Search

Yusuke Kitagawa, Hiroki Osumi, Eiji Shinozaki, Yumiko Ota, Izuma Nakayama, Takeshi Suzuki, Takeru Wakatsuki, Takashi Ichimura, Mariko Ogura, Akira Ooki, Daisuke Takahari, Mitsukuni Suenaga, Keisho Chin, Kensei YamaguchiDepartment of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, JapanPurpose: Patients with gastrointestinal neuroendocrine carcinoma (GI-NEC) have poor prognoses. Although platinum-based combination chemotherapy is commonly used as first-line treatment, the benefit of amrubicin (AMR) and salvage chemotherapy in those who develop platinum-refractory GI-NEC remains unknown. This study aimed to evaluate the efficacy and safety of AMR monotherapy in patients with platinum-refractory GI-NEC.Patients and methods: Platinum-refractory GI-NEC patients who received AMR monotherapy between April 2012 and September 2017 were retrospectively analyzed. The overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events were evaluated. PFS and OS were estimated using Kaplan-Meier methods and compared using log-rank tests.Results: In total, 16 patients were enrolled. Of them, 13 (81.3%), 1 (6.2%), and 2 (12.5%) received cisplatin plus irinotecan, cisplatin plus etoposide, and fluoropyrimidine plus platinum, respectively, before AMR monotherapy. The primary sites of NEC included the esophagus (N=3, 18.8%), stomach (N=10, 62.5%), duodenum (N=1, 6.2%) and colorectum (N=2, 12.5%). Patients were administered a median of 3 (range, 1–15) cycles of AMR. The ORR was 6.3%, and the median PFS and OS were 2.9 months (95% CI: 1.7–7.4) and 13.8 months (95% CI: 7.9–23.5), respectively. Neutropenia was the most serious adverse event. Grade 3 or higher neutropenia and febrile neutropenia occurred in 50.0% and 6.2% of patients, respectively. Other nonhematological toxicities were not severe, and no treatment-related deaths occurred. The 10 patients who received subsequent chemotherapy after AMR had significantly longer OS than those who did not (17.3 months vs 8.9 months; p=0.018). The median PFS of those who received organ-specific subsequent chemotherapy after AMR was 3.8 months, which was longer than that of those who received prior AMR.Conclusion: AMR is feasible with minimal side effects for platinum-refractory GI-NEC. Organ-specific subsequent chemotherapy after AMR may improve patient survival.Keywords: amrubicin monotherapy, platinum refractory, gastrointestinal neuroendocrine carcinoma

Background: Historical trauma and cultural loss resulting from colonialism have contributed to educational and health disparities among Pacific youth. Recognizing the protective factors is essential for mitigating disparities and enhancing the overall well-being of these youth. Objective: This review provides evidence about the current state of youth development among Pacific youth. Methods: We conducted a systematic review of the literature published between 2010 and 2020, including the fields of education, social, psychological, and medical sciences. We employed qualitative data analysis of 35 peer-reviewed studies. Results: The majority (69%) of the studies focused on program interventions among 10-19-year-old youth at-risk primarily in New Zealand among Maori (51%) and in the U.S. among Native Hawaiians and Pacific Islanders (46%). Health interventions were common in Hawai'i, while the New Zealand studies focused more on measuring youth resilience. Among the three outcomes identified, health/well-being was the most studied area, followed by social-emotional, and cognitive development. The outcomes suggest mainly positive effects on health and well-being, socio-emotional, and cognitive development related to Pacific youth. Conclusions: While the last decade has seen a growth of culturally anchored programs, more research is needed to account for wider social, economic, and political dynamics that impact youth development, which was largely unaccounted for in the extant studies. There is a need for broader developmental frameworks that would, first, align with the context and culture of the youth's community, and second, expand our horizon of the developmental patterns as they occur in diverse sociocultural contexts.

In this cross-sectional study, we investigated the multi-level educational intervention among youth in a low-income, remote community in Hawai'i, United States. The program aided with middle schoolers' transition into adulthood through youth-adult partnerships, teen mentoring, and community sustainability. Drawing upon social capital framework, we explored participants' experiences and how the intervention promoted positive developmental outcomes among the youth. We recruited youth from a rural Title I Middle School in Hawai'i. Nine youth (n[subscript boys]=6, n[subscript girls]=3; M[subscript age]=13; 44.9% Native Hawaiian or Other Pacific Islander, 44.4% Black or African American, 33.3% White, 22.2. % Asian; participants could select multiple races), teen mentors (n[subscript girls]=3; M[subscript age]=18), and an adult partner (male; 24 years old) participated in 26 virtual club meetings in Spring 2021. This qualitative study consisted of 27 participants who took part in focus groups and observations. Three themes emerged: skill development, youth-adult relationship building, and sense of belonging. These social components encouraged the sharing of knowledge and feelings among participants on horizontal and oblique directions through reciprocity and helped create a social norm of a supportive environment to make youth feel belonging to the group and the local community. Multi-level interventions that draw upon community resources and youth-adult partnerships can benefit at-risk, minority adolescent populations. We identified non-familial role models and a sense of belonging to one's community as two key protective factors that may lead to positive cognitive changes when youth transition into adulthood.

One of CYFAR's unique features is the built-in planning year for all grant recipients. We present our evaluation team's approach during year 1 to establish a foundation and plan for scholarly publications during funding years 2-5. The systematic literature review provided the team with a better understanding of the culture and context of the project's target population. Collaboration between PI/Co-PI and Evaluator served as a powerful tool to achieving this goal. Not only does this model benefit future CYFAR grant recipients' and Extension professionals' curriculum development and program evaluation, it can also inform recruitment efforts and community partnership development.

The Hippo signaling pathway plays a key role in tumorigenesis in different cancer types. We investigated the role of the Hippo effector YAP1 in the tumor immune microenvironment (TIME) of [...]

Background: This study aimed to evaluate the safety and efficacy of first-line nivolumab plus chemotherapy for real-world patients with human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer (AGC). Materials and methods: This single-institutional retrospective study enrolled patients with HER2-negative AGC who were treated with nivolumab plus chemotherapy between September 2021 and January 2024. Early tumor shrinkage (ETS) and depth of response (DpR) were assessed. Results: There were 136 patients with a median age of 65 years (range 27-83 years); 57% were men, the rate of programmed cell death ligand 1 combined positive score of

Abstract Background We have recently identified HOP hoemobox (HOPX) as a tumor suppressor gene candidate, characterized by tumor-specific promoter DNA hypermethylation in human cancers, and it can remarkably inhibit tumors’ aggressive phenotypes. In this current study, we for the first time examined methylation level of HOPX and tested the functional relevance in pancreatic cancer (PC). Methods Clinical features of HOPX promoter hypermethylation was investigated in 89 PC tissues, and immunohistochemistry was added. We also examined its functional relevance in phenotype assays such as soft agar, proliferation, invasion, and cell cycle analysis. Results PC tissues had HOPX gene hypermethylation as compared to the corresponding normal pancreas tissues, and its uniqueness was robust to discriminate tumor from normal tissues (AUC = 0.85, P Conclusion Defective expression of HOPX which is consistent with promoter DNA hypermethylation may explain aggressive phenotype of pancreatic cancer, and intense expression of HOPX in the Langerhans cells may in turn uniquely contribute to pancreatic carcinogenesis.

Abstract Background Phosphatase of regenerating liver-3 (PRL-3) has deserved attention as a crucial molecule in the multiple steps of metastasis. In the present study, we examined the mechanisms regulating PRL-3 expression, and assessed the clinical potential of PRL-3-targeted therapy in gastric cancer. Methods PRL-3 genomic amplification was analyzed using quantitative-polymerase chain reaction and/or fluorescence in situ hybridization in 77 primary gastric tumors. The anticancer activity of PRL-3 inhibitor (1-4-bromo-2-benzylidene rhodanine) treatment was evaluated against cancer cells with different genetic and expression status. Results PRL-3 genomic amplification was closely concordant with high level of its protein expression in cell lines, and was found in 20% (8/40) among human primary tumors with its expression, which were all stage III/IV disease (40%, 8/20), but in none (0/37) among those without expression. Additionally, PRL-3 genomic amplification was associated with metastatic lymph node status, leading to advanced stage and thereby poor outcomes in patients with lymph node metastasis (P = 0.021). PRL-3 small interfering RNA robustly repressed metastatic properties, including cell proliferation, invasion, and anchorage-independent colony formation. Although neither PRL-3 genomic amplification nor expression level was responsible for the sensitivity to PRL-3 inhibitor treatment, the inhibitor showed dose-dependent anticancer efficacy, and remarkably induced apoptosis on all the tested cell lines with PRL-3 expression. Conclusions We have for the first time, demonstrated that PRL-3 genomic amplification is one of the predominant mechanisms inducing its expression, especially in more advanced stage, and that PRL-3-targeted therapy may have a great potential against gastric cancer with its expression.

Background: Although the emergence of immunotherapy has benefited patients with advanced gastric cancer (AGC), the magnitude of the benefit among real-world patients with HER2-negative AGC remains unclear. Objectives: The current study aimed to evaluate the treatment features across various immunotherapy approval periods and investigate the utility of immunotherapy for patients with HER2-negative AGC in daily practice. Design: Retrospective observational study. Methods: We retrospectively evaluated the clinical outcomes of patients with HER2-negative AGC who received first-line platinum-based chemotherapy between 2011 and 2023 across different periods of immunotherapy approval in Japan: Group A (pre-immunotherapy approval): 2011–2017; Group B (approved for third-line treatment or later): 2018–2021; and Group C (approved for first-line treatment): 2022–2023. Results: A total of 949 patients were enrolled (n = 477, 344, and 128 for Groups A, B, and C, respectively). Patient characteristics were comparable between the three groups, except for the proportion of those aged ⩾75 years (p = 0.002), prior gastrectomy (p = 0.03), and liver metastases (p = 0.0005). The median overall survival (OS) was 16.2, 15.2, and 21.3 months in Groups A, B, and C, respectively, with no significant difference between the groups (log-rank p = 0.50). Patients who received first-line immunotherapy plus chemotherapy (n = 173) showed significantly better OS than did those who did not receive any immunotherapy-containing treatment from 2011 to 2017 (n = 382; hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.61–0.99; p = 0.04). Multivariate analysis showed that the use of first-line immunotherapy was not significantly associated with worse OS, whereas the use of any-line immunotherapy was significantly associated with prognosis (HR, 0.54; 95% CI, 0.47–0.63; p < 0.0001). The proportion of patients receiving any second-line treatment was comparable between the groups: 76%, 80%, and 71%, respectively. Conclusion: Our study suggests that immunotherapy has a moderate impact on improving the survival of real-world patients with HER2-negative AGC, highlighting the need for appropriate treatment strategies, including efforts to identify biomarkers and the development of other agents. [ABSTRACT FROM AUTHOR]

Schwann cells are glial cells in the peripheral nervous system (PNS); they wrap neuronal axons with their differentiated plasma membranes called myelin sheaths. Although the physiological functions, such as generating saltatory conduction, have been well studied in the PNS, the molecular mechanisms by which Schwann cells undergo their differentiation programme without apparent morphological changes before dynamic myelin sheath formation remain unclear. Here, for the first time, we report that Arf6, a small GTP/GDP-binding protein controlling morphological differentiation, and the guanine–nucleotide exchange factors cytohesin proteins are involved in the regulation of Schwann cell differentiation marker expression in primary Schwann cells. Specific inhibition of Arf6 and cytohesins by NAV-2729 and SecinH3, respectively, decreased expression of marker proteins 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) and glial fibrillary acidic protein (GFAP). Similar results using promoter assays were observed using the IMS32 Schwann cell line. Furthermore, using an affinity-precipitation technique, we identified Bcl2-like 12 (Bcl2l12) as a novel GTP-bound Arf6-interacting protein. Knockdown of Bcl2l12 using a specific artificial miRNA decreased expression of marker proteins. The knockdown also led to decreased filamentous actin extents. These results suggest that Arf6 and Bcl2l12 can trigger Schwann cell differentiation, providing evidence for a molecular relay that underlies how Schwann cells differentiate. [ABSTRACT FROM AUTHOR]