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Background: The establishment of patient-derived models for pancreatic ductal adenocarcinoma (PDAC) using conventional methods has been fraught with low success rate, mainly because of the small number of tumour cells and dense fibrotic stroma. Here, we sought to establish patient-derived model of PDAC and perform genetic analysis with responses to anticancer drug by using the conditionally reprogrammed cell (CRC) methodology., Methods: We performed in vitro and in vivo tumourigenicity assays and analysed histological characteristics by immunostaining. We investigated genetic profiles including mutation patterns and copy number variations using targeted deep sequencing and copy-number analyses. We assessed the responses of cultured CRCs to the available clinical anticancer drugs based on patient responsiveness., Findings: We established a total of 28 CRCs from patients. Of the 28 samples, 27 showed KRAS mutations in codon 12/13 or codon 61. We found that somatic mutations were shared in the primary-CRC pairs and shared mutations included key oncogenic mutations such as KRAS (9 pairs), TP53 (8 pairs), and SMAD4 (3 pairs). Overall, CRCs preserved the genetic characteristics of primary tumours with high concordance, with additional confirmation of low-AF NPM1 mutation in CRC (35 shared mutations out of 36 total, concordance rate=97.2%). CRCs of the responder group were more sensitive to anticancer agents than those of the non-responder group (P < 0.001)., Interpretation: These results show that a pancreatic cancer cell line model can be efficiently established using the CRC methodology, to better support a personalized therapeutic approach for pancreatic cancer patients., Funding: 2014R1A1A1006272, HI19C0642-060019, 2019R1A2C2008050, 2020R1A2C209958611, and 2020M3E5E204028211., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background/Aims: The benefit of second-line chemotherapy (SL) after failed first-line chemotherapy (FL) in patients with advanced pancreatic cancer has not yet been established. We evaluated the clinical characteristics affecting the benefits of SL compared to best supportive care (BSC), identified the prognostic factors, and ultimately devised a model of clinical parameters to assist in making decision between SL and BSC after the failure of gemcitabine-based FL. Methods: The records of patients who received gemcitabinebased FL for advanced pancreatic cancer at Yonsei University Hospital between January 2010 and December 2015 were retrospectively reviewed. Significant clinical parameters were assessed for their potential as predictive factors. Results: SL patients received a longer duration of FL compared with BSC patients with median duration being 16.0 weeks (range, 8.0 to 26.0 weeks) and 8.0 weeks (range, 4.0 to 16.0 weeks), respectively (p<0.001). When the SL group was stratified by their modified overall survival (mOS) (longer and shorter than 6 months), we found significant differences for several clinical factors, namely, metastasis to the peritoneum (p<0.001), number of metastases (p<0.001), thrombotic events (p=0.003), and level of carbohydrate antigen 19-9 (CA19- 9; p=0.011). In multivariate analysis, more than one site of metastasis, occurrence of thrombotic event during FL, and a CA19-9 level above 90 U/mL were significant independent prognostic factors for mOS in the SL group (p<0.05). When an attempt was made to devise a prognostic nomogram, Harrell's C-index of the final prognosis prediction model was 0.62. Conclusions: SL may be beneficial for patients without peritoneal metastasis or thrombotic events who have a single metastasis and a level of CA19-9 less than 90 U/mL. This prognostic nomogram can be used to predict mOS before the administration of SL after the failure of gemcitabinebased FL.

Background: Sodium meta-arsenite (NaAsO 2 , KML001) is a potential oral anticancer agent acting on telomerase and telomere length. This prospective study evaluated its safety, tolerability, and effectiveness as salvage chemotherapy in patients with advanced biliary tract cancer (BTC) resistant to gemcitabine-based chemotherapy., Methods: Forty-four patients (21 women and 23 men) with advanced BTC and failure history of gemcitabine-based chemotherapy, performance status (PS) 0-2, normal cardiac, hepatic, and renal function were enrolled. Daily dose of KML001 (7.5 mg. p.o.) was administered to eligible subjects for 24 weeks divided into six treatment cycles. Response was evaluated bimonthly using CT., Results: After an average of 1.5 months of treatment (range: 0.5-10.0), 3 patients (6.8%) obtained progression-free status, 23 patients (52.3%) had disease progression, and 18 patients (40.9%) dropped out before evaluation. One patient (2.3%) completed six treatment cycles without progression. During the treatment, morphine dosage kept the same or decreased in 20 patients (47.6%). Nine patients (20.5%) experienced grade-3 adverse events (AEs), while no patient experienced grade-4 AEs. The most common AEs were liver enzyme elevation (11/44, 25%) and anemia (10/44, 22.7%). KML001 was discontinued in six patients (13.6%) due to AEs, including liver toxicity (n = 3), QTc prolongation (n = 2), and abdominal pain (n = 1)., Conclusions: KML001 did not have enough anticancer effect on patients with advanced BTC resistant to gemcitabine. However, KML001 was safe and well-tolerable in terms of AEs and pain control when used as salvage therapy. Further studies are needed to establish arsenic agents as a reliable treatment option in patients with BTC., (Copyright © 2018. Published by Elsevier B.V.)

Background/aims: Palliative chemotherapy is the main treatment for advanced biliary tract cancer (BTC). However, there is a lack of established second-line chemotherapy to treat disease progression after first-line chemotherapy. We examined combination therapy with capecitabine and cisplatin for advanced BTC as a second-line regimen., Methods: We analyzed the medical records of 40 patients diagnosed with BTC who received palliative second-line chemotherapy with capecitabine and cisplatin., Results: The median overall survival from the start of second-line chemotherapy was 6.3 months. The median overall survival from diagnosis was 17.9 months. The median progression-free survival during second-line chemotherapy was 2.3 months. Nine (30%) patients experienced adverse events of grade ≥3. Eastern Cooperative Oncology Group performance score was an independent predictor of adverse events., Conclusions: Combination therapy with capecitabine and cisplatin may be an option for second-line chemotherapy in some of patients with advanced BTC., (© 2017 S. Karger AG, Basel.)

Pancreatic cancer remains one of the most lethal cancers. These patients often have multiple symptoms, and integrated supportive care is critical in helping them remain well for as long as possible. Fluorouracil-based chemotherapy is known to improve overall survival (OS) by approximately 3 months, compared to the best supportive care alone. A 1997 study comparing gemcitabine and fluorouracil treatment of advanced pancreatic cancer patients showed an improvement in OS of 1 month in patients receiving gemcitabine. Over the next 10 years, multiple randomized studies compared singleagent gemcitabine with combination chemotherapy and showed no effective survival improvement. However, the addition of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, was associated with a significant improvement in OS of approximately 2 weeks. However, adoption of this regimen has not been widespread because of its limited effect and added toxicity. Two clinical trials have recently prolonged OS in advanced pancreatic cancer patients by almost 1 year. The first compared FOLFIRINOX with gemcitabine alone, and was associated with a significant improvement in median survival. The second compared gemcitabine and nabpaclitaxel with gemcitabine alone, and was associated with improvements in OS. At present, these regimens are considered standard treatment for patients with good performance statuses.

Background: Surgical resection is the only curative treatment for extrahepatic bile duct cancer. Additionally, the recurrence rate after curative surgery is relatively high, requiring adjuvant therapy. However, the efficacy of adjuvant chemotherapy compared with surgery alone has not yet been clarified. This study aimed to evaluate the efficacy of adjuvant chemotherapy and identify prognostic factors influencing survival in extrahepatic bile duct cancer patients who underwent curative surgical resection., Methods: Ninety-seven patients with extrahepatic bile duct cancer who underwent curative resection between January 2005 and December 2010 were retrospectively analyzed., Results: Among the 97 patients, 31 underwent adjuvant chemotherapy and 66 did not. The 5-year overall survival rate was 34% for patients who underwent adjuvant chemotherapy. There was no significant difference for overall survival between patients who underwent adjuvant chemotherapy and those who did not (p = 0.228). On multivariate analysis, postoperative carbohydrate antigen 19-9 levels and histologic grade were independent prognostic factors related to long-term survival (p < 0.05)., Conclusions: Postoperative adjuvant chemotherapy did not improve survival after surgical resection for extrahepatic bile duct cancer., (© 2016 S. Karger AG, Basel.)

Goals: The aims of this study were to determine the clinical use of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) in the differential diagnosis of patients with suspected pancreatic cancer and in the determination of tumor response after concurrent chemoradiotherapy for pancreatic cancer., Background: Despite advances in diagnostic tools for pancreatic cancer, it is difficult to differentiate pancreatic cancer from mass-forming pancreatitis. Even with current imaging modalities, it is also difficult to assess tumor response to therapeutic intervention., Study: One hundred two patients with suspected pancreatic cancer were selected for this study. Dynamic computerized tomography (CT) scan and FDG-PET were used sequentially to diagnose pancreatic cancer. After diagnostic confirmation their diagnostic yields were compared. We also evaluated the treatment response in 15 patients who underwent chemoradiation therapy with dynamic CT scan and FDG-PET and compared their results., Results: In 93 out of 102 patients, pancreatic cancer was confirmed. FDG-PET showed higher diagnostic accuracy than CT scan (95.1% vs. 76.5%). FDG-PET was also superior to CT in the detection of liver metastasis. FDG-PET detected treatment response in 5 out of 15 cases after chemoradiation therapy, whereas CT could not detect any treatment response. Comparing responder and nonresponder, FDG-PET was able to predict significantly different prognosis (399 vs. 233 d, P<0.05)., Conclusions: FDG-PET is a very useful tool in diagnosing pancreatic cancer. FDG-PET may be also used as an adjunct for determining the treatment modality of pancreatic cancer and evaluating tumor response to chemoradiation therapy.

[6]-Gingerol, a major phenolic compound derived from ginger, has anti-bacterial, anti-inflammatory and anti-tumor activities. While several molecular mechanisms have been described to underlie its effects on cells in vitro and in vivo, the underlying mechanisms by which [6]-gingerol exerts anti-tumorigenic effects are largely unknown. The purpose of this study was to investigate the action of [6]-gingerol on two human pancreatic cancer cell lines, HPAC expressing wild- type (wt) p53 and BxPC-3 expressing mutated p53. We found that [6]-gingerol inhibited the cell growth through cell cycle arrest at G1 phase in both cell lines. Western blot analyses indicated that [6]-gingerol decreased both Cyclin A and Cyclin-dependent kinase (Cdk) expression. These events led to reduction in Rb phosphorylation followed by blocking of S phase entry. p53 expression was decreased by [6]-gingerol treatment in both cell lines suggesting that the induction of Cyclin-dependent kinase inhibitor, p21cip1, was p53-independent. [6]-Gingerol induced mostly apoptotic death in the mutant p53-expressing cells, while no signs of early apoptosis were detected in wild type p53-expressing cells and this was related to the increased phosphorylation of AKT. These results suggest that [6]-gingerol can circumvent the resistance of mutant p53- expressing cells towards chemotherapy by inducing apoptotic cell death while it exerts cytostatic effect on wild type p53- expressing cells by inducing temporal growth arrest.

Simple Summary: Since there is no effective subsequent-line therapy for patients with cisplatin/gemcitabine-refractory advanced biliary tract cancer, there is an urgent need for new treatment options. This phase 1 and 2a study is the first clinical trial reporting the safety and the efficacy of allogeneic NK cells ("SMT-NK") in combination with pembrolizumab in patients with chemotherapy-refractory advanced biliary tract cancer. We found that the SMT-NK can be safely administered with pembrolizumab to patients with the chemotherapy-refractory advanced biliary tract cancer, and the combinational therapy of SMT-NK and pembrolizumab showed improved efficacy outcome compared to recent trials using pembrolizumab alone. This study provides evidence for a new possible treatment option for advanced biliary tract cancer patients. Background and Aim: This study investigated the administration of combination therapy, allogeneic natural killer (NK) cells and pembrolizumab in the treatment of advanced biliary tract cancer to determine the safety and tolerability (phase 1) and the efficacy and safety (phase 2a). Methods: Forty patients (phase 1, n = 6; phase 2a, n = 34) were enrolled between December 2019 and June 2021. The patients received highly activated allogeneic NK cells ("SMT-NK") on weeks 1 and 2 and pembrolizumab on week 1. This 3-week schedule (one cycle) was repeated until confirmed disease progression, intolerable adverse events (AEs), patient withdrawal, or finishing the maximum treatment schedule. The tumor response was evaluated after every three cycles. Results: In phase 1, four patients (66.7%) experienced seven AEs, but no severe AE was observed. In phase 2a, 126 AEs occurred in 29 patients (85.3%). Severe AEs (≥grade 3) were reported in 16 patients (47.1%). The overall response rate (ORR) was 17.4% in the full analysis set and 50.0% in the per-protocol set. Conclusions: SMT-NKs plus pembrolizumab resulted in no severe AEs directly related to the drug combination. The combination therapy also exerted antitumor activity with improved efficacy compared to the recent monotherapy with pembrolizumab in patients with advanced biliary tract cancer. [ABSTRACT FROM AUTHOR]

Objectives: Although the significance of skeletal muscle mass has been investigated in pancreatic cancer, there are no reports regarding the impact of skeletal muscle mass on prognosis in patients who have undergone second-line chemotherapy. We aimed to identify prognostic factors in patients with advanced pancreatic cancer treated with second-line FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin). Methods: We retrospectively reviewed the data of 57 pancreatic cancer patients treated with second-line FOLFIRINOX. Age, sex, body mass index, Eastern Cooperative Oncology Group (ECOG) performance status, carbohydrate antigen 19-9 levels, skeletal muscle area, skeletal muscle index (SMI), progression free survival (PFS), and overall survival (OS) were analyzed. Results: The median age of the 57 patients (male, 56.1%) was 60.4 years (38–78). Median PFS and OS were 2.6 and 6.6 months. On Kaplan-Meier curves, high SMI was associated with prolonged OS and PFS (P value = 0.003 and 0.015). In multivariate analysis, baseline SMI was significant independent prognostic factor in patients treated with second-line FOLFIRINOX. Conclusion: Baseline SMI has an impact on prognosis in patients who undergoing second-line chemotherapy for pancreatic cancer. Skeletal muscle mass may warrant consideration as a predictive factor with which to identify candidates for second-line chemotherapy for advanced pancreatic cancer. [ABSTRACT FROM AUTHOR]

Purpose: Combination chemotherapy with gemcitabine and cisplatin is a standard treatment for patients with advanced biliary tract cancer. This study aimed to evaluate the efficacy and safety of gemcitabine- and cisplatin-based concurrent chemoradiotherapy in patients with unresectable biliary tract cancer.Methods: Patients with pathologically proven, unresectable, non-metastatic biliary tract cancer were enrolled. Gemcitabine was administered intravenously at a dose of 1000 mg/m(2) on days 1, 8, and 15. Cisplatin was administered intravenously at a dose of 70 mg/m(2) on day 1. All the patients underwent concurrent radiotherapy with 45 Gy in 1.8-Gy daily fractions. After treatment completion, tumor response was evaluated by using computed tomography.Results: Eighteen patients were enrolled between June 2007 and October 2011. Their median age was 61 years (range, 38-72 years). Eight patients (44.5 %) were diagnosed with gallbladder cancer, six (33.3 %) with Klatskin's tumor, and four (22.2 %) with distal common bile duct cancer. After treatment completion, partial response was achieved in five patients (27.8 %) and stable disease in 13 patients (72.2 %). The overall response rate was 27.8 %, and the disease stabilization rate was 100 %. No grade 4 adverse events or treatment-related deaths occurred. The most common grade 3 adverse events were thrombocytopenia (33.3 %) and anemia (11.1 %). The median progression-free and overall survival times were 6.8 months (range, 4.5-19.8 months) and 9.6 months (5.4-30.4 months), respectively.Conclusions: This study shows that gemcitabine- and cisplatin-based concurrent chemoradiotherapy is feasible and tolerable in patients with unresectable and non-metastatic biliary tract cancer. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy is a critical treatment option in advanced biliary tract cancer (BTC), which is often diagnosed at advanced stage and is therefore inoperable. The aim of this phase II trial was to evaluate the efficacy and safety of a combination therapy with gemcitabine and irinotecan as the first-line chemotherapy in patients with previously untreated advanced BTC. Patients and Methods: Patients with pathologically confirmed advanced BTC received gemcitabine (1,000 mg/m2 over 30 min) and irinotecan (100 mg/m2 over 2 h) on days 1 and 8 every 3 weeks. Results: Of 39 patients eligible for this trial, 6 had intrahepatic bile duct cancer, 2 had extrahepatic bile duct cancer and 31 had gallbladder cancer. A total of 193 cycles of chemotherapy were administered, with a median of 4 cycles per patient (range 1-18). The objective response rate was 20.5%, and the disease control rate was 66.7% in intention-to-treat analysis. The median progression-free survival was 4.3 months (95% CI 2.70-5.90), and overall survival was 7.6 months (95% CI 4.56-10.64). Grade 3 and 4 toxicities included anemia (20.5% of patients), thrombocytopenia (2.3%), neutropenia (10.3%), aspartate transaminase increase (10.3%), alanine transaminase increase (5.1%) and emesis (5.1%). Conclusion: Combination therapy of gemcitabine and irinotecan had an efficacy comparable to historic control and can be a viable treatment option. It was well tolerated by patients with advanced BTC. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Simple Summary: FOLFIRINOX, which is a first-line chemotherapy for metastatic pancreatic cancer, has become one of the high-risk regimens related to developing febrile neutropenia (FN). Although UGT1A1 polymorphisms are associated with the metabolism of irinotecan, their role as surrogate markers for FOLFIRINOX-induced neutropenia has not been confirmed. In this retrospective study, a total of 154 patients (FN group (n = 31) vs. non-FN group (n = 123)) were divided into three groups based on the predicted UGT1A1 phenotype (extensive metabolizer (EM) vs. intermediate metabolizer (IM) vs. poor metabolizer (PM)). The Cox regression analysis showed that female sex (hazard ratio (HR): 2.20; p = 0.031), ECOG PS = 1 (HR: 2.83; p = 0.008), UGT1A1 IM (HR: 4.30; p = 0.004), and UGT1A1 PM (HR: 4.03; p = 0.028) were independent risk factor of FN. We propose UGT1A1 as the strongest predictive factor for FN and the need for UGT1A1 screening prior to chemotherapy. FOLFIRINOX (oxaliplatin, leucovorin, irinotecan, and 5-fluorouracil) is a first-line chemotherapy for metastatic pancreatic cancer (PC). Chemotherapy-induced neutropenia is one of the most serious adverse events associated with advanced PC. Although UGT1A1 polymorphisms are associated with the metabolism of irinotecan, their role as surrogate markers for FOLFIRINOX-induced neutropenia has not been confirmed. We investigated risk factors for FN—in particular, UGT1A1 polymorphisms—in PC patients receiving FOLFIRINOX, using a single-center cohort registry. To investigate the association between UGT1A1 polymorphisms and FN, we divided patients into three groups based on the predicted UGT1A1 phenotype: extensive metabolizer (EM) vs. intermediate metabolizer (IM) vs. poor metabolizer (PM). A total of 154 patients (FN group (n = 31) vs. non-FN group (n = 123)) receiving first-line FOLFIRINOX were identified between December 2017 and July 2020. The Cox regression analysis showed that female sex (HR: 2.20; p = 0.031), Eastern Cooperative Oncology Group performance status = 1 (HR: 2.83; p = 0.008), UGT1A1 IM (HR: 4.30; p = 0.004), and UGT1A1 PM (HR: 4.03; p = 0.028) were statistically significant risk factors for FN. We propose that UGT1A1 is the strongest predictive factor for FN and that this gene should be screened prior to the administration of chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this study was to compare the efficacy and toxicity of gemcitabine-based concurrent chemoradiotherapy (CCRT) with paclitaxel-based CCRT in patients with locally advanced pancreatic cancer. Methods and materials: A total of 48 patients who had received no prior therapy were enrolled. The patients were treated with 4500 cGy radiation in 25 fractions over 5 weeks concomitant with gemcitabine 1000 mg/m2/week/intravenously (IV) and doxifluridine 600 mg/m2/day/by mouth (PO), or paclitaxel 50 mg/m2/week/IV and doxifluridine 600 mg/m2/day/PO. After a 4-week rest, the responses were evaluated and maintenance therapies (operation or chemotherapy) (gemcitabine 1000 mg/m2/week/IV and doxifluridine 600 mg/m2/day/PO) were conducted. Results: The median survival was 12 months in the gemcitabine group vs. 14 months in the paclitaxel group. The response rate was 13.6% vs. 25%, and the median time to progression was 12 months vs. 12.5 months, respectively. The positive rate of the clinical benefit response was 59.1% vs. 41.7%, respectively. Toxicities were acceptable in both groups. Conclusion: In this trial, we demonstrated that the gemcitabine-based CCRT and the paclitaxel-based CCRT in combination of doxifluridine are clearly acceptable treatment strategy, and appear more effective than the 5 fluorouracil–based CCRT for locally advanced pancreatic cancer with comparable tolerability. Furthermore, the paclitaxel-based CCRT showed similar efficacy and toxicities to the gemcitabine-based treatment when it was combined with 5-fluorouracil. [Copyright &y& Elsevier]

Purpose: To examine STI-571-induced radiosensitivity in human pancreatic cancer cells in vitro. Methods and Materials: Three human pancreatic cancer cell lines (Bxpc-3, Capan-1, and MiaPaCa-2) exhibiting different expression levels of c-Kit and platelet-derived growth factor receptor β (PDGFRβ) and showing different K-ras mutation types were used. For evaluation of the antitumor activity of STI-571 in combination with radiation, clonogenic survival assays, Western blot analysis, and the annexin V/propidium iodide assay with microscopic evaluation by 4'',6-diamidino-2-phenylindole were conducted. Results: Dramatic phosphorylated (p)-c-Kit and p-PDGFRβ attenuation, a modest dose- and time-dependent growth inhibition, and significant radiosensitization were observed after STI-571 treatment in view of apoptosis, although the levels of growth inhibition and increased radiosensitization were different according to cell lines. The grades of radiosensitivity corresponded to the attenuation levels of p-c-Kit and p-PDGFRβ by STI-571, particularly to those of p-c-Kit, and the radiosensitivity was partially affected by K-ras mutation in pancreatic cancer cells. Among downstream pathways associated with c-Kit or PDGFRβ, p-PLCγ was more closely related to radiosensitivity compared with p-Akt1 or p-extracellular signal-regulated kinase 1. Conclusion: STI-571 enhances radiation response in pancreatic cancer cells. This effect is affected by the attenuation levels of p-c-Kit or p-PDGFRβ, and K-ras mutation status. Among them, p-c-Kit plays more important roles in the radiosensitivity in pancreatic cancer compared with p-PDGFRβ or K-ras mutation status. [Copyright &y& Elsevier]