BACKGROUND:Rapid on-site evaluation enhances the diagnostic yield of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), but the cytopathologists are limited. This study aimed to assess the diagnostic capability of an artificial intelligence-assisted ROSE (AI-ROSE) for EUS-FNA. METHODS:The study included 137 patients who underwent EUS-FNA of a pancreatic mass between April 2019 and August 2021. Participants were divided into training (n = 96), validation (n = 15), and test cohorts (n = 26). From the training/validation cohort, 5157/615 digital images of cell clusters were extracted and divided into 288 × 288-pixel patches. These cell clusters were annotated and labeled into five classes. A semantic segmentation architecture was developed. From the test cohort, 120 cell clusters were extracted to compare diagnostic performance between AI-ROSE and 21 endosonographers and 5 cytotechnologists with varying experience levels in ROSE. RESULTS:In total, 1,097,840 training, 31,817 validation, and 1920 test regions were extracted. In the test cohort, AI-ROSE accuracy for three-category classification (class 1/2, class 3, and class 4/5) was 89.8%. For two-category classification (class 1/2/3 and class 4/5), sensitivity, specificity, and accuracy were 89.3%, 98.1%, and 95.1%, respectively. In the comparison cohort, AI-ROSE accuracy for two-category classification was 93.3%, significantly higher than all endosonographers (68.3%; range, 45.8%-86.7%) and cytotechnologists (76.3%; range, 72.5%-78.3%). The AI-ROSE evaluation time for 120 cell clusters was 6.04 s, much shorter than that of all endosonographers (1800; 480-6000 s) and cytotechnologists (2160; 1020-3600 s). CONCLUSIONS:The AI-ROSE model shows remarkable speed and accuracy in diagnosing pancreatic cell clusters, enabling rapid decision-making during EUS-FNA. UMIN-CTR; No. 000042212.

Pancreatic ductal adenocarcinomas (PDACs) with wild-type KRAS constitute a small fraction of PDACs, and these tumors were recently shown to harbor frequent actionable oncogenic mutations and fusions. However, the clinicopathological features of KRAS wild-type PDAC have not been well studied. Additionally, precancerous lesions occurring in patients with KRAS wild-type PDACs have rarely been characterized. Here, we investigated the clinicopathological characteristics and outcomes of 75 patients with KRAS wild-type PDAC. Molecular analyses were performed in 40 patients using targeted DNA and whole-exome sequencing and targeted RNA sequencing. We demonstrated that patients with metastatic PDAC with wild-type KRAS were younger (median 59.5 years) than those with mutated KRAS (median 67 years, p  < 0.000055). The wild-type KRAS status was not a significant prognostic factor for metastatic disease. Molecularly, genes in the RAS pathway are frequently mutated or rearranged (46%, 16/35), including mutations in BRAF , NRAS , HRAS , EGFR , MAP2K1 , FGFR1 , FGFR3 and ERBB4 and fusions of FGFR2 ( FGFR2 :: CCDC147 , FGFR2 :: CAT , FGFR2 :: TXLNA ), ALK ( STRN :: ALK , EML4 :: ALK ), and BRAF ( TRIP11 :: BRAF ). Mismatch repair deficiency was identified in 10% (4/39) of patients. Potentially actionable alterations were identified frequently in KRAS wild-type PDACs (30%, 12/40), in which nontubular-type carcinomas were significantly enriched with actionable alterations compared with tubular adenocarcinomas [67% (6/9) versus 16% (5/31); p  = 0.007]. Finally, we investigated the precursors of PDACs in 13 pancreatectomy specimens from patients with KRAS wild-type PDAC. We identified three pancreatic intraepithelial neoplasias (PanINs) and two intraductal papillary mucinous neoplasms (IPMNs) harboring oncogenic fusions of ALK and BRAF and driver mutations in BRAF and AKT1 . This study suggests that in the context of unmutated KRAS , PDAC is driven by alternative oncogenic mutations or fusions of RAS pathway genes, which may be introduced during the early phase of tumorigenesis. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Supplementary Fig. 1. DNA methylation and expression analyses in TET1

Supplementary Table 4. Relationship between TET1 methylation and Clinical features in CIMP-P CRCs (TCGA data set)

Background Adenosquamous carcinoma of the pancreas is a rare variant, with a worse prognosis than pancreatic ductal adenocarcinoma; moreover, it has characteristic clinical and histopathological features. Studies have mentioned the differentiation of intraductal papillary mucinous neoplasms into mucinous/tubular adenocarcinomas; however, their transdifferentiation into adenosquamous carcinoma remains unclear. Case presentation An 80-year-old Japanese woman was referred to our hospital for further examination of multiple pancreatic cysts. Enhanced computed tomography after close follow-up for 6 years revealed a new nodule with poor enhancement on the pancreatic body. Distal pancreatectomy and splenectomy were performed. Histopathological examination revealed an adenosquamous carcinoma with coexisting intraductal papillary mucinous neoplasms; moreover, the intraductal papillary mucinous neoplasms lacked continuity with the adenosquamous carcinoma. Immunohistochemical analysis revealed squamous cell carcinoma and differentiation from adenocarcinoma to squamous cell carcinoma. Gene mutation analysis revealed KRAS G12D and KRAS G12R mutations in adenosquamous carcinoma components and intraductal papillary mucinous neoplasm lesions, respectively, with none showing the mutation of GNAS codon 201. The final histopathological diagnosis was adenosquamous carcinoma with coexisting intraductal papillary mucinous neoplasms of the pancreas. Conclusions This is the rare case of adenosquamous carcinoma with coexisting intraductal papillary mucinous neoplasms of the pancreas. To investigate the underlying transdifferentiation pathway of intraductal papillary mucinous neoplasms into this rare subtype of pancreatic cancer, we explored gene mutation differences as a clinicopathological parameter.

PDF file, 60KB, Expression of GPC3 and HLA class I in cases 8 and 25 was determined by immunohistochemistry. Magnification = 200.

PDF file, 36KB, A 30 mg dose of peptide caused stronger local skin reactions (blushing, induration) at the injection site than did a 3.0 mg dose.

Aichi Cancer Center Hospital, Japan; Wakayama Medical University, Japan; Narita Memorial Hospital, Japan; Shubun University, Japan.

Supplementary Table 1. Clinical backgrounds of CRC patient

Supplementary Table 3. Relationship between TET1 methylation and other mutation and methylation markers in CIMP-P CRCs (in our cohort)

Supplementary Figure legends for Supplementary Fig.1 and Fig. 2

Supplementary Table 2. Primer sets for pyrosequencing methylation analysis, mutation analysis, and RT-PCR

Supplementary Fig. 2. Genetic and epigenetic alterations in CIMP-P CRCs

PDF file, 47KB, There was no significant difference in the clinical background of patients with GPC3-specific CTL frequencies ≥ 50 and those with < 50. A peptide dose of greater than 1.0 mg was required for adequate induction of GPC3-specific CTL frequences ≥ 50.

PDF file, 28KB, The levels of AFP or DCP decreased temporarily at least once in nine of the 33 patients. In seven of these nine patients, the levels of DCP fell to < 30% of baseline values.

Background/Aims:High-grade pancreatic intraepithelial neoplasia and invasive pancreatic ductal adenocarcinoma ≤10 mm are targets for early detection of pancreatic cancer. However, their imaging characteristics are unknown. We aimed to identify endoscopic ultrasound findings for the detection of these lesions. Methods:Patients diagnosed with high-grade pancreatic intraepithelial neoplasia (n=29), pancreatic ductal adenocarcinoma ≤10 mm (n=11) (who underwent surgical resection), or benign main pancreatic duct stenosis (n=20) between January 2014 and January 2021 were retrospectively included. Six features differentiating these lesions were examined by endoscopic ultrasonography: main pancreatic duct stenosis, upstream main pancreatic duct dilation, hypoechoic areas surrounding the main pancreatic duct irregularities (mottled areas without demarcation or round areas with demarcation), branch duct dilation, prominent lobular segmentation, and atrophy. Interobserver agreement was assessed by two independent observers. Results:Hypoechoic areas surrounding the main pancreatic duct irregularities were observed more frequently in high-grade pancreatic intraepithelial neoplasia (82.8%) and pancreatic ductal adenocarcinoma ≤10 mm (90.9%) than in benign stenosis (15.0%) (p<0.001). High-grade pancreatic intraepithelial neoplasia exhibited mottled hypoechoic areas more frequently (79.3% vs 18.9%, p<0.001), and round hypoechoic areas less frequently (3.4% vs 72.7%, p<0.001), than pancreatic ductal adenocarcinoma ≤10 mm. The sensitivity and specificity of hypoechoic areas for differentiating high-grade pancreatic intraepithelial neoplasia, pancreatic ductal adenocarcinoma ≤10 mm, and benign stenosis were both 85.0%, with moderate interobserver agreement. Conclusions:The hypoechoic areas surrounding main pancreatic duct irregularities on endoscopic ultrasound may differentiate between high-grade pancreatic intraepithelial neoplasia, pancreatic ductal adenocarcinoma ≤10 mm, and benign stenosis (Trial Registration: UMIN Clinical Trials Registry (UMIN000044789).

A 57-year-old woman with a sudden-onset seizure was hospitalized. Brain magnetic resonance imaging findings led to a suspicion of leptomeningeal carcinomatosis (LMC) without a brain parenchymal tumor, and abdominal computed tomography showed a tumor in the pancreatic tail. Endoscopic ultrasonography-guided fine needle aspiration of the pancreatic mass revealed adenocarcinoma. Therefore, LMC from pancreatic ductal adenocarcinoma was strongly suspected. She received three courses of nab-paclitaxel plus gemcitabine and whole-brain radiation. Shortly thereafter, she developed a severe consciousness impediment and died. A pathological autopsy showed adenocarcinoma in a wide area of the leptomeninges.

OBJECTIVE:The aim of the study was to develop a formula for predicting the probability of malignancy of mucinous cystic neoplasm (MCN) of the pancreas with ovarian-type stroma.METHODS:A total of 364 patients were enrolled. A total score was calculated as the sum of the approximate integers of the odds ratios of the predictive factors identified by multivariate analysis. The relationship between the total score and pathological results was assessed.RESULTS:A total of 321 patients had benign MCN and 43 had malignant MCN. Five possible predictive factors were analyzed: 56 years or older, high serum carcinoembryonic antigen level, high carbohydrate antigen 19-9 level, tumor size of 51 mm or greater, and the presence of mural nodules. The total score was significantly higher in patients with malignant MCN (median, 24; range, 0-37) compared with benign MCN (median, 5; range, 0-33; P < 0.001). Receiver operating characteristic curve analysis demonstrated that the area under the curve was 0.86, and the sensitivity and specificity of the total score for discriminating malignant MCNs were 72% and 83%, respectively, using a cut-off value of 22.CONCLUSIONS:The current simple formula can predict the malignancy of MCN and may thus contribute to the adequate management of patients with MCN.

Upon abdominal ultrasonography, a woman in her 36 years old was diagnosed with a hypoechoic tumor with a diameter of 60mm surrounding the bile duct in the hepatic portal region. Abdominal computed tomography and magnetic resonance cholangiopancreatography revealed a tumor-like mass in the bile duct. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) confirmed the diagnosis of schwannoma. Considering the lesion location, it appeared to rise from the hepatoduodenal ligament. She was unwilling to undergo tumor resection;however, a year after the diagnosis, no change was observed in the tumor. Here, we report a case of schwannoma in the hepatoduodenal ligament, wherein EUS-FNA was useful for establishing a diagnosis and determining a treatment strategy.

Despite recent advances in clinical treatment, pancreatic cancer remains a highly lethal malignancy. In order to improve the survival rate of patients with pancreatic cancer, the development of non-invasive diagnostic methods using effective biomarkers is urgently needed. Here, we developed a highly sensitive method to detect DNA methylation in cell-free (cf)DNA samples based on the enrichment of methyl-CpG binding (MBD) protein coupled with a digital PCR method (MBD-ddPCR). Five DNA methylation markers for the diagnosis of pancreatic cancer were identified through DNA methylation microarray analysis in 37 pancreatic cancers. The sensitivity and specificity of the five markers were validated in another independent cohort of pancreatic cancers (100% and 100%, respectively; n = 46) as well as in The Cancer Genome Atlas data set (96% and 90%, respectively; n = 137). MBD-ddPCR analysis revealed that DNA methylation in at least one of the five markers was detected in 23 (49%) samples of cfDNA from 47 patients with pancreatic cancer. Further, a combination of DNA methylation markers and the KRAS mutation status improved the diagnostic capability of this method (sensitivity and specificity, 68% and 86%, respectively). Genome-wide MBD-sequencing analysis in cancer tissues and corresponding cfDNA revealed that more than 80% of methylated regions were overlapping; DNA methylation profiles of cancerous tissues and cfDNA significantly correlated with each other (R = 0.97). Our data indicate that newly developed MBD-ddPCR is a sensitive method to detect cfDNA methylation and that using five marker genes plus KRAS mutations may be useful for the detection of pancreatic cancers.