when the SNB has metastasis. All thirty six cases were obtained to track the prognosis until 2012, for 6-7 years follow up periods.RESULTS: The final pathological results are 3 cases of follicular carcinoma, 6 cases of papillary carcinoma, 1 case of papillary carcinoma follicular type, 1 case of malignant lymphoma, 16 cases of follicular adenoma, and 9 cases of adenomatous goiter. The malignant tumor were observed in 11/36(30.6%) cases. All six papillary carcinomas were less than 20 mm, and present with follicular adenoma and adenomatous goiter, which have more than 40 mm diameter. In physical examination, tumor size of 36 cases of follicular neoplasm is more than 30 mm all at the time of surgery. The tumors were palpable somewhat stiff, such as no cystic component in 34 cases. Occasional dyspnea, dysphagia, and cough was accompanied in all 36 cases. The true ratio of correct diagnosis of preoperative US, Tl-Tc scinitigram, CT, and FNA were 17/36(47.2%), 16/36(44.4%), 24/36(66.7%), 21/36(58.3%), respectively. In 11 malignant cases, there was one SNB positive case(one lymph node metastasis in 3 SNB: 1/3). This case was changed the operative procedure from lobectomy to total thyroidectomy plus lymph node dissection(central component). There is other lymph nodes metastasis in dissected lymph nodes(4/15). For the remaining malignant 10 cases, the observations were selected without additional resection, because surgical margins and SN were negative in postoperative pathology results at the first operation. No recurrence and metastasis are allowed in 11 malignant cases, up to 7 years after post-operation. Over all, the more than 30 mm in diameter follicular neoplasms, which were suspected the malignancy in the one and more preoperative examinations, are present the malignancy by pathological diagnosis in 11/36(30.6%) cases after surgery. The non SNB metastasis cases had no symptoms of lymph nodes metastasis up to 7 years after post-operation.CONCLUSION: We think that more than 30 mm in diameter follicular neoplasms are considered as candidates of surgery from our results.
基金Supported by Natural Science Foundation of Zhejiang Province,No.LQ20H1600036 (to Wen X).
文摘BACKGROUND The molecular changes present in gastric neuroendocrine tumors(NETs)include a loss of heterozygosity or mutation of MEN1,CDKN1B gene mutation,P27 heterozygous mutation,and ATP4A gene missense mutation.We identified and are the first to report a case of type 1 histamine-producing enterochromaffin-like cell NETs(ECL-cell NETs)with a BRCA2 gene germline mutation.CASE SUMMARY The patient had a history of iron-deficient anemia for 5 years,and gastroscopic examination indicated multiple gastric tumors.Then,the patient underwent distal gastrectomy.Microscopically,multifocal tumor cells were found in the mucosa and submucosa;tumor cells were organoid and arranged in nests and cords,and the stroma was rich in sinusoids.The surrounding gastric mucosa showed atrophy with mild intestinal metaplasia or pseudopyloric gland metaplasia.Neuroendocrine cells could be seen with diffuse linear,nodular,and adenomatous hyperplasia.Immunohistochemically,the tumor cells diffusely expressed cytokeratin,chromogranin,synaptophysin,and CD56.Whole-genome highthroughput molecular sequencing revealed a pathogenic germline mutation in the BRCA2 gene,a heterozygous germline frameshift mutation in exon 11,c.6443_6444del(p.S2148Yfs*2).The final diagnosis was gastric type 1 ECL-cell NETs with a BRCA2 gene germline mutation,accompanied by autoimmune gastritis.CONCLUSION This is the first report of a case of type 1 gastric ECL-cell NETs with a pathogenic germline mutation of the BRCA2 gene.The findings of this report will expand the germline mutation spectrum of gastric NETs and increase the understanding of the molecular changes present in these tumors for their improved diagnosis in the future.
