20(S)-Ginsenoside Rh2 overcomes gemcitabine resistance in pancreatic cancer by inhibiting LAMC2-Modulated ABC transporters.

INTRODUCTION: Gemcitabine (GEM) is the first-line drug for pancreatic ductal adenocarcinoma (PDAC), but drug resistance severely restricts its chemotherapeutic efficacy. Laminin subunit γ2 (LAMC2) plays a crucial role in extracellular matrix formation in the development of GEM-resistance. However, the biological function of LAMC2 in GEM resistance and its molecular mechanisms are still unclear. 20(S)-Ginsenoside Rh2 (Rh2), one of the principal active components isolated from Ginseng Radix et Rhizoma, possesses strong anti-tumor effects. However, the effects of Rh2 on overcoming GEM resistance and its action mechanisms remain to be elucidated. OBJECTIVES: This study aimed to determine the efficacy of Rh2 on overcoming GEM resistance and to explore its underlying molecular mechanisms. METHODS: Clinical study, Western blotting, publicly available databasesand bioinformatic analyses were performed to investigate the protein expression of LAMC2 in the GEM-resistant PDAC patients and the acquired GEM-resistant PDAC cells. Then, the effects of Rh2 on overcoming the GEM resistance in PDAC were evaluated both in vitro and in vivo. Stable silencing or overexpression of LAMC2 in the GEM-resistant PDAC cells were established for validating the role of LAMC2 on Rh2 overcoming the GEM resistance in PDAC. RESULTS: The protein expression of LAMC2 was markedly increased in the GEM-resistant PDAC patient biopsies compared to the sensitive cases. The protein expression of LAMC2 was significantly higher in the acquired GEM-resistant PDAC cells than that in their parental cells. Rh2 enhanced the chemosensitivity of GEM in the GEM-resistant PDAC cells, and inhibited the tumor growth of Miapaca-2-GR cell-bearing mice and Krastm4TyjTrp53tm1BrnTg (Pdx1-cre/Esr1*) #Dam/J (KPC) mice. Rh2 effectively reversed the GEM resistance in Miapaca-2-GR and Capan-2-GR cells by inhibiting LAMC2 expression through regulating the ubiquitin-proteasome pathway. Knockdown of LAMC2 enhanced the chemosensitivity of GEM and the effects of Rh2 on overcoming the GEM resistance in PDAC cells and the orthotopic PDAC mouse model. Conversely, LAMC2 overexpression aggravated the chemoresistance of GEM and abolished the effects of Rh2 on overcoming GEM resistance via modulating ATP-binding cassette (ABC) transporters leading to the active GEM efflux. CONCLUSIONS: LAMC2 plays an important role in the GEM resistance in PDAC, and Rh2 is a potential adjuvant for overcoming the chemoresistance of GEM in PDAC.

Small non-coding RNAs and pancreatic ductal adenocarcinoma: Linking diagnosis, pathogenesis, drug resistance, and therapeutic potential.

This review comprehensively investigates the intricate interplay between small non-coding RNAs (sncRNAs) and pancreatic ductal adenocarcinoma (PDAC), a devastating malignancy with limited therapeutic options. Our analysis reveals the pivotal roles of sncRNAs in various facets of PDAC biology, spanning diagnosis, pathogenesis, drug resistance, and therapeutic strategies. sncRNAs have emerged as promising biomarkers for PDAC, demonstrating distinct expression profiles in diseased tissues. sncRNA differential expression patterns, often detectable in bodily fluids, hold potential for early and minimally invasive diagnostic approaches. Furthermore, sncRNAs exhibit intricate involvement in PDAC pathogenesis, regulating critical cellular processes such as proliferation, apoptosis, and metastasis. Additionally, mechanistic insights into sncRNA-mediated pathogenic pathways illuminate novel therapeutic targets and interventions. A significant focus of this review is dedicated to unraveling sncRNA mechanisms underlying drug resistance in PDAC. Understanding these mechanisms at the molecular level is imperative for devising strategies to overcome drug resistance. Exploring the therapeutic landscape, we discuss the potential of sncRNAs as therapeutic agents themselves as their ability to modulate gene expression with high specificity renders them attractive candidates for targeted therapy. In summary, this review integrates current knowledge on sncRNAs in PDAC, offering a holistic perspective on their diagnostic, pathogenic, and therapeutic relevance. By elucidating the roles of sncRNAs in PDAC biology, this review provides valuable insights for the development of novel diagnostic tools and targeted therapeutic approaches, crucial for improving the prognosis of PDAC patients.

Enhancing pancreatic ductal adenocarcinoma (PDAC) therapy with targeted carbon nano-onion (CNO)-mediated delivery of gemcitabine (GEM)-derived prodrugs.

Nanotechnology's potential in revolutionising cancer treatments is evident in targeted drug delivery systems (DDSs) engineered to optimise therapeutic efficacy and minimise toxicity. This study examines a novel nanocarrier constructed with carbon nano-onions (CNOs), engineered and evaluated for its ability to selectively target cancer cells overexpressing the hyaluronic acid receptor; CD44. Our results highlighted that the CNO-based nanocarrier coupled with hyaluronic acid as the targeting agent demonstrated effective uptake by CD44+ PANC-1 and MIA PaCa-2 cells, while avoiding CD44- Capan-1 cells. The CNO-based nanocarrier also exhibited excellent biocompatibility in all tested pancreatic ductal adenocarcinoma (PDAC) cells, as well as healthy cells. Notably, the CNO-based nanocarrier was successfully loaded with chemotherapeutic 4-(N)-acyl- sidechain-containing prodrugs derived from gemcitabine (GEM). These prodrugs alone exhibited remarkable efficacy in killing PDAC cells which are known to be GEM resistant, and their efficacy was amplified when combined with the CNO-based nanocarrier, particularly in targeting GEM-resistant CD44+ PDAC cells. These findings demonstrate the potential of CNOs as promising scaffolds in advancing targeted DDSs, signifying the translational potential of carbon nanoparticles for cancer therapy.

A novel role of TGFBI in macrophage polarization and macrophage-induced pancreatic cancer growth and therapeutic resistance.

Tumor-associated macrophages (TAMs), as a major and essential component of tumor microenvironment (TME), play a critical role in orchestrating pancreatic cancer (PaC) tumorigenesis from initiation to angiogenesis, growth, and systemic dissemination, as well as immunosuppression and resistance to chemotherapy and immunotherapy; however, the critical intrinsic factors responsible for TAMs reprograming and function remain to be identified. By performing single-cell RNA sequencing, transforming growth factor-beta-induced protein (TGFBI) was identified as TAM-producing factor in murine PaC tumors. TAMs express TGFBI in human PaC and TGFBI expression is positively related with human PaC growth. By inducing TGFBI loss-of-function in macrophage (MΦs) in vitro with siRNA and in vivo with Cre-Lox strategy in our developed TGFBI-floxed mice, we demonstrated disruption of TGFBI not only inhibited MΦ polarization to M2 phenotype and MΦ-mediated stimulation on PaC growth, but also significantly improved anti-tumor immunity, sensitizing PaC to chemotherapy in association with regulation of fibronectin 1, Cxcl10, and Ccl5. Our studies suggest that targeting TGFBI in MΦ can develop an effective therapeutic intervention for highly lethal PaC.

The efficacy and safety of gemcitabine-based combination therapy vs. gemcitabine alone for the treatment of advanced pancreatic cancer: a systematic review and meta-analysis.

Background: Gemcitabine (GEM) is used as a standard first-line drug to effectively alleviate symptoms and prolong survival time for advanced pancreatic cancer. Most randomized controlled trials (RCTs) show that GEM-based combination therapy is better than GEM alone, while some RCTs have the opposite conclusion. This study aimed to investigate whether GEM-based combination therapy would be superior to GEM alone by a systematic review and meta-analysis. Methods: According to the PICOS principles, RCTs (S) focused on comparing GEM-based combination therapy (I) vs. GEM alone (C) for advanced pancreatic cancer (P) were collected from eight electronic databases, outcome variables mainly include survival status and adverse events (AEs) (O). Review Manager 5.4 was used to evaluate the pooled effects of the results among selected articles. Pooled estimate of hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI) were used as measures of effect sizes. Quality assessment for individual study was performed using the Cochrane tool for risk of bias. Results: A total of 17 studies including 5,197 patients were selected in this analysis. The pooled results revealed that GEM-based combination therapy significantly improved the overall survival (OS; HR =0.84; 95% CI: 0.79 to 0.90; P<0.00001), progression-free survival (PFS; HR =0.78; 95% CI: 0.72 to 0.84; P<0.00001), overall response rate (ORR; OR =1.92; 95% CI: 1.61 to 2.30; P<0.00001), 1-year survival rate (OR =1.44; 95% CI: 1.02 to 2.03; P=0.04), respectively. Subgroup analysis showed that the efficacy of GEM plus capecitabine (CAP) and GEM plus S-1 was better than that of GEM alone, while GEM plus cisplatin (CIS) did not achieve an improved effect. GEM-based combination therapy can significantly increase the incidence of AEs, such as leukopenia (P<0.001), neutropenia (P<0.001), anemia (P<0.05), nausea (P<0.001), diarrhea (P<0.05), and stomatitis (P<0.001). No publication bias existed in our meta-analysis (P>0.10). Discussion: Our study supported that GEM-based combination therapy was more beneficial to improve patient's survival than GEM alone, while there was no additional benefits in GEM plus CIS. We also found that GEM-based combination therapy increased the incidence of AEs. Clinicians need to choose the appropriate combination therapy according to the specific situation.

Sialic Acid Conjugated Chitosan Nanoparticles: Modulation to Target Tumour Cells and Therapeutic Opportunities.

Targeted delivery of therapeutics forestalls the dreadful delocalized effects, drug toxicities and needless immunosuppression. Cancer cells are bounteous with sialic acid and the differential expression of glycosyl transferase, glycosidase and monosaccharide transporter compared to healthy tissues. The current study entails the development and characterisation of sialic acid (SA)-labelled chitosan nanoparticles encapsulating gemcitabine (GEM). Chitosan (CS) was conjugated with SA using coupling reaction and characterised spectroscopically. Furthermore, different concentrations of chitosan and tripolyphosphate (TPP) were optimised to fabricate surface modified chitosan nanoparticles. SA conjugated chitosan nanoparticles encapsulating GEM (SA-CS_GEM NPs) of 232 ± 9.69 nm with narrow distribution (PDI < 0.5) and zeta potential of - 19 ± 0.97 mV was fabricated. GEM was successfully loaded in the SA-CS NPs, depicting prolonged and biphasic drug release pattern more elated at low pH. Pronounced cellular uptake (FITC tagged) and cytotoxicity (IC50 487.4 nM) was observed in SA-CS_GEM NPs against A549 cells. IC50 for SA-CS_GEM NPs plunged with an increase in the time points from 24 to 72 h. Concentration-dependent haemolytic study confirmed significant haemocompatibility of SA-CS_GEM NPs. Pharmacokinetic study was performed on Sprague-Dawley rats and the kinetic parameters were calculated using PKSolver 2.0. Results demonstrated a consequential refinement of 2.98 times in modified SA-CS_GEM NPs with a significant increase in retention time, bioavailability and elimination half-life, and decrease in elimination rate constant and volume of distribution in comparison to CS_GEM NPs. Therefore, SA-CS shell core nanoparticles could be a beneficial approach to target and treat NSCLC (non-small cell lung cancer) and direct for research possibilities to target the other tumour cells.

Outcomes of patients with borderline resectable and resectable pancreatic adenocarcinoma treated with neoadjuvant three-week course chemoradiotherapy using capecitabine-based versus gemcitabine-based concurrent chemotherapy.

BACKGROUND: Neoadjuvant chemoradiotherapy can provide downstaging and improve margin negativity for borderline resectable and resectable pancreatic adenocarcinoma [(B)RPC]. Little is known about the relative efficacy of capecitabine (CAPE)-based vs. gemcitabine (GEM)-based 3-week chemoradiation (3WCRT) with 36 Gy in 15 fractions. This study aimed to compare the odds of achieving surgical resection, time to progression (TTP), and overall survival (OS) of patients treated with 3WCRT with concurrent CAPE versus GEM. METHODS: A retrospective cohort study was conducted, examining medical records from a single center for patients with (B)RPC treated with 3WCRT between 1/2009-12/2020. Odd ratios (OR) of achieving surgical resection were estimated using logistic regression for univariable and multivariable analyses. Median TTP (mTTP) and median OS (mOS) were estimated using the Kaplan-Meier method. Cox proportional hazards analysis was conducted to estimate hazard ratios (HR) of progression and survival in univariable and multivariable analyses. RESULTS: Thirty-one patients were included in the analysis. Twenty-two (71%) patients were treated with CAPE, while 9 (29%) were treated with GEM. All patients in the GEM group were borderline resectable, vs. 18 (82%) patients in the CAPE group, P=0.30. Nineteen (86%) patients in the CAPE group were treated with neoadjuvant FOLFIRINOX, vs. 4 (44%) patients in the GEM group, P=0.03. The CAPE group had higher odds of achieving surgical resection [OR =9.33; 95% confidence interval (CI): 1.50-58.20]. Adjusting for covariates, the odds of achieving surgical resection were still statistically higher in the CAPE group vs. the GEM group (OR =25.34; 95% CI: 1.14-563.72). The CAPE group had superior mTTP compared to the GEM group (15.4 months, 95% CI: 4.9-71.1 vs. 4.0 months, 95% CI: 0.4-14.5; P=0.01), corresponding to a hazard ratio of 0.33 (95% CI: 0.14-0.81). Adjusting for covariates this effect persisted; the adjusted hazard ratio (AHR) for progression was 0.24 (95% CI: 0.08-0.77). Cox proportional hazards analysis also demonstrated that the CAPE group had superior OS compared to the GEM group in unadjusted (HR =0.13; 95% CI: 0.04-0.40) and adjusted models (HR =0.13, 95% CI: 0.03-0.52). CONCLUSIONS: For neoadjuvant 3WCRT, this hypothesis-generating study suggests concurrent CAPE may be a more effective radiosensitizer than GEM for patients with (B)RPC.

FOXO3/TRIM22 axis abated the antitumor effect of gemcitabine in non-small cell lung cancer via autophagy induction.

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for more than 80% of the total lung cancer and gemcitabine (GEM)-based chemotherapy is the first-line therapeutic approach for NSCLC treatment. Owing to acquired chemo-resistance, the prognosis of NSCLC patients receiving GEM treatment is still poor. METHODS: Dysregulation of mRNAs in GEM-resistant (GR) NSCLC cells comparing to parental cells were profiled by analyzing GSEA6914 datasets from GEO database. Additionally, qRT-PCR were performed on clinically collected patient serum samples and transplanted tumor tissues and GEM-resistant (GR)/sensitive (GS) cell lines. In order to explore the functional role of tripartite motif protein 22 (TRIM22), gain and loss-of-function cell models were constructed in A549 and A549/GR respectively. MTT and Annexin V-FITC/propidium iodide (PI) staining assay were carried out to access the response to GEM of A549 and A549/GR cells. Observation of RFP-LC3 puncta and western blot detection of autophagy markers were used to evaluate autophagy. Bi-luciferase reporter assay was used to confirm the transcriptional regulatory relationship. Rescue experiments were carried out to confirm the FOXO3/TRIM22 regulatory axis in GEM susceptibility. RESULTS: TRIM22 was significantly upregulated in GR patient serum samples, transplanted tumor tissues and NSCLC cells which was negatively transcriptional regulated by FOXO3. TRIM22 overexpression attenuated the sensitivity of A549 to GEM and its depletion promoted the sensitivity of A549/GR to GEM. Additionally, TRIM22 promoted GEM-induced pro-survival autophagy to protected NSCLC cells from apoptosis. CONCLUSIONS: TRIM22 was significantly upregulated in GR lung adenocarcinoma cell line A549 which is negatively transcriptional regulated by FOXO3. Due to the enhancement of pro-survival autophagy induced by TRIM22, the A549 cells became less sensitive to GEM. This study may provide a basis for screening target of liquid biopsy for predicting GEM sensitivity in NSCLC.

The phenotype of target pancreatic cancer cells influences cell death by magnetic hyperthermia with nanoparticles carrying gemicitabine and the pseudo-peptide NucAnt.

In this paper we show that conjugation of magnetic nanoparticles (MNPs) with Gemcitabine and/or NucAnt (N6L) fostered their internalization into pancreatic tumor cells and that the coupling procedure did not alter the cytotoxic potential of the drugs. By treating tumor cells (BxPC3 and PANC-1) with the conjugated MNPs and magnetic hyperthermia (43 °C, 60 min), cell death was observed. The two pancreatic tumor cell lines showed different reactions against the combined therapy according to their intrinsic sensitivity against Gemcitabine (cell death, ROS production, ability to activate ERK 1/2 and JNK). Finally, tumors (e.g. 3 mL) could be effectively treated by using almost 4.2 × 105 times lower Gemcitabine doses compared to conventional therapies. Our data show that this combinatorial therapy might well play an important role in certain cell phenotypes with low readiness of ROS production. This would be of great significance in distinctly optimizing local pancreatic tumor treatments.

Gemcitabine-loaded Folic Acid Tagged Liposomes: Improved Pharmacokinetic and Biodistribution Profile.

BACKGROUND: Gemcitabine (GEM) is found effective in the treatment of many solid tumors. However, its use is restricted due to its small circulation half-life, fast metabolism and low capacity for selective tumor uptake. Folate receptors (FRs) have been recognized as cellular surface markers, which can be used for cancer targeting. PEGylated liposomes decorated with folic acid have been investigated for several anticancer agents not only to extend plasma half-life but also for tumor targeting via folic acid receptors which overexpressed on tumor cell surface. OBJECTIVE: Therefore, the objective of the present study was to prepare GEM-loaded folic acid tagged liposomes to improve the pharmacokinetics and tumor distribution of GEM. METHODS: The blank folate-targeted liposomes composed of HSPC/DSPE-mPEG2000/DSPE-mPEG-Folic acid were prepared first by thin film hydration technique. GEM was then loaded into liposomes by remote loading technique. The optimized liposomal formulations were evaluated in vitro for GEM release using dialysis technique, HeLa cell uptake using FACS technique, and cytotoxicity using MTT dye reduction assay. The comparative in vivo pharmacokinetic and biodistribution characteristics of radiolabeled (99mTc-labeled) plain GEM solution, and all liposomal formulations (conventional:CLs; stealth: SLs; folate targeted: FTLs) were evaluated in mice model. RESULTS: GEM-loaded FTLs showed sustained release profile, efficient uptake by HeLa cells and greater cytotoxicity. Further, FTLs displayed significantly improved pharmacokinetics, and biodistribution profile of loaded GEM. CONCLUSION: In conclusion, the developed GEM-loaded folic acid receptor-targeted liposomal formulation could be a promising and potential alternative formulation for further development.

Recombinant human thrombopoietin combined with interleukin-2 improves the effects of chemosensitivity and thrombocytopenia on a basic gemcitabine and carboplatin combination therapy for non-small cell lung cancer in a nude mouse model.

BACKGROUND: To investigate the effects of recombinant human thrombopoietin (rhTPO) and interleukin-2 (IL-2) on a basic gemcitabine (GEM) plus carboplatin (GC) treatment regimen in a murine lung carcinoma model. METHODS: Fifty nude mice with subcutaneous tumors derived from human lung cancer cells were divided into 5 groups, each comprised of 10 mice: A blank group (intraperitoneal injection of saline), a control group (GC) (intraperitoneal injections of GC), a rhTPO group (same as the control group plus subcutaneous injection of rhTPO), an IL-2 group (same as the control group plus subcutaneous injection of IL-2) and a rhTPO + IL-2 group (same as the rhTPO group plus subcutaneous injection of IL-2). Tumor development and histology as well as CD4+, phosphorylated-adenosine monophosphate-activated protein kinase (p-AMPK), phosphorylated-protein kinase B (p-AKT), phosphorylated-extracellular signal-regulated kinase (p-ERK), phosphorylated-phosphoinositide 3-kinase (p-pI3K) and GTPase RAS1 expression in tumor tissues were measured and blood analyses performed. RESULTS: Tumor sizes from all treated mice were significant smaller than the controls, as were the tumors of IL-2 plus GC treated mice compared to other treated groups. CD4+ expressing cells were increased in tumors after IL-2 and rhTPO treatment and the application of rhTPO significantly restored the blood platelet count. The expression of p-AMPK, p-AKT, p-ERK, p-pI3K and RAS1 in tumor cells were all significantly diminished after the addition of rhTPO and IL-2 to the GC regimen. CONCLUSIONS: The supplementation of rhTPO and IL-2 to a GC regime effectively reduced tumor sizes and restored the platelet count in a human lung cancer mouse model.

Pathologic complete response after gemcitabine and S-1 chemotherapy for far advanced intrahepatic cholangiocarcinoma.

We report the case of a 72-year-old man who was initially diagnosed with far advanced intrahepatic cholangiocarcinoma, associated with bulky lymph node metastasis involving the common hepatic artery and moderate amount of ascites around the liver. After 10 cycles of systemic chemotherapy combining gemcitabine and S-1 with well-tolerated toxicities, a CT scan showed a marked shrinkage of the liver mass and lymph nodes (clinical partial response) with disappearance of ascites, which could permit a radical resection of the tumor. He underwent left lobectomy of the liver with lymph node dissection, and histopathological examination revealed pathologic complete response. Seven years after surgery, he is in a good overall condition.

Discovery of a novel chimeric ubenimex-gemcitabine with potent oral antitumor activity.

Herein, a novel mutual prodrug BC-A1 was discovered by integrating ubenimex and gemcitabine into one molecule. Biological characterization revealed that compound BC-A1 could maintain both the anti-CD13 activity of ubenimex and the cytotoxic activity of gemcitabine in vitro. Further characterization also demonstrated that compound BC-A1 exhibited significant anti-invasion and anti-angiogenesis effects in vitro. The preliminary stability test of BC-A1 revealed that it could release gemcitabine in vitro. The in vivo anti-tumor results in liver cancer showed that at the same dosage, oral administration of BC-A1 was as potent as intraperitoneal administration of gemcitabine. This warranted the further research and development of the orally active prodrug BC-A1 because gemcitabine can not be orally administrated in clinic.

Dose modification and efficacy of nab-paclitaxel plus gemcitabine vs. gemcitabine for patients with metastatic pancreatic cancer: phase III MPACT trial.

BACKGROUND: Dose modifications following adverse events (AEs) are an important part of the management of patients with pancreatic cancer treated with chemotherapy. While dose modifications are utilized to ensure patient safety, the subsequent influence of dose adjustments on treatment exposure and efficacy have not been reported in detail. This exploratory analysis examined the influence of dose modifications on treatment exposure and efficacy in the phase III MPACT trial, which demonstrated superior efficacy of nab-paclitaxel (nab-P) plus gemcitabine (Gem) to Gem alone for the treatment of metastatic pancreatic cancer. METHODS: Patients received either nab-P 125 mg/m(2) + Gem 1,000 mg/m(2) on days 1, 8, and 15 every 4 weeks or Gem 1,000 mg/m(2) weekly for the first 7 of 8 weeks (cycle 1) and then days 1, 8, and 15 every 4 weeks (cycle ≥2). The protocol allowed up to 2 dose reductions per agent. Dose delays were also used to manage toxicities. RESULTS: Toxicities that most commonly led to dose modifications were neutropenia, peripheral neuropathy, thrombocytopenia, and fatigue for nab-P and neutropenia, thrombocytopenia, and fatigue for Gem alone. Baseline characteristics were similar in patients with dose modifications and the intent-to-treat (ITT) population. Among the 421 treated patients in the nab-P + Gem arm, all patients initiated treatment at the per-protocol nab-P starting dose of 125 mg/m(2); 172 (41%) had a nab-P dose reduction, and 300 (71%) had a nab-P dose delay during the study. Most dose modifications occurred after the first 3 months (2 cycles) of treatment. The majority of patients (104/172, 60%) required only 1 nab-P dose reduction, and over half of patients (163/300) had either 1 or 2 dose delays. Patients who underwent dose modifications of nab-P had greater treatment exposure than those who did not in terms of treatment duration, number of cycles administered, and cumulative dose of nab-P delivered. Overall survival (OS) was shorter in the nab-P + Gem arm for patients who did not vs. did undergo dose reduction [median, 6.9 vs. 11.4 months; hazard ratio (HR), 1.93; 95% CI, 1.53-2.44; P<0.0001] and for those who did not vs. did undergo a dose delay (median, 6.2 vs. 10.1, HR, 2.05; 95% CI, 1.60-2.63; P<0.0001). Progression-free survival (PFS) and overall response rate (ORR) were also improved in patients with dose modifications. Similar trends were observed in the Gem-alone arm. Multivariate analyses confirmed that both dose delay and dose reduction were significantly associated with OS. CONCLUSIONS: This analysis suggests that although most doses of nab-P were given at the starting dose of 125 mg/m(2) the first 3 of 4 weeks, dose reductions and delays were effective when necessary to ameliorate toxicity allowing greater treatment exposure without compromising efficacy.

microRNA-218 promotes gemcitabine sensitivity in human pancreatic cancer cells by regulating HMGB1 expression.

OBJECTIVE: The purpose of this study was to examine the effect of gemcitabine (GEM) on microRNA-218 (miR-218) expression in human pancreatic cancer cells. METHODS: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to examine the differences in miR-218 expression between the GEM-sensitive BxPC-3 pancreatic cancer cells and GEM-resistant PANC-1 cells. The effect of GEM on the expression of miR-218 in PANC-1 cells was also investigated. PANC-1 cells were transfected either with HMGB1 siRNA to knock down the expression of HMGB1 or with the recombinant HMGB1 expression vector (pcDNA3.1-HMGB1) to overexpress HMGB1. The effect of ectopic expression of HMGB1 on the apoptosis of miR-218-transfected and GEM-treated PANC-1 cells was examined by flow cytometric analysis. RESULTS: The miR-218 expression level was lower in GEM-resistant PANC-1 cells compared to GEM-sensitive BxPC-3 cells (P<0.05). The percentage of apoptotic PANC-1 cells was significantly increased in the miR-218 mimic + GEM group compared to the mimic ctrl + GEM group and the normal control group (P<0.01). The HMGB1 expression level was markedly decreased in PANC-1 cells transfected with HMGB1 siRNA but was significantly increased in PANC-1 cells transfected with the recombinant HMGB1 expression vector, pcDNA3.1-HMGB1 (P<0.01). The proportion of apoptotic PANC-1 cells was significantly lower in the miR-218 mimic + GEM + pcDNA3.1-HMGB1 group compared to the miR-218 mimic + GEM + HMGB1 siRNA group (P<0.01). CONCLUSIONS: The expression level of miR-218 was downregulated in the GEM-resistant cell line. miR-218 promoted the sensitivity of PANC-1 cells to GEM, which was achieved mainly through regulating the expression of HMGB1 in PANC-1 cells.

Gemcitabine-based adjuvant chemotherapy for patients with advanced gallbladder cancer.

AIM: We investigated effects of gemcitabine-based adjuvant chemotherapy (GEM) on prognosis of patients with gallbladder cancer. PATIENTS AND METHODS: We retrospectively analyzed outcomes of 36 patients who underwent radical resection for gallbladder cancer from 2001 through to 2012, using χ(2) for prognostic factors and Kaplan-Meier estimator and log-rank tests for survival data. RESULTS: The GEM group had higher rates of lymph node positivity and distant metastasis, higher UICC stage and fewer R0 resections; their 5-year survival rate (60%) did not significantly differ from that of the controls (70.0%), nor was GEM a significant prognostic factor in univariate analysis. However, among patients who underwent R1 and R2 resections, GEM significantly improved prognosis in both univariate and multivariate analyses. Median survival of the R1/2 GEM group (66.4 months) was significantly better than that of controls (5.4 months) (p=0.002). CONCLUSION: GEM improved prognosis of patients with gallbladder cancer after R1/R2 resections.

Gemcitabine plus Nab-Paclitaxel with chemoradiation in locally advanced pancreatic cancer (LAPC).

Gemcitabine (GEM) is a cytotoxic agent that is potent against pancreatic adenocarcinoma. Nab-paclitaxel (nab-P), an albumin-bound formulation of paclitaxel, appears to decrease levels of cytidine deaminase, which is the primary gemcitabine catabolic enzyme, this likely increases sensitivity to GEM when these agents are combined. Here we present a case of a 52 year old female with locally advanced pancreatic cancer with elevated CA19-9 at diagnosis who received GEM + nab-P followed by GEM based chemoradiation who underwent surgical resection despite persistent stable disease on radiographic studies and was found to have complete pathologic response.

Effects of anticancer agents on cell viability, proliferative activity and cytokine production of peripheral blood mononuclear cells.

We investigated the effects of anticancer agents on peripheral blood mononuclear cells for the purpose of providing data to support new translational chemoimmunotherapy regimens. Peripheral-blood mononuclear cells were treated with one of four anticancer agents (5-fluorouracil, irinotecan, cisplatin, and gemcitabine) for 2 h, after which cell viability was determined. For assessment of effects of each drug on proliferation and cytokine production, cells were stimulated with phytohemagglutinin for 48 h. As a result, the anticancer agents did not affect cell viability. Cell proliferation was unaffected by 5-fluorouracil and irinotecan but inhibited by cisplatin and gemcitabine. Treatment with gemcitabine enhanced the production of IFN-γ and decreased the number of regulatory T cells. gemcitabine treatment increased IFN-γ production among CD4 T cells but not among CD8 T cells. The results indicated that GEM had immunoregulatory properties that might support immune response against cancer. This finding has implications for designing chemoimmunotherapy strategies.

Three cases of locally advanced pancreatic cancer successfully treated with chemoradiation and chemotherapy.

We report three cases with unresectable locally advanced pancreatic cancer (PC) treated with a combination of chemoradiotherapy (CRT) and systemic chemotherapy, using gemcitabine (GEM) and/or S-1. All three cases were diagnosed as having locally advanced unresectable PC without distant metastatic lesions based on computed tomography, endoscopic retrograde pancreatography and/or blushing cytology. In Cases 1 and 2, we applied a so-called sandwich therapy, which consisted of induction chemotherapy before CRT and maintenance chemotherapy after CRT. The induction and maintenance chemotherapy in Cases 1 and 2 used a combination of GEM and S-1, whereas maintenance therapy with GEM or S-1 was applied in Case 3. S-1-based CRT was performed in Cases 1 and 2, and GEM-based CRT in Case 3. Survivals were 27 and 65 months, respectively, in two cases, and the disease remained stable in the other case 30 months after diagnosis. We show three cases with unresectable locally advanced PC who achieved long-term survival (27-65 months) after treatment with a combination of CRT and systemic chemotherapy, using GEM and/or S-1. Our findings indicate that sandwich therapy might be particularly effective for locally advanced PC.