Cancers

Background/Objectives: Biliary tract cancers (BTCs) are rare, heterogeneous malignancies that frequently present with biliary obstruction and require complex multidisciplinary care. Decisions regarding biliary drainage, future liver remnant (FLR) optimization, and major hepatobiliary surgery may influence perioperative risk and treatment eligibility. This narrative review evaluates the evidence supporting selective centralization and proposes a network-based framework that considers tumor subtype, procedural complexity, and access to care. Methods: The scope and principal topics were defined during the multidisciplinary COST Training School “Biliary Tract Cancers: Practical Approaches in Challenging Environments”, held in Barcelona, Spain, on 20–21 March 2026. Members of the author group conducted topic-specific PubMed/MEDLINE searches within their areas of expertise. Guidelines, systematic reviews, meta-analyses, and relevant clinical studies were synthesized narratively. BTC-specific findings were distinguished from evidence derived from mixed populations. No formal risk-of-bias assessment or consensus voting process was undertaken. Results: Preoperative biliary drainage should be selective, with the indication, target, and modality determined by clinical status, biliary anatomy, treatment intent, and planned intervention. FLR assessment should integrate volume and function, particularly in patients with cholestasis or cholangitis. Evidence supporting augmentation strategies varies by technique and population. Observational studies associate higher procedural volumes with favorable outcomes, although patient selection and case-mix differences limit causal interpretation. Tumor-specific pathways distinguish perihilar, intrahepatic, and distal cholangiocarcinoma and gallbladder cancer. The proposed network combines expert-center coordination of complex interventions with regional care supported by shared protocols, defined responsibilities, escalation pathways, and outcome monitoring. Conclusions: Selective centralization offers an organizational approach to balancing specialist expertise with timely and equitable access. Prospective multicenter evaluation is needed to assess safety, treatment delays, access to curative therapy, patient-centered outcomes, and resource use before wider clinical or policy adoption.

Background/Objectives: The stem cell transcription factor SOX2 is expressed in more than 20 types of cancer. SOX2 expression is also elevated by a wide range of clinically used drugs and has been linked causally to drug and radiation resistance. Hence, SOX2 is recognized as an important therapeutic target. This study set out to identify a small molecule inhibitor that reduces SOX2 in a wide range of tumor types. Methods: In this study, the WNT inhibitor, PRI-724 (Foscenvivint), was tested for its ability to downregulate SOX2 in ten tumor cell lines using western blot analysis. We also used western blot analysis to examine whether PRI-724 blocks the upregulation of SOX2 by clinically used drugs and radiation. Additionally, we examined the overall effects of PRI-724 on the transcriptome by performing RNA-Seq and STRING analysis. Results: PRI-724 not only downregulated SOX2 in ten different tumor cell lines representing eight different tumor types, but also blocked the upregulation of SOX2 induced by vemurafenib, gemcitabine and radiation. Besides downregulating SOX2 at the protein and RNA level, without altering the stability of SOX2 RNA, PRI-724 significantly modified the transcriptome. STRING analysis of the upregulated and downregulated genes indicates that PRI-724 altered the expression of genes involved in stress-response pathways, including endoplasmic reticulum (ER) stress. Conclusions: The WNT inhibitor PRI-724 downregulates SOX2 expression in a wide range of tumor cell types and blocks the upregulation of SOX2 by clinically used regimens. PRI-724 also modulates the expression of genes associated with stress-response pathways.

Background/Objectives: Vitamin D supplementation effects may vary according to receptor genotype and tumor receptor abundance. We examined whether treatment effects differed according to FokI genotype and tumor nuclear vitamin D receptor (VDR) expression after surgery for digestive tract cancer. Methods: This exploratory post hoc analysis used data from the double-blind AMATERASU randomized trial (UMIN000001977), which assigned 417 patients with resected stage I–III digestive tract cancers to vitamin D₃ (2000 IU/day) or placebo. FokI genotype was determined by sequencing and nuclear VDR expression by immunohistochemistry. Unadjusted Cox analyses were supplemented by pooled treatment-by-subgroup interaction models adjusted for age, sex, and pathological stage, with baseline hazards stratified by tumor site. Results: The joint analysis included 359 patients (213 vitamin D; 146 placebo). VDR expression varied across tumor sites. Among patients with the FokI CC genotype and VDR expression in quintiles 2–5 (n = 110), the unadjusted treatment hazard ratio (HR) for relapse or death was 0.30 (95% confidence interval [CI], 0.12–0.73), compared with 1.02 (95% CI, 0.61–1.71) in the complementary subgroup (n = 249; nominal interaction p = 0.02). After adjustment, the HR in the CC/VDR Q2–5 subgroup was 0.44 (95% CI, 0.18–1.10; interaction p = 0.211). For all-cause mortality, the adjusted HR was 0.46 (95% CI, 0.14–1.51; interaction p = 0.135). Conclusions: The unadjusted exploratory findings were attenuated after accounting for clinicopathological factors. Differential supplementation benefit according to the joint classification was not established. Independent validation is required before clinical use.