Gemcitabine Group Research Articles

Comparing efficacy and safety of in-house gemcitabine to mitomycin for bladder instillation in intermediate-risk NMIBC

IntroductionIntermediate-risk (IR) Non-Muscle Invasive Bladder Cancer (NMIBC) is associated with a high rate of tumor recurrence. To improve patient outcomes, it is recommended to use adjuvant intravesical therapy, by mitomycin C (MMC) or Bacillus Calmette Guerin (BCG). Gemcitabine (GMC) is a known molecule used in urothelial cancer. We aimed to study the efficacy and safety profile of a gemcitabine solution, compared to mitomycin C, in the treatment of IR NMIBC. MaterialIn this retrospective study, patients with IR NMIBC treated between 2016 and 2020 were selected from two participating centers using either gemcitabine (center A) as the intravesical chemotherapy regimen or mitomycin C (center B). The primary endpoint was recurrence rate and secondary end points were treatment interruption and its causes. ResultsIn our cohort of 102 IR NMIBC patients, 49 patients received GMC and 53 MMC with a median follow-up of 30 months. Overall recurrence rate was 42.1% with 22.4% in the GMC group and 60.3% in the MMC group (P<0.01). This difference was also found in the multifactorial analysis. Course interruption was observed in 14.7% of all patients, primarily attributed to adverse events (46.6%), without difference between groups. ConclusionAdjuvant intravesical gemcitabine in patients with IR NMIBC seems to be an interesting option associated with a lower tumor recurrence rate and a favorable tolerance profile when compared to MMC. Larger scale prospective randomized trials are needed to validate our findings. Level of evidenceIII.

Efficacy and safety of different chemotherapy regimens in patients with disseminated pancreatic cancer over 65 years old

Aim. To evaluate the effectiveness and tolerability of systemic chemotherapy in elderly patients with metastatic pancreatic cancer (mPC) in real clinical practice.Materials and methods. The study included patients with mPC over 65 years of age who received first-line chemotherapy at the N. N. Blokhin National Medical Research Center of Oncology for the period from 2004 to 2023. Any previous antitumor chemotherapy for mPC was an exclusion criterion. The primary endpoint was 1-year overall survival (OS), and the secondary endpoints were ORR, median progression-free survival, median OS, chemotherapy tolerability.Results. The study included 148 patients aged 65 to 86 years with mPC who received first-line chemotherapy. Median progression-free survival among the entire population was 5.2 months. One-year OS among all patients was 32 %. The 1-year OS in mFOLFIRINOX group was 43.4 % and in gemcitabine group – 19.6 %. In a subgroup analysis, median OS with combination treatment was higher than in the gemcitabine monotherapy group (median OS 8.4 months vs. 6.8 months, p = 0.009). Patients with ECOG 2–3 also benefited from combination chemotherapy. Median OS was 8.9 months versus 3.9 months in gemcitabine (p = 0.008). The frequency of an objective response with triple chemotherapy was 66.1 %. In 30.8 % of cases, grade 3–4 neutropenia developed with mFOLFIRINOX, but febrile neutropenia developed only in three patients (5.8 %). The incidence of grade 3–4 adverse events was low, and these chemotherapy regimens were well tolerated.Conclusion. Conducting a triple chemotherapy regimen in elderly patients with mPC is an effective treatment option with an acceptable range of toxicity.

Is the gemcitabin cisplatin doublet the optimal induction chemotherapy for non-Asian patients with NPC? Insights from a northeastern Moroccan cohort.

e18057 Background: According to the latest guidelines for NPC, induction chemotherapy followed by concomitant chemoradiation therapy (CCRT) is recommended as the preferred standard of care for patients with locally advanced nasopharyngeal carcinoma (stage III-Iva). However, the optimal regimen for induction chemotherapy (IC) in patients with locally advanced NPC remains uncertain. Methods: We conducted a retrospective study between January 2016 and October 2022 at the "CHU Hassan II" Oncology Hospital in Fes, Morocco, to compare the efficacy and tolerability of two platinum-based induction therapy regimens: cisplatin gemcitabine (GC) and cisplatin doxorubicin (DP), in the treatment of newly diagnosed locally advanced NPC. The main objectives of this study were to compare the efficacy including objective response rates (ORR), PFS ,OS and safety. Results: After eligibility assessment, we included 105 cases (62 patients in the DP group and 43 in the GC group), including 65 men and 40 women, with a mean age of 49.5 years (range = 19-79years) and a Karnofsky score ranging from 87% to 100%. 34% of patients were diagnosed at stage IVA. In the DP group, 3% of patients (2 out of 62) achieved a complete response CR, 60% achieved a partial response PR,25% remained stable SD and 19% experienced progression. In the GC group, 2% of patients (1 out of 43) achieved a CR, 39.5% achieved a PR, 39.5% remained stable, and 19% experienced progression. A statistically significant difference in PR was observed between the two groups (p = 0.028) ,and the difference in terms of progression is approaching the limit of significance (p=0,06) after a median follow-up of 27 months (5,3 -82). The 2-year progression-free survival (PFS) was 70% in the DP group compared to 80% in the GC group; the 2-year overall survival (OS) was 75% in the DP group and 90% in the GC group. No significant survival difference was observed between the two groups Patients in the DP group exhibited less grade 3-4 thrombocytopenia but more grade 3-4 leukopenia and neutropenia compared to the GC group. Conclusions: In patients with locally advanced nasopharyngeal carcinoma, GC-based induction chemotherapy demonstrated superior ORR over the DP regimen with acceptable toxicities. Further studies are needed to validate these results.

Cordycepin Enhanced Therapeutic Potential of Gemcitabine against Cholangiocarcinoma via Downregulating Cancer Stem-Like Properties.

Cordycepin, a valuable bioactive component isolated from Cordyceps militaris, has been reported to possess anti-cancer potential and the property to enhance the effects of chemotherapeutic agents in various types of cancers. However, the ability of cordycepin to chemosensitize cholangiocarcinoma (CCA) cells to gemcitabine has not yet been evaluated. The current study was performed to evaluate the above, and the mechanisms associated with it. The study analyzed the effects of cordycepin in combination with gemcitabine on the cancer stem-like properties of the CCA SNU478 cell line, including its anti-apoptotic, migratory, and antioxidant effects. In addition, the combination of cordycepin and gemcitabine was evaluated in the CCA xenograft model. The cordycepin treatment significantly decreased SNU478 cell viability and, in combination with gemcitabine, additively reduced cell viability. The cordycepin and gemcitabine co-treatment significantly increased the Annexin V+ population and downregulated B-cell lymphoma 2 (Bcl-2) expression, suggesting that the decreased cell viability in the cordycepin+gemcitabine group may result from an increase in apoptotic death. In addition, the cordycepin and gemcitabine co-treatment significantly reduced the migratory ability of SNU478 cells in the wound healing and trans-well migration assays. It was observed that the cordycepin and gemcitabine cotreatment reduced the CD44highCD133high population in SNU478 cells and the expression level of sex determining region Y-box 2 (Sox-2), indicating the downregulation of the cancer stem-like population. Cordycepin also enhanced oxidative damage mediated by gemcitabine in MitoSOX staining associated with the upregulated Kelch like ECH Associated Protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) expression ratio. In the SNU478 xenograft model, co-administration of cordycepin and gemcitabine additively delayed tumor growth. These results indicate that cordycepin potentiates the chemotherapeutic property of gemcitabine against CCA, which results from the downregulation of its cancer-stem-like properties. Hence, the combination therapy of cordycepin and gemcitabine may be a promising therapeutic strategy in the treatment of CCA.

Efficacy and safety of short-term intravesical gemcitabine vs. long-term intravesical epirubicin in the treatment of moderate to high-risk non-muscle-invasive bladder cancer: a pilot study

PurposeLong-term bladder instillation therapy will bring more infusion side effects and economic consumption to patients. This study aims to compare short-term gemcitabine vs. long-term epirubicin for intravesical chemotherapy in patients diagnosed with moderate- to high-risk NMIBC treated using transurethral resection of bladder tumor (TURBT).Materials and methodsThis randomized controlled trial enrolled patients diagnosed with pT1 bladder cancer who underwent TURBT at Tianjin Medical University Cancer Institute from (01/2015- 07/2018), randomized 1:1 to gemcitabine vs. epirubicin. Recurrence-free survival (RFS) and progression-free survival (PFS) were monitored by cystoscopy. Side-effects after intravesical instillation and QLQ-C30 questionnaire were collected.ResultsFinally, 208 patients were enrolled. The median follow-up was 50.6 (6–69) months. The median RFS of the gemcitabine vs. epirubicin groups were 46.7 (6–69) vs. 47.2 (8–69) months, respectively (P > 0.05); the median PFS was 51.3 (9–69) vs. 50.9 (27–69) months, respectively (P > 0.05). The incidence rates of lower urinary tract symptoms, dysuria, hypo gastralgia, and gastrointestinal symptoms in the epirubicin group were 33.3%, 6.7%, 17.7%, and 18.3%, compared with 8.5%, 3.4%, 8.5% and, 1.2%, respectively, for gemcitabine. The gemcitabine group had a better quality of life than epirubicin in global health status (82.8 ± 8.5 vs. 79.6 ± 4.2, P = 0.01) and pain symptom domain (1.1 ± 2.8 vs. 2.4 ± 3.8, P = 0.04).ConclusionsThere are no significant differences in efficacy between gemcitabine and epirubicin for intravesical chemotherapy in patients with moderate to high-risk NMIBC to prevent tumor recurrence or progression for patients intolerant to BCG or those for whom BCG is not accessible. Patients with gemcitabine suffer fewer adverse events and have a better health status than with epirubicin.

Gemcitabine/nab-paclitaxel vs gemcitabine/carboplatin for advanced urothelial carcinoma.

To compare in a phase III trial the efficacy and safety of nanoparticle albumin-bound (nab)-paclitaxel plus gemcitabine (GA) with that of carboplatin plus gemcitabine (GCb) as a first-line treatment for patients with cisplatin-ineligible metastatic urothelial cancer (mUC). Treatment-naive, cisplatin-ineligible patients with mUC were assigned randomly to either the GA (both nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on Days 1 and 8, every 21 days) or GCb group (carboplatin area under the free carboplatin plasma concentration versus time curve of 4.5 on Day 1, gemcitabine 1000 mg/m2 on Days 1 and 8, every 21 days). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), safety, and patient-reported outcomes (PROs). The trial was terminated early because of slow accrual after 54 patients were enrolled: 26 in in the GA group and 28 in the GCb groups. The median PFS was 6.7 vs 5.9 months for the GA and GCb groups, respectively (P = 0.248). The median OS time was 12.1 vs 10.7 months for the GA and GCb groups, respectively (P = 0.837). The ORR and DCR were 40% vs 46.4% (P = 0.637) and 72% vs 68% (P = 0.188) in the GA and GCb groups, respectively. Patients treated with GA showed significantly lower incidence of Grade 3-4 thrombocytopenia and does reduction and delay. Although peripheral sensory neuropathy was higher in the GA arm, no Grade 3 neuropathy occurred. There was no difference in the PROs between the two groups. While not powered for comparison, first-line GA showed similar efficacy and better tolerability and might be considered a rational alternative to GCb.

Engineering of surface-altered polydopamine nanocomposites for successive drug release and in vivo antitumor effects in cervical cancer therapy: Investigation of antiproliferative effects and apoptosis

Extreme side effects and drug resistance are common with single-drug chemotherapy, reducing its efficacy as a treatment. Photothermal therapy (PTT) is a promising technique for treating cancer since it is noninvasive, can be controlled from a distance, and is highly targeted. Nanomedicines having synergistic chemo-photothermal characteristics may be more effective at combating tumors. To deliver gemcitabine (GEM) for targeted cancer therapy, we fabricated polydopamine (PDA)-loaded with polyethylene glycol and folic acid (FA). The findings demonstrated this delivery vehicle's narrow size distribution and nanoscale particle size. During the stability test, no substantial drug leakage or particle aggregation occurred. This system's photothermal conversion performance in near-infrared laser (NIR) irradiation was remarkable because of the PDA layer. HeLa cells were severely reduced in their ability to recover, and apoptosis was triggered in cancer cells after FA modification increased intracellular absorption of nanoparticles. To prevent drug-related cardiotoxicity, the nanoparticle group decreased GEM levels in the heart compared to the free GEM group. HeLa cervical carcinoma was reduced in an in vivo investigation by injecting fabricated nanoformulations intravaginally into female mice. Histological data from the NPs-treated mouse model demonstrates tumour reduction by H&E. Rats with tumors would benefit significantly from the suggested nanoformulation loaded with GEM. Using chemo-photothermal treatment, it was demonstrated in vitro and in vivo that cervical cancers could be totally removed, and the lives of survivors may be significantly prolonged.

Hepatic safety profile of pancreatic cancer‑bearing mice fed a ketogenic diet in combination with gemcitabine.

Ketogenic diets (KDs) are actively being evaluated for their potential anticancer effects. Although KDs are generally considered safe, their safety profile when combined with chemotherapy remains unknown. It is known that a KD enhances the anticancer effect of gemcitabine (2',2'-difluoro-2'-deoxycytidine) in LSL-KrasLSL-G12D/+Trp53R172H/+Pdx-1-Cre (KPC) tumor-bearing mice. In the present study, whether a KD in combination with gemcitabine affected the liver safety profile in KPC mice was evaluated. For this purpose, male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD; % kcal: 20% fat, 65% carbohydrate, 15% protein) + gemcitabine [control plus gemcitabine group (CG)] or a KD (% kcal: 84% fat, 15% protein, 1% carbohydrate) + gemcitabine [ketogenic plus gemcitabine group (KG)] for two months. After two months of treatment, no significant differences in body weight were observed between CGs and KGs. Moreover, the KD did not significantly alter the serum protein expression levels of liver enzymes, including aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase. In addition, the KD did not alter markers of liver-lipid accumulation as well as serum cholesterol and triglyceride levels, compared with the CG-treated group. Upon histologic examination, steatosis was rare, with no notable differences between treatment groups. When examining liver fatty acid composition, KD treatment significantly increased the content of saturated fatty acids and significantly decreased levels of cis-monounsaturated fatty acids compared with the CG. Finally, the KD did not affect liver markers of inflammation and oxidative stress, nor the protein expression levels of enzymes involved in ketone bodies, such as 3-hydroxy-3-methylglutaryl-CoA lyase and hidroximetilglutaril-CoA sintasa, and glucose metabolism, such as hexokinase 2, pyruvate dehydrogenase and phosphofructokinase. In summary, a KD in combination with gemcitabine appears to be safe, with no apparent hepatotoxicity and these data support the further evaluation of a KD as an adjuvant dietary treatment for pancreatic cancer.

A comprehensive analysis of tumor-stromal collagen in relation to pathological, molecular, and immune characteristics and patient survival in pancreatic ductal adenocarcinoma

BackgroundAbundant collagen deposition is a hallmark of pancreatic ductal adenocarcinomas (PDACs). This study clarified the interactive relationship between tumor-stromal collagen, molecular and immune characteristics, and tumor pr ogression in human PDAC.MethodsWe performed a comprehensive examination using an integrative molecular pathological epidemiology database on 169 cases with resected PDAC . The amount of tumor-stromal collagen was quantified through digital imaging analysis for Elastica van Gieson-stained whole-section tumor slides. We analyzed the association of tumor-stromal collagen with gene alterations (KRAS, TP53, CDKN2A/p16, and SMAD4), immune parameters (CD4+ tumor-infiltrating lymphocytes [TILs], CD8+ TILs, FOXP3+ TILs, and tertiary lymphoid structures), and patient prognosis.ResultsLow amounts of tumor-stromal collagen were associated with poor differentiation (multivariable OR = 3.82, 95%CI = 1.41–12.2, P = 0.008) and CDKN2A/p16 alteration (OR [95%CI] = 2.06 [1.08–4.02], P = 0.03). Tumors with low collagen levels had shorter overall survival (HR [95%CI] = 2.38 [1.59–3.56], P < 0.0001). In the S-1 and gemcitabine (GEM) treatment groups, low tumor-stromal collagen was linked to poor prognosis of patients with PDAC (S-1 group: multivariable HR [95%CI] = 2.76 [1.36–5.79], P = 0.005; GEM group: multivariate HR [95%CI] = 2.91 [1.34–6.71], P = 0.007). Additionally, low amounts of tumor-stromal collagen were also linked to low levels of CD4+ TILs (P = 0.046), CD8+ TILs (P = 0.09), and tertiary lymphoid structures (P = 0.001).ConclusionsTumor-stromal collagen deposition may play a crucial role in modulating tumor-immune microenvironment and determining response to adjuvant chemotherapy and patient survival outcomes.

A Ketogenic Diet in Combination with Gemcitabine Mitigates Pancreatic Cancer-Associated Cachexia in Male and Female KPC Mice.

Cancer-associated cachexia (CAC) is a critical contributor to pancreatic ductal adenocarcinoma (PDAC) mortality. Thus, there is an urgent need for new strategies to mitigate PDAC-associated cachexia; and the exploration of dietary interventions is a critical component. We previously observed that a ketogenic diet (KD) combined with gemcitabine enhances overall survival in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. In this study, we investigated the effect and cellular mechanisms of a KD in combination with gemcitabine on the maintenance of skeletal muscle mass in KPC mice. For this purpose, male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD), a KD, a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. We observed that a KD or a KG-mitigated muscle strength declined over time and presented higher gastrocnemius weights compared CD-fed mice. Mechanistically, we observed sex-dependent effects of KG treatment, including the inhibition of autophagy, and increased phosphorylation levels of eIF2α in KG-treated KPC mice when compared to CG-treated mice. Our data suggest that a KG results in preservation of skeletal muscle mass. Additional research is warranted to explore whether this diet-treatment combination can be clinically effective in combating CAC in PDAC patients.

Efficacy of apatinib on advanced ovarian cancer patients who failed first and second-line chemotherapy

Purpose: To investigate the efficacy and safety of apatinib in the treatment of advanced epithelial ovarian cancer (EOC) patients who failed first and second-line chemotherapy.&#x0D; Methods: The clinical data of 100 patients diagnosed with advanced ovarian cancer were retrospectively analyzed. They were divided into two groups, with 50 patients in each group. One group was treated with apatinib mesylate (Apatinib group), while the other group was treated with gemcitabine (Gemcitabine group). Clinical efficacy, adverse reactions, and quality-of-life scores were were assessed, while the survival status of patients was recorded during follow-up.&#x0D; Results: After treatment, the objective response rate (ORR) and disease control rate (DCR) were 24.0 % (12/50) and 70.0 % (35/50) in Apatinib group, and 12.0 % (6/50) and 52.0 % (26/50) in Gemcitabine group. In terms of adverse reactions, the incidence of hand-foot syndrome and hypertension were significantly higher in Apatinib group than in Gemcitabine group, but the incidence of nausea and vomiting, anemia, neutropenia, and thrombocytopenia were significantly lower in Apatinib group than in Gemcitabine group (p &lt; 0.05). Follow-up results revealed the median overall survival (OS) of patients to be 10.1 and 9.0 months, respectively, in Apatinib and Gemcitabine groups. Results of the log-rank test showed that OS in Apatinib group was significantly longer than that of Gemcitabine group.&#x0D; Conclusion: Apatinib demonstrates clear effectiveness and a superior safety profile than Gemcitabine in the management of patients with advanced ovarian cancer who did not respond effectively to multiple rounds of chemotherapy.

Thymoquinone affects the gemcitabine sensitivity of pancreatic cancer by regulating collagen via hypoxia inducible factor-1α.

Objective: To clarify the potential therapeutic effects of thymoquinone (TQ) on pancreatic cancer and its gemcitabine (GEM) sensitivity. Methods: The expression levels of hypoxia inducible factor-1α (HIF-1α), collagens (COL1A1, COL3A1, and COL5A1), and transforming growth factor-β1 (TGFβ1) in pancreatic cancer and para-carcinoma tissues were compared using immunohistochemical methods, and their relationships with TNM staging were analyzed. The effects of TQ on apoptosis, migration, invasion, and GEM sensitivity of pancreatic cancer cells were assessed using in vitro and in vivo experiments. Western blot and immunohistochemistry were used to detect the expression levels of HIF-1α, extracellular matrix (ECM) production pathway-related proteins, and TGFβ/Smad signaling pathway-related proteins. Results: The expression levels of HIF-1α, COL1A1, COL3A1, COL5A1, and TGFβ1 in pancreatic cancer tissues were significantly higher than those in para-carcinoma tissues and correlated with TNM staging (p < 0.05). TQ and GEM administration inhibited the migration and invasion of the human pancreatic cancer cell line PANC-1 and promoted the apoptosis of PANC-1 cells. The combination of TQ and GEM was more effective than GEM alone. Western blot analysis showed that the expression levels of HIF-1α, ECM production pathway-related proteins, and TGFβ/Smad signaling pathway-related proteins were significantly decreased when TQ was used to treat PANC-1 cells (p < 0.05), and the expression levels of these proteins in the TQ + GEM group were significantly more decreased than those in the GEM group. Overexpression or knockdown of HIF-1α in PANC-1 cells showed the same effects as those induced by TQ administration. In vivo experiments showed that in PANC-1 tumor-bearing mice, tumor volume and tumor weight in mice treated with GEM and TQ were significantly lower than those in control or GEM-treated mice, whereas cell apoptosis was significantly increased (p < 0.05). Western blot and immunohistochemistry results showed that the levels of HIF-1α, ECM production pathway-related proteins, and TGFβ/Smad signaling pathway-related proteins in the GEM + TQ treatment group were further decreased compared to the control group or the GEM treatment group (p < 0.05). Conclusion: In pancreatic cancer cells, TQ can promote apoptosis, inhibit migration, invasion, and metastasis, and enhance the sensitivity to GEM. The underlying mechanism may involve the regulation of ECM production through the TGFβ/Smad pathway, in which HIF-1α plays a key role.

The application of gemcitabine and pirarubicin in patients with non-muscle invasive bladder cancer.

To investigate the value of gemcitabine and pirarubicin in patients with non-muscle-invasive bladder cancer (NMIBC). 405 patients with non-muscle invasive bladder cancer admitted to our hospital from January 2012 to December 2020 who underwent transurethral bladder tumor electronic resection were studied. 177 patients were treated with gemcitabine (Gemcitabine group) and 228 patients were treated with pirarubicin (Pirarubicin group) after surgery. The efficacy and adverse effects of the two groups were observed and the patients were followed up. No differences were found when comparing age, gender, smoking, bladder mass, number of masses, hypertension, diabetes, coronary artery disease, hematuria and tumor diameter between the 2 groups (P > 0.05). In the Gemcitabine group, bladder irritation signs, meatus hematuria, fever, nausea and vomiting were lower than those in the Pirarubicin group (P < 0.05). The recurrence rates were 6.21% and 12.28% at 1year, 11.86% and 23.68% at 2years, 15.82% and 25.88% at 3years in the Gemcitabine and Pirarubicin groups respectively, with the Gemcitabine group having a significantly lower recurrence rate than the Pirarubicin group (P < 0.05). The tumor recurrence-free survival rate for 5years of gemcitabine was significantly higher than that of the Pirarubicin group (P < 0.05). Gemcitabine and pirarubicin are both effective in treating patients with non-muscle invasive bladder cancer, with gemcitabine having a lower incidence of adverse reactions, a higher safety rating, a lower recurrence rate and an improved survival outcome.

Comparison of Sequential Intravesical Gemcitabine and Docetaxel vs Bacillus Calmette-Guérin for the Treatment of Patients With High-Risk Non–Muscle-Invasive Bladder Cancer

Due to the ongoing bacillus Calmette-Guérin (BCG) shortage, sequential intravesical gemcitabine and docetaxel has been increasingly used as first-line therapy for high-risk non-muscle-invasive bladder cancer (NMIBC). However, data directly comparing these 2 therapies are lacking. To compare the outcomes of patients with high-risk NMIBC treated with gemcitabine and docetaxel vs BCG. This retrospective cohort study was conducted from January 1, 2011, to December 31, 2021. The median (IQR) duration of follow-up was 23 (12-33) months for patients receiving gemcitabine and docetaxel and 49 (27-79) months for patients receiving BCG. All patients were treated at the University of Iowa tertiary care center. A total of 312 patients with high-risk treatment-naive NMIBC were included; 174 patients were treated with BCG therapy and 138 were treated with gemcitabine and docetaxel therapy. After undergoing complete transurethral resection of bladder tumor, patients received either sequential intravesical gemcitabine, 1 g, and docetaxel, 37.5 mg, or 1 vial of BCG. Induction treatments were administered once per week for 6 weeks. Maintenance regimens were initiated if the patient was disease free at the first follow-up visit. The primary outcome was high-grade recurrence-free survival (RFS). Survival probabilities were estimated using the Kaplan-Meier method. Cox regression models were used to evaluate the association of covariates with outcomes. Adverse events were reported using the Common Terminology Criteria for Adverse Events, version 5. Among 312 patients, the median (IQR) age was 73 (66-79) years; 255 patients (81.7%) were male and 292 (93.6%) were White. Baseline clinicopathological characteristics such as sex, smoking status, and pretreatment tumor pathology were similar between treatment groups. High-grade RFS estimates were 76% (95% CI, 69%-82%) at 6 months, 71% (95% CI, 64%-78%) at 12 months, and 69% (95% CI, 62%-76%) at 24 months in the BCG group and 92% (95% CI, 86%-95%) at 6 months, 85% (95% CI, 78%-91%) at 12 months, and 81% (95% CI, 72%-87%) at 24 months in the gemcitabine and docetaxel group. Multivariable Cox regression analyses controlled for age, sex, treatment year, and presence of carcinoma in situ revealed that treatment with gemcitabine and docetaxel was associated with better high-grade RFS (hazard ratio, 0.57; 95% CI, 0.33-0.97; P = .04) and RFS (hazard ratio, 0.56; 95% CI, 0.34-0.92; P = .02) than treatment with BCG. Induction therapy for BCG was associated with greater treatment discontinuation than induction therapy for gemcitabine and docetaxel (9.2% vs 2.9%; P = .02). In this cohort study, gemcitabine and docetaxel therapy was associated with less high-grade disease recurrence and treatment discontinuation than BCG therapy. These findings suggest that, while awaiting results from an ongoing randomized clinical trial during the current BCG shortage, use of gemcitabine and docetaxel can be considered for recommendation in updated practice guidelines.

Anticancer effect of miR-124-loaded liposomal nanoparticles on pancreatic cancer progression

Pancreatic cancer (PC) is a common malignancy that is characterized by strong invasiveness and rapid development. With lack of effective treatments, patients still suffer from poor outcome. In this study, we established liposomal nanoparticles carrying microRNA-124 (Ls/miR-124) and detected their inhibitory effect on PC cells. Ls/miR-124 nanoparticles were prepared and co-cultured with PC cells (Ls/miR-124 group), as some PC cells were treated with pure liposome particles (Ls group), or gemcitabine (gemcitabine group) and some untreated were treated as control group. Flow cytometry and transwell assay were used to determine apoptosis and migration of PC cells. Bax, Bcl-2, and Caspase-3 expressions were measured. The Ls/miR-124 nanoparticles presented around 100 nm size at 3:1 molar ratio of DOTAP/Chol, with stable properties and high potential. The fluorescence intensity of the cells in the Ls/miR-124 group and gemcitabine group were higher than Ls and blank groups. RT-qPCR analysis confirmed the up-regulation of miR-124 with high transfection efficiency of 85%. Proliferation of cells in each group increased upon culture. Administration of either Ls/miR-124 nanoparticles or gemcitabine significantly decreased PC cell proliferation and increased apoptosis at similar apoptotic rate of 29.76±3.78% and 30.15±3.57. Besides, the Ls/miR-124 and gemcitabine groups had cell cycle arrest in G0/G1 phase (67.98±3.45%) and exhibited decreased migration of 19.78±2.97% and invaded cells (42.56±6.98%). The expression of Bax in both groups decreased, while expressions of Bcl-2 and Caspase-3 increased. In conclusion, administration of Ls/miR-124 nanoparticles decreased cell viability and migration of PC cells, inhibiting cell cycle progression but increasing apoptosis and restraining development of PC.

Synergistic Antitumor Effect of Everolimus Combined with Gemcitabine on Diffuse Large B-Cell Lymphoma

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. 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. 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). 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.

The different predictive value of mean platelet volume-to-lymphocyte ratio for postoperative recurrence between non-muscular invasive bladder cancer patients treated with intravesical chemotherapy and intravesical chemohyperthermia.

The inflammatory response plays a potential role in postoperative recurrence in patients with non-muscular invasive bladder cancer (NMIBC). We aimed to investigate whether platelet-to-lymphocyte ratio (PLR), mean platelet volume to lymphocyte ratio (MPVLR), and the systemic immune-inflammatory index (SII) have prognostic values in NMIBC treated with conventional intravesical chemotherapy or intravesical Chemohyperthermia (CHT) and the differences between them. A retrospective cohort study was conducted on 222 patients with NMIBC treated with Intravesical Chemotherapy or Intravesical CHT between January 2016 and December 2020. Within a week before surgery, PLR, MPVLR, and SII were determined based on routine blood settling. The optimal cutoff value of each index was determined using the receiver operating characteristic curve, and various groups were categorized accordingly. The factors influencing the prognosis of NMIBC patients receiving various treatments were investigated using the Kaplan- Meier survival curve and the Cox regression model. 69 cases (46.3%) in the gemcitabine (GEM) group had tumor recurrence and 19 (12.8%) of them progressed to muscle-invasive bladder cancer (MIBC) or got metastasis, while 19 cases (26.0%) in the CHT group recurred and 2 (2.7%) progressed. Elevated PLR, MPVLR, and SII were associated with higher recurrence rates in the GEM group. Meanwhile, PLR and MPVLR were the independent risk factors. While in the CHT group, high PLR and SII were related to postoperative recurrence and none of them were independent risk factors. The preoperative clinical inflammatory indexes PLR, SII, and MPVLR have certain predictive value for the postoperative recurrence-free survival (RFS) in NMIBC patients treated with intravesical chemotherapy while PLR and SII can predict the prognosis of NMIBC patients treated with intravesical CHT, which indicates that intravesical CHT may stop tumor recurrence by influencing the effect of mean platelet volume on tumor growth through some unknown mechanisms.

Effect of a MUC5AC Antibody (NPC-1C) Administered With Second-Line Gemcitabine and Nab-Paclitaxel on the Survival of Patients With Advanced Pancreatic Ductal Adenocarcinoma

Treatment options are limited for patients with advanced pancreatic ductal adenocarcinoma (PDAC) beyond first-line 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), with such individuals commonly being treated with gemcitabine and nab-paclitaxel. To determine whether NPC-1C, an antibody directed against MUC5AC, might increase the efficacy of second-line gemcitabine and nab-paclitaxel in patients with advanced PDAC. This multicenter, randomized phase II clinical trial enrolled patients with advanced PDAC between April 2014 and March 2017 whose disease had progressed on first-line FOLFIRINOX. Eligible patients had tumors with at least 20 MUC5AC staining by centralized immunohistochemistry review. Statistical analysis was performed from April to May 2022. Patients were randomly assigned to receive gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) administered intravenously on days 1, 8, and 15 of every 4-week cycle, with or without intravenous NPC-1C 1.5 mg/kg every 2 weeks. The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate (ORR), and safety. Pretreatment clinical variables were explored with Cox proportional hazards analysis. A total of 78 patients (median [range] age, 62 [36-78] years; 32 [41%] women; 9 [12%] Black; 66 [85%] White) received second-line treatment with gemcitabine plus nab-paclitaxel (n = 40) or gemcitabine plus nab-paclitaxel and NPC-1C (n = 38). Median OS was 6.6 months (95% CI, 4.7-8.4 months) with gemcitabine plus nab-paclitaxel vs 5.0 months (95% CI, 3.3-6.5 months; P = .22) with gemcitabine plus nab-paclitaxel and NPC-1C. Median PFS was 2.7 months (95% CI, 1.9-4.1 months) with gemcitabine plus nab-paclitaxel vs 3.4 months (95% CI, 1.9-5.3 months; P = .80) with gemcitabine plus nab-paclitaxel and NPC-1C. The ORR was 3.1% (95% CI, 0.4%-19.7%) in the gemcitabine plus nab-paclitaxel and NPC-1C group and 2.9% (95% CI, 0.4%-18.7%) in the gemcitabine plus nab-paclitaxel group. No differences in toxicity were observed between groups, except that grade 3 or greater anemia occurred more frequently in patients treated with gemcitabine plus nab-paclitaxel and NPC-1C than gemcitabine plus nab-paclitaxel (39% [15 of 38] vs 10% [4 of 40]; P = .003). The frequency of chemotherapy dose reductions was similar in both groups (65% vs 74%; P = .47). Lower performance status, hypoalbuminemia, PDAC diagnosis less than or equal to 18 months before trial enrollment, lymphocyte-to-monocyte ratio less than 2.8, and CA19-9 greater than 2000 IU/mL were independently associated with poorer survival. In this randomized clinical trial of advanced PDAC, NPC-1C did not enhance the efficacy of gemcitabine/nab-paclitaxel. These data provide a benchmark for future trials investigating second-line treatment of PDAC. ClinicalTrials.gov Identifier: NCT01834235.

Immediate surgery compared with short-course neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX, or chemoradiotherapy in patients with borderline resectable pancreatic cancer (ESPAC5): a four-arm, multicentre, randomised, phase 2 trial

Patients with borderline resectable pancreatic ductal adenocarcinoma have relatively low resection rates and poor survival despite the use of adjuvant chemotherapy. The aim of our study was to establish the feasibility and efficacy of three different types of short-course neoadjuvant therapy compared with immediate surgery. ESPAC5 (formerly known as ESPAC-5f) was a multicentre, open label, randomised controlled trial done in 16 pancreatic centres in two countries (UK and Germany). Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, biopsy proven pancreatic ductal adenocarcinoma in the pancreatic head, and were staged as having a borderline resectable tumour by contrast-enhanced CT criteria following central review. Participants were randomly assigned by means of minimisation to one of four groups: immediate surgery; neoadjuvant gemcitabine and capecitabine (gemcitabine 1000 mg/m2 on days 1, 8, and 15, and oral capecitabine 830 mg/m2 twice a day on days 1-21 of a 28-day cycle for two cycles); neoadjuvant FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, folinic acid given according to local practice, and fluorouracil 400 mg/m2 bolus injection on days 1 and 15 followed by 2400 mg/m2 46 h intravenous infusion given on days 1 and 15, repeated every 2 weeks for four cycles); or neoadjuvant capecitabine-based chemoradiation (total dose 50·4 Gy in 28 daily fractions over 5·5 weeks [1·8 Gy per fraction, Monday to Friday] with capecitabine 830 mg/m2 twice daily [Monday to Friday] throughout radiotherapy). Patients underwent restaging contrast-enhanced CT at 4-6 weeks after neoadjuvant therapy and underwent surgical exploration if the tumour was still at least borderline resectable. All patients who had their tumour resected received adjuvant therapy at the oncologist's discretion. Primary endpoints were recruitment rate and resection rate. Analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN, 89500674, and is complete. Between Sept 3, 2014, and Dec 20, 2018, from 478 patients screened, 90 were randomly assigned to a group (33 to immediate surgery, 20 to gemcitabine plus capecitabine, 20 to FOLFIRINOX, and 17 to capecitabine-based chemoradiation); four patients were excluded from the intention-to-treat analysis (one in the capecitabine-based chemoradiotherapy withdrew consent before starting therapy and three [two in the immediate surgery group and one in the gemcitabine plus capecitabine group] were found to be ineligible after randomisation). 44 (80%) of 55 patients completed neoadjuvant therapy. The recruitment rate was 25·92 patients per year from 16 sites; 21 (68%) of 31 patients in the immediate surgery and 30 (55%) of 55 patients in the combined neoadjuvant therapy groups underwent resection (p=0·33). R0 resection was achieved in three (14%) of 21 patients in the immediate surgery group and seven (23%) of 30 in the neoadjuvant therapy groups combined (p=0·49). Surgical complications were observed in 29 (43%) of 68 patients who underwent surgery; no patients died within 30 days. 46 (84%) of 55 patients receiving neoadjuvant therapy were available for restaging. Six (13%) of 46 had a partial response. Median follow-up time was 12·2 months (95% CI 12·0-12·4). 1-year overall survival was 39% (95% CI 24-61) for immediate surgery, 78% (60-100) for gemcitabine plus capecitabine, 84% (70-100) for FOLFIRINOX, and 60% (37-97) for capecitabine-based chemoradiotherapy (p=0·0028). 1-year disease-free survival from surgery was 33% (95% CI 19-58) for immediate surgery and 59% (46-74) for the combined neoadjuvant therapies (hazard ratio 0·53 [95% CI 0·28-0·98], p=0·016). Three patients reported local disease recurrence (two in the immediate surgery group and one in the FOLFIRINOX group). 78 (91%) patients were included in the safety set and assessed for toxicity events. 19 (24%) of 78 patients reported a grade 3 or worse adverse event (two [7%] of 28 patients in the immediate surgery group and 17 [34%] of 50 patients in the neoadjuvant therapy groups combined), the most common of which were neutropenia, infection, and hyperglycaemia. Recruitment was challenging. There was no significant difference in resection rates between patients who underwent immediate surgery and those who underwent neoadjuvant therapy. Short-course (8 week) neoadjuvant therapy had a significant survival benefit compared with immediate surgery. Neoadjuvant chemotherapy with either gemcitabine plus capecitabine or FOLFIRINOX had the best survival compared with immediate surgery. These findings support the use of short-course neoadjuvant chemotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma. Cancer Research UK.

Cytokine-Induced Killer Cell Immunotherapy Combined With Gemcitabine Reduces Systemic Metastasis in Pancreatic Cancer: An Analysis Using Preclinical Adjuvant Therapy-Mimicking Pancreatic Cancer Xenograft Model.

To evaluate the efficacy and safety of cytokine-induced killer (CIK) cell therapy in pancreatic cancer. An orthotopic murine model of pancreatic cancer and adjuvant therapy-mimicking xenograft murine model that underwent splenectomy was created. Eighty mice were randomized into four groups: the control, gemcitabine alone, CIK alone, and CIK with gemcitabine groups. The tumor growth was monitored using bioluminescence imaging once weekly. In the orthotopic murine model, the treatment groups showed a significantly longer survival than the control group (median: not reached vs 125.0 days; 95% confidence interval, 119.87-130.13; P = 0.04); however, the overall survival did not differ significantly among the treatment groups (P = 0.779). The metastatic recurrence rate and overall survival were also not significantly different among the groups in the adjuvant therapy-mimicking xenograft murine model (P = 0.497). However, the CIK and gemcitabine combination suppressed the metastatic recurrence effectively, with recurrence-free survival being significantly longer in the CIK with gemcitabine group than in the control group (median, 54 days; 95% confidence interval, 25.00-102.00; P = 0.013). The combination of CIK and gemcitabine suppressed systemic metastatic recurrence, with promising efficacy and good tolerability in an adjuvant setting of pancreatic cancer.