Stage IV malignant transformation of mature cystic teratoma palliatively treated with concurrent chemoradiotherapy:A case report

BACKGROUND Malignant transformation(MT)of mature cystic teratoma(MCT)has a poor prognosis,especially in advanced cases.Concurrent chemoradiotherapy(CCRT)has an inhibitory effect on MT.CASE SUMMARY Herein,we present a case in which CCRT had a reduction effect preoperatively.A 73-year-old woman with pyelonephritis was referred to our hospital.Computed tomography revealed right hydronephrosis and a 6-cm pelvic mass.Endoscopic ultrasound-guided fine-needle biopsy(EUS-FNB)revealed squamous cell carci-noma.The patient was diagnosed with MT of MCT.Due to her poor general con-dition and renal malfunction,we selected CCRT,expecting fewer adverse effects.After CCRT,her performance status improved,and the tumor size was reduced;surgery was performed.Five months postoperatively,the patient developed dis-semination and lymph node metastases.Palliative chemotherapy was ineffective.She died 18 months after treatment initiation.CONCLUSION EUS-FNB was useful in the diagnosis of MT of MCT;CCRT suppressed the disea-se and improved quality of life.

Mucosa color and size may indicate malignant transformation of chicken skin mucosa-positive colorectal neoplastic polyps

BACKGROUND Lipid metabolism reprogramming is suspected to exist in pre-cancerous lesions,including colorectal adenoma.Screening colonoscopy frequently reveals chicken skin mucosa(CSM;white or yellow-white speckled mucosa)surrounding colo-rectal polyps,caused by macrophages engulfing and accumulating the lipids decomposed by colon cells or adjacent tumors.CSM-positive colorectal polyps are associated with various diseases;however,their prognosis varies greatly.Cold snare polypectomy is commonly used to resect lesions up to 10 to 15 mm in diameter without signs of submucosal invasion but is controversial for CSM-positive colorectal polyps.Improved imaging is required to diagnose and treat CSM-positive colorectal polyps.METHODS This retrospective cohort study included 177 patients with CSM-positive colorectal polyps diagnosed using endoscopy.All patient-related information was extracted from the Goldisc soft-clinic DICOM system or electronic medical record system.Based on the pathological results,patients were classified as non-neoplastic polyps(five juvenile polyps),neoplastic polyps,non-invasive high-grade neoplasia(NHGN),or submucosal invasive carcinoma(SM stage cancer).We analyzed and compared the clinical features,suspected risk factors for malignant transformation of neoplastic polyps,and early infiltration of sub-mucosal carcinoma.RESULTS The diameters of NHGN and SM polyps were much smaller than those of neoplastic polyps.Most NHGN polyps had a deeper red mucosal color.On logistic regression analyses,diameter and deeper red mucosal color were independent risk factors for malignant transformation of neoplastic polyps.Type 1 CSM was more common in high-grade intraepithelial neoplasia and SM;type 2 CSM was more common in neoplastic polyps.Logistic regression analyses revealed no significant differences in the malignant transformation of neoplastic polyps or early submucosal invasion of CSM-positive colorectal cancer.Changes in the CSM mucosa surrounding neoplastic polyps and submucosal invasion of colorectal cancer disappeared within 12 months.No tumor recurrence was found during either partial or complete endoscopic resection of the CSM.CONCLUSION CSM-positive colorectal polyps>1 cm in diameter or with deeper red mucosa may be related to NHGN.Resection of CSM surrounding colorectal adenomas did not affect tumor recurrence.

Adenomyoepithelioma of the breast with malignant transformation and repeated local recurrence:A case report

BACKGROUND Adenomyoepithelioma(AME)of the breast is a rare type of benign breast tumor.Many AMEs show benign behavior,but reports of the malignant type are rare.We present the case of a patient with AME with repeated local recurrences and further malignant transformation.CASE SUMMARY A 53-year-old woman visited our hospital with a 16-mm palpable mass in the right breast.A core needle biopsy was performed.The pathological diagnosis was AME.Lumpectomy with a safety margin was performed without axillary lymph node dissection(ALND).Two years later,local recurrence developed,and the patient again underwent lumpectomy with a safety margin.The pathology showed malignant AME,and the margin was negative.Eight months later,local recurrence developed again in the same location,and a total mastectomy was performed without ALND.The pathological diagnosis was malignant AME.The patient was disease-free for three years posttreatment.CONCLUSION The treatment of AME requires caution,as it may exhibit repeated recurrences after local excision as well as malignant transformation.

Risk assessment models of integrative medicine indicators for malignant transformation of chronic atrophic gastritis:A registry study protocol

Objective:Traditional Chinese medicine(TCM)and modern medicine have both been used in arresting malignant transformation of chronic atrophic gastritis(CAG)in China with good therapeutic effect.However,no studies have been undertaken to assess the risk of malignant transformation in CAG patients using both modern medicine and TCM features.Our study aimed to develop risk assessment models for malignant transformation of CAG combining indicators of both TCM and modern medicine.These models will facilitate early warning and control of malignant transformation of CAG from the perspective of evidence-based integrative medicine.Methods:In the proposed registry study,a total of 1000 eligible CAG patients will be recruited from four hospitals in China.A 10-year follow-up study will be conducted both on-site and off-site to track the events of malignant transformation.Frequency analysis and chi-squared tests will be used to perform the comparative analysis on the prevalence of malignant transformation events and indicators in TCM or modern medicine in different groups.A multivariate Cox proportional hazard model will be used to perform correlation analyses of malignant transformation events and factors of TCM or modern medicine.Conclusion:The proposed study has been designed with a large sample size and long follow-up period,in which wide-ranging modern medicine and TCM indicators can be gathered over the whole process of malignant transformation of CAG.Based on this study,risk assessment models for malignant transformation ofCAGmaybe constructed fromthe perspective of integrative medicine.This may provide clinicians and patients with an optimized early warning system as well as prevention strategies for malignant transformation of CAG.

O6-methylguanine DNA methyltransferase is upregulated in malignant transformation of gastric epithelial cells via its gene promoter DNA hypomethylation

BACKGROUND O_(6)-methylguanine-DNA methyltransferase(MGMT)is a suicide enzyme that repairs the mispairing base O_(6)-methyl-guanine induced by environmental and experimental carcinogens.It can transfer the alkyl group to a cysteine residue in its active site and became inactive.The chemical carcinogen N-nitroso compounds(NOCs)can directly bind to the DNA and induce the O_(6)-methylguanine adducts,which is an important cause of gene mutation and tumorigenesis.However,the underlying regulatory mechanism of MGMT involved in NOCs-induced tumorigenesis,especially in the initiation phase,remains largely unclear.AIM To investigate the molecular regulatory mechanism of MGMT in NOCs-induced gastric cell malignant transformation and tumorigenesis.METHODS We established a gastric epithelial cell malignant transformation model induced by N-methyl-N’-nitro-N-nitrosoguanidine(MNNG)or N-methyl-N-nitroso-urea(MNU)treatment.Cell proliferation,colony formation,soft agar,cell migration,and xenograft assays were used to verify the malignant phenotype.By using quantitative real-time polymerase chain reaction(qPCR)and Western blot analysis,we detected the MGMT expression in malignant transformed cells.We also confirmed the MGMT expression in early stage gastric tumor tissues by qPCR and immunohistochemistry.MGMT gene promoter DNA methylation level was analyzed by methylation-specific PCR and bisulfite sequencing PCR.The role of MGMT in cell malignant transformation was analyzed by colony formation and soft agar assays.RESULTS We observed a constant increase in MGMT mRNA and protein expression in gastric epithelial cell malignant transformation induced by MNNG or MNU treatment.Moreover,we found a reduction of MGMT gene promoter methylation level by methylation-specific PCR and bisulfite sequencing PCR in MNNG/MNU-treated cells.Inhibition of the MGMT expression by O_(6)-benzylguanine promoted the MNNG/MNU-induced malignant phenotypes.Overexpression of MGMT partially reversed the cell malignant transformation process induced by MNNG/MNU.Clinical gastric tissue analysis showed that MGMT was upregulated in the precancerous lesions and metaplasia tissues,but downregulated in the gastric cancer tissues.CONCLUSION Our finding indicated that MGMT upregulation is induced via its DNA promoter hypomethylation.The highly expressed MGMT prevents the NOCs-induced cell malignant transformation and tumorigenesis,which suggests a potential novel approach for chemical carcinogenesis intervention by regulating aberrant epigenetic mechanisms.

AKT1 and AKT2 Promote Malignant Transformation in Human Brain Glioma LN229 Cells

OBJECTIVE To confirm the role played by AKT1 and AKT2 in the β- catenin/Tcf-4 signaling pathway in promoting malignant transfor- mation of glioma cells. METHODS LN229 cells were divided into five groups： a control group, acetone （ACE）group, acetylsalicylic acid （ASA; aspirin） group, ASA＋AKT1 plasmid group and ASA＋AKT2 plasmid group. Western blot and PCR were used to detect the expression of AKT1 and AKT2 after dealing with ASA and transferring AKTI/2 genes into LN229 cells. Cell proliferation was determined by flow cytometry, cell invasion was evaluated by transwell assay and cell apoptosis was detected with annexin V staining. The molecules regulating proliferation and invasion were examined by western blot analysis. RESULTS Aspirin down-regulates AKT1 and AKT2 expression by modulating β-cateninfrcf-4 activity. AKT1 and AKT2 can enhance cell proliferation and invasion by up-regulating the expression of cyclin-D and matrix metalloprotein-9 （MMP-9） in LN229 glioma cells. CONCLUSION AKT1 and AKT2 play an important role in the β- catenin/Tcf-4 signaling pathway promoting malignant transformation; AKT1 is more effective than AKT2. AKT1 and AKT2 may be potential targets for brain glioma therapy and an effective way to prevent metastasis of gliomas.

Malignant transformation of pulmonary bronchiolar adenoma into mucinous adenocarcinoma:A case report

BACKGROUND Bronchiolar adenoma(BA)and ciliated muconodular papillary tumor are rare tumors that have bilayered cell proliferation and continuous expression of p40 and CK5/6 in the basal cell layer.Diagnosis is difficult because of the limited knowledge of these tumors and their morphological similarities to malignant tumors,including invasive mucinous adenocarcinoma,especially based on the histopathology of intraoperative frozen sections.These tumors are now considered to be benign neoplasms,with malignant transformation reported in only a few cases.CASE SUMMARY A 57-year-old woman presented with a 17.0 mm×7.0 mm nodule in the lower lobe of the left lung.Hematoxylin-eosin staining and immunohistochemistry of a surgical specimen were performed.The tumor consisted of a BA area and a mucinous adenocarcinoma(MA)area.In the BA area,the tumor had a bilayered structure of luminal cells and basal cells.The basal cells were positive for CK5/6 and p40,but the MA area was negative for these biomarkers.The Ki-67 proliferation index was low(1%-2%).The patient was diagnosed with BA accompanied by MA,and had a favorable outcome.CONCLUSION The present study indicated that BA may be carcinogenic,and suggests that clinicians should be aware of its potential for malignant transformation.

Malignant transformation of biliary adenofibroma combined with benign lymphadenopathy mimicking advanced liver carcinoma:A case report

BACKGROUND Biliary adenofibromas(BAFs)are rare primary hepatic neoplasms,some of which can potentially undergo malignant transformation.Here,we describe a rare case of malignant transformation of BAF.CASE SUMMARY A 51-year-old female was referred to our hospital with epigastric pain.Computed tomography showed a solitary liver mass combined with the enlargement of multiple mediastinal and cervical lymph nodes,clinically mimicking a liver carcinoma with extensive lymph node metastasis.However,core needle biopsy suggested BAF with malignant transformation.Finally,the patient underwent curative resection of the neoplasm and was recurrence-free for 12 mo.CONCLUSION Our case serves as an example of a rare manifestation of BAF.Our report and the previously published experience,reinforce that curative resection should be considered the primary treatment for BAFs with malignant transformation,leading to a favorable prognosis.

Radiotherapy delays malignant transformation and prolongs survival in patients with IDH-mutant gliomas

Objective:IDH-mutant lower-grade gliomas(LGGs,grade 2 or 3)eventually transform into secondary grade 4 astrocytomas(sAIDHmut/G4).Here,we sought to describe the transformation time,risk factors,and outcomes in malignant transformation of IDHmutant LGGs.Methods:We screened data for 108 patients with sAIDHmut/G4 in the Chinese Glioma Genome Atlas who had initial IDH-mutant LGGs and underwent reoperation during 2005–2021.We evaluated the transformation time from IDH-mutant LGGs to sAIDHmut/G4,and associated risk factors and outcomes.Malignant transformation was defined as pathological confirmation of grade 4 astrocytoma.Results:The median age of the 108 patients with IDH-mutant LGGs was 35 years(range,19–54);the median age at transformation was 40 years(range,25–62);and the median follow-up time for all patients was 146 months(range,121–171).The average transformation time was 58.8 months for all patients with LGGs(range,5.9–208.1);63.5 and 51.9 months for grade 2 and 3 gliomas,respectively;and 58.4 and 78.1 months for IDH-mutant/1p/19q-non-codeleted astrocytomas and IDH-mutant/1p/19q-codeleted oligodendrogliomas,respectively.Univariate and multivariate analysis indicated that radiotherapy[hazard ratio(HR),0.29;95%confidence interval(CI),0.137–0.595;P=0.001]and non-A blood type(HR,0.37;95%CI,0.203–0.680;P=0.001)were protective factors against delayed malignant transformation.Radiotherapy was associated with improved survival after transformation(HR,0.44;95%CI,0.241–0.803;P=0.008),overall survival(HR,0.50;95%CI,0.265–0.972;P=0.041),and progression-free survival(HR,0.25;95%CI,0.133–0.479;P<0.0001)in patients with IDH-mutant gliomas.Conclusions:Radiotherapy is associated with delayed malignant transformation and improved survival in patients with IDHmutant gliomas.

Malignant transformation of primary mature teratoma of colon:A case report

BACKGROUND Mature teratoma is a common benign ovarian germ cell tumor,accounting for about 20%of ovarian tumors.The malignant transformation of this tumor is less than 2%.The most common type is squamous cell carcinoma,followed by adenocarcinoma.Malignant transformation of colonic mature teratoma is extremely rare.We here report a case of malignant transformation of primary mature teratoma of the colon.The type of malignant transformation was adenocarcinoma.CASE SUMMARY A 63-year-old woman was admitted to our hospital due to persistent pain in her right lower abdomen for 1 mo,and she had no nausea,vomiting,blood in the stools,or other symptoms.Preoperative colonoscopy showed uplift of the sigmoid colon mucosa and submucosa.The biopsy showed squamous epithelium.However,contrast-enhanced computed tomography of abdomen and pelvis showed a localized thickening of the sigmoid wall,suggesting colon cancer.Endoscopic ultrasonography(EUS)revealed that the structure of the intestinal wall at the base of the lesion was destroyed,and the boundary between the lesion and the surroundings was unclear.According to the findings of the EUS,the patient did not undergo endoscopic submucosal dissection,but underwent radical resection of the tumor.Histologically,squamous epithelium was seen on the mucosal surface of the colon wall,cartilage and glands were seen under the epithelium,and adenocarcinoma was seen on the muscular layer and serous surface.The final pathological diagnosis was malignant teratoma of the colon.We have followed up the patient for 2 mo since the operation,and the patient recovered well.CONCLUSION This case suggests the possibility of mature teratoma in the colon and recognition of malignant types,and it should not be considered as an exclusively ovarian tumor.

Reduced delay in diagnosis of odontogenic keratocysts with malignant transformation:A case report

BACKGROUND In rare cases,odontogenic keratocysts(ODs)transform into squamous cell carcinoma.Intervals between the first attendance of a patient and the diagnosis of OD with malignant transformation vary from weeks to years.In this article,we report a case of malignancy derived from OD with a five-day delay in diagnosis.CASE SUMMARY A 54-year-old woman was referred to Tongji Hospital in Wuhan,China with complaints of moderate pain,recurrent swelling,and pus discharge around her left maxillary lateral incisor for over 10 years.Physical examination revealed a fistula at the palatine-side mucoperiosteum of the left maxillary lateral incisor and enlarged lymph node in the left neck.Cone beam computed tomography revealed a cystic lesion with massive bone destruction from the left maxillary central incisor to the left secondary maxillary premolar and local bony destruction in the left first mandibular molar.The patient was clinically diagnosed with OD.Enucleation rather than marsupialization was performed given the risk factors of long history,recent aggravated pain,and massive bony destruction.Malignant transformation of OD was confirmed by pathologists 3 d after the operation.Radical surgery was performed,and lymph node metastasis was observed.The patient was subjected to postoperative radiotherapy and synchronous chemotherapy,and no local recurrence or distant metastasis was noted at one-year follow-up.CONCLUSION Our case suggests that clinicians should be aware of the malignant transformation of OD,especially when patients present with a long history,massive cyst,chronic inflammation,recent persistent infections,aggravated pain,numbness around the cystic lesion,and lymph node enlargement.

FURTHER STUDIES ON THE MALIGNANT TRANSFORMATION OF SYRIAN GOLDEN HAMSTER EMBRYO CELLS IN VITR0 BY THORIUM DIOXIDE AND RARE EARTH IRON MINERAL DUSTS

Malignant transformation of hamsterembryo cells was induced in vitro by rareearth iron mineral dusts(MP),naturalthorium(Th02) and MP plus Th02.Dusts of MP,MP plus Th02 or Th02 were added into themedium with the final concentration of 17.0,

Clinical Variants, Rates of Post-Operative Recurrence and Malignant Transformation of Sino-Nasal Inverted Papilloma

Background: Inverted Papilloma (IP) is the most common benign neoplasms arising from the mucosal lining of the of the Sino-Nasal tract with single or multifocal attachment sites. The high propensity to recur, local aggressive behavior and possibility of malignant transformation attract considerable interest. Objective: To assess the factors affecting Sino-nasal IP, malignant transformation rate, and post-operative recurrence rate. Methods: A retrospective study was carried out on all cases diagnosed as Sino-Nasal Papilloma between January 2010 and December 2020 at Salmaniya Medical Complex, Bahrain. Data gathered from medical records were analyzed using SPSS. A total of 49 Sino-Nasal Papilloma cases were recorded of which 37 were IP. Factors affecting Sino-Nasal IPs are presented. Results: Sino-Nasal IP was recorded in 37 cases, composed of 28 males and 9 females with first presentation average age of 45.86 years. These involved 20 cases in the left side, 14 in the right side and 3 were bilateral. Recurrence in males and females was found to be 35.7% and 33%, respectively, with an average of 12.6 months. The symptoms include nasal blockage (97.3%), epistaxis and postnasal drip (13.5% each), headache (8.1%) and hyposmia and rhinorrhea (5.4%, each). The main recurrence was at stage T2 (60.5%), while in smokers (26.7%) and non-smokers (50%). Malignant transformation occurred in one patient only (2.6%). Conclusion: IP is the most common type of SNP with male predominance. The recurrence rate is high with an average of a year and the malignant transformation occurred in 2.6 % of the cases.

Retrorectal Cystic Hamartoma with Malignant Transformation

Retrorectal cystic hamartomas are rare congenital lesions that can undergo malignant transformation, and adenocarcinoma is the most frequently described histological type. The authors describe a case of a 53-year-old female patient with a localized well-differentiated adenocarcinoma that developed in a retrorectal cystic hamartoma. The patient was submitted to surgery (a Kraske procedure), with an R1 resection, followed by adjuvant radio-chemotherapy. After 23 months of follow up, the patient remains free from disease recurrence. Given the rarity of this entity, this case allows us to reflect on the differential diagnosis, therapeutic approach and patients’ follow-up.

mir-3168 targeted inhibition of TP53 promotes malignant transformation and cisplatin resistance of AGS and AGS/DDP gastric cancer cells

Objective:To investigate the effect of mir-3168 on the malignant transformation and cisplatin resistance of AGS and AGS/DDP gastric cancer cells,and to verify its target gene.Methods:The expression of mir-3168 in AGS and AGS/DDP gastric cancer cells was detected by qPCR,and mir-3168 mimic,inhibitor and negative control were synthesized.They were transfected into AGS and AGS/DDP gastric cancer cells,respectively.The expression of mir-3168 and TP53 mRNA was detected by qPCR.Cell viability was detected by CCK8 under gradient cisplatin treatment and non treatment,apoptosis was detected by flow cytometry,cell invasion was detected by Transwell,and TP53 protein expression was detected by western blot,The database predicted the binding sites of mir-3168 and TP53.According to the binding sites,the double luciferase experiment was used to verify the binding of mir-3168 and TP53.Results:Compared with cisplatin sensitive gastric cancer cell AGS,mir-3168 was significantly overexpressed in cisplatin resistant gastric cancer cell AGS/DDP;mir-3168 mimic promotes cisplatin resistance,proliferation and invasion of AGS and AGS/DDP gastric cancer cells,and inhibits apoptosis of AGS and AGS/DDP gastric cancer cells;mir-3168 inhibitor inhibits cisplatin resistance,proliferation and invasion of AGS and AGS/DDP gastric cancer cells,and promotes apoptosis of AGS and AGS/DDP gastric cancer cells;mir-3168 mimic inhibits the expression of TP53 mRNA and protein,and mir-3168 inhibitor promotes the expression of TP53 mRNA and protein;Targetscan database predicted that there was a binding point between mir-3168 and TP53,and the double luciferase experiment suggested that mir-3168 was bound to TP53 through the predicted binding site.Conclusion:mir-3168 may promote the malignant transformation of AGS and AGS/DDP gastric cancer cells and cisplatin resistance by targeting TP53.

Granulocyte-macrophage colony-stimulating factor and interleukin 4 induce the malignant transformation of the bone marrow- derived human adult mesenchymal stem cells

Background The purpose of the study was to examine the effects of granulocyte-macrophage colony-stimulating factor （GM-CSF） and interleukin 4 （IL-4） on the bone-marrow-derived human adult mesenchymal stem cells （hMSCs）. Methods The hMSCs were isolated and cultured with GM-CSF and IL-4 for a period of one month. A single colony of transformed cells was then isoloated and their phenotype was characterized by morphology, surface marker expression, and in vivo tumorigenesis.Results After one month culture, the transformed mesenchymal cells exhibited the morphology and phenotype similar to those of tumor cells, and also caused multiple fast growing lung deposits when it was injected into immunodeficient mice.Conclusion Cytokines-driven malignant transformation of hMSCs may be a useful model for studying signaling pathways initiating malignant transformation of hMSC.

Primary malignant tumours and malignant transformation of cysts in the retrorectal space:MRI diagnosis and treatment outcomes

Background:There are no clear guidelines for the diagnosis and treatment of malignant retrorectal tumours.The purpose of this study was to increase preoperative diagnostic knowledge and to describe the outcomes of treatment for these patients.Methods:This retrospective study was conducted on patients who underwent complete retrorectal tumour resection between May 2006 and July 2018,and had confirmed post-operative pathology reports.Demographic and clinical data(including imaging,perioperative,pathological,and prognostic data)were collected and analysed.Results:Malignant lesions were identified in 15(9[60%],female)patients.The median age of the patients was 59 years(range,34–72 years).Primary malignant tumours were identified in seven patients with solid tumours,in which gastrointestinal stromal tumours accounted for 71.4%(five of seven)and the remainder were chordoma or mucinous adenocarcinoma.Malignant transformation of cysts occurred in another eight patients with heterogeneous tumours,while histopathological features were present in 75%(six of eight)of patients with mucinous adenocarcinoma,and the remainder were squamouscell carcinoma or neuroendocrine tumour(Grade 2).The malignant characteristics of the solid portions observed using magnetic resonance imaging(MRI)were as follows:the cyst wall of the tumour was irregularly thickened;the surface was convex or lobed;the solid tumour had no capsule,or the capsule was destroyed;and the surface had a gyrus-like morphology.At a median follow-up time of 52 months(range,13–100 months),the overall recurrence-free survival rate was 40.0%and the survival rate was 46.7%.Conclusion:Some MRI features can be used to distinguish malignant retrorectal tumours from benign retrorectal tumours.The survival rate of patients with malignant retrorectal tumours is poor.

Biomarkers of malignant transformation in oral leukoplakia:from bench to bedside

Oral leukoplakia is a common precursor lesion of oral squamous cell carcinoma,which indicates a high potential of malignancy.The malignant transformation of oral leukoplakia seriously affects patient survival and quality of life;however,it is difficult to identify oral leukoplakia patients who will develop carcinoma because no biomarker exists to predict malignant transformation for effective clinical management.As a major problem in the field of head and neck pathologies,it is imperative to identify biomarkers of malignant transformation in oral leukoplakia.In this review,we discuss the potential biomarkers of malignant transformation reported in the literature and explore the translational probabilities from bench to bedside.Although no single biomarker has yet been applied in the clinical setting,profiling for genomic instability might be a promising adjunct.

Inhibition of the Hedgehog Signaling Pathway Depresses the Cigarette Smoke-Induced Malignant Transformation of 16HBE Cells on a Microfluidic Chip

Background：The hedgehog signaling system （HHS） plays an important role in the regulation of cell proliferation and differentiation during the embryonic phases.However,little is known about the involvement of HHS in the malignant transformation of cells.This study aimed to detect the role of HHS in the malignant transformation of human bronchial epithelial （16HBE） cells.Methods：In this study,two microfluidic chips were designed to investigate cigarette smoke extract （CSE）-induced malignant transformation of cells.Chip A contained a concentration gradient generator,while chip B had four cell chambers with a central channel.The 16HBE cells cultured in chip A were used to determine the optimal concentration of CSE for inducing malignant transformation.The 16HBE cells in chip B were cultured with 12.25% CSE （Group A）,12.25% CSE ± 5 μmol/L cyclopamine （Group B）,or normal complete medium as control for 8 months （Group C）,to establish the in vitro lung inflammatory-cancer transformation model.The transformed cells were inoculated into 20 nude mice as cells alone （Group 1） or cells with cyclopamine （Group 2） for tumorigenesis testing.Expression of HHS proteins was detected by Western blot.Data were expressed as mean ± standard deviation.The t-test was used for paired samples,and the difference among groups was analyzed using a one-way analysis of variance.Results：The optimal concentration of CSE was 12.25%.Expression of HHS proteins increased during the process of malignant transformation （Group B vs.Group A,F =7.65,P 〈 0.05）.After CSE exposure for 8 months,there were significant changes in cellular morphology,which allowed the transformed cells to grow into tumors in 40 days after being inoculated into nude mice.Cyclopamine could effectively depress the expression of HHS proteins （Group C vs.Group B,F =6.47,P 〈 0.05） and prevent tumor growth in nude mice （Group 2 vs.Group 1,t=31.59,P〈 0.01）.Conclusions：The activity of HHS is upregulated during the CSE-induced malignant transformation of 16HBE cells.Cyclopamine can effectively depress expression of HHS proteins in vitro and prevent tumor growth of the transformed cells in vivo.

Huge pelvi-abdominal malignant inflammatory myofibroblastic tumor with rapid recurrence in a 14-year-old boy

Inflammatory myofibroblastic tumor(IMT) is an uncommon benign neoplasm with locally aggressive behavior but malignant change is rare.We report an unusual case of pelvic-abdominal inflammatory myofibroblastic tumor with malignant transformation in a 14-year-old boy presenting with abdominal pain and 9 kg body weight loss in one month.Computed tomography revealed a huge pelvi-abdominal mass(30 cm),possibly originating from the pelvic extraperitoneal space,protruding into the abdomen leading to upward displacement of the bowel loops,downward displacement of the urinary bladder,massive central necrosis,a well-enhanced peripheral solid component with prominent peritumoral vascularity.Subsequent examination confirmed the computed tomographic findings.Histopathologic examination revealed proliferative epitheloid and spindle cells,inflammatory cell infiltration and high mitotic counts.Immunohistochemistry was strongly positive for anaplastic lymphoma kinase and revealed a high proliferative index(ki-67 = 40%).DNA sequencing and electronic microscopy further confirmed the primitive fibroblastic cell phenotype of the tumor and a final diagnosis of inflammatory myofibroblastic tumor with malignant transformation was established.Rapid tumor recurrence was noted 20 d after radical tumor resection.To our knowledge,this is the largest documented case of IMT in a pediatric patient and the first report of IMT with malignant transformation originating from the pelvic extraperitoneal space.