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Increasing lines of evidence show that the malignant behavior of cancer is not exclusively attributable to cancer cells but also radically influenced by cancerous stroma activity and controlled through various mechanisms by the microenvironment. In addition to structural components, such as the extracellular matrix, stromal cells, such as macrophages, endothelial cells, and specifically cancer-associated fibroblasts (CAFs), have attracted substantial attention over recent decades. CAFs provide routes for aggressive carcinomas and contribute to invasion and metastasis through the biochemical alteration and regulation of cancer-related pathways. However, another facet of CAFs that has been neglected by numerous studies is that CAFs might serve as a negative regulator of cancer progression under certain circumstances. The various origins of CAFs, the diverse tissues in which they reside and their interactions with different cancer cells appear to be responsible for this inconsistency. This review summarizes the latest knowledge regarding CAF heterogeneity and offers a novel perspective and a beneficial approach for obtaining an improved understanding of CAFs.

Although vascular endothelial growth factor (VEGF) promotes the immunosuppressive microenvironment, the efficacy of bevacizumab (Bev) on tumor immunity has not been fully investigated. The present study used 47 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naïve Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory Bev group). The paired samples of the initial and post‐Bev recurrent tumors from 9 patients were included. The expression of programmed cell death‐1 (PD‐1)/PD ligand‐1 (PD‐L1), CD3, CD8, Foxp3, and CD163 was analyzed by immunohistochemistry. The PD‐L1+ tumor cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The PD‐1+ cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The amount of CD3+ and CD8+ T cell infiltration increased in the refractory Bev group compared with the naïve Bev group (CD3, P < .01; CD8, P = .06). Both Foxp3+ regulatory T cells and CD163+ tumor‐associated macrophages significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (Foxp3, P < .01 for each; CD163, P < .01 for each). These findings were largely confirmed by comparing paired initial and post‐Bev recurrent tumors. Bevacizumab restores the immunosupportive tumor microenvironment in glioblastomas, and this effect persists during long‐term Bev therapy. The present study showed, using human glioblastoma specimens resected at 3 different settings, that bevacizumab (Bev) downregulates the expression of programmed cell death‐1 and programmed cell death ligand‐1 immune checkpoint molecules, reduces immunosuppressing regulatory T cells, and tumor‐associated macrophages, and possibly increases the infiltration of cytotoxic T cells. Most of those changes began immediately after the initial Bev treatment and persisted during long‐term Bev therapy. Although vascular endothelial growth factor promotes immunosuppressive microenvironment, this study is the first to elucidate the overall picture of the key molecules/cells in tumor immunity regarding antiangiogenic therapy in actual human specimens. These findings suggest that the immune microenvironment under Bev therapy is persistently favorable, and novel strategies with the combination of Bev and some certain cancer immunotherapies appear to be reasonable treatment.

Vascular endothelial growth factor (VEGF) is an attractive target of antiangiogenic therapy in glioblastomas. Bevacizumab (Bev), a humanized anti-VEGF antibody, is associated with the improvement of progression-free survival and performance status in patients with glioblastoma. However, randomized trials uniformly suggest that these favorable clinical effects of Bev do not translate into an overall survival benefit. The mechanisms of action of Bev appear to include the inhibition of tumor angiogenesis, as well as indirect effects such as the depletion of niches for glioma stem cells and stimulation of antitumor immunity. Although several molecules/pathways have been reported to mediate adaptation and resistance to Bev, including the activation of alternative pro-angiogenic pathways, the resistance mechanisms have not been fully elucidated; for example, the mechanism that reinduces tumor hypoxia remains unclarified. The identification of imaging characteristics or biomarkers predicting the response to Bev, as well as the better understanding of the mechanisms of action and resistance, is crucial to improve the overall clinical outcome and optimize individual therapy. In this article, the authors review the results of important clinical trials/studies, the current understanding of the mechanisms of action and resistance, and the knowledge of imaging characteristics and biomarkers predicting the response to Bev.

Purpose Distinguishing between primary central nervous system lymphoma (PCNSL) and isocitrate dehydrogenase (IDH)-wildtype glioblastoma is important for therapeutic decision-making. This study aimed to compare the performance of 11 C-methionine (MET) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for distinguishing between these two major malignant brain tumors. Methods We retrospectively conducted qualitative and semiquantitative analyses of pre-treatment MET and FDG PET/computed tomography (CT) images of 22 patients with PCNSL and 64 patients with IDH-wildtype glioblastoma. For semiquantitative analysis, we calculated the tumor-to-normal tissue (T/N) ratio by dividing the maximum standardized uptake value (SUV) for the tumor (T) by the average SUV for the normal tissue (N). For performance evaluation, we employed receiver operating characteristic curve analysis and calculated the areas under the curve (AUC) values. Results In the qualitative analysis, all PCNSLs and IDH-wildtype glioblastomas were MET-positive, while 95% and 84% of PCNSLs and IDH-wildtype glioblastomas, respectively, were FDG-positive. Eleven patients were excluded from the FDG PET/CT semiquantitative analysis because of hyperglycemia. There was no difference in MET T/N ratio between PCNSL and IDH-wildtype glioblastoma (p = 0.37). FDG T/N ratio was significantly higher in PCNSL than in IDH-wildtype glioblastoma (p < 0.001). The AUC value for distinguishing PCNSL from IDH-wildtype glioblastoma was significantly higher for the FDG T/N ratio (0.871) than for the MET T/N ratio (0.565) (p = 0.0027). Conclusion MET PET could detect both PCNSL and IDH-wildtype glioblastoma, but unlike FDG PET, it could not distinguish between these two major malignant brain tumors.

Glioblastoma multiforme (GBM) acquires resistance to bevacizumab (Bev) treatment. Bev affects angiogenic factors other than vascular endothelial growth factor (VEGF), which are poorly understood. We investigated changes in angiogenic factors under and after Bev therapy, including angiopoietin-1 (ANGPT1), angiopoietin-2 (ANGPT2), placental growth factor (PLGF), fibroblast growth factor 2, and ephrin A2 (EphA2). Fifty-four GBM tissues, including 28 specimens from 14 cases as paired specimens from the same patient obtained in three settings: initial tumor resection (naïve Bev), tumors resected following Bev therapy (effective Bev), and recurrent tumors after Bev therapy (refractory Bev). Immunohistochemistry assessed their expressions in tumor vessels and its correlation with recurrent MRI patterns. PLGF expression was higher in the effective Bev group than in the naïve Bev group ( p  = 0.024) and remained high in the refractory Bev group. ANGPT2 and EphA2 expressions were higher in the refractory Bev group than in the naïve Bev group ( p  = 0.047 and 0.028, respectively). PLGF expression was higher in the refractory Bev group compared with the naïve Bev group for paired specimens ( p  = 0.036). PLGF was more abundant in T2 diffuse/circumscribe patterns ( p  = 0.046). This is the first study to evaluate angiogenic factors other than VEGF during effective and refractory Bev therapy in patient-derived specimens.

Recent studies have shown that D-allose, a rare sugar, elicits antitumor effects on different types of solid cancers, such as hepatocellular carcinoma, non-small-cell lung cancer, and squamous cell carcinoma of the head and neck. In this study, we examined the effects of D-allose on the proliferation of human glioblastoma (GBM) cell lines (i.e., U251MG and U87MG) in vitro and in vivo and the underlying mechanisms. D-allose treatment inhibited the proliferation of U251MG and U87MG cells in a dose-dependent manner (3–50 mM). However, D-allose treatment did not affect cell cycles or apoptosis in these cells but significantly decreased the cell division frequency in both GBM cell lines. In a subcutaneous U87MG cell xenograft model, intraperitoneal injection of D-allose (100 mg/kg/day) significantly reduced the tumor volume in 28 days. These data indicate that D-allose-induced reduction in cell proliferation is associated with a subsequent decrease in the number of cell divisions, independent of cell-cycle arrest and apoptosis. Thus, D-allose could be an attractive additive to therapeutic strategies for GBM.

Objectives Precut sphincterotomy is often performed when bile duct cannulation is difficult; however, the former has a higher risk of complications than conventional methods. Early precut reduces the risk of post‐endoscopic retrograde cholangiopancreatography pancreatitis (PEP). This study aimed to determine the appropriate timing for precut sphincterotomy to minimize the incidence of PEP. Methods This retrospective study analyzed 320 patients who underwent precut sphincterotomy during their first endoscopic retrograde cholangiopancreatography at a single center. The optimal precut timing was identified using receiver operating characteristic analysis. Patients were divided into an optimized precut group (≤12 min, n = 198) and a delayed group (>12 min, n = 122). The incidence and risk factors of PEP were evaluated using multivariate analyses. Results Receiver operating characteristic analysis identified 12.5 min as the optimal cutoff for transitioning to precut sphincterotomy (area under the curve, 0.613; sensitivity, 61.5%; specificity, 63.9%). The incidence of PEP was significantly lower in the optimized precut group than in the delayed precut group (5.1% vs. 13.1%, p = 0.02). Multivariate analysis identified delayed precut timing (odds ratio [OR], 3.134; p = 0.04) and the absence of endoscopic pancreatic stenting (OR, 0.284; p = 0.01) as independent risk factors for PEP. Conclusion Precut sphincterotomy within 12.5 min of a cannulation attempt reduces the risk of PEP while maintaining procedural safety. Additionally, endoscopic pancreatic stenting can reduce PEP, even in precut scenarios.

Chronic inflammation has a crucial role in cancer development and the progression of various tumors, including pancreatic ductal adenocarcinoma (PDAC). The arachidonate cascade is a major inflammatory pathway that produces several metabolites, such as prostaglandin E2. The enzyme 15‐hydroxyprostaglandin dehydrogenase (15‐PGDH) degrades prostaglandin and is frequently decreased in several types of cancer; however, the molecular mechanisms of 15‐PGDH suppression are unclear. The current study was carried out to elucidate the molecular mechanisms and clinical significance of 15‐PGDH suppression in PDAC. Here, we showed that interleukin‐1β (IL‐1β), a pro‐inflammatory cytokine, downregulates 15‐PGDH expression in PDAC cells, and that IL‐1β expression was inversely correlated with 15‐PGDH levels in frozen PDAC tissues. We also found that activated macrophages produced IL‐1β and reduced 15‐PGDH expression in PDAC cells. Furthermore, the number of CD163‐positive tumor‐associated macrophages was shown to be inversely correlated with 15‐PGDH levels in PDAC cells by immunohistochemical staining of 107 PDAC samples. Finally, we found that low 15‐PGDH expression was significantly associated with advanced tumors, presence of lymph node metastasis and nerve invasion, and poor prognosis in PDAC patients. Our results indicate that IL‐1β derived from TAMs suppresses 15‐PGDH expression in PDAC cells, resulting in poor prognosis of PDAC patients. IL‐1β derived from activated macrophages down‐regulates 15‐PGDH expression in PDAC cells. Down‐regulation of 15‐PGDH promotes PDAC cell growth and leads to poor prognosis in PDAC patients.

Glioblastoma is characterized by a strong self-renewal potential and poor differentiated state. We have reported previously that the (pro)renin receptor [(P)RR] is a potential target for glioma therapy by silencing the (P)RR gene. Here, we have examined the effects of a monoclonal antibody against (P)RR on gliomagenesis. Human glioma cell lines (U251MG and U87MG) and a glioma stem cell line (MGG23) were used for the in vitro study. The expressions of the Wnt/β-catenin signaling pathway (Wnt signaling pathway) components and stemness markers were measured by Western blotting. The effects of the (P)RR antibody on cell proliferation, sphere formation, apoptosis and migration were also examined. Subcutaneous xenografts were also examined in nude mice. Treatment with the (P)RR antibody reduced expression of Wnt signaling pathway components and stemness markers. Furthermore, the (P)RR antibody reduced cell proliferation and decreased sphere formation significantly. The treatment also suppressed migration and induced apoptosis. In a subcutaneous xenograft model, systemic administration of the (P)RR antibody reduced tumor volume significantly. These data show that treatment with the (P)RR antibody is a potential therapeutic strategy for treating glioblastoma.

Background Primary central nervous system lymphoma (PCNSL) can be differentiated from glioblastoma multiforme (GBM) using positron emission tomography (PET) with [ 18 F]fluoro-2-deoxy-D-glucose (FDG). However, differentiation is often difficult with magnetic resonance imaging (MRI) or FDG PET alone. We have used various PET tracers to aid glioma diagnosis; here, we assessed whether multiple PET tracers improve the distinction between GBM and PCNSL. Methods We studied 148 patients with newly diagnosed brain tumors: 96 with GBM and 52 with PCNSL (according to the 2016 World Health Organization classification). Tumor-to-normal tissue ratios (TNRs) were calculated for FDG, L[methyl[ 11 C]]methionine, and 3′deoxy3′[ 18 F]fluorothymidine (FLT). Tumor-to-blood ratio (TBR) was measured for [ 18 F]fluoromisonidazole (FMISO). Results Median FDG TNR was 1.52 (interquartile range [IQR], 1.13–2.13) for GBM and 2.89 (IQR, 1.95–3.85) for PCNSL. MET TNR was 6.38 (IQR, 4.68–7.48) for GBM and 4.01 (IQR, 3.28–7.52) for PCNSL. FLT TNR was 17.35 (IQR, 11.10–22.28) for GBM and 25.61 (IQR, 15.91–55.30) for PCNSL. FMISO TBR was 2.72 (IQR, 2.22–3.62) for GBM and 1.58 (IQR, 1.04–1.93) for PCNSL. Receiver operating characteristic analysis showed areas under the curve of 0.78 (FDG), 0.62 (MET), 0.69 (FLT), and 0.85 (FMISO). FLT TNR had the highest sensitivity of 83.2% while FMISO TBR had the highest specificity of 84.2%. Among the four tracers, FLT showed the highest sensitivity and FMISO showed the highest specificity. Dual‑tracer combinations did not improve overall diagnostic accuracy beyond the best single tracers. Conclusions Among four PET tracers, FMISO was most effective in distinguishing GBM from PCNSL. Diagnostic accuracy was highest when each tracer was used individually.