High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity Graphical abstract Highlights d HFD augments intestinal stemness through PPARd and PPARa d A PPAR-FAO program enhances stemness and tumorigenicity in a HFD d Loss or inhibition of Cpt1a-mediated FAO blunts the HFDenhancing effects in ISCs d Early intestinal tumors arising from HFD ISCs are highly sensitive to FAO inhibition

Clinicopathologic features of undetected dysplasia found in total colectomy or proctocolectomy specimens of patients with inflammatory bowel disease Aims: It remains controversial as to whether targeted biopsies should completely replace random biopsies for dysplasia surveillance in patients with inflammatory bowel disease (IBD). Several histologic patterns of nonconventional dysplasia have been described in IBD. This study aimed to investigate the rate and clinicopathologic features of dysplastic lesions found in total colectomy or proctocolectomy specimens that were undetected on prior colonoscopy. Methods and results:The study analyzed 207 consecutive IBD patients who underwent a total colectomy or proctocolectomy and had at least one highdefinition colonoscopy prior to colectomy. Dysplasia found in the colectomy specimens was classified as undetected, only when there was no corresponding site of dysplasia detected on previous colonoscopic biopsies. Twenty-seven (13%) patients had 49 undetected dysplastic lesions found only at colectomy, while 22 (11%) had 31 previously detected dysplastic lesions only. The remaining 158 (76%) patients had no dysplasia. A greater proportion of the undetected (19%) or previously detected (23%) dysplasia group had concurrent primary sclerosing cholangitis compared with only 3% in the group without dysplasia (P < 0.001). The undetected dysplastic lesions were more likely to have nonconventional dysplastic features (76%), low-grade dysplasia (94%), and a flat/invisible gross appearance (73%) compared with the previously detected dysplastic lesions (13%, 68%, and 48%, respectively) (P < 0.05). Almost all patients with undetected dysplasia (93%) had a colonoscopy within 1 year of colectomy. Conclusion:The rate of undetected dysplasia is not insignificant (13%), suggesting that increased random biopsies may improve the rate of dysplasia detection, including nonconventional dysplasia.

Ossifying fibroma of the craniofacial bones is a fibro-osseous lesion characterized by varied patterns of bone formation in a fibroblastic stroma. Ossifying fibroma is a putatively benign lesion with no reports of malignant transformation or metastasis. Differentiation from other fibro-osseous lesions can be challenging necessitating synthesis of clinical, radiological and pathological findings. The molecular pathogenesis of ossifying fibroma is poorly understood but recent studies have reported MDM2 gene amplification and chromosomal copy number changes in a subset of ossifying fibromas. MDM2 amplification in ossifying fibroma, if true, presents a diagnostic problem because this genetic event, at least among craniofacial fibro-osseous lesions, was previously considered specific for low-grade osteosarcoma. In the present study, we investigated the utility of MDM2 and CDK4 immunohistochemistry, and fluorescence in situ hybridization for MDM2 gene amplification, in the diagnosis of 44 craniofacial bone ossifying fibromas. Focal MDM2 and CDK4 nuclear immunoreactivity was found in 11 and 1 ossifying fibromas, respectively, but none demonstrated MDM2 amplification by fluorescence in situ hybridization. A single tumor displayed MDM2 amplification without nuclear immunoreactivity to either MDM2 or CDK4. Our data suggest that while focal MDM2 and CDK4 nuclear expression may be detected in a minority of ossifying fibromas, this expression does not correlate with MDM2 amplification. In addition, MDM2 amplification is extremely rare in ossifying fibroma so the detection of this genetic abnormality should continue to raise concern for osteosarcoma.

Background Ossifying fibroma (OF) of the craniofacial skeleton is a fibro-osseous lesion characterized by various patterns of bone formation in a cellular fibroblastic stroma. The molecular landscape of OF remains mostly unknown. There are a few known pathogenic abnormalities in OF, including HRPT2 mutations in conventional OF and SATB2 translocations in juvenile psammomatoid OF. On the other hand, conflicting reports exist regarding MDM2 gene amplification and chromosomal copy number alterations (CNA) in OF. Methods Surgically removed biopsies and curettage specimens from OF patients were obtained. Clinical, radiographic, and pathologic features of tumors were reviewed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded blocks of tumor tissue. Capture-based DNA next-generation sequencing targeting the coding regions 529 cancer genes and select introns was performed. ResultsWe identified 17 OF cases from 8 male and 8 female patients with mean age of 22 years (range 1-58 years). Nine case occurred in the gnathic bones and 8 in the extragnathic craniofacial bones. These cases included 3 juvenile psammomatoid OF, 6 conventional OF and 8 juvenile trabecular OF. Large-scale CNAs were present in 6 of 17 cases. Seven cases (41%) had focal amplifications including FOSB (n = 2, 11%), FOS (n = 4, 23%), COL1A1 (n = 4, 23%) and TBX3 (n = 5, 29%). Three cases (17%) had pathogenic CDC73 mutations. No cases showed focal MDM2 amplification. Conclusions Here, we provided a comprehensive molecular characterization of OF that reveals a heterogeneous genetic profile with occasional large-scale CNAs (n = 6, 35%). FOS, FOSB, and TBX3 genes that regulate AP-1 transcriptional complex are frequently altered in OF (n = 7, 41%), chiefly in juvenile trabecular OF. These genes encode transcription factors that act as downstream effectors of the MAP kinase signaling pathway. MDM2 amplification is an exceedingly rare event in OF, if present at all, so identification of this event should continue to raise concern for low-grade gnathic osteosarcoma. In summary, our findings suggest that OF represents a heterogeneous group of tumors at the genetic level but dysregulation of the AP-1 pathway may play a role in pathogenesis of juvenile trabecular OF.

No abstract