Akihisa Ohno's research while affiliated with Kyushu University and other places

Background Recently, two molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) have been proposed: the “Classical” and “Basal-like” subtypes, with the former showing better clinical outcomes than the latter. However, the “molecular” classification has not been applied in real-world clinical practice. This study aimed to establish patient-derived organoids (PDOs) for PDAC and evaluate their application in subtype classification and clinical outcome prediction. Methods We utilized tumor samples acquired through endoscopic ultrasound-guided fine-needle biopsy and established a PDO library for subsequent use in morphological assessments, RNA-seq analyses, and in vitro drug response assays. We also conducted a prospective clinical study to evaluate whether analysis using PDOs can predict treatment response and prognosis. Results PDOs of PDAC were established at a high efficiency (> 70%) with at least 100,000 live cells. Morphologically, PDOs were classified as gland-like structures (GL type) and densely proliferating inside (DP type) less than 2 weeks after tissue sampling. RNA-seq analysis revealed that the “morphological” subtype (GL vs. DP) corresponded to the “molecular” subtype (“Classical” vs. “Basal-like”). The “morphological” classification predicted the clinical treatment response and prognosis; the median overall survival of patients with GL type was significantly longer than that with DP type ( P < 0.005). The GL type showed a better response to gemcitabine than the DP type in vitro, whereas the drug response of the DP type was improved by the combination of ERK inhibitor and chloroquine. Conclusions PDAC PDOs help in subtype determination and clinical outcome prediction, thereby facilitating the bench-to-bedside precision medicine for PDAC.

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Background The bidirectional association between pancreatic cancer (PaC) and diabetes mellitus (DM) is well-established. PaC-related DM (PRDM) is characterized by low insulin secretion and insulin resistance. Aims To investigate the diabetic state and PRDM, and assess whether these markers have predictive value for survival in patients with PaC. Methods We retrospectively examined the clinical factors, glucagon stimulation test results, and homeostasis model assessment of insulin resistance (HOMA-IR) scores in patients with PaC. PRDM was defined as if fasting blood glucose was ≥ 126 mg/dL or if hemoglobin A1c (HbA1c) was ≥ 6.5%. We reviewed new-onset PRDM without diabetes treatment history. Increments in C-peptide levels after glucagon stimulation (ΔC-peptide) was examined. Kaplan–Meier curves and log-rank tests were used for data analysis. Results The ΔC-peptide value was ≥ 1 ng/ml in 77.3% of the patients with PaC, of which 13.8% demonstrated a HOMA-IR score > 2.5 and 42.2% of them showed PRDM. The presence of PRDM was significantly shorter overall survival (OS). Patients with ΔC-peptide < 1ng/ml did not show significantly shorter OS than those with ≥ 1 ng/ml (median, 546 [95%CI, 373–900] vs. 567 [514–772] days, p = 0.59). The group with HOMA-IR ≥ 2.5 also did not show a significantly shorter median OS than the group with HOMA-IR < 2.5 (median, 371 [528–710] vs. 571 [221–954] days, p = 0.068) Conclusions The ΔC-peptide values and HOMA-IR score were not significant predictors of survival although PRDM could be related with prognosis.

Background Streptozocin has been used to treat neuroendocrine tumors in Europe and the USA; however, its actual status in Japan has not been fully clarified owing to the rarity of this disease and the relatively recent approval of streptozocin in Japan. Methods We retrospectively analyzed 53 patients with gastroenteropancreatic neuroendocrine tumors who were treated with streptozocin-based chemotherapy at two Japanese hospitals between January 2004 and June 2023. Results The overall response and disease control rates were 27.7 and 74.5%, respectively, and the median progression-free survival and overall survival were 7.1 and 20.3 months, respectively. Performance status ≥1 showed a significant negative correlation with progression-free survival, and performance status ≥1 and liver tumor burden ≥25% showed a significant negative correlation with overall survival. No significant differences were observed in the treatment response between pancreatic and gastrointestinal neuroendocrine tumors. No treatment-related serious adverse events were observed; however, 87.7% of patients expressed a decrease in the estimated glomerular filtration rate, which negatively correlated with the duration of streptozocin treatment (r = 0.43, P = 0.0020). In the streptozocin re-administration group (n = 5), no differences were found in efficacy between the initial and second streptozocin treatments. Conclusions Although streptozocin is a safe, streptozocin-induced renal dysfunction is a dilemma in streptozocin responders. Streptozocin may benefit patients with gastroenteropancreatic neuroendocrine tumors, especially those with a good performance status; however, in some cases, planned streptozocin withdrawal or switching to other drugs should be considered.

The incidence of pancreatic neuroendocrine neoplasms (PanNENs) has been increasing worldwide due to improved disease recognition and advances in diagnostic modalities such as computed tomography and endoscopic ultrasound. The number of older adult patients with PanNENs is expected to increase in Japan's rapidly aging society. Therefore, it is important to establish treatment strategies for older adult patients. The only curative treatment for PanNENs is surgical resection, which can be safely performed in older adult patients when selected appropriately. Depending on age, comorbidities, and tumor size, nonsurgical management, such as observation and systemic therapy, should also be considered. Systemic therapies, including somatostatin analogs, targeted therapies, cytotoxic chemotherapy, and peptide receptor radionuclide therapy, are available for patients with unresectable or metastatic pancreatic neuroendocrine tumors (PanNETs). When administering these therapies to older adult patients with PanNETs, it is important to balance the treatment, and the adverse events which can be linked to it, with the patient's comorbidities and cognitive function. Further studies on older adult patients with PanNETs are warranted to establish an optimal treatment strategy.

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