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Objective To investigate the in vitro effect of lncRNA UCA1 on gemcitabine (GEM) resistance of bladder cancer cell line T24 and its related molecular mechanism. Methods The mRNA expression of UCA1 in T24 cells and in T24/GEM cells was detected by RT-qPCR. The T24/GEM cells were incubated with varying concentrations (0.1, 1, and 10 μmol/L) of GEM for 48 hrs. LC3 staining microscopy was employed to visualize autophagic puncta, while the expression of autophagy-related proteins was assessed by Western blot. UCA1-shRNA and UCA1-shRNA+ pcDNA-Bcl-2 were transferred into T24/GEM cells, the sensitivity of cells to GEM was evaluated by MTT method and flow cytometry; the expressions of p53 and Bcl-2 were detected by Western blot. Results The expression level of UCA1 in T24/GEM cells was significantly higher than that of parental T24 cells (P＜0.05). The concentration of GEM in the range of 0-10 μmol/L significantly induced dose-dependent autophagy in T24/GEM cells (P＜0.05). Knockdown of UCA1 enhanced the sensitivity of T24/GEM cells to GEM (P＜0.05), while reducing autophagy (P＜0.05) and down-regulating the expression of p53 and Bcl-2(P＜0.05). Over-expression of Bcl-2 partially reversed the GEM sensitization and autophagy inhibition of UCA1-shRNA in T24/GEM cells (P＜0.05). Conclusions Knockdown of lncRNA UCA1 reduces GEM resistance of T24/GEM cells by inhibiting Bcl-2 mediated autophagy.

Abstract Background With poor prognosis and high mortality, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Standard of care therapies for PDAC have included gemcitabine for the past three decades, although resistance often develops within weeks of chemotherapy initiation through an array of possible mechanisms. Methods We reanalyzed publicly available RNA-seq gene expression profiles of 28 PDAC patient-derived xenograft (PDX) models before and after a 21-day gemcitabine treatment using our validated analysis pipeline to identify molecular markers of intrinsic and acquired resistance. Results Using normalized RNA-seq quantification measurements, we first identified oxidative phosphorylation and interferon alpha pathways as the two most enriched cancer hallmark gene sets in the baseline gene expression profile associated with intrinsic gemcitabine resistance and sensitivity, respectively. Furthermore, we discovered strong correlations between drug-induced expression changes in glycolysis and oxidative phosphorylation genes and response to gemcitabine, which suggests that these pathways may be associated with acquired gemcitabine resistance mechanisms. Thus, we developed prediction models using baseline gene expression profiles in those pathways and validated them in another dataset of 12 PDAC models from Novartis. We also developed prediction models based on drug-induced expression changes in genes from the Molecular Signatures Database (MSigDB)’s curated 50 cancer hallmark gene sets. Finally, pathogenic TP53 mutations correlated with treatment resistance. Conclusion Our results demonstrate that concurrent upregulation of both glycolysis and oxidative phosphorylation pathways occurs in vivo in PDAC PDXs following gemcitabine treatment and that pathogenic TP53 status had association with gemcitabine resistance in these models. Our findings may elucidate the molecular basis for gemcitabine resistance and provide insights for effective drug combination in PDAC chemotherapy.

Abstract Cholangiocarcinoma (CCA) is often diagnosed late, leading to incomplete tumor removal, drug resistance and reduced chemotherapy efficacy. Curcumin has the potential for anti-cancer activity through various therapeutic properties and can improve the efficacy of chemotherapy. We aimed to investigate the synergistic effect of a combination of curcumin and gemcitabine against CCA, targeting the LAT2/glutamine pathway. This combination synergistically suppressed proliferation in gemcitabine-resistant CCA cells (KKU-213BGemR). It also resulted in a remarkable degree of CCA cell apoptosis and cell cycle arrest, characterized by a high proportion of cells in the S and G2/M phases. Knockdown of SLC7A8 decreased the expressions of glutaminase and glutamine synthetase, resulting in inhibited cell proliferation and sensitized CCA cells to gemcitabine treatment. Moreover, in vivo experiments showed that a combination curcumin and gemcitabine significantly reduced tumor size, tumor growth rate and LAT2 expression in a gemcitabine-resistant CCA xenograft mouse model. Suppression of tumor progression in an orthotopic CCA hamster model provided strong support for clinical application. In conclusion, curcumin synergistically enhances gemcitabine efficacy against gemcitabine-resistant CCA by induction of apoptosis, partly via inhibiting LAT2/glutamine pathway. This approach may be an alternative strategy for the treatment of gemcitabine-resistant in CCA patients.

Abstract Background Classical Hodgkin lymphoma (cHL) is a highly curable disease, while novel therapy is needed for refractory or relapsed (R/R) patients. This phase II trial aimed to evaluate the role of camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in R/R cHL patients. Methods Transplant-eligible patients with R/R cHL were enrolled and received two 14-day cycles of camrelizumab 200 mg intravenously (IV) and two 28-day cycles of camrelizumab 200 mg IV, gemcitabine 1000 mg/m2 IV, and oxaliplatin 100 mg/m2 IV on days 1 and 15. Patients with partial response (PR) or stable disease received an additional cycle of combination therapy. Those who achieved complete response (CR) or PR proceeded to autologous stem cell transplantation (ASCT). The primary endpoint was the CR rate at the end of protocol therapy before ASCT. Results Forty-two patients were enrolled. At the end of protocol therapy, the objective response rate and CR rate were 94.9% (37/39) and 69.2% (27/39) in the evaluable set, and 88.1% (37/42) and 64.3% (27/42) in the full analysis set, respectively. Twenty-nine patients (69.0%) proceeded to ASCT, and 4 of 5 patients with PR achieved CR after ASCT. After a median follow-up of 20.7 months, the 12-month progression-free survival rate was 96.6% and the 12-month overall survival rate was 100%. Grade 3 or higher treatment emergent adverse events occurred in 28.6% of patients (12/42), mainly hematological toxicity. Conclusions Camrelizumab combined with GEMOX constitutes an effective salvage therapy for R/R cHL, proving to be relatively well-tolerated and facilitating ASCT in most patients, thus promoting sustained remission. Trial registration ClinicalTrials.gov NCT04239170. Registered on January 1, 2020.

Background: Squamous-cell carcinoma (SCC) of the lung is a kind of non-small-cell lung carcinoma. Cytotoxic chemotherapy has been found to deliver benefits to patients in advanced disease settings. Objective: To compare response rate and side effects between first-line chemotherapies vinorelbine, gemcitabine, and taxanes in patients with metastatic SCC of the lung. Patients and Methods: This is a retrospective study including 45 patients with metastatic lung SCC. All patients had received platinum-based doublet chemotherapy for 4-6 cycles. Patients were allocated into three groups based on the additional treatment protocol, with fifteen patients per group. A reduction in tumor size was assessed from tumor measurements for patients who had at least two evaluable assessments with computed tomography. The side effects of each drug were evaluated. Results: The reduction in tumor size in the gemcitabine, taxan, and vinorelbine arms was -5.59±35.62 cm3, 1.3±39.98 cm3 and -10.55±14.62 cm3, respectively, with no significant differences. The response rates in the taxan, gemcitabine, and vinorelbine arms were 73.33%, 80%, and 86.67%, respectively, with no significant differences. The side effects, including nausea, alopecia, diarrhea, arthralgia, and peripheral neuropathy, were, in particular, more common in patients in the taxan arm than in other arms, with significant differences. Conclusion: The three therapeutic arms, vinorelbine, gemcitabine, and taxanes, had similar efficiency based on response rate, with a mild preponderance of vinorelbine.

Primary cardiac tumors are rare. The cardiac sarcomas are the most common malignant cardiac tumors. These tumors have a dismal prognosis with an overall median survival of 25 months. Clinical features include dyspnea, arrhythmias, pericardial effusions, heart failure, and sudden cardiac death. The diagnosis is often challenging. Therefore, the cardiac imaging workup plays a central role in addition to a high clinical suspicion in the setting of atypical presentations that do not respond to standard therapies. The echocardiography, computed tomography, and cardiac MRI are crucial in clinching the diagnosis. Multimodal treatment with surgery, chemotherapy, and radiotherapy has been shown to improve outcomes, as opposed to using either of these modalities alone. We describe the case of a 30-year-old gentleman with COVID-19 infection who developed recurrent hemorrhagic pericardial effusions refractory to standard treatment and was eventually diagnosed as a case of pericardial angiosarcoma after his biopsy revealed the diagnosis and staging was performed using PET–CT–FDG scan. Our case re-emphasizes the importance of considering a malignant etiology early in the course of the disease presentation, especially in recurrent hemorrhagic effusions despite an inflammatory cytologic diagnosis of fluid. It also highlights the place for cardiac CT and MRI to ascertain the location and spread and to plan the further course of treatment. If diagnosed early, the estimated survival time can be prolonged by instituting a multimodal approach.

Present bladder cancer therapies have relatively limited therapeutic impact and account for one of the highest lifetime treatment costs per patient. Therefore, there is an urgent need to explore novel and optimized treatment strategies. The present study investigated the effects of inhibiting endogenous hydrogen sulfide (H2S) production on bladder cell viability and in vivo tumor progression. We targeted the H2S-producing enzyme, cystathionine γ-lyase, in 5637 cells using propargylglycine (H2S inhibitor) and performed cytofluorimetric analysis to evaluate cell viability. We then tested the efficacy of propargylglycine alone or in combination with gemcitabine (conventional chemotherapy) in an intravesical murine model of bladder cancer. Magnetic resonance imaging and immunohistochemical staining for cell proliferation, apoptosis, immune-cell infiltration, and neovascularization were performed to evaluate tumor response. Compared to control conditions or cohorts, propargylglycine administration significantly attenuated bladder cancer cell viability in vitro (p < 0.0001) and tumor growth (p < 0.002) and invasion in vivo. Furthermore, propargylglycine enhanced the anti-cancer effects of gemcitabine, resulting in tumor regression (p < 0.0001). Moreover, propargylglycine induced cleaved PARP-1-activated apoptosis (p < 0.05), as well as intratumoral CD8+ T cell (p < 0.05) and F4/80+ macrophage (p < 0.002) infiltration. Propargylglycine also reduced intratumoral neovascularization (p < 0.0001) and cell proliferation (p < 0.0002). Importantly, the pro-apoptotic and anti-neovascularization effects of gemcitabine were enhanced by propargylglycine co-administration. Our findings suggest that inhibition of endogenous H2S production can be protective against bladder cancer by enhancing the chemotherapeutic action of gemcitabine and may be a novel pharmacological target and approach for improved bladder cancer diagnosis and treatments in the future.

Objective To investigate the efficacy and safety of traditional AG regimen [gemcitabine （1 000 mg/m, d1, d8） + albumin-bound paclitaxel（125 mg/m, d1, d8）, 21 days as a cycle] and other gemcitabine-based regimen [gemcitabine alone or combined with S-1（tegafur, gimeracil and oteracil potassium）/oxaliplatin/arotinib] in the treatment of advanced and metastatic pancreatic cancer. Methods From January 2017 to January 2022, 64 patients with advanced and metastatic pancreatic cancer were retrospectively collected from Sir Run Run Hospital of Nanjing Medical University. There were 33 patients received traditional AG therapy and 31 patients received chemotherapy mainly with gemcitabine. Survival analysis was conducted based on follow-up data, with the study endpoints being overall survival (OS） and progression free survival （PFS）, and the secondary study endpoint being the incidence of grade 3/4 adverse reactions. Results The median OS of the AG regimen group and the gemcitabine group were 12.2 months and 7.9 months, respectively, and there was no significant difference between two groups （χ=1.517, P=0.218）. The median PFS of the AG regimen group and the gemcitabine group was 7.0 months and 3.3 months, respectively（χ=8.683, P=0.003）. There was no significant difference in the incidence of grade 3/4 adverse events between the two groups of patients（P＞0.05）. Conclusion The first-line treatment of albumin-bound paclitaxel combined with gemcitabine in patients with advanced pancreatic cancer has significant clinical effects, which significantly controls the disease progress and extends the PFS of patients.

Simple Summary: Pancreatic cancer is associated with poor survival, despite advances in anti-cancer treatment. Most patients are diagnosed at an advanced stage, so the treatment goal is prolongation of survival and maintenance of quality of life instead of cure. In this context, integrative therapeutic approaches have become increasingly important in recent years. Integrative therapies are usually not used alone but complementary to conventional treatment to optimize its effect. Positive effects have been described for symptom alleviation, e.g., pain and quality of life improvement by the additional use of integrative therapies. However, the available data are not sufficient for a conclusive assessment regarding a possible influence on survival. The present work sought to describe the outcome of patients with advanced or metastatic pancreatic cancer not amenable to curative treatment, who received either conventional therapy or additional complementary integrative mistletoe and/or hyperthermia. This retrospective analysis investigated the influence of integrative therapies in addition to palliative chemotherapy in patients with advanced pancreatic cancer, treated at a single institution specialized in integrative oncology between January 2015 and December 2019. In total, 206 consecutive patients were included in the study, whereof 142 patients (68.9%) received palliative chemotherapy (gemcitabine/nab-paclitaxel 33.8%; FOLFIRINOX 35.9%; gemcitabine 30.3%) while the remainder were treated with best supportive and integrative care. Integrative therapies were used in 117 of 142 patients (82.4%) in addition to conventional chemotherapy, whereby mistletoe was used in 117 patients (82.4%) and hyperthermia in 74 patients (52.1%). A total of 107/142 patients (86.3%) died during the observation period, whereby survival times differed significantly depending on the additional use of integrative mistletoe or hyperthermia: chemotherapy alone 8.6 months (95% CI 4.7–15.4), chemotherapy and only mistletoe therapy 11.2 months (95% CI 7.1–14.2), or a combination of chemotherapy with mistletoe and hyperthermia 18.9 months (95% CI 15.2–24.5). While the survival times observed for patients with advanced pancreatic cancer receiving chemotherapy alone are consistent with pivotal phase-III studies and German registry data, we found significantly improved survival using additional mistletoe and/or hyperthermia. [ABSTRACT FROM AUTHOR]

Background: Cancer stem cells (CSCs) are different from regular cancer cells because of their self-renewal feature and differentiation potential, which establishes the backbone of the vital role of CSCs in the progress and drug resistance of hepatocellular carcinoma (HCC). The objective of this study was to evaluate the effects of blood exosome-derived miRNA-30d-5p on the stemness and gemcitabine resistance of HCC cells and the underlying mechanisms. Methods: The expression data of HCC-related miRNAs and mRNAs were downloaded from TCGA database and analyzed for differences. Employing the databases of starBase, TargetScan, miRDB, and mirDIP, we conducted target gene prediction upstream of mRNA. The expression of miRNA-30d-5p and SOCS3 mRNA was assayed by qRT-PCR, and the binding between them was validated by dual luciferase assay. CCK-8 was employed to evaluate cell viability and the IC50 value of gemcitabine. Cells were subjected to a sphere-forming assay to assess their ability to form spheres. Western blot was applied to evaluate the levels of cell surface marker proteins (Nanog, CD133, and Oct4) and exosome markers (CD9, CD81, and FLOT1). Results: Bioinformatics analysis found that SOCS3 expression was down-regulated in HCC. qRT-PCR showed that SOCS3 expression was notably lower in HCC cell lines than in normal liver cell WRL68. At the cellular functional level, SOCS3 overexpression inhibited the viability, sphere-forming ability, stemness, and gemcitabine resistance of HCC cells. Bioinformatics analysis demonstrated that miRNA-30d-5p was the upstream regulator of SOCS3 and highly expressed in HCC tissues and cells. Dual luciferase assay demonstrated that miRNA-30d-5p could bind SOCS3. Rescue experiments showed that upregulating SOCS3 could reverse the effects of miRNA-30d-5p overexpression on the viability, sphere-forming ability, and gemcitabine sensitivity of HCC cells. Conclusions: Blood exosome-derived miRNA-30d-5p promoted the stemness and gemcitabine resistance of HCC cells by repressing SOCS3 expression. Hence, the miRNA-30d-5p/SOCS3 axis might be a therapeutic target for chemotherapy resistance and a feasible marker for the prognosis of HCC patients.

Objective(s): Gemcitabine is a first-line drug for the treatment of bladder cancer. One of the most important mechanisms of gemcitabine resistance is the low expression of cellular membrane transporter hENT1. Various derivatives containing fatty acid side chains have been developed in order to facilitate gemcitabine uptake and prolong its retention in cells, such as CP-4126. In this study, the anti-tumor effect and mechanism of a new derivative of gemcitabine named SZY-200 on bladder cancer cells were investigated. SZY-200 was assembled from the gemcitabine-lauric acid conjugate.Materials and Methods: Antiproliferative activities of SZY-200 and lauric acid were evaluated using CCK-8 assay and clonogenic survival assay. The hENT1 inhibitor NBMPR was employed to determine the role of hENT1 in the apoptotic activity of GEM, CP-4126, and SZY-200. RT-qPCR, flow cytometry, fluorescence microscope, western blotting, and wound healing assay were used to study the mechanisms of SZY-200. The target genes were predicted using the BATMAN-TCM database.Results: Our data showed that SZY-200 could inhibit the proliferation of bladder cancer cells by inducing cell cycle arrest and apoptosis. The inhibitory effects were comparable to gemcitabine and CP-4126. SZY-200 does not rely on hENT1 to help it enter bladder cancer cells. Also, we found that lauric acid could inhibit the proliferation of bladder cancer cells. SZY-200 could down-regulate the expressions of PPARG and PTGS2 which were related to the occurrence and development of bladder cancer.Conclusion: SZY-200 has the same or more advantages as CP-4126 and could be an ideal candidate drug for further in vivo investigation.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly malignant hematological tumor derived from the precursor cells of plasmacytoid dendritic cells. BPDCN that primarily originates in the nasal cavity is clinically rare and easily misdiagnosed or missed. At present, there is no standard treatment for BPDCN in China and abroad. This article reported a female patient with BPDCN primarily in the nasal cavity. The regimen of Azacitidine combined with GemOx had a good clinical effect on this patient and significantly controlled the condition and improved the clinical symptoms. This article analyzed and discussed the clinical diagnosis and treatment of this patient, aiming to improve clinicians' understanding of rare BPDCN.

Extracellular vesicles (EVs) are nowadays a target of interest in cancer therapy as a successful drug delivering tool. Based on their many beneficial biocompatible properties are designed to transport nucleic acids, proteins, various nanomaterials or chemotherapeutics. Extracellular vesicles derived from mesenchymal stem/stromal cells (MSCs) possess their tumor-homing abilities. This inspired us to engineer the MSC's EVs to be packed with chemotherapeutic agents and deliver it as a Trojan horse directly into tumor cells. In our study, human dental pulp MSCs (DP-MSCs) were cultivated with gemcitabine (GCB), which led to its absorption by the cells and subsequent secretion of the drug out into conditioned media in EVs. Concentrated conditioned media containing small EVs (potentially exosomes) significantly inhibited the cell growth of pancreatic carcinoma cell lines in vitro. DP-MSCs were simultaneously engineered to express a suicide gene fused yeast cytosinedeaminase:uracilphosphoribosyltransferase (yCD::UPRT). The product of the suicide gene converts non-toxic prodrug 5-fluorocytosine (5-FC) to highly cytotoxic chemotherapeutic drug 5-fluorouracil (5-FU) in the recipient cancer cells. Conversion of 5-FC to 5-FU had an additional effect on cancer cell's growth inhibition. Our results showed a therapeutic potential for DP-MSC-EVs to be designed for successful delivering of chemotherapeutic drugs, together with prodrug suicide gene therapy system.

Drug metabolism by the microbiome can influence anticancer treatment success. We previously suggested that chemotherapies with antimicrobial activity can select for adaptations in bacterial drug metabolism that can inadvertently influence the host’s chemoresistance. We demonstrated that evolved resistance against fluoropyrimidine chemotherapy lowered its efficacy in worms feeding on drug-evolved bacteria (Rosener et al., 2020). Here, we examine a model system that captures local interactions that can occur in the tumor microenvironment. Gammaproteobacteria-colonizing pancreatic tumors can degrade the nucleoside-analog chemotherapy gemcitabine and, in doing so, can increase the tumor’s chemoresistance. Using a genetic screen in Escherichia coli, we mapped all loss-of-function mutations conferring gemcitabine resistance. Surprisingly, we infer that one third of top resistance mutations increase or decrease bacterial drug breakdown and therefore can either lower or raise the gemcitabine load in the local environment. Experiments in three E. coli strains revealed that evolved adaptation converged to inactivation of the nucleoside permease NupC, an adaptation that increased the drug burden on co-cultured cancer cells. The two studies provide complementary insights on the potential impact of microbiome adaptation to chemotherapy by showing that bacteria–drug interactions can have local and systemic influence on drug activity.

Abstract Bladder cancer treatment remains a challenge to every oncologist. We report the case of a 57‐year‐old man with BCG‐refractory bladder cancer who had a complete response to intravesical gemcitabine to highlight the role of gemcitabine as a bladder sparing treatment in BCG‐failure patients.

A sixty-six-years old male patient was evaluated in the dermatology outpatient clinic with extensive hyperpigmented macules and two tumoral lesions approximately three cm diameter around the umblicus. Antimycotic and corticosteroid treatment was administered. However, as the complaints increased, a diagnosis of mycosis fungoides was made as a result of a skin biopsy. Six cures of single- agent gemcitabine chemotherapy were administered by the hematology outpatient clinic and a complete response was obtained. A case of mycosis fungoides is presented to increase awareness of this rare disease. [Med-Science 2022; 11(1.000): 416-8]

Despite oncological advances over the past years, survival outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. For most PDAC patients, the disease is often asymptomatic at early phases and is therefore typically diagnosed at the advanced or metastatic stage. As a result, up to 85% of the cases are unresectable, and systemic chemotherapy is the predominant treatment modality for this patient population. While the current therapeutic strategies for the local disease include surgical resection and adjuvant chemotherapy, FOLFIRINOX and gemcitabine plus nab-paclitaxel regimens are the frontline standard of care in the unresectable locally advanced and metastatic settings. In Switzerland, nanoliposomal irinotecan (nal-IRI) is currently the only regimen approved in the second line following progression on gemcitabine plus nab-paclitaxel, based on the results from the phase III NAPOLI-1 trial. Recently, olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, and larotrectinib, a first-in-class tropomyosin receptor kinases (TRK) inhibitor, were added to the treatment armamentarium of patients with a molecularly-defined subset of metastatic adenocarcinoma of the pancreas. This article provides an overview of the current treatment landscape of pancreatic cancer in Switzerland. In addition, we report a case of a long-term survivor with advanced pancreatic adenocarcinoma who achieved a notably good response to nal-IRI plus 5-FU/LV after progression on gemcitabine plus nab-paclitaxel.

Background Pancreatic ductal adenocarcinoma (PDAC) has the worst five-year overall survival rate among all cancer types. Acquired chemoresistance is considered one of the main reasons for this dismal prognosis, and the mechanism of chemoresistance is unknown. Methods We previously identified a subpopulation of chemoresistant CD44high-expressing PDAC cells. Subsequently, we selected the candidate gene, gamma-aminobutyric acid receptor subunit Pi (GABRP), from three Gene Expression Omnibus datasets as the potential CD44 downstream target mediating the gemcitabine resistance. Loss and gain of function such as stable knockdown of CD44 by small hairpin (sh) RNA-mediated silencing technique and overexpression (O/E) of CD44s had been studied for comparing the gemcitabine resistance among CD44high-expressing cells, shCD44 cells, CD44low-expressing cells and O/E CD44s expressing cells. Functional assays including cell viability, colony formation, invasion, quantitative PCR and western blotting techniques were performed to validate the roles of CD44 and GABRP playing in mediating the gemcitabine resistance in pancreatic cancer cells. Results CD44s depletion significantly reduced gemcitabine resistance in shCD44 single clone cells compared to CD44high-expressing cells. Knockdown of CD44 cells formed less colonies, became less invasive and remarkably decreased the mRNA level of GABRP. While overexpression of CD44s had the opposite effect on gemcitabine resistance, colony formation and invasive property. Of note, long term gemcitabine resistant pancreatic cancer cells detected increased expression of CD44 and GABRP. Clinically, GABRP expression was significantly upregulated in the tissues of patients with pancreatic cancer compared to the normal samples, and the overall survival rate of patients with low GABRP expression was longer. CD44 and GABRP co-expression was positively correlated in 178 pancreatic cancer patients. Conclusion Our findings suggest that GABRP may serve as a CD44s downstream target to diminish gemcitabine resistance in pancreatic cancer, and both CD44s and GABRP molecules have the potential to become prognostic biomarkers for PDAC patients with gemcitabine resistance.

Background: A well-established first-line chemotherapy standard for metastatic nasopharyngeal carcinoma is yet lacking. Objectives: To compare the efficacy and safety of gemcitabine plus platinum versus docetaxel plus platinum regimen as first-line therapies for distal metastatic nasopharyngeal carcinoma. Study Design and Participants: A single center, randomized, open-label, parallel-arm study. The study included 120 patients with metastatic nasopharyngeal carcinoma who met the study requirements. Interventions: Participants were randomized in a 1:1 ratio through a sealed envelope selection. Gemcitabine 1000 mg/m2/d intravenously (IV) for >30 min (days 1 and 8) or docetaxel 75 mg/m2/d IV for 1 h (day 1) were administered to the respective group participants. Nedaplatin 75 mg/m2/d, IV (day 1), cisplatin 75 mg/m2/d IV (day 1) or carboplatin (area under the curve set as 5) IV (day 1) were used in both groups. One cycle duration was 21 days, with 4–6 cycles for all participants. Outcomes: The primary assessed outcomes were progression-free survival (PFS) and overall survival (OS), and the secondary outcomes were short-term efficacy [i.e., response rate (RR) and disease control rate (DCR)] and safety. Results: Seven patients withdrew from the study, and efficacy and adverse reactions were obtained for 113 patients (gemcitabine: 56; docetaxel: 57). Compared with the docetaxel plus platinum group, the gemcitabine plus platinum group had significantly higher RR (71.4% vs. 52.6%, P < 0.05); mPFS (9.7 vs. 7.8 months, P < 0.05), and mOS (20.6 vs. 16.8 months, P < 0.01). The significance was not associated with increased adverse reactions, as both groups showed similar Grades 3 and 4 adverse reactions (P > 0.05). DCR was non-significantly higher in the gemcitabine group (85.7% vs. 75.4%, P > 0.05). Multivariable analysis revealed that time to disease progression, number of involved organs, liver metastasis, and grouping were associated with mPFS and mOS (all P < 0.05). Conclusion: The combination of gemcitabine with platinum is likely superior to that of docetaxel with platinum as first-line treatment for metastatic nasopharyngeal carcinoma.

Introduction. The randomized MPACT study showed that nab-paclitaxel plus gemcitabine results in statistically significantly longer life expectancy. The objective of this retrospective study is to obtain relevant data on the efficacy of this combination in real clinical practice in Russia. Materials and methods. The study included patients with morphologically proven locally advanced or metastatic pancreatic cancer, with a general condition assessed on the ECOG scale between 0-2, which received gemcitabine and nab-paclitaxel. Immediate and long-term treatment outcomes were evaluated. Results. 142 patients, who received treatment from 2009 to 2019 in 17 centers from 11 regions of Russia, were included in the study. Assessment of the objective effect was made in 134 patients. Objective effects were detected in 34 (25.4%) cases. The median time-to-progression was 6.1 months (95% confidence interval (CI) 4.8-7.4), the median length of life was 14.2 months (95% CI 10.6-17.9). An elevated CA19-9 level is the only independent adverse prognostic factor for progression-free survival (RR = 8.0, 95% CI 1.4 -43.8, p = 0.02) according to Cox multivariate regression analysis. The number of previously conducted chemotherapy lines (p = 0.34), ECOG status (p = 0.70), age over 70 years (p = 0.45), serious comorbidity (p = 0.97) did not have a statistically significant effect on progression-free survival. Findings. The gemcitabine and nab-paclitaxel combination has a relatively higher efficacy in advanced pancreatic cancer. The immediate and long-term results of its use in real clinical practice in Russia are consistent with data obtained in the Western countries.

Abstract Gemcitabine induce thrombocytopenia and thrombocytosis as toxicity. In this report, we show detailed time‐course for platelet fluctuation. Our case emphasis attention to monitor see‐saw‐like toxicity on platelet count.

Dying (or dead) cells are increasingly recognized to impose significant biological influence within their tissues of residence—exerting paracrine effects through proteins and metabolites that are expressed or secreted during cellular demise. For example, certain molecules function as potent mitogens, promoting the repopulation of neighboring epithelial cells. And other myriad of factors—classified as damage-associated molecular patterns (DAMPs)—function as “find me” (attractant), “eat me” (engulfment), or “danger” (activation) signals for recruiting and activating effector immune cells (e.g., dendritic cells) to initiate inflammation. Since the discovery of immunogenic cell death (ICD), the current dogma posits DAMPs as immunological adjuvants for innate immune cell mobilization and activation, which ultimately leads to the antitumoral cross-priming of CD8+ T cells. However, what is currently unknown is how these immunostimulatory DAMPs are counteracted to avoid immune-overactivation. Our recent work builds on these fundamentals and introduces prostaglandin E2 (PGE2) as an ‘inhibitory’ DAMP—a new variable to the ICD equation. Prostaglandin E2 functions as an immunosuppressive counterpoise of adjuvant DAMPs; and thus, mechanistically precludes ICD. Furthermore, the long-debated immunogenicity of gemcitabine chemotherapy was revealed to be contingent on inhibitory DAMP blockade and not due to its inability to promote DAMP expression (i.e., calreticulin) as previously reported. These findings were intriguing. First, despite the presence of gemcitabine-induced hallmark DAMPs, the inhibitory DAMP (i.e., PGE2) was sufficient to hinder the ICD-induced antitumoral immune response (Fig. 1a). And second, rather than pharmacologically substantiating immunostimulatory DAMPs as conventionally approached, the mitigation of the inhibitory DAMP—tipping the immunostimulatory and inhibitory DAMP balance in favor of immunostimulatory DAMPs—was sufficient to render the cell death immunogenic and converted gemcitabine into an ICD-inducing therapy (Fig. 1b). In this microreview, we extrapolate our findings and implicate the value of inhibitory DAMP(s) in drug discovery, its use for clinical prognosis, and as target(s) for therapeutic intervention.

Gemcitabine (Gem)-based chemotherapy is one of the first-line treatments for pancreatic ductal adenocarcinoma (PDAC). However, its clinical effect is limited due to development of chemoresistance. Various naturally occurring compounds, including Berberine (BBR), provide an anti-cancer efficacy with time-tested safety, individually and in combination with chemotherapeutic drugs. Accordingly, we hypothesized that BBR might enhance the chemosensitivity to Gem in PDAC. In this study, cell culture studies using MIA PaCa-2 and BxPC-3 cells, followed by analysis in patient-derived organoids were performed to evaluate the anti-cancer effects of BBR in PDAC. Considering that cancer is a significant manifestation of increased chronic inflammatory stress, systems biology approaches are prudent for the identification of molecular pathways and networks responsible for phytochemical-induced anti-cancer activity, we used these approaches for BBR-mediated chemosensitization to Gem. Firstly, Gem-resistant (Gem-R) PDAC cells were established, and the combination of BBR and Gem revealed superior anti-cancer efficacy in Gem-R cells. Furthermore, the combination treatment induced cell cycle arrest and apoptosis in Gem-R PDAC cells. Transcriptomic profiling investigated the Rap1 and PI3K-Akt signaling pathway as a key regulator of Gem-resistance and was a key mediator for BBR-mediated chemosensitization in PDAC cells. All cell culture-based findings were successfully validated in patient-derived organoids. In conclusion, we demonstrate that BBR-mediated reversal of chemoresistance to Gem manifests through Rap1/PI3K-Akt signaling in PDAC.

In this work, new heterocyclic compounds 1,2,3-triazoline derivatives starting from gemcitabine were synthesized. At first, gemcitabine was converted to 2-azido gemcitabine (G) through the reaction of gemcitabine with sodium azide. 1,2,3-Triazolines were prepared from the reaction of 2-azido gemcitabine with some unsaturated compounds such as malic anhydride, cinamic acid and acryl amide by click reaction. The products were identified by Fourier-transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance (1H-NMR) technique. The α-glucosidase inhibitory activities of all the synthesized compounds were determined in vitro. All the tested compounds showed α-glucosidase inhibitory activity of IC50 = 144.8 ± 1.74, 212.9 ± 3.4 and 345 ± 4.5 μM against the α-glucosidase enzyme when compared to the standard drug acarbose IC50 = 824 ± 1.73 μM.

Background: Gemcitabine is a frequently used chemotherapeutic agent but its effects on the immune system are incompletely understood. Recently, the randomized NVALT19-trial revealed that maintenance gemcitabine after first-line chemotherapy significantly prolonged progression-free survival (PFS) compared to best supportive care (BSC) in malignant mesothelioma. Whether these effects are paralleled by changes in circulating immune cell subsets is currently unknown. These analyses could offer improved mechanistic insights into the effects of gemcitabine on the host and guide development of effective combination therapies in mesothelioma. Methods: We stained peripheral blood mononuclear cells (PBMCs) and myeloid-derived suppressor cells (MDSCs) at baseline and 3 weeks following start of gemcitabine or BSC treatment in a subgroup of mesothelioma patients included in the NVALT19-trial. In total, 24 paired samples including both MDSCs and PBMCs were included. We performed multicolour flow-cytometry to assess co-inhibitory and-stimulatory receptor- and cytokine expression and matched these parameters with PFS and OS. Findings: Gemcitabine treatment was significantly associated with an increased NK-cell- and decreased T-regulatory cell proliferation whereas the opposite occurred in control patients. Furthermore, myeloid-derived suppressor cells (MDSCs) frequencies were lower in gemcitabine-treated patients and this correlated with increased T-cell proliferation following treatment. Whereas gemcitabine variably altered co-inhibitory receptor expression, co-stimulatory molecules including ICOS, CD28 and HLA-DR were uniformly increased across CD4+ T-helper, CD8+ T- and NK-cells. Although preliminary in nature, the increase in NK-cell proliferation and PD-1 expression in T cells following gemcitabine treatment was associated with improved PFS and OS. Interpretation: Gemcitabine treatment was associated with widespread effects on circulating immune cells of mesothelioma patients with responding patients displaying increased NK-cell and PD-1 + T-cell proliferation. These exploratory data provide a platform for future on treatment-biomarker development and novel combination treatment strategies.

FOLFIRINOX is superior to gemcitabine in patients with pancreatic cancer, but this regimen is associated with toxicity and biomarkers for response are warranted. MicroRNAs can mediate drug resistance and could provide predictive information. Altered expressions of several microRNAs including miR-21-5p, miR-10b-5p and miR-34a-5p have been previously linked to a worse response to gemcitabine. We investigated the influence of expression levels in tumor tissue of those three microRNAs on outcome to FOLFIRINOX. Twenty-nine patients with sufficient formalin-fixed paraffin-embedded tumor tissue were identified. There was no significant association between high and low expression groups for these three microRNA. We conclude that polychemotherapy combination can overcome intrinsic negative prognostic factors.

This study investigated the clinical efficacy, safety and tolerance of endostatin combined with gemcitabine and carboplatin for patients with advanced nonsmall cell lung cancer (NSCLC).

The development of fast and easy-to-use methods for gemcitabine detection is of great interest for pharmaceutical formulation control in both research laboratories and hospitals. In this study, we report a simple, fast and direct electrochemical method for gemcitabine detection using a boron-doped diamond electrode. The electrochemical oxidation of gemcitabine on a boron-doped diamond electrode was found to be irreversible in differential pulse voltammetry, and scan rate influence studies demonstrated that the process is diffusion-controlled. The influence of the pH and supporting electrolytes were also tested, and the optimized differential pulse voltammetry method was linear in the range of 2.5–50 μg/mL, with a detection limit of 0.85 μg/mL in phosphate-buffered saline (pH 7.4; 0.1 M). An amperometric method was also optimized for gemcitabine detection. The linear range of the method was 0.5–65 μg/mL in phosphate-buffered saline of pH 7.4 as well as pH 5.5, the limit of detection being 0.15 μg/mL. The optimized differential pulse voltammetry and amperometric detection strategies were successfully applied to pharmaceutical formulations, and the results were compared to those obtained by high-performance liquid chromatography and UV-Vis spectrophotometry with good correlations.

Pancreatic cancer is one the most malignant cancers in human. A great percentage of patients die annually due to lack of early detection as well as efficient treatment strategies. Only five-year survival rate is still only seen in 5% of patients. Major problem of this deadly disease is the intrinsic and acquired resistance to current chemotherapeutic agents such as gemcitabine. So far, different molecular mechanisms are attributed to gemcitabine resistance. For instance, genetic mechanisms, aberrant gene expression in cellular signaling pathways, cancer stem cells, impaired apoptosis related genes, epigenetic changes and potential role of microRNAs have been identified in gemcitabine resistance of pancreatic cancer. Improving the drug efficacy and overcoming to drug resistance is the current goal in treatment of pancreatic cancer. Understanding the cellular and molecular mechanisms of resistance can help us to develop novel therapeutic approaches leading to increased effectiveness of current treatments. In this review, we summarized the molecular mechanisms involved in gemcitabine resistance in pancreatic cancer.

Abstract Background Intrahepatic cholangiocarcinoma is an aggressive tumor originating in the epithelium of the bile duct, often associated with distant dissemination. The prognosis is poor and treatment is challenging due to low response rate to standard chemotherapy and lack of targeted therapies. Case presentation Here we report the case of a 74-year-old white woman affected by intrahepatic cholangiocarcinoma with metastatic involvement of spleen, lung, peritoneum, and intra-abdominal lymph nodes. As first-line chemotherapy, she was given cisplatin-gemcitabine chemotherapy. The treatment was well tolerated with the exception of grade 1 constipation and a single episode of grade 4 thrombocytopenia occurring after the fourth course. After the first three courses of chemotherapy a computed tomography scan evaluation demonstrated no change; her CA19-9 levels were slightly decreased. However, after the sixth course of chemotherapy a computed tomography scan revealed a dimensional enlargement of the lung metastases; her CA19-9 levels increased. She was then treated with gemcitabine alone. After 2 months of gemcitabine monotherapy a significant regression of lung and spleen metastases, as well a CA19-9 level reduction, occurred. Eight months after the start of gemcitabine monotherapy no signs of progression were reported. Conclusions Treatment of metastatic intrahepatic cholangiocarcinoma with gemcitabine as maintenance therapy after first-line chemotherapy could be continued until clear evidence of disease progression since delayed responses are possible.

Abstract Background The incidence of gemcitabine-induced hemolytic uremic syndrome has already been described in adults. Several approaches have been employed in the treatment of gemcitabine-induced hemolytic uremic syndrome with different outcomes. One of the most promising agents is eculizumab, which is a monoclonal antibody directed against C5 complement protein. Case presentation We reported the case of a 3-year-old white boy with medulloblastoma who underwent high-dose chemotherapy and craniospinal irradiation. Afterwards he started maintenance chemotherapy with gemcitabine and oxaliplatin. After five courses he presented a progressive clinical worsening, which resulted in a systemic thrombotic microangiopathy. Initially he was treated with rituximab without clinical improvement. Therefore he started therapy with repeated cycles of eculizumab. After seven infusions he showed a gradual improvement and finally a complete remission of gemcitabine-induced hemolytic uremic syndrome. Conclusions Eculizumab prevents serious complement-mediated vascular damage for chemotherapy-induced thrombotic microangiopathy in pediatric cases.

Objective: The objective of this study was to determine incidence and severity of vascular pain following modified dilulent for gemcitabine solution. Gemcitabine (1,000-1,250 mg/m2) was diluted in 250 ml of normal saline for cancer patients. Methods: The observational study design was conducted in cancer care unit at our University based hospital. Cancer patients who were treated with gemcitabine based regimen during June to November 2015 were enrolled in the study. Gemcitabine was diluted in 250 ml of normal saline and infused over 30 minutes peripherally. Vascular pain incidence and severity were assessed during and at the end of drug administration by using standard pain assessment tools including pain numeric rating scale, or visual analogue scale (VAS). Incidences of vascular pain were collected and analyzed by descriptive statistics. Results: One hundred cancer patients receiving pre-specified gemcitabine based regimen were enrolled in the study. The vascular pain incidence was reported in 36 of patients (36%). Among patients with vascular pain, 28 patients (78%) and 8 patients (22%) reported mild and moderate pain severity, respectively. Severe pain was not found in this study. Mean vascular pain score was 1.3±0.56. Conclusion: This study demonstrated that using 250 ml of normal saline as diluent for gemcitabine chemotherapy, the vascular pain incidence was 36% and the pain score appeared to be minimal. Mean±SD of pain score was 1.3±0.56 and there was no incidence of severe pain.

Abstract Background The incidence of invasive cancer within a mucinous cystic neoplasm of the pancreas varies between 6 and 36%. Polycystic ovarian syndrome is a disorder characterized by hyperandrogenism and anovulatory infertility. One surgical treatment that can restore endocrine balance and ovulation in polycystic ovarian syndrome is partial ovarian destruction. Successful pregnancies following preconception pancreaticoduodenectomies (Whipple procedures) and chemoradiation to treat pancreatic neoplasms have been reported rarely but none were diagnosed with pre-cancer polycystic ovarian syndrome-associated infertility. Gemcitabine is an antimetabolite drug used for the treatment of pancreatic cancer that can have profound detrimental effects on oogenesis and ovarian function. Whether the ovarian destructive property of gemcitabine could act as a method to restore ovulation potential in polycystic ovarian syndrome is unknown. Case presentation A 40-year-old white American woman with a history of pancreatic cancer treatment with a Whipple procedure and chemoradiation with gemcitabine had a successful pregnancy after years of pre-cancerous anovulatory infertility and polycystic ovarian syndrome. She received no fertility agents and delivered full term via a spontaneous vaginal delivery with no pregnancy complications. Conclusion Gemcitabine treatment for pancreatic cancer may result in resumption of ovulation in women with polycystic ovarian syndrome and these women should be counseled accordingly.

We explored whether the combination of lurbinectedin (PM01183) with the antimetabolite gemcitabine could result in a synergistic antitumor effect in pancreatic ductal adenocarcinoma (PDA) mouse models. We also studied the contribution of lurbinectedin to this synergism. This drug presents a dual pharmacological effect that contributes to its in vivo antitumor activity: (i) specific binding to DNA minor grooves, inhibiting active transcription and DNA repair; and (ii) specific depletion of tumor-associated macrophages (TAMs). We evaluated the in vivo antitumor activity of lurbinectedin and gemcitabine as single agents and in combination in SW-1990 and MIA PaCa-2 cell-line xenografts and in patient-derived PDA models (AVATAR). Lurbinectedin-gemcitabine combination induced a synergistic effect on both MIA PaCa-2 [combination index (CI)=0.66] and SW-1990 (CI=0.80) tumor xenografts. It also induced complete tumor remissions in four out of six patient-derived PDA xenografts. This synergism was associated with enhanced DNA damage (anti-γ-H2AX), cell cycle blockage, caspase-3 activation and apoptosis. In addition to the enhanced DNA damage, which is a consequence of the interaction of the two drugs with the DNA, lurbinectedin induced TAM depletion leading to cytidine deaminase (CDA) downregulation in PDA tumors. This effect could, in turn, induce an increase of gemcitabine-mediated DNA damage that was especially relevant in high-density TAM tumors. These results show that lurbinectedin can be used to develop ‘molecularly targeted’ combination strategies.

The natural alkaloid protopine (PRO) exhibits pharmacological properties including anticancer activity. We investigated the effects of PRO, alone and in combination with the chemotherapeutic gemcitabine (GEM), on human tumor cell lines and non-tumor human dermal fibroblasts (HDFs). We found that treatments with different PRO/GEM combinations were cytotoxic or cytoprotective, depending on concentration and cell type. PRO/GEM decreased viability in pancreatic cancer MIA PaCa-2 and PANC-1 cells, while it rescued the GEM-induced viability decline in HDFs and in tumor MCF-7 cells. Moreover, PRO/GEM decreased G1, S and G2/M phases, concomitantly with an increase of subG1 phase in MIA PaCa-2 and PANC-1 cells. Differently, PRO/GEM restored the normal progression of the cell cycle, altered by GEM, and decreased cell death in HDFs. PRO alone increased mitochondrial reactive oxygen species (ROS) in MIA PaCa-2, PANC-1 cells and HDFs, while PRO/GEM increased both intracellular and mitochondrial ROS in the three cell lines. These results indicate that specific combinations of PRO/GEM may be used to induce cytotoxic effects in pancreatic tumor MIA PaCa-2 and PANC-1 cells, but have cytoprotective or no effects in HDFs.

Operable pancreatic cancer is characterized by a high risk of recurrence. Efforts are made to incorporate new therapies. Throughout the world there is a lack of uniform recommendations concerning the adjuvant treatment of pancreatic cancer patients, due to confusing evidence-based data. The patients recruited to clinical trials differ from the population of patients treated in everyday practice. These differences have an influence on tolerance of treatment, toxicity and results of therapy. The decision on administration of adjuvant treatment is made individually and differs from center to center. A review of the literature concerning both results and tolerance of postoperative chemoradiotherapy of pancreatic cancer patients is presented.

K-ras is currently accepted as the most frequently mutated oncogene in non-small cell lung cancer (NSCLC, including squamous carcinoma, adenocarcinoma, and large cell carcinoma). NSCLC patients with the K-ras mutation appear to be refractory to the majority of systemic therapies. In the present study, the in vitro antitumor effects and correlated molecular mechanisms of sorafenib combined with gemcitabine or pemetrexed were explored in the K-ras mutation-positive NSCLC A549 cell line. Sorafenib was seen to exhibit dose-dependent growth inhibition in the A549 cells, while sorafenib combined with pemetrexed demonstrated a greater synergism compared with sorafenib combined with gemcitabine. Sorafenib arrested the cell cycle at the G1 phase, while gemcitabine and pemetrexed caused arrest at the S phase. The molecular mechanism of this synergism was due to the downstream signalling pathways, which were efficiently suppressed by sorafenib, therefore increasing the incidence of the entry of the chemotherapeutic drugs into the apoptotic pathways. Moreover, sorafenib and pemetrexed demonstrated stronger synergism, demonstrating that inhibiting the Ras/Raf/Mek/Erk and Ras/PI3K/Akt pathways concurrently may achieve improved antitumor effects.

Bladder cancer (BC) is an important clinical and scientific challenge. In 2013, in Russia, the absolute number of patients with first-ever diagnosis of bladder cancer was 12 992 people. There is an increasing proportion of detection of bladder cancer stage I–II disease patterns: 2003–50.8% in 2013–69.6%, while the number of newly diagnosed patients in III and IV clinical stages remains at 30%. The proportion of individuals who completed the treatment of the number of newly diagnosed patients with bladder cancer in 2013, was as follows: only surgical method — 65.4%, 33.5% combined. Purpose. Improvement of the results of treatment of patients with locally advanced bladder cancer. Materials and methods. The main treatment for muscle-invasive bladder cancer is radical cystectomy. In the combined treatment of bladder cancer chemotherapy is the component that systemic exposure to the tumor, the way of regional and distant metastases. The study included 132 patients with locally advanced bladder cancer who were treated for 2005–2013, divided into four groups: NACT + CE — 27 people (20.5%), CE + ACT — 21 (15.9%), NACT + CE + ACT — 21 (15.9%) only CE — 63 (47.7%). An important component of treatment has been the use of platinum (cisplatin or carboplatin) in Schemes M–VAC and GP. An objective response is possible in 44.7%, and the stabilization process in 40.4% of patients.Results. The clinical effect is evaluated in all patients. In the group of NACT 21% of patients survived for more than 4 years, but did not survive the 5‑year mark. In the group of CE + ACT the indicator achieved only 3‑year survival rate, which amounted to 43%. In the group of CE — none of the patients did not live up to 3 years, with 2‑year survival rate was 30%. In the group of ACT + NCT + CE 3 patients (15%) were alive at the time, passed the threshold of the 5‑year survival rate, there is no progression of cancer.Conclusion. Combined treatment mode NACT + CE + ACT can achieve significantly longer time to tumor progression and better overall survival; the reverse side is to increase the frequency of postoperative complications.