High-resolution pancreatic computed tomography for assessing pancreatic ductal adenocarcinoma resectability: a multicenter prospective study.

OBJECTIVE: This prospective multicenter study aimed to evaluate the diagnostic performance of 80-kVp thin-section pancreatic CT in determining pancreatic ductal adenocarcinoma (PDAC) resectability according to the recent National Comprehensive Cancer Network (NCCN) guidelines. METHODS: We prospectively enrolled surgical resection candidates for PDAC from six tertiary referral hospitals (study identifier: NCT03895177). All participants underwent pancreatic CT using 80 kVp tube voltage with 1-mm reconstruction interval. The local resectability was prospectively evaluated using NCCN guidelines at each center and classified into three categories: resectable, borderline resectable, and unresectable. RESULTS: A total of 138 patients were enrolled; among them, 60 patients underwent neoadjuvant therapy. R0 resection was achieved in 103 patients (74.6%). The R0 resection rates were 88.7% (47/53), 52.4% (11/21), and 0.0% (0/4) for resectable, borderline resectable, and unresectable disease, respectively, in 78 patients who underwent upfront surgery. Meanwhile, the rates were 90.9% (20/22), 76.7% (23/30), and 25.0% (2/8) for resectable, borderline resectable, and unresectable PDAC, respectively, in patients who received neoadjuvant therapy. The area under curve of high-resolution CT in predicting R0 resection was 0.784, with sensitivity, specificity, and accuracy of 87.4% (90/103), 48.6% (17/35), and 77.5% (107/138), respectively. Tumor response was significantly associated with the R0 resection after neoadjuvant therapy (odds ratio [OR] = 38.99, p = 0.016). CONCLUSION: An 80-kVp thin-section pancreatic CT has excellent diagnostic performance in assessing PDAC resectability, enabling R0 resection rates of 88.7% and 90.9% for patients with resectable PDAC who underwent upfront surgery and patients with resectable PDAC after neoadjuvant therapy, respectively. KEY POINTS: • The margin-negative (R0) resection rates were 88.7% (47/53), 52.4% (11/21), and 0.0% (0/4) for resectable, borderline resectable, and unresectable pancreatic ductal adenocarcinoma (PDAC), respectively, on 80-kVp thin-section pancreatic CT in the 78 patients who underwent upfront surgery. • Among the 60 patients who underwent neoadjuvant therapy, the R0 rates were 90.9% (20/22), 76.7% (23/30), and 25.0% (2/8) for resectable, borderline resectable, and unresectable PDAC, respectively. • Tumor response, along with the resectability status on pancreatic CT, was significantly associated with the R0 resection rate after neoadjuvant therapy.

Controversial benefit of 5-fluorouracil/leucovorin-based adjuvant chemotherapy for ampullary cancer: a propensity score-matched analysis.

BACKGROUND: Although surgery is the primary treatment for ampullary cancer (AC), the benefit of adjuvant chemotherapy (CTx) has not yet been confirmed. METHODS: AC patients who were administered 5-fluorouracil(FU)/leucovorin(LV)-based CTx after curative intent surgery between 2011 and 2019 were included. Prognosis was compared between the observation (OB) and CTx groups after propensity score matching (PSM) using perioperative variables to control differences in patient characteristics. RESULTS: Before PSM, of 475 patients, those in the CTx group (n = 281) had worse 5-year overall survival (OS) (82.1% vs. 78.5%, p = 0.017) and worse 5-year recurrence-free survival (RFS) (54.9% vs. 75.7%, p < 0.001) than those in the OB group (n = 194). In addition, the CTx group had a higher rate of poor prognostic factors such as a high T stage (p < 0.001), node metastasis (p < 0.001), and poor differentiation (p < 0.001). After PSM, perioperative outcomes were comparable. In addition, there were no significant differences in OS (hazard ratio [HR], 1.085; 95% confidence interval [CI], 0.688-1.710; p = 0.726) or RFS (HR, 0.883; 95% CI, 0.613 1.272; p = 0.505) between the CTx (n = 123) and OB (n = 123) groups even after stratification by TNM stage. Intestinal subtype showed better 5-year OS (83.7% vs 33.2%, p = 0.015) and RFS (46.5% vs 24.9%, p = 0.035) rate compared with pancreatobiliary/mixed subtype. CONCLUSION: Patients who received adjuvant chemotherapy based on 5-FU/LV showed comparable oncologic outcomes to patients in the OB group even after stratification by tumor stage. The patients with intestinal subtype showed oncologic benefit for adjuvant 5-FU/LV CTx compared with pancreatobiliary or mixed subtypes.

Tumour-derived Dilp8/INSL3 induces cancer anorexia by regulating feeding neuropeptides via Lgr3/8 in the brain.

In patients with advanced-stage cancer, cancer-associated anorexia affects treatment success and patient survival. However, the underlying mechanism is poorly understood. Here, we show that Dilp8, a Drosophila homologue of mammalian insulin-like 3 peptide (INSL3), is secreted from tumour tissues and induces anorexia through the Lgr3 receptor in the brain. Activated Dilp8-Lgr3 signalling upregulated anorexigenic nucleobinding 1 (NUCB1) and downregulated orexigenic short neuropeptide F (sNPF) and NPF expression in the brain. In the cancer condition, the protein expression of Lgr3 and NUCB1 was significantly upregulated in neurons expressing sNPF and NPF. INSL3 levels were increased in tumour-implanted mice and INSL3-treated mouse hypothalamic cells showed Nucb2 upregulation and Npy downregulation. Food consumption was significantly reduced in intracerebrospinal INSL3-injected mice. In patients with pancreatic cancer, higher serum INSL3 levels increased anorexia. These results indicate that tumour-derived Dilp8/INSL3 induces cancer anorexia by regulating feeding hormones through the Lgr3/Lgr8 receptor in Drosophila and mammals.

Pancreatic Cancer CT: Prediction of Resectability according to NCCN Criteria.

Purpose To evaluate the diagnostic performance of CT in the determination of pancreatic cancer resectability according to the National Comprehensive Cancer Network (NCCN) criteria to predict R0 resection. Materials and Methods Structured reports of pancreatic CT clinically prepared by board-certified abdominal radiologists from January 2014 to March 2017 were retrospectively reviewed to assess resectability (resectable, borderline resectable, or unresectable) according to NCCN criteria (version 1.2017) in 616 patients (369 men, 247 women; mean age, 63 years ± 10 [standard deviation]) with pancreatic cancer. Negative resection margin (R0) rates were assessed based on CT resectability status in patients who underwent upfront surgery. R0 resection-associated factors were identified by using logistic regression analysis. Results In 371 patients who underwent surgery, R0 resection rates were 73% (171 of 235), 55% (57 of 104), and 16% (five of 32) for resectable, borderline resectable, and unresectable disease, respectively (P < .001). At multivariable analysis, tumor diameter larger than 4 cm (P < .001) and abutment to the portomesenteric vein (P < .001) were significantly associated with margin-positive resection in patients with resectable disease at CT. R0 resection rates were 80% (123 of 154) for resectable disease without portomesenteric vein abutment, 59% (48 of 81) for resectable disease with portomesenteric vein abutment, 83% (57 of 69) for resectable disease 2 cm or smaller, and 29% (five of 17) for tumors larger than 4 cm. Conclusion CT resectability is used to stratify patients with pancreatic cancer according to the possibility of R0 resection. Larger tumor size and tumor abutment to the portomesenteric vein are associated with margin-positive resection in patients with resectable pancreatic cancer. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Fowler in this issue.

A drug-repositioning screen for primary pancreatic ductal adenocarcinoma cells identifies 6-thioguanine as an effective therapeutic agent for TPMT-low cancer cells.

Pancreatic cancer is one of the most difficult cancers to cure due to the lack of early diagnostic tools and effective therapeutic agents. In this study, we aimed to isolate new bioactive compounds that effectively kill pancreatic ductal adenocarcinoma (PDAC) cells, but not untransformed, human pancreatic ductal epithelial (HPDE) cells. To this end, we established four primary PDAC cell lines and screened 4141 compounds from four bioactive-compound libraries. Initial screening yielded 113 primary hit compounds that caused over a 50% viability reduction in all tested PDAC cells. Subsequent triplicate, dose-dependent analysis revealed three compounds with a tumor cell-specific cytotoxic effect. We found that these three compounds fall into a single category of thiopurine biogenesis. Among them, 6-thioguanine (6-TG) showed an IC50 of 0.39-1.13 µm toward PDAC cells but had no effect on HPDE cells. We propose that this cancer selectivity is due to differences in thiopurine methyltransferase (TPMT) expression between normal and cancer cells. This enzyme is responsible for methylation of thiopurine, which reduces its cytotoxicity. We found that TPMT levels were lower in all four PDAC cell lines than in HPDE or Panc1 cells, and that knockdown of TPMT in HPDE or Panc1 cells sensitized them to 6-TG. Lastly, we used a patient-derived xenograft model to confirm that 6-TG has a significant antitumor effect in combination with gemcitabine. Overall, our study presents 6-TG as a strong candidate for use as a therapeutic agent against PDAC with low levels of TPMT.

Synergistic effect of a drug loaded electrospun patch and systemic chemotherapy in pancreatic cancer xenograft.

Pancreatic cancer has a high rate of local recurrence and poor prognosis even with adjuvant chemotherapy after curative resection. The aim of this study was to investigate if local drug delivery combined with low dose systemic chemotherapy can increase the therapeutic effect of chemotherapy while reducing systemic toxicities. Poly-L-lactic acid-based 5-FU releasing patch was fabricated by electrospinning, and its tumour killing effects were first confirmed in vitro. The 5-FU patch directly adhered to the tumour in subcutaneous and orthotopic murine models, and induced a significant decrease in tumour size. Systemic gemcitabine treatment group, 5-FU drug releasing patch group, and systemic gemcitabine plus 5-FU patch group were compared by tumour size measurement, non-invasive bio-imaging, and histology in subcutaneous models. Combination of local drug patch and systemic chemotherapy led to increased tumour suppression effects that lasted longer, as well as increased survival rate. Histology revealed higher degree of apoptosis in the combined group. Systemic toxicity was recovered within 7 days after the treatment in all mice. Conclusively, local drug delivery using biocompatible polymer patch significantly inhibited tumour growth, and combination with systemic chemotherapy was more effective than single systemic chemotherapy.

Generation and molecular characterization of pancreatic cancer patient-derived xenografts reveals their heterologous nature.

Pancreatic ductal adenocarcinoma (PDAC) is the most challenging type of cancer to treat, with a 5-year survival rate of <10%. Furthermore, because of the large portion of the inoperable cases, it is difficult to obtain specimens to study the biology of the tumors. Therefore, a patient-derived xenograft (PDX) model is an attractive option for preserving and expanding these tumors for translational research. Here we report the generation and characterization of 20 PDX models of PDAC. The success rate of the initial graft was 74% and most tumors were re-transplantable. Histological analysis of the PDXs and primary tumors revealed a conserved expression pattern of p53 and SMAD4; an exome single nucleotide polymorphism (SNP) array and Comprehensive Cancer Panel showed that PDXs retained over 94% of cancer-associated variants. In addition, Polyphen2 and the Sorting Intolerant from Tolerant (SIFT) prediction identified 623 variants among the functional SNPs, highlighting the heterologous nature of pancreatic PDXs; an analysis of 409 tumor suppressor genes and oncogenes in Comprehensive Cancer Panel revealed heterologous cancer gene mutation profiles for each PDX-primary tumor pair. Altogether, we expect these PDX models are a promising platform for screening novel therapeutic agents and diagnostic markers for the detection and eradication of PDAC.

Anodic aluminium oxide membranes for immunoisolation with sufficient oxygen supply for pancreatic islets.

Immunoisolation membranes have been developed for various cell encapsulations for therapeutic purposes. However effective encapsulation systems have been hindered by low oxygen (O2) permeability or imperfect immunoisolation caused by either low porosity or non-uniform pore geometry. Here, we report an encapsulation method that uses an anodic aluminum oxide membrane formed by polyethylene oxide self-assembly to obtain nanochannels with both high selectivity in excluding immune molecules and high permeability of nutrients such as glucose, insulin, and O2. The extracorporeal encapsulation system composed of these membranes allows O2 flux to meet the O2 demand of pancreatic islets of Langerhans and provides excellent in vitro viability and functionality of islets.

Prospective efficacy and safety study of neoadjuvant gemcitabine with capecitabine combination chemotherapy for borderline-resectable or unresectable locally advanced pancreatic adenocarcinoma.

BACKGROUND: To determine the safety and efficacy of neoadjuvant gemcitabine/capecitabine followed by surgery for the treatment of locally advanced pancreatic adenocarcinoma (LAPC). METHODS: Patients with histologically confirmed LAPC were given 3-6 cycles of fixed-dose rate gemcitabine/capecitabine every 3 weeks. At the end of chemotherapy, patients were restaged and underwent surgery if the disease was not classified as unresectable. Our institutional criteria were used to classify respectability, which was recategorized on the basis of National Comprehensive Cancer Network (NCCN) criteria retroactively. The primary end point was rate of microscopic curative resection. RESULTS: Forty-three eligible patients (18 with borderline resectable disease and 25 with unresectable disease on the basis of NCCN criteria) were enrolled. The radiologic response rate was 18.6%. Grade three or worse adverse events were mainly hand-foot syndrome (11%), and there were no grade four adverse events. Surgery was performed in 17 patients (39.5%); pathologic curative resection (R0) was achieved in 14 patients (32.5%) among total 43 patients, and 82.3% (14/17) among the 17 resected patients. With 43-month follow-up, the median overall was 16.6 months with a median progression-free survival of 10.0 months. Median overall survival was 23.1 months in patients who underwent surgery and 13.2 months in patients who could not complete the surgery (P = .017). CONCLUSION: A subset of patients with borderline or unresectable pancreatic cancer could be performed curative tumor resection after neoadjuvant chemotherapy. Some patients might be benefit on survival from neoadjuvant chemotherapy after surgical resection.

Dryopteris crassirhizoma has anti-cancer effects through both extrinsic and intrinsic apoptotic pathways and G0/G1 phase arrest in human prostate cancer cells.

AIM OF THE STUDY: The inhibitory effect of Dryopteris crassirhizoma on the proliferation of human metastatic prostate PC3-MM2 cells and the mechanism of action were examined to identify its anti-cancer properties. The effect of the extract on cell cycle progression and its combined cytotoxic effect with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on PC3-MM2 cells were also investigated. MATERIALS AND METHODS: The anti-proliferative effects of Dryopteris crassirhizoma were examined by culturing PC3-MM2 cells in the presence or absence of various concentrations of Dryopteris crassirhizoma extract, and the inhibitory effects on cell proliferation were determined by Cell Counting Kit (CCK)-8 analysis. The quantities of apoptosis-inducing proteins were measured by western blotting analysis. Cell cycle progression was analyzed by PI staining using flow cytometry. RESULTS: Dryopteris crassirhizoma (50 and 100 microg/ml) inhibited markedly the proliferation of PC-3 and PC3-MM2 cells without cytotoxicity to normal (spleen) cells from BALB/C mice. Dryopteris crassirhizoma (100 microg/ml) effectively induced apoptosis through the activation of caspase-3, -8, -9, bid, and PARP in PC3-MM2 cells. The cells exposed to Dryopteris crassirhizoma increased significantly the accumulation of the DNA contents in the G0/G1 phase and sub-G1 phase in contrast to the control. The combined cytotoxic effects of Dryopteris crassirhizoma and TRAIL induced the increased activity of 29% in contrast to the sum of the inhibitory effects of each agent alone. CONCLUSIONS: Dryopteris crassirhizoma has anti-cancer properties by inducing cell cycle arrest and apoptosis through the extrinsic and intrinsic pathway in PC3-MM2 cells. The extract also showed a combined effect with TRAIL on the inhibition of proliferation in the cells. These findings suggest that possibly its extract could be used for treating androgen-independent prostate cancer with minimal side effects.

Anti-inflammatory effects of Artemisia princeps in antigen-stimulated T cells and regulatory T cells.

OBJECTIVES: The aim was to investigate the anti-inflammatory effects of Artemisia princeps extract on the activity of anti-CD3/CD28-stimulated CD4(+)CD25(-) T cells and antigen-expanded regulatory T cells. METHODS: CD4(+)CD25(-) T cells were activated with coated anti-CD3 and anti-CD28 and cultured in the presence or absence of various concentrations of A. princeps extract. The cultures were pulsed on Day 6 with [(3)H]thymidine and, after harvesting the cells, [(3)H]thymidine incorporation was measured. For analysis of interleukin-2 and interferon-gamma secreted from CD4(+)CD25(-) T cells, culture supernatants were collected on Days 2 and 6. For the analysis of interleukin-10 secreted from the CD4(+)CD25(-) T cells and expanded regulatory T cells, supernatants were collected after 2 and 7 days, respectively. Cytokine levels were determined using an enzyme-linked immunosorbent assay. Potential medicinal components of the A. princeps extract were determined using gas chromatography-mass spectrometry. KEY FINDINGS: A. princeps (30 microg/ml) effectively suppressed proliferation of CD4(+)CD25(-) T cells that were stimulated with anti-CD3/CD28 without causing cytotoxicity in spleen cells incubated under conditions lacking antigen stimulation. A. princeps inhibited production of the pro-inflammatory cytokines interleukin-2 and interferon-gamma in anti-CD3/CD28-stimulated CD4(+)CD25(-) T cells. Also, the extract slightly increased production of the anti-inflammatory cytokine interleukin-10 in these cells. In regulatory T cells expanded by anti-CD3/CD28, A. princeps increased production of interleukin-10 and Foxp3. CONCLUSIONS: The results suggest that A. princeps may be useful in the treatment of autoimmune diseases and organ transplantation rejection by inhibiting proliferation of inflammatory T cells, suppressing inflammatory processes in antigen-stimulated CD4(+)CD25(-) T cells and increasing activity of expanded regulatory T cells.

Anti-inflammatory action of Cudrania tricuspidata on spleen cell and T lymphocyte proliferation.

This study examined whether an extract of Cudrania tricuspidata shows anti-proliferative effects in anti-CD3/CD28-mediated spleen and CD4+CD25- T cells and decreases the production of the proinflammatory cytokines interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) in anti-CD3/CD28-mediated CD4+CD25- T cells. The proliferation of anti-CD3/CD28-mediated spleen cells and CD4+CD25- T cells was effectively suppressed by C. tricuspidata. This extract, however, did not show cytotoxicity in spleen cells under conditions where the antigen was not stimulated using CCK-8 analysis. C. tricuspidata also decreased the production of the pro-inflammatory cytokines IL-2 and IFN-gamma by selective inhibition of this extract on proliferating cells in anti-CD3/CD28-mediated CD4+CD25- T cells. These results suggest that C. tricuspidata may be useful in the treatment of autoimmune diseases and organ transplantation through the inhibitory action of T cells in inflammation.