Two different mutational types of familial gastrointestinal stromal tumors:Two case reports

BACKGROUND Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal(GI)tract,and cases of GISTs tend to be of the disseminated type,with a global incidence of 10 to 15 cases/million each year.The rarer familial GISTs,which often represent a population,differ in screening,diagnosis,and treatment.Familial GISTs include primary familial GISTs with predominantly KIT/PDGFRA mutations and wild-type GISTs.However,whether the same genetic family has different phenotypes has not been reported.CASE SUMMARY We report two cases of rare GISTs in the same family:A male patient with the V561D mutation in exon 12 of the PDGFRA gene,who has been taking the targeted drug imatinib since undergoing surgery,and a female patient diagnosed with wild-type GIST,who has been taking imatinib for 3 years since undergoing surgery.The favorable prognosis of these patients during the 7-year follow-up period validates the accuracy of our treatment strategy,and we have refined the entire process of diagnosis and treatment of familial GISTs in order to better manage this rare familial disease.CONCLUSION Different mutation types of familial GISTs in the same family are very rare,thus it is very important to make the correct diagnosis and treatment strategies according to the results of molecular detection for the management of familial GISTs.

Familial gastrointestinal stromal tumors with KIT germline mutation in a Chinese family:A case report

BACKGROUND Familial gastrointestinal stromal tumors(GISTs)is a rare autosomal dominant disorder characterized by an array of clinical manifestations.Only 35 kindreds with germline KIT mutations and six with germline PDGFRA mutations have been reported so far.It is often characterized by a series of manifestations,such as multiple lesions and hyperpigmentation.However,the effect of imatinib treatment in these patients is still uncertain.CASE SUMMARY Here,we report two patients(father and daughter)in a Chinese family(for the first time)with germline KIT mutation,and described their pathology,genetics and clinical manifestations.A 25-year-old Chinese woman went to hospital because of abdominal pain,and computed tomography showed multiple tumors in the small intestine.Small pigmented spots appeared on the skin within a few months after birth.Her father also had multiple pigmented spots and a history of multifocal GISTs.Multiple GISTs associated with diffuse interstitial Cajal cells(ICCs)hyperplasia were positive for CD117 and DOG-1.Gene sequencing revealed a germline mutation at codon 560 of exon 11(p.V560G)of KIT gene in these two patients.Imatinib therapy showed the long-lasting disease stability after resection.Remarkably,the hypopigmentation of the skin could also be observed.Luckily germline KIT mutation has not been identified yet in the 3-year-old daughter of the female patient.CONCLUSION Diagnosis of familial GISTs depends on combination of diffuse ICCs hyperplasia,germline KIT/PDGFRA mutation,hyperpigmentation and family history.

Tumor necrosis family receptor superfamily member 9/tumor necrosis factor receptor-associated f

Hepatitis C virus(HCV)infection is an excellent immunological model for understanding the mechanisms developed by non-cytopathic viruses and tumors to evade the adaptative immune response.The antigen-specific cytotoxic T cell response is essential for keeping HCV under control,but during persistent infection,these cells become exhausted or even deleted.The exhaustion process is progressive and depends on the infection duration and level of antigenemia.During high antigenic load and long duration of infection,T cells become extremely exhausted and ultimately disappear due to apoptosis.The development of exhaustion involves the impairment of positive co-stimulation induced by regulatory cytokines,such as transforming growth factor beta 1.This cytokine downregulates tumor necrosis factor receptor(TNFR)-associated factor 1(TRAF1),the signal transducer of the T cell co-stimulatory molecule TNFR superfamily member 9(known as 4-1BB).This impairment correlates with the low reactivity of T cells and an exhaustion phenotype.Treatment with interleukin-7 in vitro restores TRAF1 expression and rescues T cell effector function.The process of TRAF1 loss and its in vitro recovery is hierarchical,and more affected by severe disease progression.In conclusion,TRAF1 dynamics on T cells define a new pathogenic model that describes some aspects of the natural history of HCV,and sheds light on novel immunotherapy strategies for chronic viral infections and cancer.

Recent advances in the management of gastrointestinal stromal tumor

Gastrointestinal stromal tumor(GIST)is a rare but an important clinical entity seen in our clinical practice.It is the most common mesenchymal tumor of the gastrointestinal tract and most common malignancy of the small intestine.Although the exact prevalence of GIST is not known,the incidence of GIST has been increasing.GISTs arise from interstitial cells of Cajal.Most of the GISTs occur due to mutation in c-kit gene or platelet derived growth factor receptor alpha gene.15%of GISTs do not have these mutations and they are called wildtype GISTs.Almost all GISTs express KIT receptor tyrosine kinase.Histologically,GISTs look like spindle cell tumors most of the time but they can be epitheloid or mixed type.The median size of GISTs varies from 2.7 cm to 8.9 cm.Clinically,patients with small GISTs remain asymptomatic but as the GIST size increases,patients present with various symptoms depending on the location of the GIST.Most of GISTs are located in the stomach or small bowel.Diagnosis is suspected on imaging and endoscopic studies,and confirmed by tissue acquisition with immunohistochemical staining.The aggressiveness of GISTs depends on the size,mitotic index and location.Surgical resection is the treatment of choice.But various endoscopic modalities of resection are increasingly being tried.Tyrosine kinase inhibitors are extremely useful in the management of large GISTs,unresectable GISTs and metastatic GISTs.Treatment options for metastatic GISTs also include radiotherapy,chemotherapy,hepatic artery embolization,chemoembolization and radiofrequency ablation.

Delayed hippocampal neuronal death in young gerbil following transient global cerebral ischemia is related to higher and longer-term expression of p63 in the ischemic hippocampus

The tumor suppressor p63 is one of p53 family members and plays a vital role as a regulator of neuronal apoptosis in the development of the nervous system. However, the role of p63 in mature neuronal death has not been addressed yet. In this study, we first compared ischemia-induced effects on p63 expression in the hippocampal regions （CA1-3） between the young and adult gerbils subjected to 5 minutes of transient global cerebral ischemia. Neuronal death in the hippocampal CA1 region of young gerbils was significantly slow compared with that in the adult gerbils after transient global cerebral ischemia, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons in the sham-operated young group was significantly low compared with that in the sham-operated adult group, p63 immunoreactivity was apparently changed in ischemic hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. In the ischemia-operated adult groups, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons was significantly decreased at 4 days post-ischemia; however, p63 immunoreactivity in the ischemia-operated young group was significantly higher than that in the ischemia-operated adult group. At 7 days post-ischemia, p63 immunoreactivity was decreased in the hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. Change patterns of p63 level in the hippocampal CA1 region of adult and young gerbils after ischemic damage were similar to those observed in the immunohistochemical results. These findings indicate that higher and longer-term expression of p63 in the hippocampal CA1 region of the young gerbils after ischemia/reperfusion may be related to more delayed neuronal death compared to that in the adults.

RNA editingof SLC22A3 causes early tumor progression in familial esophageal cancer patients

Subject Code:H16With the support by the National Natural Science Foundation of China,a collaborative study by the Research groups led by Prof.Fu Li(付利)from the Cancer Research Center,Shenzhen University School of Medicine and Prof.Guan Xinyuan(关新元)from the University of Hong Kong reported that an