Melatonin Enhances the Chemosensitivity to Gemcitabine in Pancreatic Cancer(PANC-1)Via the Ferroptosis and Autophagy Pathways / 医药导报

Objective To explore the effect and potential mechanisms of melatonin combined with gemcitabine on the chemosensitivity of human pancreatic cancer cell line PANC-1.Methods Human pancreatic cancer cell line PANC-1 was trea-ted with gemcitabine alone or in combination with melatonin.Cell viability was assessed using CCK-8.Effect of melatonin and gem-citabine alone or in combination on the clonogenic capacity of PANC-1 cells were observed through colony formation experiments.Scratch assays and transwell experiments were conducted to evaluate cell migration ability.Reactive oxygen species(ROS)and mitochondrial membrane point JC-1 assay kit were used to determine reactive oxygen species synthesis and membrane potential levels.Intracellular Fe2+level was measured using ferrous ion fluorescent probe.The protein expression levels of LC3,P62,GPX4 and SLC7A11 in different treatment groups were detected by immunofluorescence and Western blotting.Results CCK-8 results showed that the viability of PANC-1 cells was inhibited by gemcitabine alone after 48 h and 72 h of treatment in a time-and dose-dependent manner.The cell viability of gemcitabine combined with melatonin group was significantly lower than that of gemcitabine group,and the cell viability decreased with the increase of melatonin concentration.Scratch assays,transwell experiments,and plate colony formation assay results demonstrated that the proliferation and migration of cells in the gemcitabine combined with the me-latonin group were significantly inhibited compared with the gemcitabine group.The levels of reactive oxygen species and Fe2+in PANC-1 in gemcitabine combined with the melatonin group were higher than those in the gemcitabine group,and the mitochondri-al membrane potential was significantly decreased(P＜0.01).Western blotting and immunofluorescence results showed that the ra-tio of autophagy-related protein LC3-Ⅱ/LC3-Ⅰ in gemcitabine combined with the melatonin group was lower than that in the gem-citabine group,and the expression of P62 was up-regulated,and the expression of anti-iron death-related protein GPX4 and SLC7A11 was significantly inhibited(P＜0.05),suggesting that melatonin combined with gemcitabine can inhibit autophagy and promote ferroptosis in PANC-1 cells.Conclusion Melatonin enhances the chemosensitivity of pancreatic cancer cell PANC-1 to gemcitabine by inhibiting autophagy and promoting ferroptosis of tumor cells.

A bleeding heart: case report and review of pericardial angiosarcoma

Abstract 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.

Modified FOLFIRINOX compared to Gemcitabine & nab-Paclitaxel in advanced pancreatic ductal adenocarcinoma - results of a match-pair analysis

Background & objectives: FOLFIRINOX and gemcitabine plus nab-paclitaxel (GN) are the most commonly used regimens in advanced pancreatic ductal adenocarcinomas (PDACs). As there is limited data on comparison of these two regimens, the present study was aimed to compare survivals and tolerance for both regimens through a match-pair analysis. Methods: The data of 350 patients with metastatic and locally advanced PDAC, treated between January 2013 and December 2019, were retrieved. A 1:1 matching, using age and performance status, without replacement was performed by using nearest neighbour matching method. Results: A total of 260 patients (130 modified FOLFIRINOX and 130 GN) were matched. The median overall survival (OS) was 12.98 months [95% confidence interval (CI) 7.257-8.776 months] in modifications of FOLFIRINOX (mFOLFIRINOX) cohort and 12.06 months (95% CI 6.690-8.88 months) in GN group (P=0.080). The incidence of grade 3 and 4 infections, diarrhoea, oral mucositis, and fatigue was higher with mFOLFIRINOX. Patients who received second line therapy had improved OS as compared to those who did not (14.06 vs. 9.07 months, P<0.001). Interpretation & conclusions: GN and mFOLFIRINOX appear to have similar survival outcomes in an unselected match paired patient population with advanced PDAC. A markedly increased incidence of non-myelosuppressive grade 3 and grade 4 side-effects and lack of survival improvements suggest a need for nuanced use of the mFOLFIRINOX regimen. Administration of second-line chemotherapy improves OS in patients with advanced PDAC.

Effects of centralized volume-based procurement policy on the use of drugs for non-small cell lung cancer in a third-grade class-A cancer hospital / 中国药房

OBJECTIVE To analyze the effects of centralized volume-based procurement policy （hereinafter referred to as “centralized procurement”） on the use of anti-tumor drugs in medical institutions. METHODS The interrupted time series model was used to analyze the changes in the monthly purchase volume and purchase amount of docetaxel， gemcitabine and pemetrexed disodium in a third-grade class-A cancer hospital in Shanxi province from January 2018 to December 2021. RESULTS & CONCLUSIONS After the implementation of the centralized procurement policy， both the selected drugs and the non-selected drugs had different degrees of price reduction， and the price reduction of the selected drugs was far greater than that of the non- selected drugs； average monthly purchase volume and amount of docetaxel decreased significantly in that month after the implementation of the policy， while those of gemcitabine and pemetrexed disodium increased significantly （P＜0.05 or P＜0.01）. After the implementation of the policy， the average monthly purchase volume and amount of gemcitabine showed a downward trend， while those of docetaxel and pemetrexed disodium showed an upward trend （P＜0.05 or P＜0.01）. It is suggested that hospitals should strengthen pharmaceutical administration， and avoid adopting a “one size fits all” approach to non-selected drugs； relevant departments should further expand the collection range of anti-tumor drugs or carry out special collection of anti-tumor drugs， so as to save medical insurance funds and reduce medical expenses.

Synergistic Antitumor Effect of Everolimus Combined with Gemcitabine on Diffuse Large B-Cell Lymphoma / 中国实验血液学杂志

OBJECTIVE@#To investigate the effects of mTOR inhibitors everolimus (EVE) and gemcitabine (GEM) on the proliferation, apoptosis and cell cycle of diffuse large B-cell lymphoma (DLBCL) cell line U2932, and further explore the molecular mechanisms, so as to provide new ideas and experimental basis for the clinical treatment of DLBCL.@*METHODS@#The effect of EVE and GEM on the proliferation of U2932 cells was detected by CCK-8 assay, the IC50 of the two drugs was calculated, and the combination index (CI=) of the two drugs was calculated by CompuSyn software. The effect of EVE and GEM on apoptosis of U2932 cells was detected by flow cytometry with AnnexinV-FITC/PI staining. Flow cytometry with propidium iodide (PI) staining was used to detect the effect of EVE and GEM on the cell cycle of U2932 cells. Western blot assay was used to detect the effects of EVE and GEM on the channel proteins p-mTOR and p-4EBP1, the anti-apoptotic proteins MCL-1 and Survivin, and the cell cycle protein Cyclin D1.@*RESULTS@#Both EVE and GEM could significantly inhitbit the proliferation of U2932 cells in a time- and dose-dependent manner (r=0.465, 0.848; 0.555, 0.796). According to the calculation of CompuSyn software, EVE combined with GEM inhibited the proliferation of U2932 cells at 24, 48 and 72 h with CI=<1, which had a synergistic effect. After treated U2932 cells with 10 nmol/L EVE, 250 nmol/L GEM alone and in combination for 48 h, both EVE and GEM induced apoptosis, and the difference was statistically significant compared with the control group (P<0.05). The apoptosis rate was significantly enhanced after EVE in combination with GEM compared with single-agent (P<0.05). Both EVE and GEM alone and in combination significantly increased the proportion of cells in G1 phase compared with the control group (P<0.05). The proportion of cells in G1 phase was significantly increased when the two drugs were combined (P<0.05). The expression of p-mTOR and effector protein p-4EBP1 was significantly downregulated in the EVE combined with GEM group, the expression of anti-apoptotic proteins MCL-1, Survivin and cell cycle protein cyclin D1 was downregulated too (P<0.05).@*CONCLUSION@#EVE combined with GEM can synergistically inhibit the proliferation of U2932 cells, and the mechanism may be that they can synergistically induce apoptosis by downregulating the expression of MCL-1 and Survivin proteins and block the cell cycle progression by downregulating the expression of Cyclin D1.

Drug resistance factors in postoperative gemcitabine chemotherapy after radical resection of pancreatic cancer / 中华消化外科杂志

Objective:To investigate the drug resistance factors in postoperative gemci-tabine chemotherapy after radical resection of pancreatic cancer.Methods:The retrospective case-control study was constructed. The clinicopathological data of 255 patients with pancreatic cancer who were firstly admitted to the Department of Hepatobiliary Surgery of the First Affiliated Hospital of Xi ′an Jiaotong University from January 2018 to June 2021 were collected. There were 140 males and 115 females, aged (59±10)years. All patients underwent radical resection of pancreatic cancer and received postoperative gemcitabine-based adjuvant chemotherapy. Observation indicators: (1) follow-up; (2) postoperative chemotherapy; (3) drug resistance and changing of regimen; (4) factors influencing postoperative chemotherapy resistance. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the independent sample t test. Measurement data with skewed distribution were represented as M( Q1, Q3), and compari-son between groups was conducted using the Mann-Whitney U test. Count data were described as absolute numbers, and comparison between groups was conducted using the Pearson chi-square test. Univariate analysis was conducted using the corresponding statistical methods based on data type. Multivariate analysis was conducted using the Logistic regression model with forward method. Kaplan-Meier method was used to draw survival curve, and Log-Rank test was used for survival analysis. Results:(1) Follow-up. All 255 patients were followed up for 18.6(16.7,21.4)months. The median survival time of 255 patients was 18.2[95% confidence interval ( CI) as 15.8-20.6]months. (2) Postoperative chemotherapy. Of the 255 patients, there were 5 cases receiving postoperative chemotherapy as gemcitabine monotherapy, 167 cases receiving postoperative chemotherapy as the AG combination (gemcitabine plus albumin-bound paclitaxel), 74 cases receiving postoperative chemotherapy as the GS combination (gemcitabine plus S-1) and 9 cases receiving postoperative chemotherapy as the GP combination (gemcitabine plus platinum). (3) Drug resistance and changing of regimen. Of the 255 patients, 81 cases completed the course of postoperative chemotherapy and evaluation. Of the 81 patients, there were 18 cases with no recurrence or metastasis of tumor, 10 cases with tumor local recurrence, 40 cases with tumor lymph node metastasis or distant metas-tasis, 3 cases with tumor local recurrence combined with distant metastasis, 10 cases with elevation of CA19-9. Of the 81 patients, 18 cases responded to chemotherapy, 63 cases underwent resistant to chemotherapy, including 11 cases with primary resistance and 52 cases with acquired resistance. The 63 patients with chemotherapy resistance underwent changing of regimen. (4) Factors influencing postoperative chemotherapy resistance. Results of multivariate analysis showed that chemotherapy cycle<6 is an independent risk factor for postoperative chemotherapy resistance in patients ( hazard ratio=17.18, 95% CI as 2.07-142.28, P<0.05). Conclusion:Adjuvant chemotherapy cycle <6 is an independent risk factor for postoperative chemotherapy resistance for gemcitabine based chemo-therapy in pancreatic cancer patients receiving radical resection.

Efficacy and safety of radiotherapy combined with targeted therapy, immunotherapy and chemotherapy for unresectable intrahepatic cholangiocarcinoma / 中华放射医学与防护杂志

Objective:To evaluate the efficacy and safety of quadruple therapy involving radiotherapy (RT), lenvatinib, anti-PD-1 antibody and GEMOX (oxaliplatin and gemcitabine) chemotherapy (quadruple therapy) in treatment cohort of patients with unresectable intrahepatic cholangiocarcinoma (ICC).Methods:The patients with recurrent, metastatic, or unresectable ICC underwent quadruple therapy at Zhongshan Hospital, Fudan University between September 2018 and May 2022 were selected. The data about efficacy and safety of quadruple therapy were collected in the hospital electronic medical record system. All patients were followed up regularly to obtain the long-term prognostic data until December 31, 2022. The efficacy, prognosis, and toxicity data were collected and analyzed.Results:A total of 41 patients were included in the analysis. After a median follow-up period of 15 months, disease progression was diagnosed in 36 patients (18 patients died), while 3 patients were lost to follow-up. The causes of death included liver failure induced by intrahepatic tumor progression ( n=6), distant metastases (lungs or brain, n=6), abdominal lymph node metastases ( n=3), cancer cachexia ( n=2), and unknown cause ( n=1). The median progression-free survival (PFS) was 11 months (95% CI: 9.2-12.8), and the median overall survival (OS) was 35 months (95% CI: 17.0-52.0). All patients experienced treatment-related adverse events (AEs) during the study treatment period. Of the 41 patients, 13 patients experienced at least once grade 3 or worse treatment-related AE, but all were manageable with symptomatic treatment. No treatment-related deaths were reported during the follow-up period. Conclusions:Radiotherapy (RT), lenvatinib, anti-PD-1 antibody and GEMOX in the treatment of unresectable ICC shows significant efficacy and good safety, which is worthy of clinical application.

Inhibitory effects of gemcitabine hydrochloride combined with ferroptosis inducers on the proliferation of PANC-1 cells / 药学实践与服务

Objective To study the effects of three ferroptosis inducers Erastin (Era), sulfasalazine (SASP) and artesunate (Art) alone or combined with gemcitabine hydrochloride (hcGEM) on the proliferation inhibition of Human pancreatic cell line PANC -1. Methods The CCK-8 method was used to detect the inhibitory effects of different concentrations of Era, SASP and Art alone or combined with hcGEM on the proliferation of PANC-1, and the combination index (CI) was used to judge whether three ferroptosis inducers combined with hcGEM had synergistic inhibitory effect on PANC-1. Results The three ferroptosis inducers and hcGEM alone or in combination could significantly inhibit the activity of PANC-1. The inhibitory effects were enhanced with the concentration increasing. The CI values of hcGEM-Era 4∶1 or 1∶4 combination group and hcGEM-SASP 1∶400 combination group were less than 1.The CI values of hcGEM-Art 1∶4 or 1∶16 combination group were less than 1 only within a certain concentration range. Conclusion The inhibitory effects of the three ferroptosis inducers and hcGEM alone or in combination were dose-dependent. The combination of hcGEM and three ferroptosis inducers could synergistically inhibit the proliferation of PANC-1.

Correlation of ARK5 expression in peripheral blood circulating tumor cells with curative efficacy and prognosis for gemcitabine chemotherapy in pancreatic cancer patients / 中华胰腺病杂志

Objective:To detect the expression of ARK5 in peripheral blood circulating tumor cells (CTCs) from pancreatic cancer patients and explore its correlation with the efficacy and prognosis for gemcitabine chemotherapy.Methods:A total of 175 peripheral blood samples of pancreatic cancer patients who were treated in the Department of Hepatobiliary Surgery, Second Affiliated Hospital of Jiaxing University from January 2016 to June 2021 were collected. CTCs were enriched by nano-microfluidic chip technology. The expression of ARK5 in CTCs was detected by immunofluorescence. According to the expression of ARK5, the patients were divided into two groups: positive group and negative group. The differences on clinicopathological features, the efficacy of chemotherapy, median survival and progression-free survival time between the two groups were compared.Results:CTCs were enriched in 98 of 175 patients (55.6%), including 70 ARK5 positive and 28 ARK5 negative patients. There were no significant differences on clinical features between the two groups, and the two groups were comparable. In the 70 ARK5 positive patients, 64 patients (91.4%) were resistant to gemcitabine, while only 12 of the 28 ARK5 negative patients (42.8%) were resistant to gemcitabine. The incidence of gemcitabine resistance in ARK5 positive patients was significantly higher than that in ARK5 negative patients, and the difference was statistically significant ( P<0.001). The median survival time was 11.5 months in ARK5 positive group and 14 months in ARK5 negative expression group, and the progression-free survival time was 6 months in ARK5 positive expression group and 8 months in negative expression group. The survival time of ARK5 positive group was significantly shorter than that of ARK5 negative group, and the difference was statistically significant ( P<0.05). Conclusions:The pancreatic cancer patients with ARK5 positive CTCs have significantly higher incidence of gemcitabine resistance and shorter survival time than those with ARK5 negative CTCs. Detection of ARK5 expression in CTCs may be a new method to judge chemotherapy efficacy and prognosis for pancreatic cancer patients.

Gemcitabine-induced Exosomes Derived from Pancreatic Cancer Cells Promote the Proliferation and Invasion of Pancreatic Cancer Cells / 医学研究杂志

Objective To explore the effects of exosomes derived from pancreatic cancer cells treated with or without gemcitabine on the proliferation and invasion of pancreatic cancer cells.Methods Exosomes were extracted from supernatant of pancreatic cancer cells treated with or without gemcitabine.Transmission electron microscopy,nanoparticle tracking analysis and Western blot method were used to identify exosomes and the concentration and size of exosomes were determined.Incubation of exosomes with pancreatic cancer cells was performed to detect the proliferation and invasion of pancreatic cancer cells,and Western blot method was used to detect the expression of CD147.Results Exosome-specific markers were highly expressed in extracted exosomes.There was no significant difference of concen-tration and size of exosomes derived from pancreatic cancer cells treated with or without gemcitabine.Incubation with exosomes derived from pancreatic cancer cells promoted the proliferation and invasion of pancreatic cancer cells,and incubation with exosomes derived from pancreatic cancer cells treated with gemcitabine promoted the proliferation and invasion further,and the expression level of CD 147 was up-regulated significantly in gemcitabine-induced exosomes.Conclusion Gemcitabine-induced exosomes derived from pancreatic cancer cells can promote the proliferation and invasion of pancreatic cancer cells.

BCG + piroxicam versus BCG + gemcitabine for prevention of postoperative recurrence in intermediate- and high-risk bladder cancer and effects on serum AGR and PON1 / 中国临床药理学与治疗学

AIM: To investigate the effect of BCG + piroxicam versus BCG + gemcitabine in the prevention of postoperative recurrence in intermediate - to high-risk bladder cancer and the effect on serum albumin / globulin ratio (AGR) and paraoxonase 1 (PON1). METHODS: Eighty patients with medium-high risk bladder cancer in our hospital from October 2021 to April 2022 were randomly divided into two groups with 40 cases each. Both groups received transurethral resection of bladder tumor. The control group received postoperative bladder perfusion of pirubicin combined with BCG vaccine, and the study group received postoperative bladder perfusion of gemcitabine combined with BCG vaccine. The therapeutic effect, serum tumor markers secretory protein Dickkopf (DKK), bladder cancer specific nuclear matrix protein-1 (BLCA-1), β2-microglobulin (β2-MG), new angiogenesis factorsvascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), AGR and PON were compared between the two groups 1. Level, quality of lifeCore Quality of Life Questionnaire Scale (EORTC QLQ-C30), functional status Functional status Scoring Scale (KPS), adverse reactions, The recurrence rates at 1 year after surgery were compared between the two groups. RESULTS: The total effective rate of the study group was 92.50%(37/40) higher than that of the control group 75.00%(30/40) (P<0.05). The serum levels of DKK, BLCA-1, β2-MG, VEGF, FGF and AGR in the study group were lower than those in the control group at 1 month, 3 months and 6 months after surgery, while the level of PON1 was higher than that in the control group (P<0.05). The EORTC QLQC30 and KPS scores of the study group were higher than those of the control group at 1, 3 and 6 months after surgery (P<0.05). The incidence of nausea/vomiting, diarrhea, leukopenia and cystitis in the study group was lower than that in the control group (P<0.05). The recurrence rate of the study group 1 year and 2 years after surgery was lower than that of the control group (P<0.05). CONSLUSION: Compared with pirubicin combined with BCG vaccine, gemcitabine combined with BCG vaccine is more effective in the treatment of middle and high-risk bladder cancer, which can inhibit tumor angiogenesis, regulate AGR and PON1 levels, prevent postoperative recurrence, improve quality of life, improve functional status, and have higher safety.

Effects of CDA-G208A gene polymorphism on the efficacy of gemcitabine in the first-line treatment of lung squamous cell carcinoma / 中国临床药理学与治疗学

AIM: To investigate the effect of CDAG208A gene polymorphism on the efficacy and safety of gemcitabine in the first-line treatment of lung squamous cell carcinoma. METHODS: Sixty-five first-line treated patients with locally advanced or metastatic lung squamous cell carcinoma in The First Affiliated Hospital of Wannan Medical College hospital were screened. Group A included 31 patients tested with the GG (wild homozygous) CDAG208A gene, and group B included 34 patients without testing. All patients received gemcitabine plus platinum chemotherapy for at least 2 cycles. The efficacy and safety were evaluated following the RECIST 1.1 standard and the NCI-CTC 5.0 standard, respectively. The primary study endpoint was progression-free survival (PFS), overall survival (OS) and the secondary study endpoints included objective effective rate (ORR), disease control rate (DCR), adverse reactions, and influencing factors of PFS. RESULTS: The results showed that the DCR was 74.5% and 50% in group A and group B, respectively (P=0.045); mPFS was 6.1 months and 5.0 months in group A and group B, respectively (P=0.034); and the mOS was 13.3 months and 12.0 months in group A and group B, respectively, and there was no statistical difference (P=0.388). The number of cases of grade III-IV neutropenia in group A and group B was 2 and 10, respectively (P=0.017); grade III-IV neutropenia was an independent prognostic factor affecting patients with PFS (P=0.045); the group with unknown G208A gene status was more likely to develop grade III-IV neutrophils (P= 0.029). The AUC of CDA-G208A gene predicting neutropenia caused by gemcitabine chemotherapy was 0.756. CONCLUSION: Non-GG type of CDAG208A gene can reduce the metabolic rate of gemcitabine in the body and cause neutropenia after chemotherapy. In severe cases, it can indirectly reduce the clinical efficacy of gemcitabine. The detection of CDA-G208A gene status before treatment can predict the neutropenia caused by gemcitabine chemotherapy.

Does systemic anticancer gemcitabine compromise oral soft tissue wound healing? / ¿La gemcitabina anticancerígena sistémica compromete la cicatrización de heridas en tejidos blandos orales?

Background: Numerous types of cancer are of substantial medical and social concern, posing a major challenge to modern medicine. Chemotherapeutic drugs include the use of nucleosides, which are composed of nucleic acid and sugar. Objective: This study aims to assess the impact of systemic chemotherapeutic drugs at a therapeutic dose on the wound healing process of the oral mucosa. Material and Methods: 30 healthy rats were randomly divided into two main groups based on the study material, 15 rats in each group. Group A (control) was given a single dose of normal saline (1ml/kg, intraperitoneal), and Group B (study) a single injection of gemcitabine (50 mg /Kg, intraperitoneal). After anesthesia, a full-thickness soft tissue incision (0.5 cm length) on the right side of the buccal mucosa was made in the animals of both groups. Each group was subdivided according to the time of sacrifice into 3, 7, 14 days after surgery, at the end of the experimental periods, specimens were collected for histopathological study, and samples of blood were obtained from retro-orbital venous plexus and collected in microfuge tubes and levels of antioxidant enzymes were measured by ELISA. The data were analyzed statistically at a 0.05 level of significance. Results: Gemcitabine delayed the onset of wound cascade (inflammation and re-epithelization) which lead to worsening healing of the oral tissue; it also resulted in a decrease of the antioxidant activity of glutathione peroxidase and catalase, as well as activated caspase 3, which induces cell apoptosis. Conclusion: Gemcitabine showed negative feedback on oral tissue wound healing through delayed wound healing cascade and by inducing apoptosis.

Antecedentes: numerosos tipos de cáncer son motivo de gran preocupación médica y social, lo que representa un gran desafío para la medicina moderna. Los fármacos quimioterapéuticos incluyen el uso de nucleósidos, que están compuestos de ácido nucleico y azúcar. Objetivo: Este estudio tiene como objetivo evaluar el impacto de los fármacos quimioterapéuticos sistémicos a una dosis terapéutica en el proceso de cicatrización de heridas de la mucosa oral. Material y Métodos: 30 ratas sanas se dividieron aleatoriamente en dos grupos principales según el material de estudio, 15 ratas en cada grupo. Al grupo A (control) se le administró una dosis única de solución salina normal (1 ml/kg, intraperitoneal) y al grupo B (estudio) una inyección única de gemcitabina (50 mg/kg, intraperitoneal). Después de la anestesia, se realizó una incisión de tejido blando de espesor total (0,5 cm de longitud) en el lado derecho de la mucosa bucal en los animales de ambos grupos. Cada grupo se subdividió de acuerdo al tiempo de sacrificio en 3, 7, 14 días después de la cirugía, al final de los períodos experimentales se colectaron especímenes para estudio histopatológico, se obtuvieron muestras de sangre del plexo venoso retroorbitario y se recolectaron en tubos de microcentrífuga y los niveles de enzimas antioxidantes se midieron por ELISA. Los datos se analizaron estadísticamente a un nivel de significación de 0,05. Resultados: La gemcitabina retrasó el inicio de la cascada de heridas (inflamación y reepitelización) que condujo a un empeoramiento de la cicatrización del tejido oral; también resultó en una disminución de la actividad antioxidante de la glutatión peroxidasa y la catalasa, así como de la caspasa 3 activada, que induce la apoptosis celular. Conclusión: La gemcitabina mostró retroalimentación negativa sobre la cicatrización de heridas del tejido oral a través de una cascada de cicatrización retardada y mediante la inducción de apoptosis.

Evaluation of Gemcitabine-Cisplatin Vs Gemcitabine-Oxaliplatin in The Treatment of Advanced Biliary Tract Carcinoma: A Tertiary Care Hospital Study in Bangladesh

Background: Biliary tract carcinoma is highly fatal and one of the commonest cancers in Bangladesh. Chemotherapy is the mainstay of treatment as it is present in an advanced stage. Gemcitabine-Cisplatin association has been a standard of care for first-line regimens in advanced biliary tract cancer. Nevertheless, the Gemcitabine-Oxaliplatin regimen is frequently preferred. There has been no nationwide study to compare the effectiveness of these two platinum groups. Therefore, this study compared the efficacy and toxicities of Gemcitabine-Cisplatin (Gem-Cis) with Gemcitabine-Oxaliplatin (GEMOX) combination chemotherapy for the treatment of ABTC.Material & Methods:In this quasi-experimental study, a total number of eighty patients (40 patients in arm A and 40 patients in arm B), who had histopathologically or cytopathological proven ABTC with no history of previous treatment were included. The study has done between the periods of January 2019 to June 2020. The patients received Gemcitabine (1000 mg/m2 i.v. on day 1 and day 8) plus Cisplatin (25 mg/m2 i.v. on day 1 and 8) every 3 weeks for 6 cycles in Arm A. In another group, Gemcitabine (1000 mg/m2 i.v. on day 1) plus Oxaliplatin (100 mg/m2 i.v. on day 2) every 2 weeks for 6 cycles in Arm B was given. All the patients were followed up according to the set follow-up criteria up to 6 weeks after completion of treatment.Results:At the end of the treatment, Response rates (CR+PR+SD) were analyzed. No patient from both the arms showed Complete Response (CR). 37.5% and 45% of patients of the Arm A and Arm B groups showed Partial Response (PR) respectively. Meanwhile, 45% and 40% of patients from Arm A and B showed Stable Disease (SD) respectively. P-value was 0.410 (>0.05). Seven patients (17%) in Arm A and six patients (15%) in Arm B developed Progressive disease (PD). The most common treatment-related grade 3 toxicities were more experienced in the Arm A group. For Arm A versus Arm B that were as follows: neutropenia (15% versus 5%), anemia (15% versus 8%), thrombocytopenia (10% versus 2.5%), nausea (10% versus 5%), vomiting (5%versus 2.5%), peripheral neuropathy (0% versus 15%) and renal toxicity (7.5% versus 0%). For none of them, the p-value was <0.05 except for neutropenia, anemia, thrombocytopenia, renal toxicity, and peripheral neuropathy in which the p-value was 0.042, 0.001, 0.014, 0.0001, and 0.00001 respectively. For both Arms, there were no treatment-related Grade 4 toxicities.Conclusion:The study exhibited that treatment with the Gemcitabine-Oxaliplatin regimen was well tolerated, less toxic, and convenient with similar effectiveness compared to the Gemcitabine-Cisplatin regimen in loco regional control of advanced biliary tract cancer.

The Outcome of Gemcitabine-Cisplatin Versus Gemcitabine-Oxaliplatin in The Treatment of Advanced Biliary Tract Carcinoma

Background: Biliary tract carcinoma is highly fatal and one of the commonest cancers in Bangladesh. Chemotherapy is the mainstay of treatment as it is present in an advanced stage. Gemcitabine-Cisplatin association has been a standard of care for first-line regimens in advanced biliary tract cancer. Nevertheless, the Gemcitabine-Oxaliplatin regimen is frequently preferred. There has been no nationwide study to compare the effectiveness of these two platinum groups. Therefore, this study compared the efficacy and toxicities of Gemcitabine-Cisplatin (Gem-Cis) with Gemcitabine-Oxaliplatin (GEMOX) combination chemotherapy for the treatment of ABTC.Material & Methods:In this quasi-experimental study, a total number of eighty patients (40 patients in arm A and 40 patients in arm B), who had histopathologically or cytopathologically proven ABTC with no history of previous treatment were included. The study has done between the periods of January 2019 to June 2020. The patients received Gemcitabine (1000 mg/m2 i.v. on day 1 and day 8) plus Cisplatin (25 mg/m2i.v. on day 1 and 8) every 3 weeks for 6 cycles in Arm A. In another group, Gemcitabine (1000 mg/m2 i.v. on day 1) plus Oxaliplatin (100 mg/m2 i.v. on day 2) every 2 weeks for 6 cycles in Arm B was given. All the patients were followed up according to the set follow-up criteria up to 6 weeks after completion of treatment.Results:At the end of the treatment, Response rates (CR+PR+SD) were analyzed. No patient from both the arms showed Complete Response (CR). 37.5% and 45% of patients of the Arm A and Arm B groups showed Partial Response (PR) respectively. Meanwhile, 45% and 40% of patients from Arm A and B showed Stable Disease (SD) respectively. P-value was 0.410 (>0.05). Seven patients (17%) in Arm A and six patients (15%) in Arm B developed Progressive disease (PD). The most common treatment-related grade 3 toxicities were more experienced in the Arm A group. For Arm A versus Arm B that were as follows: neutropenia (15% versus 5%), anemia (15% versus 8%), thrombocytopenia (10% versus 2.5%), nausea (10% versus 5%), vomiting (5%versus 2.5%), peripheral neuropathy (0% versus 15%) and renal toxicity (7.5% versus 0%). For none of them, the p-value was <0.05 except for neutropenia, anemia, thrombocytopenia, renal toxicity, and peripheral neuropathy in which the p-value was 0.042, 0.001, 0.014, 0.0001, and 0.00001 respectively. For both Arms, there were no treatment-related Grade 4 toxicities.Conclusion:The study exhibited that treatment with Gemcitabine-Oxaliplatin regimen was well tolerated, less toxic, and convenient with similar effectiveness compared to Gemcitabine-Cisplatin regimen in loco regional control of advanced biliary tract cancer.

Chronic gemcitabine-induced thrombotic microangiopathy in the kidneys / Microangiopatía trombótica crónica localizada en riñones asociada al uso de gemcitabina

Abstract Thrombotic microangiopathies (TMAs) are characterized by microvascular occlusion secondary to diffuse endothelial damage which produces inflammation, platelet aggregation and red blood cell destruction, causing ischemic injury to the affected organ. They are clinically characterized by Coombs-negative microangiopathic hemolytic anemia, and multiple organ damage (mainly of the kidneys, central nervous system, cardiovascular apparatus and gastrointestinal tract). They may occur systemically or locally, and they have multiple etiologies. In patients with cancer, determining the cause of thrombotic microangiopathy is a great diagnostic challenge, with the most frequent etiologies being active malignant neoplasms, disseminated intravascular coagulation, infections and antineoplastic drugs. We present the clinical case of a patient with unresectable pancreatic adenocarcinoma on chronic gemcitabine treatment, and highlight the importance of suspecting and distinguishing chemotherapy-induced TMAs from neoplasm-induced TMAs, as their prognosis and treatment are very different. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2249).

Resumen Las microangiopatías trombóticas (MAT) se caracterizan por la oclusión microvascular como consecuencia de una lesión endotelial difusa que produce inflamación, agregación plaquetaria y destrucción de glóbulos rojos, causando daño isquémico del órgano afectado. Se caracterizan clínicamente por anemia hemolítica microangiopática, Coombs negativo, daño multiorgánico (principalmente de riñones, sistema nervioso central, aparato cardiovascular y tracto gastrointestinal). Su presentación puede ser sistémica o localizada y sus etiologías son múltiples. En los pacientes con cáncer es un gran reto diagnóstico establecer la causa de la microangiopatía trombótica, siendo las etiologías más frecuentes la neoplasia maligna activa, la coagulación intravascular diseminada, infecciones y medicamentos antineoplásicos. Se presenta el caso clínico de una paciente con adenocarcinoma cáncer de páncreas irresecable, en manejo crónico con gemcitabina y se resalta la importancia de sospechar y distinguir la MAT inducida por quimioterapia, de la causada por la neoplasia ya que el pronóstico y tratamiento son muy diferentes. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2249).

Reevaluation of systematic evaluation of gemcitabine combined with cisplatin in the treatment of advanced non- small cell lung cancer / 中国药房

OBJECTIVE To reevaluate the system atic evaluation of g emcitabine combined with cisplatin in the treatment of advanced non-small cell lung cancer （NSCLC），in order to provide evidence-based evidence for the treatment of NSCLC. METHODS Retrieved from Wanfang database ，CNKI，VIP，PubMed，Embase，systematic evaluation of gemcitabine combined with cisplatin versus pemetrexed/vinorelbine combined with cisplatin in the treatment of advanced NSCLC was included from the inception to Dec. 2021. RevMan 5.3 system evaluation software was used for meta-analysis of various outcome indicators ； AMSTAR2 scale was used for methodological quality evaluation ，and GRADE tool was used for evidence quality evaluation. RESULTS A total of 9 literatures were included. Meta-analysis showed that the effective rate of gemcitabine combined with cisplatin was significantly lower than pemetrexed combined with cisplatin ，but was similar to vinorelbine combined with cisplatin. The 1-year survival rate of gemcitabine combined with cisplatin was equivalent to that of pemetrexed combined with cisplatin ，but was superior to vinorelbine combined with cisplatin. There was no significant difference in the incidence of nausea and vomiting between gemcitabine combined with cisplatin and pemetrexed/vinorelbine combined with cisplatin. Gemcitabine combined with cisplatin had a higher incidence of thrombocytopenia than pemetrexed/vinorelbine combined with cisplatin. The incidence of neutropenia and leukopenia in gemcitabine combined with cisplatin were higher than pemetrexed combined with cisplatin ，but were significantly lower than vinorelbine combined with cisplatin. The evaluation results of AMSTAR 2 scale showed that 6 systematic evaluation were of low quality in methodology and 3 were of very low quality. The results of the GRADE tool showed that 31％ of the outcome indicators were of medium quality （14 items），27％ were of low quality （12 items），and 42％ were of very low quality（19 items）. Research limitations and publication bias were the most frequently downgraded factors. CONCLUSIONS Gemcitabine combined with cisplatin has advantages over 154854280@qq.com vinorelbine combined with cisplatin in the efficacy and safety of ad vanced NSCLC ，especially in the 1-year survival rate ，the incidence of neutropenia and leucopenia. The efficacy and safety of gemcitabine combined with cisplatin are inferior to those of pemetrexed combined with cisplatin. However ，the methodological quality and evidence level of systematic evaluation are not high on the whole ，and the overall quality of research needs to be improved.

Engineering a folic acid-decorated ultrasmall gemcitabine nanocarrier for breast cancer therapy: Dual targeting of tumor cells and tumor-associated macrophages

Combination of passive targeting with active targeting is a promising approach to improve the therapeutic efficacy of nanotherapy. However, most reported polymeric systems have sizes above 100 nm, which limits effective extravasation into tumors that are poorly vascularized and have dense stroma. This will, in turn, limit the overall effectiveness of the subsequent uptake by tumor cells via active targeting. In this study, we combined the passive targeting via ultra-small-sized gemcitabine (GEM)-based nanoparticles (NPs) with the active targeting provided by folic acid (FA) conjugation for enhanced dual targeted delivery to tumor cells and tumor-associated macrophages (TAMs). We developed an FA-modified prodrug carrier based on GEM (PGEM) to load doxorubicin (DOX), for co-delivery of GEM and DOX to tumors. The co-delivery system showed small particle size of ∼10 nm in diameter. The ligand-free and FA-targeted micelles showed comparable drug loading efficiency and a sustained DOX release profile. The FA-conjugated micelles effectively increased DOX uptake in cultured KB cancer cells that express a high level of folate receptor (FR), but no obvious increase was observed in 4T1.2 breast cancer cells that have a low-level expression of FR. Interestingly, in vivo, systemic delivery of FA-PGEM/DOX led to enhanced accumulation of the NPs in tumor and drastic reduction of tumor growth in a murine 4T1.2 breast cancer model. Mechanistic study showed that 4T1.2 tumor grown in mice expressed a significantly higher level of FOLR2, which was selectively expressed on TAMs. Thus, targeting of TAM may also contribute to the improved in vivo targeted delivery and therapeutic efficacy.

Efficacy of anti-CD 20 monoclonal antibody in combination with Gemcitabine-based chemotherapy regimen in children with recurrent diffuse large B-cell lymphoma / 中华实用儿科临床杂志

Objective:To investigate the efficacy of anti-CD 20 monoclonal antibody in combination with Gemcitabine-based chemotherapy regimen in children with recurrent diffuse large B-cell lymphoma (DLBCL). Methods:The clinical data of 62 children with DLBCL admitted to the Department of Pediatrics, Yantai Mountain Hospital of Yantai City and the Department of Pediatrics, Muping District Traditional Chinese Medicine Hospital in Yantai City from January 2010 to January 2018 were analyzed retrospectively.Different treatment options were selected according to the children′s stage and the presence of risk factors such as huge tumors.Among them, 32 cases in the control group were treated with the Gemcitabine-based treatment plan (Gemcitabine+ Cisplatin+ Dexamethasone treatment). Thirty patients in the study group were treated with anti-CD 20 monoclonal antibody on the basis of the control group for a total of 4 cycles (21 d per cycle). After 4 cycles of treatment, the clinical efficacy, the positive expression of forkhead box protein P1 (FOXP1) and B-cell lymphoma factor-6 (Bcl-6) before and after treatment, the occurrence of adverse reactions and survival[3-year progression-free survival (PFS), 3-year overall survival (OS)] were evaluated.The measurement data that meets the normal distribution is expressed that the t test is used, and the counting data is represented by (%), and the χ2 test is used.Level data is compared with ranking and inspection. Results:All patients were followed up to March 2021.The total response rate (RR) and disease control rate (DCR) of the study group were 93.33% (28/30 cases) and 96.67% (29/30 cases), respectively.The RR and DCR of the control group were 68.75% (22/32 cases) and 81.25% (26/32 cases), respectively.The RR of the study group was higher than that of the control group ( χ2=5.995, P<0.05), and there was no statistical difference in DCR between the two groups ( χ2=3.674, P>0.05). After treatment, the positive expression rate of FOXP1 in the study group and the control group was lower than before treatment[23.33% (7/30 cases) vs. 76.67% (23/30 cases); 50.00% (16/32 cases) vs. 75.00% (24/32 cases), χ2=17.067, 4.267, all P<0.05], and the positive expression rate of the study group was lower than that of the control group ( χ2=4.179, P<0.05). After treatment, the positive expression rate of Bcl-6 in the study group and the control group was higher than before treatment[86.67% (26/30 cases) vs. 26.67% (8/30 cases); 62.50% (20/32 cases) vs. 31.25% (10/32 cases), χ2=21.991, 6.275, all P<0.05], and the positive expression rate of the study group was higher than that of the control group ( χ2=4.723, P<0.05). There was no significant difference between the study group and the control group in the level of gastrointestinal reactions, elevated transa-minase, and decreased white blood cell ( Z=-1.074, -1.078, -0.834, all P>0.05). There was a difference between the 3-year PFS survival curve and the 3-year OS survival curve between the two groups ( χ2=3.997, 4.723, all P<0.05). Conclusions:Anti-CD 20 monoclonal antibody combined with Gemcitabine-based chemotherapy is effective for children with DLBCL, and will not significantly increase the adverse reactions in children.

Effects of 5-Aza-dC combined with chemotherapy regimens on the apoptosis of lung adenocarcinoma cells / 中国综合临床

Objective:To investigate the effect of different chemotherapy drugs combined with DNA methylase inhibitor 5-Aza-2'-deoxycytidine (5-Aza-dC) on the apoptosis of lung adenocarcinoma cells.Methods:In the prospective randomized controlled study, lung adenocarcinoma A549 cells were treated with cisplatin plus paclitaxel (TP) or gemcitabine (GP) with or without 5-Aza-dC. According to different drug intervention methods, they were divided into control group, cisplatin combined with paclitaxel (TP) group, cisplatin combined with gemcitabine (GP) group, and 5-Aza-dC combined with TP group, 5-Aza-dC combined with GP group. CCK-8 assay was used to detect the proliferation of A549 cells. Transwell migration and invasion assay were used to detect the effect that each group of drugs on the migration and invasion ability of A549 cells. Quantitative Real-time Polymerase Chain Reaction was used to evaluate the effect of each treatment on the expression of apoptotic genes. One-way analysis of variance was used to compare the degree of cell proliferation in different drug treatment groups, and LSD- t method was used for pairwise comparison within groups. Results:The inhibition rates of lung adenocarcinoma cells in the TP regimen at different time points at 24, 48, and 72 h were as follows (20.00±4.23) %, (35.00±2.80) %, and (56.00±3.11) %. The inhibition rate of 5-Aza-dC combined with TP regimen on lung adenocarcinoma cells was significantly increased, at different time points of 24, 48 and 72 h, respectively (38.00±3.80) %, (50.00±3.25) %, (93.00±4.33) %. The inhibition rates of cells at different time points at 24, 48, and 72 h in the GP regimen were (33.00±5.10) %, (54.00±3.80) %, and (74.00±2.82) %, respectively; while 5-Aza-dC combined with GP regimen could significantly reduce the rate of cell growth, the inhibition rates of cells at 24, 48, and 72 h different time points were as follows (54.00±3.00) %, (67.00±5.30) %, and (95.00±1.13) %. The inhibitory effect of the same drug on lung adenocarcinoma cells increased with time (TP group: F=35.93, P<0.001; 5-Aza-dC combined with TP group: F=97.33, P<0.001; GP group: F =41.73, P<0.001; 5-Aza-dC combined with GP group: F=79.00, P<0.001), and at different time points, the differences were statistically different (all P<0.05). 5-Aza-dC combined with TP and GP chemotherapy regimens can inhibit the migration and invasion of lung adenocarcinoma cell A549, and the inhibitory effect is stronger than that of TP or GP regimens alone. The expression of Caspase 8 was significantly elevated ( t=5.87, P=0.004) in cells treated with 5-Aza-dC combined with GP when compared with GP regimen alone. The expression of Caspase 8 ( t=3.94, P=0.017), Caspase 6 ( t=5.81, P=0.004) and BBC3 (BCL-2 binding component 3) ( t=6.53, P=0.003) were increased when drugged with 5-Aza-dC combined TP regimen compared with TP regimen alone. Conclusion:5-Aza-dC might serve as a chemotherapeutic sensitizer to increase the sensitivity of lung adenocarcinoma cells.