Combination immunohistochemistry for CK5/6, p63, GATA6, and HNF4a predicts clinical outcome in treatment-naïve pancreatic ductal adenocarcinoma.

Although sequence-based studies show that basal-like features lead to worse prognosis and chemotherapy-resistance compared to the classical subtype in advanced pancreatic ductal adenocarcinoma (PDAC), a surrogate biomarker distinguishing between these subtypes in routine diagnostic practice remains to be identified. We aimed to evaluate the utility of immunohistochemistry (IHC) expression subtypes generated by unsupervised hierarchical clustering based on staining scores of four markers (CK5/6, p63, GATA6, HNF4a) applied to endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) materials. EUS-FNAB materials taken from 190 treatment-naïve advanced PDAC patients were analyzed, and three IHC patterns were established (Classical, Transitional, and Basal-like pattern). Basal-like pattern (high co-expression of CK5/6 and p63 with low expression of GATA6 and HNF4a) was significantly associated with squamous differentiation histology (p < 0.001) and demonstrated the worst overall survival among our cohort (p = 0.004). IHC expression subtype (Transitional, Basal vs Classical) was an independent poor prognosticator in multivariate analysis [HR 1.58 (95% CI 1.01-2.38), p = 0.047]. Furthermore, CK5/6 expression was an independent poor prognostic factor in histological glandular type PDAC [HR 2.82 (95% CI 1.31-6.08), p = 0.008]. Our results suggest that IHC expression patterns successfully predict molecular features indicative of the Basal-like subgroup in advanced PDAC. These results provide the basis for appropriate stratification for therapeutic selection and prognostic estimation of advanced PDAC in a simplified manner.

RAS Family Gene Mutations, Clinicopathological Features, and Spread Patterns of Inverted Urothelial Papilloma of the Bladder.

Inverted urothelial papilloma (IUP) is a benign neoplasm characterized by a downgrowth of the urothelium beneath the surface of morphologically normal urothelial cells; however, the molecular features of IUP and their association with clinicopathological characteristics are unclear. In this study, we aimed to investigate the mutational landscape, clinicopathological features, genotype-phenotype associations, and spread patterns of IUP. We performed targeted next-generation sequencing of 39 consecutive IUP cases, the largest series investigated to date, and identified oncogenic driver mutations in RAS family genes in 34 cases (87%). HRAS mutations were the most prevalent (28 cases), which included Q61R (15 cases), followed by KRAS (5 cases) and NRAS (1 case) mutations. Characteristic mutations observed in urothelial carcinoma, including those in FGFR3 , TP53 , or the TERT promoter, were absent. HRAS -mutated IUPs were associated with a history of smoking ( P = 0.017) and streaming morphology ( P < 0.001), corresponding to the trabecular subtype. In contrast, all KRAS -mutated IUPs occurred in never-smoking patients ( P = 0.001) and showed cystic changes in morphology ( P = 0.005), corresponding to the glandular subtype. RAS Q61R immunohistochemistry visually revealed the neoplastic nature of the overlying cells and distinct spread patterns of IUP cells within the surface, including pseudoinfiltrative spread. No recurrence or carcinoma development was observed in any of the IUP cases during the follow-up period. Thus, we confirmed the importance of RAS pathway activation in IUP pathogenesis, an association between RAS family gene mutations and IUP subtypes, and the spread patterns of IUP cells within the surface.

MHC class I loss is associated with biliary/progenitor cell features and "cold" tumor-immune microenvironment in hepatocellular carcinoma.

Hepatocellular carcinomas (HCCs) with biliary/progenitor cell features frequently show increased programmed death-ligand 1 (PD-L1) expression, but their response to immunotherapy is not high. One possible explanation for this phenomenon could be the loss of major histocompatibility complex (MHC) class I expression on tumor cells, which impairs the presentation of tumor antigens to cytotoxic T cells. However, the potential correlation between MHC class I loss, biliary/progenitor cell features, and the tumor-immune microenvironment remains largely unexplored. Herein, we hypothesized that MHC class I loss could be associated with biliary/progenitor cell features and potentially impact the tumor-immune microenvironment. To evaluate this hypothesis and gain insight into the characteristics of tumor cells and the tumor-immune microenvironment in HCCs with MHC class I loss, we examined a consecutive series of 397 HCC cases. MHC class I loss was observed in 32 HCCs (8.1%). Lipid-less cytologic morphology was significantly associated with MHC class I loss (P = 0.02). CK19 expression and decreased ARG1 expression, both known as biliary/progenitor cell features, were significantly associated with MHC class I loss (P < 0.05). PD-L1 expression was irrelevant to the MHC class I status. HCCs with MHC class I loss exhibited significantly lower infiltration of CD8+, CD4+, CD20+, and FOXP3+ cells than those with intact MHC class I (all Ps < 0.01). Our study reveals an association between MHC class I loss, biliary/progenitor cell features, and a "cold" tumor-immune microenvironment in HCCs. These insights highlight the potential impact of MHC class I loss on tumor cells and the tumor-immune microenvironment.

Anal tuberculosis presenting as refractory perianal abscess.

Although most cases occur in immunocompromised individuals, anal tuberculosis can occur in the absence of HIV infection. Anal tuberculosis should be considered in the differential diagnosis of chronic or recurrent anal fistulas.

Reduced H3K27me3 levels in diffuse gliomas: association with 1p/19q codeletion and difference from H3K27me3 loss in malignant peripheral nerve sheath tumors.

Trimethylation of histone H3 at lysine 27 (H3K27me3) acts as a transcriptional repressor of target genes. Recent immunohistochemical studies have reported a loss of H3K27me3 modification in diffuse (especially 1p/19q-codeleted) gliomas. However, we did not observe H3K27me3 loss in diffuse gliomas using routine immunostaining conditions for the detection of H3K27me3 loss in malignant peripheral nerve sheath tumors (MPNSTs). Therefore, we conducted immunohistochemical analysis of surgically resected specimens to understand the differences in the H3K27me3 status in MPNSTs and diffuse gliomas and evaluate the diagnostic utility of H3K27me3 immunohistochemistry. Staining with a standard 1:200 dilution of the C36B11 antibody showed a complete loss of H3K27me3 in 5 out of 11 MPNSTs, whereas most diffuse gliomas (149/151, 98.7%) showed diffuse immunoreactivity. At a 1:2000 antibody dilution, 12.6% (19/151) of the diffuse gliomas showed H3K27me3 loss, which was significantly associated with 1p/19q codeletion (P < 0.001). H3K27me3 loss predicted 1p/19q codeletion in IDH-mutant gliomas with lower sensitivity (56.2%) and higher specificity (100%) than ATRX retention or p53 negative result. In conclusion, reduction in H3K27me3 levels was associated with 1p/19q codeletion in diffuse gliomas; however, the extent of reduction differed from that in MPNSTs, and the results depended on the immunostaining conditions.

[A Case of Phrenic Nerve Paralysis During Adjuvant Chemotherapy for Rectal Cancer].

A man aged 66 years presented with pneumaturia as a major complaint. Cancer of the sigmoid colon with infiltration to the urinary bladder was diagnosed and the patient underwent colectomy of the sigmoid colon and partial cystectomy of the bladder in May 2015. Histopathologic examinations revealed pT4b, Si(bladder), pN(-), cM0, fStage II . Because intestinal sub-obstruction and lymphatic invasion were present, CapeOX was administered as an adjunctive chemotherapy for the high-risk Stage II cancer. Because Grade 2 peripheral neuropathy appeared as a side effect, the dose was decreased to 80% from the 3 cycle. After the 7 cycle, cough and disturbed breathing appeared. The chest CT scans did not reveal drug-induced interstitial pneumonia, but indicated an elevated right diaphragm and zosteroid changes in the medial lobe of the right lung due to discoid atelectatic condition. The Grade 1 respiratory symptoms were mild, and the lung field was considered to exhibit no problems. Thus, the 8 cycle was administered. The symptoms disappeared after about 2 weeks following completion of oral administration of capecitabine. The diaphragm also recovered to its original height. In the attached document, the frequency is unknown and "dyspnea" is written for L-OHP and capecitabine, respectively. It is unknown whether phrenic nerve paralysis occurs. However, because other organic lesions were absent and the symptoms appeared during chemotherapy, the possibility is not deniable. At present, 2 years postoperatively, recurrent lesions in the mediastinum and recurrent respiratory difficulties are absent. Generally, although phrenic nerve paralysis is not considered to be a specific side effect, it was considered that for respiratory difficulties, CT reveals not only the affected condition in the lung fields, but is also useful for detection.