👤 Hiroki Takigawa

Malignant phyllodes tumors (MPTs) are rare fibroepithelial breast tumors with no standard treatment for metastatic or recurrent cases. Comprehensive genomic profiling (CGP) has been conducted for MPT; however, its association with treatment remains unclear. A retrospective study was conducted on patients with advanced or recurrent MPTs treated with chemotherapy between 2013 and 2022 at two hospitals, analyzing clinical data, CGP, treatment outcomes, and survival. Five patients with metastatic MPTs who had received chemotherapy were identified. The median age was 55 years (range, 50-66), and all patients were female. As first-line treatment, four patients received doxorubicin plus ifosfamide (AI) combination therapy, while one received doxorubicin monotherapy. Among those treated with AI therapy, the best responses were partial response in three patients and stable disease in one. The median progression-free survival (PFS) for patients treated with AI therapy was 5.3 months. Of the five patients two proceeded to second-line therapy, and one patient received up to fourth-line treatment. Next-generation sequencing-based CGP testing was performed in four cases. One patient with an FGFR1-N546K-mutated MPT achieved a relatively long PFS of 6.8 months with pazopanib therapy, a multi-kinase inhibitor targeting FGFR1 among other kinases, as fourth-line therapy. AI therapy is useful for advanced or recurrent MPTs. The observed clinical benefit of pazopanib in a patient with FGFR1 N546K-mutated MPT suggests that FGFR1 kinase domain mutations may be a relevant factor in responsiveness of FGFR1-targeted therapy. Further data accumulation is warranted. Show less

An 80-year-old woman with a history of endoscopic balloon dilation for esophageal stricture caused by accidental ingestion of caustic soda during infancy presented with dysphagia. Upper gastrointestinal endoscopy revealed a 10-cm-long, highly white, elevated lesion with a feathered appearance. This lesion was determined to be the cause of dysphagia and was completely resected via endoscopic submucosal dissection. Histopathological examination revealed a thick keratin layer on the surface of the stratified squamous epithelium, with a prominent granular layer underneath and some areas showing nuclear atypia. The lesion was diagnosed as a well-differentiated squamous cell carcinoma, pT1a-LPM, derived from epidermoid metaplasia. Cancer genome analysis revealed mutations in TP53 as well as amplification of MYC, FGFR1, chromosome 7, and chromosome 20q. This case suggests that epidermoid metaplasia caused by chronic irritation from an esophageal stricture may have been exacerbated by the dilation procedure. Show less

Resveratrol is a natural phytoalexin that has anti-inflammatory properties, reverses doxorubicin resistance, and inhibits epithelial-mesenchymal transition (EMT) in many types of cancer cells. Fusobacterium nucleatum is reportedly enriched in oral squamous cell carcinoma (OSCC) tissues compared to adjacent normal tissues, sparking interest in the relationship between F. nucleatum and OSCC. Recently, F. nucleatum was shown to be associated with EMT in OSCC. In the present study, we aimed to investigate the effects of the natural plant compound resveratrol on F. nucleatum-induced EMT in OSCC. F. nucleatum was co-cultured with OSCC cells, with a multiplicity of infection (MOI) of 300:1. Resveratrol was used at a concentration of 10 μM. Cell Counting Kit-8 and wound healing assays were performed to examine the viability and migratory ability of OSCC cells. Subsequently, real-time RT-PCR was performed to investigate the gene expression of EMT-related markers. Western blotting and immunofluorescence analyses were used to further analyze the expression of the epithelial marker E-cadherin and the EMT transcription factor SNAI1. Co-cultivation with F. nucleatum did not significantly enhance cell viability. The co-cultured cells displayed similarities to the positive control of EMT, exhibiting enhanced migration and expression changes in EMT-related markers. SNAI1 was significantly upregulated, whereas E-cadherin, was significantly downregulated. Notably, resveratrol inhibited F. nucleatum-induced cell migration, decreasing the expression of SNAI1. Resveratrol inhibited F. nucleatum-induced EMT by downregulating SNAI1, which may provide a target for OSCC treatment. Show less

Germline mutation and functional loss of EXT1 or EXT2 are commonly found in multiple osteochondromas and predispose to the development of chondrosarcoma. Mutations of EXT1 and EXT2 have rarely been detected in sporadic secondary chondrosarcomas from osteochondroma; these frequently display loss of heterozygosity at the EXT1 and EXT2 loci, but primary chondrosarcomas typically do not. To evaluate promoter methylation (which is an epigenetic gene silencing mechanism) of EXT1 and EXT2, we performed methylation-specific polymerase chain reaction (PCR) for 20 chondrosarcoma cases (12 primary, 3 secondary to osteochondroma, 2 secondary to enchondromatosis, 2 extraskeletal ordinary, and 1 clear cell) and in five cell lines. In addition, mutation analysis of the EXT1 and EXT2 coding regions was performed using PCR-single-strand conformation polymorphism and sequencing analysis for 12 of the 20 chondrosarcoma cases (8 primary, 1 secondary to enchondromatosis, 1 secondary to osteochondroma, and 2 extraskeletal ordinary) and five cell lines. Promoter methylation of EXT1 and EXT2 was not detected in any of the cases, and both EXT1 and EXT2 were expressed in all cell lines. Two missense mutations in EXT2 (D227E and R299H) were detected among the chondrosarcoma cases. When considering tumor development in primary chondrosarcoma, we should include mutations in EXT2, along with the status of other members of the EXT gene family. Show less

We studied the genetic control of murine contact photosensitivity (CPS)1 to 3,3',4',5-tetrachlorosalicylanilide (TCSA) that was induced by subcutaneous injection of TCSA-photomodified epidermal cells (photoTCSA-EC) and spleen cells (photoTCSA-SC). With regard to the H-2 locus, sensitization with both types of photohaptenated cells showed the same pattern of CPS responses: H-2k and H-2b,d haplotypes were closely associated with low and high responders, respectively. On the other hand, the Igh locus affected the CPS reaction induced by photoTCSA-SC but not -EC; the Igh-1d allotype was related to low responsiveness, while high responders possessed Igh-1a,b. Thus, the photoTCSA-SC sensitization was controlled by H-2 and Igh in a codominant manner. The photoTCSA-SC-induced responses of H-2k but not Igh-1d mice were enhanced by CY pretreatment, suggesting that the mechanisms of low responsiveness in H-2k and Igh-1d mice were different. H-2 identity between donors of photoTCSA-EC and recipients was sufficient for effective sensitization, whereas both H-2 and Igh between donors of photoTCSA-SC and recipients should be identical to obtain maximum sensitization. This further confirmed the involvement of the Igh complex in the genetic control of CPS evoked by photoTCSA-SC. B cells as well as macrophages served as an effective presentation template for the photoTCSA-SC sensitization in the high responder Igh-1a mice, whereas B cells failed in inducing the CPS reaction in the low responder Igh-1d mice. These results suggest that B cells play an essential role in the Igh control phenomenon seen in the photoTCSA-SC sensitization. The present study demonstrated that CPS induced by photohapten-modified cells are differentially regulated by the H-2 and Igh gene loci depending on the cell type used for sensitization. Show less