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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

According to the alarming statistical analysis of global cancer, there are over 19 million new diagnoses and more than 10 million deaths each year. One such cancer is the oral squamous cell carcinoma (OSCC), which requires new therapeutic strategies. Ficus septica extract has been used in traditional medicine to treat infectious diseases. In this study, we examined the anti-proliferative effects of an extract of F. septica bark (FSB) in OSCC cells. Our results showed that FSB caused a concentration-dependent reduction in the viability of SCC2095 OSCC cells, as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, and was less sensitive to fibroblasts. In addition, FSB induced apoptosis by activating caspases, accompanied by the modulation of Akt/mTOR/NF-κB and mitogen-activated protein kinase signaling. Moreover, FSB increased reactive oxygen species generation in a concentration-dependent manner in SCC2095 cells. Furthermore, FSB inhibited cell migration and modulated the levels of the cell adhesion molecules including E-cadherin, N-cadherin, and Snail in SCC2095 cells. Pinoresinol, a lignan isolated from FSB, showed antitumor effects in SCC2095 cells, implying that this compound might play an important role in FSB-induced OSCC cell death. Taken together, FSB is a potential anti-tumor agent against OSCC cells.

Post-transplant cyclophosphamide (PT-Cy) and calcineurin inhibitors used in peripheral blood haplo-identical stem cell transplantation (haploSCT) increase the risk of acute/chronic graft-versus-host disease (GVHD). Whether ATG/PT-Cy is feasible for Asian patients undergoing haploSCT is unclear, and an optimal strategy for GVHD prophylaxis is needed.We retrospectively analyzed 61 hematologic malignancy patients who underwent peripheral blood haploSCT using ATG/PT-Cy from January 2013 to December 2018. We also compared the effects of ATG/PT-Cy (ATG group; n = 61) with historical data from patients who underwent haploSCT using sirolimus/PT-Cy (non-ATG group; n = 22).Cumulative incidences of grades II-IV acute GVHD and moderate to severe chronic GVHD did not differ significantly. The ATG group had higher incidence of Epstein-Barr virus (EBV) reactivation, but neither group had post-transplant lymphoproliferative disorders. The ATG group also had a higher OS rate (2-year OS in ATG group vs. non-ATG group: 43.4% vs. 27.3%, respectively; P = 0.071).ATG/PT-Cy is an acceptable strategy for GVHD prophylaxis in Asian patients undergoing haploSCT.

Secondary metabolites in marine organisms exhibit various pharmacological activities against diseases, such as cancer. In this study, the anti-proliferative effect of JBIR-100, a macrolide isolated from Streptomyces sp., was investigated in breast cancer cells. Cell growth was inhibited in response to JBIR-100 treatment concentration- and time-dependently in both MCF-7 and MDA-MB-231 breast cancer cells. JBIR-100 caused apoptosis, as verified by caspase activation and the cleavage of PARP. Western blotting revealed that JBIR-100 modulated the expression of Akt/NF-κB signaling components and Bcl-2 family members. Overexpression of Mcl-1 partially rescued MCF-7 cells from JBIR-100-induced cytotoxicity. In addition, transmission electron microscopy analyses, confocal analysis, and western blot assay indicated that JBIR-100 inhibited autophagy in MCF-7 cells. Exposure to the autophagy inhibitor did not synergize JBIR-100-induced apoptosis. In summary, our results suggested that JBIR-100 may be potentially used for breast cancer therapy.

Liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI + 5-FU/LV) treatment has demonstrated survival benefits but noticeable side effects in patients with pancreatic ductal adenocarcinoma (PDAC) that is refractory to gemcitabine-based therapy. This study aimed to explore whether combining albumin with the neutrophil-to-lymphocyte ratio (NLR), herein known as the albumin and neutrophil-to-lymphocyte ratio score (ANS), could be utilized as a simple tool to predict survival and safety profiles in such patient groups. We retrospectively enrolled 434 consecutive PDAC patients treated with nal-IRI + 5-FU/LV between 2018 and 2020 at nine medical centers in Taiwan. Patients were divided into three groups: ANS 0 (high albumin and low NLR), ANS 1 (low albumin or high NLR), and ANS 2 (low albumin and high NLR), for comparison. The median overall survival times for the ANS 0, 1, and 2 groups were 8.7 months (95% confidence interval (CI), 7.0-10.3 months), 5.2 months (95% CI, 4.3-6.0 months), and 2.6 months (95% CI, 1.9-3.3 months), respectively. The ANS was found to be an independent variable for overall survival and time-to-treatment failure in multivariate analyses. Patients in the ANS 2 group had significantly higher incidences of grade 3 or higher treatment-related adverse events than those in the other two groups. The present study showed that the ANS was an independent prognosticator in PDAC patients receiving nal-IRI + 5-FU/LV therapy. The ANS can be a simple predictor of survival outcome and safety profiles in PDAC patients treated with nal-IRI + 5-FU/LV.

Elderly patients with advanced pancreatic adenocarcinoma (APC) are conceived to be frailer and susceptible to treatment toxicity that has led to disparity in lower likelihood of receiving chemotherapy and survival. Optimal chemotherapy is an unmet medical need for elderly patients with APC.Patients with chemo-naive APC, age ≥70 years, and Eastern Cooperative Oncology Group (ECOG) performance score ≤2 were eligible. The treatment was consisted of biweekly gemcitabine 800 mg/mOf the 49 enrolled patients, the median age was 76 years, ECOG performance score ≥1 in 59.2%, metastatic diseases in 65.3%, Vulnerable Elders Survey-13 score ≥3 in 71.4%, and Geriatric 8 score ≤14 in 93.9%. After a median 11 cycles of treatment, the overall response rate and disease control rate were 26.5% and 75.5%, respectively. The median progression-free and overall survivals were 6.6 months (95% confidence interval [CI], 5.4-9.2) and 12.5 months (95% CI, 8.9-14.7), respectively. The most common grade 3-4 treatment-related toxicities were anaemia (20.4%), neutropenia (18.4%), and mucositis (12.2%). Patients had improved emotional function and global health status scores during the GSL treatment.The study met its primary end-point, which supports further investigation on the merit of GSL in Asian elderly APC patients.

Background: The nomogram derived from the pivotal phase III NAPOLI-1 study demonstrated a significant ability to predict median overall survival (OS) in gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) treated with liposomal irinotecan plus fluorouracil and leucovorin (nal-IRI+5-FU/LV). However, the NAPOLI-1 nomogram has not been validated in a real-world setting and therefore the applicability of the NAPOLI-1 nomogram in daily practice remains unknown. This study aims to evaluate the NAPOLI-1 nomogram in a multicenter real-world cohort. Methods: The NAPOLI-1 nomogram was applied to a previously established cohort of metastatic PDAC patients treated with nal-IRI+5-FU/LV in nine participating centers in Taiwan. Patients were divided into three risk groups according to the NAPOLI-1 nomogram. The survival impact of relative dose intensity at 6 weeks (RDI at 6 weeks) in different risk groups was also investigated. Results: Of the 473 included patients, the median OSs of patients classified as low (n = 156), medium (n = 186), and high (n = 131) risk were 10.9, 6.3, and 4.3 months, respectively (p < 0.0001). The survival impact of RDI at 6 weeks remained significant after stratification by risk groups, adjustment with Cox regression, inverse probability weighting, or propensity score matching. Conclusions: Our results support the usefulness of the NAPOLI-1 nomogram for risk stratification in gemcitabine-refractory metastatic PDAC treated with nal-IRI+5-FU/LV in daily practice. We further showed that the RDI at 6 weeks is an independent prognostic factor beyond the NAPOLI-1 nomogram.

Nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (NalFL) comprises the current standard for gemcitabine-failed metastatic pancreatic ductal adenocarcinoma (PDAC). As liposomes generally accumulate in the spleen, we evaluated the impact of spleen volume on prognosis. We enrolled patients with metastatic PDAC who failed gemcitabine-based therapy and were initiated on NalFL between August 2018 and November 2020. The spleen volume before NalFL administration was evaluated. They were stratified into dose subgroups (i.e. low, < 48 mg/m(2); intermediate, 48 - < 64 mg/m(2); high, ≥ 64 mg/m(2)) by the average nal-IRI dose during the entire treatment, and multivariate analysis of overall survival (OS) was performed. We included 547 patients with a median age of 63 years (range, 27-89 years) and a median of 1 (range, 0-7) palliative chemotherapy regimen. The median spleen volume was 245 mL (range, 82-817 mL). Among patients with splenomegaly (≥ 245 mL), the low-dose subgroup had the worst median time to treatment failure (TTF, 1.8 months vs. 2.5 months vs. 2.5 months, P = 0.020) and OS (3.3 months vs. 5.9 months vs. 6.6 months, P = 0.018) as against no prognostic impact in patients without splenomegaly. In the multivariate analysis of patients with splenomegaly, performance status (PS) ≥ 2, body surface area (BSA) < 1.6 m(2), prior fluoropyrimidine use, liver metastasis, and low-dose subgroup were independent poor prognostic factors. A low average nal-IRI dose was significantly associated with poor prognosis, especially among patients with splenomegaly. Further pharmacological studies should validate the relevance of spleen volume on the treatment outcomes of nal-IRI.

IntroductionThis multicenter, real-world cohort study aimed to evaluate the effectiveness of early cumulative dose administration and dosing pattern of liposomal irinotecan plus fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (mPDAC).Material and MethodsThe electronic medical records of mPDAC patients treated with nal-IRI+5-FU/LV in nine participating centers were manually reviewed. To accommodate to the NAPOLI-1 study population, only patients with an Eastern Cooperative Oncology Group Performance Score of 0–1 were included. The survival impact of the relative 6-week cumulative dose and dosing pattern (standard vs. reduced starting dose, with and without further dose modification) were investigated.ResultsOf the 473 included patients, their median overall survival (mOS) was 6.8 [95% CI, 6.2–7.7] months. The mOS of patients who received a relative 6-week cumulative dose of >80%, 60%–80%, and ConclusionOur results support the use of nal-IRI+5-FU/LV in gemcitabine-refractory mPDAC and suggest that a lower starting dose followed by a re-escalation strategy could achieve clinical outcomes comparable to those with standard starting doses in real-world practice.

The global, randomized NAPOLI‐1 phase 3 trial reported a survival benefit with liposomal irinotecan (nal‐IRI) plus 5‐fluorouracil/leucovorin (nal‐IRI+5‐FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) after previous gemcitabine‐based therapy. Median overall survival (OS) with nal‐IRI+5‐FU/LV was 6.1 vs 4.2 months with 5‐FU/LV alone (unstratified hazard ratio [HR] = 0.67, P = .012). Herein, we report efficacy and safety results from a post‐hoc subgroup analysis of Asian patients treated at Asian centers. Primary study endpoint was OS; secondary endpoints included progression‐free survival (PFS), objective response rate (ORR), and safety. Patients receiving nal‐IRI+5‐FU/LV (n = 34) had significantly longer median OS versus 5‐FU/LV (n = 35) (8.9 vs 3.7 months; unstratified HR = 0.51, P = .025). Patients had significantly increased median PFS with nal‐IRI+5‐FU/LV versus 5‐FU/LV (4.0 vs 1.4; unstratified HR = 0.48, P = .011), and increased ORR (8.8% vs 0; P = .114). nal‐IRI monotherapy (n = 50) numerically improved efficacy endpoints versus 5‐FU/LV (n = 48): median OS was 5.8 versus 4.3 months (HR = 0.83, P = .423) and median PFS was 2.8 versus 1.4 months (HR = 0.69, P = .155). Grade ≥3 neutropenia was reported more frequently with nal‐IRI+5‐FU/LV versus 5‐FU/LV (54.5% vs 3.4%), and incidence of grade ≥3 diarrhea was comparable between the two arms (3.0% vs 6.9%). This subgroup analysis confirms nal‐IRI+5‐FU/LV as an efficacious treatment option that improves survival in Asian patients with mPDAC that progressed after gemcitabine‐based therapy, with a safety profile agreeing with previous findings. The nal‐IRI+5‐FU/LV regimen should represent a new standard of care for these patients in Asia. (Clinicaltrials.gov: NCT01494506), The global NAPOLI‐1 phase 3 trial (NCT01494506) evaluated the safety and efficacy of liposomal irinotecan (nal‐IRI) and 5‐fluorouracil/leucovorin (5‐FU/LV) compared with 5‐FU/LV in patients with metastatic pancreatic adenocarcinoma that progressed following gemcitabine‐based therapy. We report data from a post‐hoc subgroup analysis focusing on Asian patients at centers in South Korea and Taiwan. Our findings are consistent with those from the primary analysis and show that, despite association with higher incidence of manageable grade 3‐4 neutropenia, the nal‐IRI+5‐FU/LV regimen is an effective treatment option in Asian patients with gemcitabine‐failed metastatic pancreatic cancer.

Background The prognosis of advanced oral squamous cell carcinoma is poor. We investigated the effect of cetuximab-based sequential therapy as a primary treatment. Methods Forty-seven treatment-naive patients with advanced tumors originating from the oral cavity or oropharynx were enrolled. Neoadjuvant cetuximab, paclitaxel, and cisplatin were administered, followed by cetuximab-based radiotherapy. Immunohistochemical staining was applied to study the tissues. Results The best overall response rate was 70.2%, including 4 patients with a complete response and 29 with a partial response. The median progression-free and overall survival rates were 10.3 and 15.2 months, respectively. Patients with more than 50% tumor reduction with neoadjuvant therapy had better survival outcomes. Twenty-two patients had severe adverse events with mostly dermatological complications. Of the 16 patients who received operations, 9 had increased PD-L1 staining compared to pretreatment biopsy in the post hoc study. Conclusion The regimen was effective in selected patients. Increased PD-L1 suggested altered tumor features.

The purposes of this study were to develop the Chinese-version betel quid dependence instrument (BQDI) and to test its reliability and validity. An item pool relevant to betel quid dependence was generated. A panel of three experts assessed content validity including content relevance, clarity, and domain coverage. A cross-sectional study was conducted, consisting of 113 participants from a construction site, betel quid stalls, and a teaching hospital in Taichung, Taiwan. Construct validity was assessed by hypothesizing a significant correlation between the BQDI score and number of pieces-years for betel quid chewing and betel quid biomarkers. The overall Cronbach's alpha coefficient was 0.94. Factor analysis indicated the BQDI consisted of a three-factor structure, including physical and psychological cravings, lack of resistance to betel quid, and maladaptive use. We observed significant associations of BQDI total and factor scores with arecaidine (adjusted odds ratio [OR] for medium total BQDI score: 12.87, 95% CI: 1.45–114.5; high total BQDI score: 28.9, 3.53–236.6) and N-methylnipecotate (medium total BQDI score: 6.18, 1.21–31.62; high total BQDI score: 13.10, 2.72–63.03, respectively). Our results provide preliminary good internal consistency and construct validation of the Chinese-version BQDI as a measure of betel quid dependence in community adults.

4088 Background: In the randomized, double-blind, phase 3 KEYNOTE-394 trial (NCT03062358), pembro + BSC vs PBO + BSC as 2L therapy significantly reduced the risk of death by 21% (HR 0.79, 95% CI 0.63-0.99, P= 0.0180), prolonged PFS (HR 0.74, 95% CI 0.60-0.92, P= 0.0032), and improved ORR (estimated difference 11.4%, 95% CI 6.7-16.0, P= 0.00004) with a manageable safety profile in pts in Asia with advanced HCC and progression on or intolerance to sorafenib or oxaliplatin-based chemotherapy. Here we present the results of prespecified exploratory HRQoL analyses. Methods: EORTC QLQ-C30 and EuroQol-5D3L (EQ5D-3L) questionnaires were administered at baseline (BL); wks 3, 6, 9, 12, 18; every 9 wks thereafter up to 1 yr or end of treatment; at treatment discontinuation, and at the 30-day safety follow-up visit. Pts who received ≥1 dose of study treatment and completed ≥1 HRQoL assessment were included in the analyses. Least squares mean (LSM) score changes from BL to wk 12 were compared using a constrained longitudinal data analysis model, including treatment by study visit interaction and stratification factors as covariates. Kaplan-Meier method was used to estimate time to deterioration (TTD) (time to 1st onset of ≥10-point decline from BL/confirmed by a 2nd adjacent ≥10-point decline from BL) for EORTC QLQ-C30 global health status (GHS)/QoL. Stratified Cox proportional hazards model was used to assess the magnitude of the treatment difference (HR) between treatment arms in TTD with nominal, one-sided P value calculated. Results: The HRQoL population included 450 pts (298 pembro; 152 PBO). HRQoL compliance rate at wk 12 was 95.7% for pembro for both questionnaires and 94.4% for EORTC QLQ-C30 and 95.3% for EQ5D-3L for PBO. There was a statistically significant difference in LSM for change from BL to wk 12, between the two arms for the QLQ-C30 GHS/QoL score and EQ-5D VAS score, with more decline observed in the PBO arm. Difference in LSM for QLQ-C30 GHS/QoL score between pembro (-3.97; 95% CI, -6.38, -1.56) and PBO (-8.40; 95% CI, -11.71, -5.10) arms was 4.43 (95% CI, 0.47, 8.40; P= 0.0142). Difference in LSM for EQ-5D VAS score between pembro (-2.74; 95% CI, -4.51, -0.96) and PBO (-6.94; 95% CI, -9.40, -4.48) arms was 4.20 (95% CI, 1.21, 7.19; P= 0.0030). GHS/QOL mean scores generally remained stable over time in pembro arm. TTD in EORTC QLQ-C30 GHS/QoL score was similar between arms (HR, 0.85; 95% CI, 0.58, 1.25; P= 0.1993). Conclusions: Over 12 wks, pts treated with PBO + BSC showed more decline in HRQoL than those receiving pembro + BSC. Combined with the efficacy and safety results from KEYNOTE-394, as well as other global 2L trials with pembro, including KEYNOTE-240 and KEYNOTE-224, our data support the benefit of pembro as 2L therapy for pts with advanced HCC. Clinical trial information: NCT03062358.

660 Background: Nal-IRI is irinotecan (as known as CPT-11) encapsulated in a nanoliposome drug delivery system (nanoliposomal irinotecan; nal-IRI). Nal-IRI + 5-FU/LV has been approved in patients with metastatic pancreatic cancer after gemcitabine-based therapy through the NAPOLI-1 study. TAS-102 is a combination drug of trifluridine (FTD), an antineoplastic thymidine analog, and tipiracil hydrochloride (TPI), a thymidine phosphorylase inhibitor. TAS-102 has been approved in metastatic colorectal cancer and gastric or gastroesophageal junction adenocarcinoma. Given both drugs show antitumor activity in various cancers, this study is to identify the MTD (maximum tolerated dose) and recommended phase II dose (RP2D), and to explore the preliminary efficacy of nal-IRI and TAS-102 combination in solid tumors. Methods: This multi-center phase I study consists of a classical 3 + 3 dose finding portion and an expansion portion. Eligible patients have pathologically confirmed solid malignancies with no standard treatment available. Patients will be treated with nal-IRI at dose of 60, 70, 80 mg/m2 over 90 minutes on day 1, and oral TAS-102 25, 30, 35 mg/m2 twice daily on day 1-5, every 14 days. Patients who have homozygous for the UGT1A1*28 allele ( TA7/TA7) or UGT1A1*6 allele ( A/A), or double heterozygous for both UGT1A1*28 allele ( TA6/TA7) and UGT1A1*6 allele ( G/A) will be excluded from the dose finding portion. This trial is registered with ClinicalTrials.gov, NCT 03810742. Results: From February 2019 to May 2021, a total of 43 (male/female: 27/16; median age 56, range 25-69) patients (pts) were treated, including 28 in the dose finding portion in which 3, 3, 3, 3, 7, 3 and 6 pts were at levels 1, 2A, 2B, 3, 4A, 4B and 5, respectively, and 15 pts in the expansion portion. The results here are reported from the dose finding portion. The most common cancer types were cholangiocarcinoma (N = 6), neuroendocrine tumor (N = 3), and ampulla of Vater (N = 3). DLTs were noted at one patient who had G4 sepsis and G3 diarrhea at level 4A (80/30), and two subjects who had G3 diarrhea and G3 dehydration at level 5 (80/35). The dosage of the level 4A is determined to be the MTD and it is also the RP2D for the expansion phase. Most common treatment related toxicities during the DLT observation period (the first 2 cycles) are neutropenia, thrombocytopenia, diarrhea, fatigue, and vomiting. In this dose finding portion, 4 pts had partial response and 17 pts had stable disease as the best response. Conclusions: The MTD of Nal-IRI in combination with TAS-102 every 2 weeks is 80/30 mg/m2, which is also the RP2D for expansion study. The clinical benefit was observed in pts at different dose levels. The expansion portion of the study is still ongoing and pts will be followed until disease progression or consent withdrawal. Clinical trial information: NCT03810742.

Total body irradiation (TBI) is frequently used in hematopoietic stem cell transplantation (HSCT) and is associated with many complications due to radiation injury to the normal cells, including normal stem cells. Nevertheless, the effects of TBI on the mesenchymal stromal stem cell (MSC) are not fully understood. Bone marrow-derived MSCs (BM-MSCs) isolated from normal adults were irradiated with 200 cGy twice daily for consecutive 3 days, a regimen identical to that used in TBI-conditioning HSCT. The characteristics, differentiation potential, cytogenetics, hematopoiesis-supporting function, and carcinogenicity of the irradiated BM-MSCs were then compared to the non-irradiated control. The irradiated and non-irradiated MSCs shared similar morphology, phenotype, and hematopoiesis-supporting function. However, irradiated MSCs showed much lower proliferative and differentiative potential. Irradiation also induced clonal cytogenetic abnormalities of MSCs. Nevertheless, the carcinogenicity of irradiated MSCs is low in vitro and in vivo. In parallel with the ex vivo irradiation experiments, decreased proliferative and differentiative abilities and clonal cytogenetic abnormalities can also be found in MSCs isolated from transplant recipients who had received TBI-based conditioning previously. Thus, TBI used in HSCT drastically injury MSCs and may contribute to the development of some long-term complications associated with clonal cytogenetic abnormality and poor adipogenesis and osteogenesis after TBI.

Background In pancreatic cancer, toxicities associated with current chemotherapeutic regimens remain concerning. A modified combination of gemcitabine, S-1, and leucovorin (GSL) was used as the first-line treatment for newly diagnosed locally advanced or metastatic pancreatic adenocarcinoma patients. Methods GSL was administered every 2 weeks—intravenous gemcitabine 800 mg/m2 at a fixed-dose rate of 10 mg/m2/min on day 1 and oral S-1 (80–120 mg/day) plus leucovorin 30 mg twice daily on days 1–7. We retrospectively analyzed the feasibility of GSL and patient outcomes in three medical centers in Taiwan. Results Overall, 49 patients received GSL with a median follow-up of 24.9 months from May 2015 to March 2019. The median patient age was 68 years (range, 47–83 years), with a marginally higher number of females (57.1%). Among the 44 patients who underwent image evaluation, 13 demonstrated a partial response (29.5%) and 17 presented with stable disease (38.6%). The partial response rate and stable disease rate was 26.5% and 34.7%, respectively, in the intent-to-treat analysis. The median time-to-treatment failure was 5.79 months (95% C.I., 2.63–8.94), progression-free survival was 6.94 months (95% C.I., 5.55–8.33), and overall survival time was 11.53 months (95% C.I., 9.94–13.13). For GSL treatment, the most common grade 3 or worse toxicities were anemia (18.3%), neutropenia (6.1%), nausea (4.1%), and mucositis (4.1%). Treatment discontinuation was mostly due to disease progression (65.3%). Conclusions The modified GSL therapy can be a promising and affordable treatment for patients with advanced and metastatic pancreatic cancer in Taiwan. A prospective trial of modified GSL for elderly patients is currently ongoing in Taiwan.

1082 Background: Our previous study ( Clin Cancer Res. 2015;21(8):1851) demonstrated that bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for breast cancer (BC) patients (pts) with brain metastases (BM) progressing from WBRT. We conducted a randomized phase II study A-PLUS (NCT02185352) to test whether using BEEP as an induction therapy could enhance the efficacy of WBRT and provide systemic control. Methods: BC pts with measurable BM not suitable for surgery/radiosurgery and had not received WBRT were randomized (2:1) to experimental arm: induction BEEP for 3 cycles (~2 months [ms]) followed by WBRT or control arm: upfront WBRT. The BEEP regimen consists of bevacizumab 15 mg/kg on day 1, and etoposide 70 mg/m2/day on days 2-4, cisplatin 70 mg/m2 on day 2, followed by prophylaxis GCSF, every 21 days. After WBRT in both arms, pts received treatment of physician’s choice except BEEP until BM progression. Stratification was based on the Graded Prognostic Assessment score. Primary endpoint was brain-specific progression free survival (BS-PFS) based on RECIST 1.1, with a total of 108 pts, power of 0.8 at the 2-sided α level of 0.2. Results: Of 112 enrolled pts, 74 were in experimental arm and 38 in control arm. Baseline patient characteristics were generally balanced between arms. With median follow up of 28.7 ms, median BS-PFS was 8.1 vs. 6.5 ms ( p= 0.146; HR 0.71 [95% CI 0.44-1.13]), which met the primary endpoint (pre-defined α level of 0.2). Results of preplanned analysis included: 2-month brain-specific objective response rate of BEEP alone vs. WBRT was 41.9% vs. 52.6% ( p= 0.613); 8-month BS-PFS rate was 48.7% vs. 26.3% ( p= 0.027); median PFS was 6.4 vs. 4.7 ms ( p= 0.071; HR 0.67 [95% CI 0.43-1.04]), and extra-BM PFS was 7.9 vs. 5.0 ms ( p= 0.141; HR 0.71 [95% CI 0.46-1.12]). Median overall survival was 15.6 vs. 13.6 ms ( p= 0.855; HR 0.96 [95% CI 0.59-1.55]), with 31.6% of pts in control arm received BEEP regimen treatment after BM progression. The most common all-grade adverse events (AEs) in experimental arm were neutropenia (30.2%), nausea (27.9%), anemia (27.4%), and leukopenia (24.2%). Most AEs were mild to moderate in severity. Two pts discontinued BEEP treatment due to grade 4 nephrotoxicity and grade 3 infection, respectively. Conclusions: BEEP as induction treatment followed by WBRT for BC pts with BM may improve control of both BM and systemic disease. Further validation by a phase III study is necessary. Clinical trial information: NCT02185352 .

Pyruvate kinase M2 (PKM2) is a key enzyme responsible for the final step of glycolysis. It is still unclear whether PKM2 is involved in reactive oxygen species (ROS)-mediated cytotoxicity in gastrointestinal cancer, and what mechanisms are involved. One duodenal (AZ521) and two gastric (NUGC and SCM-1) cancer cell lines were treated with an indole-3-carbinol derivative OSU-A9, which caused cytotoxicity in acute myeloid leukemia through ROS generation. OSU-A9 caused a dose- and time-dependent cytotoxicity and induced apoptosis in duodenal and gastric cancer cells through ROS generation. Pretreatment with ROS scavengers rescued cancer cells from apoptosis and concomitant poly (ADP-ribose) polymerase cleavage, implying a key role of ROS in OSU-A9-induced cell death. Moreover, OSU-A9-induced ROS generation decreased protein levels of pTyr105-PKM2, and this effect was rescued by pretreatment with ROS scavengers. Interestingly, pTyr105-PKM2 protein levels decreased in the cell nucleus rather than in the cytoplasm. PKM2 overexpression partially rescued the survival of duodenal and gastric cancer cells treated with OSU-A9. Furthermore, the anticancer activity of OSU-A9 extended in vivo, as OSU-A9 administered by oral gavage suppressed the growth of AZ521 xenograft tumors in nude mice without obvious toxicity. In conclusion, OSU-A9 inhibited duodenal and gastric cancer cell proliferation through ROS generation and caused a subsequent decrease in nuclear pTyr105-PKM2 protein. These findings provide evidence for the non-canonical activity of PKM2 in cancer cell survival. Furthermore, they highlight the potential role of PKM2 as a future therapeutic target for duodenal and gastric cancer.

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Oral squamous cell carcinoma (OSCC) is the fifth common cause of cancer mortality in Taiwan with high incidence and recurrence and needs new therapeutic strategies. In this study, ursolic acid (UA), a triterpenoid, was examined the antitumor potency in OSCC cells. Our results showed that UA inhibited the proliferation of OSCC cells in a dose- and time-dependent manner in both Ca922 and SCC2095 oral cancer cells. UA induced caspase-dependent apoptosis accompanied with the modulation of various biological biomarkers including downregulating Akt/mTOR/NF-κB signaling, ERK, and p38. In addition, UA inhibited angiogenesis as evidenced by abrogation of migration/invasion and blocking MMP-2 secretion in Ca922 cells. Interestingly, UA induced autophagy in OSCC cells, as manifested by LC3B-II conversion and increased p62 expression and accumulation of autophagosomes. Inhibition by autophagy inhibitor enhanced UA-mediated apoptosis in Ca922 cells. The experiment provides a rationale for using triterpenoid in the treatment of OSCC.

The peroxisome proliferator-activated receptor &gamma, (PPAR&gamma, ) is a nuclear receptor that plays a key role in regulating cellular metabolism, and is a therapeutic target for cancer therapy. To search for potential PPAR&gamma, activators, a compound library comprising 11 marine compounds was examined. Among them, a sterol, 3&beta, 11-dihydroxy-9,11-secogorgost-5-en-9-one (compound 1), showed the highest PPAR&gamma, activity with an IC50 value of 8.3 &mu, M for inhibiting human breast adenocarcinoma cell (MCF-7) growth. Western blotting experiments showed that compound 1 induces caspase activation and PARP cleavage. In addition, compound 1 modulated the expression of various PPAR&gamma, regulated downstream biomarkers including cyclin D1, cyclin-dependent kinase (CDK)6, B-cell lymphoma 2 (Bcl-2), p38, and extracellular-signal-regulated kinase (ERK). Moreover, compound 1 increased reactive oxygen species (ROS) generation, upregulated the phosphorylation and expression of H2AX, and induced autophagy. Interestingly, pre-treatment with the autophagy inhibitor 3-methyladenine rescued cells from compound 1-induced growth inhibition, which indicates that the cytotoxic effect of compound 1 is, in part, attributable to its ability to induce autophagy. In conclusion, these findings suggest the translational potential of compound 1 in breast cancer therapy.

Background Bile acids have been implicated in the development of digestive tract malignancy by epidemiological, clinical and animal studies. The growth and transformation signaling by most of the bile acids is thought to be related to the induced cyclooxygenase-2 (COX-2) expression and increased production of prostaglandin E2 (PGE2). The highly hydrophobic bile acids such as chenodeoxycholic acid (CD) and deoxycholic acid can promote carcinogenesis and stimulate the invasion of colon cancer cells. On the contrary, ursodeoxycholic acid (UDCA), a less hydrophobic stereoisomer of CD, inhibits proliferation and induces apoptosis in colon cancer cells. We examined the effects of bile acid on human gastric cancer cells MKN-74. Methods Early-passage human gastric cancer MKN-74 cells were used for drug treatment, preparation of whole cell lysates, subcellular extracts and Western blot analysis. The levels of PGE2 released by the cells were measured by enzyme inummoassay to indicate COX-2 enzymatic activity. Cellular invasion assay was performed in Boyden chamber. Results Exposure of CD led to activation of protein kinase C (PKC) alpha, increased COX-2 expression and increased PGE2 synthesis. The induced COX-2 protein expression could be detected within 4 h exposure of 200 μM CD, and it was dose- and time-dependent. PGE2 is the product of COX-2, and has been reported to cause tumor invasion and angiogenesis in animal study. Safingol (SAF), a PKC inhibitor, suppressed the COX-2 protein expression and PGE2 production by CD in MKN-74. Furthermore, UDCA suppressed PGE2 production by CD but did not affect COX-2 protein expression induced by CD. Using a Boyden chamber invasion assay, both SAF and UDCA impeded CD induced tumor invasiveness of MKN-74 by 30–50%. Conclusions Our results indicate that signaling of hydrophobic bile acid such as CD in gastric cancer cells is through PKC activation and COX-2 induction, which leads to increased cellular invasion. By perturbing the bile acid pool, UDCA attenuates CD-induced PGE2 synthesis and tumor invasiveness.

This study investigated the epidemiology and risk factors associated with invasive fungal infections (IFIs) during induction chemotherapy in a cohort of Taiwanese patients with newly-diagnosed acute myeloid leukemia (AML). IFIs are a significant complication in the management of immunocompromised cancer patients; such infections are associated with a high incidence of morbidity and mortality, particularly in many South-Asian countries, where IFI rates are increasing. We retrospectively analyzed IFI incidence data from 105 patients with newly diagnosed AML at a single center undergoing their first course of induction chemotherapy without primary antifungal prophylaxis between November 2008 and December 2014. Of 21 cases documented as proven/provable IFIs 16 (76%) were invasive aspergillosis, 2 (10%) were mucormycosis infections, and 3 (14%) were proven yeast infections. The lung was the most commonly affected site (n = 16; 76%); 2 patients (10%) developed fungal sinusitis. IFI cases were more often males (P = 0.020). In multivariate analysis, patients with neutropenia lasting>30 days were more than twice as likely to develop IFI (OR, 2.24 [95% CI, 2.81-31.11], P