Mucosal change of the stomach with low-grade mucosa-associated lymphoid tissue lymphoma after eradication of Helicobacter pylori:Follow-up study of 48cases

Low-grade mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach has been demonstrated to be closely linked to Helicobacter pylori (H. pylori) and to be frequently remissioned after the cure of H. pylori infection. Several previous studies have focused on proliferating lymphocytes but little is known about gastric epithelial change and the duration of the remission after the cure of H. pylori infection. We performed a long-term follow-up investigation on the effects of anti-H. pylori treatment on MALT lymphoma and chronic gastritis at the histologic and molecular levels. Forty-eight patients with low-grade gastric MALT lymphoma and 28 chronic gastritis patients in whom H. pylori infection was eradicated were studied. After eradication, 43 MALT lymphoma patients showed complete histologic remission and continuous remission was observed during follow-up for up to 43 months (mean, 17.8 months). As for epithelial changes after eradication, "emptiness of lamina propria" was more pronounced in the mucosa with MALT lymphoma than that with chronic gastritis, and its severity in MALT lymphoma cases significantly decreased during the observation period whereas the glandular area increased. Cystic change of the fundic gland also occurred more frequently in MALT lymphoma cases than chronic gastritis cases. B-cell clonality before eradication analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) was detected in almost all MALT lymphoma cases (43cases), but rare in chronic gastritis cases (6cases). After eradication, in spite of histologic regression, 21 MALT lymphoma patients had a persistent monoclonal population during the follow-up period. B-cell monoclonality preceding the malignant transformation was noted in 4 cases. These observations indicate that 1) complete histologic remission of low-grade gastric MALT lymphomas seems stable even if a monoclonal B cell population is detectable in some cases, 2) there may be a stage of disease where monoclonal B cells are present but there is no histologic evidence of MALT lymphoma, and 3) regenerative change of the damaged glands may occur in histologic regressed MALT lymphoma cases

Multifaceted Analysis of IL-23A-and/or EBI3-Including Cytokines Produced by Psoriatic Keratinocytes

Interleukin (IL) 23 (p19/p40) plays a critical role in the pathogenesis of psoriasis and is upregulated in psoriasis skin lesions. In clinical practice, anti-IL-23Ap19 antibodies are highly effective against psoriasis. IL-39 (p19/ Epstein-Barr virus-induced (EBI) 3), a newly discovered cytokine in 2015, shares the p19 subunit with IL-23. Anti-IL-23Ap19 antibodies may bind to IL-39; also, the cytokine may contribute to the pathogenesis of psoriasis. To investigate IL23Ap19- and/or EBI3-including cytokines in psoriatic keratinocytes, we analyzed IL-23Ap19 and EBI3 expressions in psoriasis skin lesions, using immunohistochemistry and normal human epidermal keratinocytes (NHEKs) stimulated with inflammatory cytokines, using quantitative real-time polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and liquid chromatography-electrospray tandem mass spectrometry (LC-Ms/Ms). Immunohistochemical analysis showed that IL-23Ap19 and EBI3 expressions were upregulated in the psoriasis skin lesions. In vitro, these expressions were synergistically induced by the triple combination of tumor necrosis factor (TNF)-alpha, IL-17A, and interferon (IFN)-gamma, and suppressed by dexamethasone, vitamin D3, and acitretin. In ELISA and LC-Ms/Ms analyses, keratinocyte-derived IL-23Ap19 and EBI3, but not heterodimeric forms, were detected with humanized anti-IL-23Ap19 monoclonal antibodies, tildrakizumab, and anti-EBI3 antibodies, respectively. Psoriatic keratinocytes may express IL-23Ap19 and EBI3 proteins in a monomer or homopolymer, such as homodimer or homotrimer

Factors Related to the Outcome of M-VAC in 101 Patients with Advanced Urothelial Cancer

The objective of this study is to identify factors related to the results of intravenous methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) for 101 patients with advanced urothelial cancer. The effects of various factors on response and survival were evaluated using univariate and multivariate analyses. The factors included in the analyses were sex, age, performance status (PS), primary site, histological type, grade, T category, N category, M category, prior chemotherapy, prior radiotherapy, and dose of chemotherapeutic drugs. Univariate analysis revealed that M category and prior chemotherapy had a significant correlation with the response, and that factors significantly related to survival were PS, primary site, N category, M category, prior chemotherapy and prior radiotherapy. A multiple logistic regression model showed that N category, M category and prior chemotherapy were related to response. The response rates of patients with N1-4 or M1 or prior chemotherapy were lower than those with N0 or M0 or without prior chemotherapy. A Cox regression model demonstrated that PS and M category independently contributed to survival. Patients with high grade PS or distant metastases showed a lower survival rate than those with low grade PS or localized diseases. M category was the most important factor related to response and survival. These results seem to indicate the low effectiveness of M-VAC for distant metastases, and the inability of this regimen to improve the outcome of patients with advanced urothelial cancer

Topical application of activator protein-1 inhibitor T-5224 suppresses inflammation and improves skin barrier function in a murine atopic dermatitis-like dermatitis

Background: Selective activator protein (AP)-1 inhibitors are potentially promising therapeutic agents for atopic dermatitis (AD) because AP-1 is an important regulator of skin inflammation. However, few studies have investigated the effect of topical application of AP-1 inhibitors in treating inflammatory skin disorders. Methods: Immunohistochemistry was conducted to detect phosphorylated AP-1/c-Jun expression of skin lesions in AD patients. In the in vivo study, 1 % T-5224 ointment was topically applied for 8 days to the ears of 2,4 dinitrofluorobenzene challenged AD-like dermatitis model mice. Baricitinib, a conventional therapeutic agent Janus kinase (JAK) inhibitor, was also topically applied. In the in vitro study, human epidermal keratinocytes were treated with T-5224 and stimulated with AD-related cytokines. Results: AP-1/c-Jun was phosphorylated at skin lesions in AD patients. In vivo, topical T-5224 application inhibited ear swelling (P < 0.001), restored filaggrin (Flg) expression (P < 0.01), and generally suppressed immune-related pathways. T-5224 significantly suppressed Il17a and l17f expression, whereas baricitinib did not. Baricitinib suppressed Il4, Il19, Il33 and Ifnb expression, whereas T-5224 did not. Il1a, Il1b, Il23a, Ifna, S100a8, and S100a9 expression was cooperatively downregulated following the combined use of T-5224 and baricitinib. In vitro, T-5224 restored the expression of FLG and loricrin (LOR) (P < 0.05) and suppressed IL33 expression (P < 0.05) without affecting cell viability and cytotoxicity. Conclusions: Topical T-5224 ameliorates clinical manifestations of AD-like dermatitis in mice. The effect of this inhibitor is amplified via combined use with JAK inhibitors

Clinicopathological and mutational analyses of colorectal cancer with mutations in the POLE gene

Abstract Here, we investigated the clinicopathological and mutation profiles of colorectal cancer (CRC) with POLE mutations. Whole‐exome sequencing was performed in 910 surgically resected primary CRCs. Tumors exceeding 500 counts of nonsynonymous single nucleotide variants (SNVs) were classified as hypermutators, whereas the remaining were classified as nonhypermutators. The hypermutators were subdivided into 2 groups. CRCs harboring more than 20% C‐to‐A and less than 3% C‐to‐G transversions were classified as POLE category tumors, whereas the remaining were classified as common‐hypermutators. Gene expression profiling (GEP) analysis was performed in 892 (98.0%) tumors. Fifty‐seven (6.3%) and 10 (1.1%) tumors were classified common‐hypermutators and POLE category tumors, respectively. POLE category tumors harbored a significantly higher SNV count than common‐hypermutators, and all POLE category tumors were associated with exonuclease domain mutations, such as P286R, F367C, V411L, and S297Y, in the POLE gene. Patients with POLE category tumors were significantly younger than those with nonhypermutators and common‐hypermutators. All POLE mutations in the early‐onset (age of onset ≤50 years old) POLE category (7 tumors) were P286R mutations. GEP analysis revealed that PD‐L1 and PD‐1 gene expression levels were significantly increased in both common‐hypermutators and POLE category tumors compared with those in nonhypermutators. CD8A expression was significantly upregulated in POLE category tumors compared with that in nonhypermutators. Thus, we concluded that CRCs with POLE proofreading deficiency had characteristics distinct from those of other CRCs. Analysis of POLE proofreading deficiency may be clinically significant for personalized management of CRCs