Nobuyuki Ohike

Undifferentiated carcinoma (UC) is a rare, highly aggressive subtype of pancreatic cancer; UC with rhabdoid features (UCRF) is particularly associated with poor prognosis. This study aimed to compare clinicopathologic characteristics and outcomes of UC between groups of patients defined by presence versus absence of RF. We retrospectively reviewed patients diagnosed with UC by EUS‐guided tissue acquisition from 2017 to 2024. Histologically, 11 patients were classified as anaplastic UC and two had UC with osteoclast‐like giant cell. Six patients had UCRF. Only 2 patients underwent surgery, while 8 received chemotherapy; 5 of these were treated with gemcitabine plus nab‐paclitaxel. One patient (17%) in the UCRF group was INI‐1–negative. CK7 was positive in 3 UCRF patients (50%) and in all 7 UC patients without RF. In the overall cohort, median OS showed no statistically significant difference between UCRF and UC without RF (3.9 vs. 12.9 months; log‐rank p = 0.188). However, after excluding two patients with UCOGC, Kaplan–Meier analysis demonstrated a significantly shorter OS in UCRF ( p = 0.009). These findings suggest that RF represents a potential adverse prognostic factor in pancreatic UC. Further studies are warranted to clarify biologic significance and treatment implications of RF in pancreatic UC.

Background: Large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive lung neuroendocrine neoplasm with poor prognosis. Recently, DLL3‐targeted bispecific T‐cell engagers (BiTEs) have shown promising efficacy in small cell lung cancer, and clinical trials are ongoing in LCNEC. This study evaluated DLL3 expression and CD8+ tumor‐infiltrating lymphocytes (TILs) infiltration in LCNEC and investigated their clinical significance and association with tarlatamab efficacy. Methods: We retrospectively reviewed consecutive patients who were diagnosed with LCNEC. Immunohistochemical analyses for DLL3 and CD8 were performed. DLL3 positivity was defined as staining in ≥ 1% of tumor cells. CD8+ TIL infiltration was graded as low, moderate, or high. Results: Among 77 screened LCNEC cases, 44 were eligible for analysis. The median age was 75 years. DLL3 expression was observed in 70.5% of cases and was associated with worse survival. Low CD8+ TIL infiltration was observed in 59.1% of cases. Patients with high CD8+ TIL infiltration demonstrated significantly longer survival than those with low infiltration ( p = 0.03). Among representative clinical cases, a patient with DLL3 (+)/CD8 TILs (−) LCNEC achieved marked tumor shrinkage, whereas a patient with DLL3 (−)/CD8 TILs (−) LCNEC showed no response. Conclusions: DLL3 is frequently expressed in LCNEC and correlates with a poorer prognosis. A majority of LCNEC cases are immunologically characterized as cold tumors lacking CD8+ TILs, which contributes to unfavorable clinical outcomes. Tarlatamab induced a robust antitumor response even in a DLL3 (+) cold tumor. DLL3‐BiTE represents a promising therapeutic strategy for DLL3 (+) LCNEC.

Serial pancreatic juice aspiration cytological examination (SPACE) has recently been recognized as a useful method for detecting high‐grade pancreatic intraepithelial neoplasia (high‐grade PanIN). However, the cytological features of high‐grade PanIN are heterogeneous, and some cases remain difficult to diagnose. We examined the cytological findings of two surgically resected cases of high‐grade PanIN detected by SPACE. Quantitative image analysis was performed to evaluate nuclear atypia and chromatin heterogeneity. In addition, hyperspectral imaging analysis was conducted in one case to assess intranuclear spectral heterogeneity. Case 1 demonstrated focal high‐grade PanIN with relatively mild cytological atypia, whereas Case 2 showed multifocal high‐grade PanIN with numerous markedly atypical cells. Despite these differences, both cases shared heterogeneous nuclear chromatin staining within the same epithelial clusters. Image analysis demonstrated significantly increased nuclear area, decreased circularity, decreased mean nuclear brightness, and increased intranuclear brightness standard deviation in Case 2 compared with Case 1, indicating differences in the severity of nuclear atypia. In contrast, overlapping distributions of intranuclear brightness standard deviation were observed in both cases, suggesting shared intranuclear chromatin heterogeneity. Furthermore, hyperspectral imaging analysis demonstrated increased intercellular spectral heterogeneity in high‐grade PanIN compared with normal pancreatic ductal epithelium, supporting the presence of chromatin heterogeneity from an optical perspective. Although the cytological appearance of high‐grade PanIN varies among cases, nuclear chromatin heterogeneity may represent a common and diagnostically important feature. Image analysis and hyperspectral imaging may provide useful objective approaches for evaluating such heterogeneity.

Aim: Abemaciclib, a cyclin‐dependent kinase 4/6 inhibitor, is a standard treatment for hormone receptor‐positive and HER2‐negative breast cancer. However, liver dysfunction induced by abemaciclib is a significant clinical issue. Methods: We report three cases of drug induced liver injury caused by abemaciclib with characteristic liver atrophy. Case 1: A woman in her seventies developed acute liver failure 2 months after initiation of letrozole and abemaciclib for breast cancer and bone metastases. A contrast‐enhanced CT (CECT) scan revealed liver atrophy accompanied by Chilaiditi syndrome. Despite steroid pulse therapy, she progressed to coma. Her liver failure improved, but she died due to worsening of the underlying disease. Case 2: A woman in her seventies developed liver dysfunction 2 months after initiation of anastrozole and abemaciclib to prevent recurrence. A CECT scan revealed liver atrophy and Chilaiditi syndrome. After admission, she progressed to acute liver failure and coma, and steroid pulse therapy was initiated. Hepatic encephalopathy improved with conservative treatment, and liver failure resolved with continued steroid administration. Case 3: A woman in her fifties. After breast cancer surgery, tamoxifen and abemaciclib were started as adjuvant therapy. Blood tests revealed liver dysfunction 2 months later. A CECT scan revealed liver atrophy and Chilaiditi syndrome, which improved with liver support therapy alone without progressing to liver failure. Results and Conclusion: This report is the first highlighting the imaging characteristics of rapid‐onset hepatic atrophy associated with abemaciclib‐induced liver injury. These findings may provide useful insights for distinguishing abemaciclib‐induced liver injury from other etiologies.

We report a case of pancreatic ductal adenocarcinoma (PDAC) in a 51‐year‐old woman with PRSS1 ‐associated hereditary pancreatitis (HP) and a history of chronic alcohol and tobacco use. Following neoadjuvant chemotherapy, she underwent total pancreatectomy. Histological analysis of the entire pancreas revealed no high‐grade PanINs and scattered low‐grade PanINs, with and without KRAS mutations, indicating molecular heterogeneity. Genomic profiling identified multiple driver alterations, comprising both clonal and subclonal events, including mutations in KRAS, CDKN2A/B, SMAD4, ATRX, MSH3 , and the TERT promoter. Immunohistochemistry showed strong nuclear p53 overexpression despite the absence of TP53 mutation, suggesting a chromosomal instability phenotype. These findings support the hypothesis of a chromothripsis‐like catastrophic genomic event contributing to rapid oncogenesis, bypassing the conventional PanIN sequence. The background of chronic inflammation, advanced lipomatous atrophy, and environmental exposures may have facilitated this transformation. This case underscores the need to consider alternative, nonlinear pathways of PDAC development in genetically predisposed individuals and highlights the potential utility of molecular surveillance for early detection and risk stratification.

A gastric neuroendocrine tumor (NET) with pancreatic acinar cell differentiation is extremely rare. We report the case of an 87‐year‐old woman with a submucosal tumor in the gastric body on a background of atrophic gastritis. She also had Sjögren's syndrome. Initially 17.8 × 6.5 mm, the tumor enlarged over 10 years, leading to wedge resection. The resected mass (45 × 40 × 30 mm) was solid with a pale yellow to gray‐white cut surface. Histologically, it showed trabecular or solid nests of epithelial cells with round nuclei and eosinophilic cytoplasm. Immunohistochemistry showed positivity for CKAE1/3, VMAT2, neuroendocrine markers, and pancreatic acinar markers. Ki‐67 index was 11.2%. The tumor co‐expressed PDX1 and ARX and showed loss of menin and ATRX. These findings support a diagnosis of gastric ECL‐cell NET G2 arising in autoimmune gastritis, with secondary pancreatic acinar differentiation. This tumor may represent a variant of type 1 gastric NET.

Introduction: Secondary bladder tumor is rare. We report a case of a bladder tumor initially thought to be a recurrence of non‐muscle invasive bladder cancer that was ultimately identified as metastasis from gastric cancer treated 16 years prior.Case presentation: A 75‐year‐old male with a history of gastric, prostate, and recurrent non‐muscle invasive bladder cancer was diagnosed to have multiple bone metastases. Open bone biopsy and cancer gene panel testing identified the primary origin of the metastases as gastric cancer. Retrospective evaluation revealed that what was initially suspected as recurrent bladder tumors were actually metastases from the gastric cancer.Conclusion: In cases of metastases with an unknown primary origin, detailed evaluation, including biopsy of the metastatic lesion and genomic testing, is recommended.