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In pancreatic ductal adenocarcinoma (PDAC), metabolic rewiring and resistance to standard therapy are closely associated. PDAC cells show enormous requirements for glucose‐derived citrate, the first rate‐limiting metabolite in the synthesis of new lipids. Both the expression and activity of citrate synthase (CS) are extraordinarily upregulated in PDAC. However, no previous relationship between gemcitabine response and citrate metabolism has been documented in pancreatic cancer. Here, we report for the first time that pharmacological doses of vitamin C are capable of exerting an inhibitory action on the activity of CS, reducing glucose‐derived citrate levels. Moreover, ascorbate targets citrate metabolism towards the de novo lipogenesis pathway, impairing fatty acid synthase (FASN) and ATP citrate lyase (ACLY) expression. Lowered citrate availability was found to be directly associated with diminished proliferation and, remarkably, enhanced gemcitabine response. Moreover, the deregulated citrate‐derived lipogenic pathway correlated with a remarkable decrease in extracellular pH through inhibition of lactate dehydrogenase (LDH) and overall reduced glycolytic metabolism. Modulation of citric acid metabolism in highly chemoresistant pancreatic adenocarcinoma, through molecules such as vitamin C, could be considered as a future clinical option to improve patient response to standard chemotherapy regimens.

Abstract Exosomes, a specific subset of extracellular vesicles, have diverse functions in various biological processes. In the field of cancer research, there has been a growing interest in the potential of exosomes to act as versatile vehicles for targeted tumor imaging and therapy. In this study, we constructed a targeted delivery platform using hypoimmunogenic exosomes by genetically modifying β2‐microglobulin knocking‐out HEK‐293F cells to express a fusion protein, referred to as αMUC1‐Exo, which comprises the exosomal membrane‐enriched platelet‐derived growth factor receptor, intracellular nanoluciferase, and extracellular anti‐MUC1 single‐chain variable fragment. The findings of this study indicate that αMUC1‐Exos exhibited notable drug delivery properties toward MUC1‐positive pancreatic cancer cells, resulting in a substantial inhibition of tumor growth. Moreover, these exosomes demonstrated a high level of biosafety and the absence of any adverse effects. The application of engineered exosomes as a vehicle for drug delivery holds promise for enhancing the immunogenicity of neoplastic cells following treatment, thereby inducing antitumor immune memory in mice with intact immune systems, and also improving the response to anti‐PD1 therapy. This approach utilizing engineered exosomes for Gemcitabine administration holds promise as a potential strategy for overcoming drug resistance in pancreatic carcinoma thereby improving the overall treatment efficacy.

Abstract Introduction Osteosarcoma is the most common primary malignancy of the bone. There is a lack of effective treatments for patients who experience relapsed osteosarcoma. One treatment for relapsed patients is gemcitabine and docetaxel combination chemotherapy (GEMDOX). This systematic review aimed to establish the efficacy of this chemotherapy regimen, as well as identify the common severe toxicities that are associated with it. Resistant osteosarcoma cell lines developed from MG‐63 and HOS‐143B were used to represent relapsed osteosarcoma patients in a pre‐clinical study. Results We identified 11 retrospective and Phase II studies that were suitable for inclusion in our review. 10.65% of patients had a response to gemcitabine and docetaxel combination therapy and the disease control rate was 35% (n = 197). 36%, 35.3% and 18.04% of patients experienced grade 3 or 4 neutropenia, thrombocytopenia and anaemia respectively (n = 133). Male patients (X2 = 9.14, p

ABSTRACT Background Bazedoxifene is a third‐generation selective estrogen receptor modulator that inhibits the IL6/IL6R/GP130 signaling pathway by inhibiting IL6‐induced homodimerization of GP130. Considering that the IL6/IL6R/GP130 signaling pathway is important in tumorigenesis and metastasis, bazedoxifene is thought to have an antitumor effect, which has been proven preliminarily in breast cancer and pancreatic cancer but has not yet been studied in non–small cell lung cancer (NSCLC). This study is aimed at evaluating the antitumor effect of bazedoxifene in NSCLC. Methods A549 and H1299 NSCLC cell lines were employed and exposed to various concentrations of bazedoxifene, paclitaxel, gemcitabine, and their combinations for cell viability, colony formation, and wound healing assays to demonstrate the antitumor effect of bazedoxifene with or without paclitaxel or gemcitabine. Results MTT cell viability, colony formation, and wound healing assays showed that bazedoxifene was capable of inhibiting cell viability, colony formation, and cell migration in a dose‐dependent manner. In addition, bazedoxifene was capable of working with paclitaxel or gemcitabine synergistically to inhibit cell viability, colony formation, and cell migration. Conclusion This study demonstrated the potential antitumor effect of bazedoxifene and its ability to improve the treatment efficacy of paclitaxel and gemcitabine.

Abstract Background Although adjuvant gemcitabine (GEM) monotherapy improves the overall survival (OS) of patients with resected pancreatic cancer, its efficacy requires further improvement. This multicenter, phase II study investigated the efficacy of adjuvant portal vein infusion (PVI) chemotherapy followed by GEM therapy in patients with resected pancreatic cancer. Methods 5‐fluorouracil (250 mg/day) and heparin (2000 IU/day) PVI chemotherapy were combined with systemic administration of mitomycin C (4 mg; days 6, 13, 20, and 27) and cisplatin (10 mg; days 7, 14, 21, and 28) for 4 weeks (PI4W), followed by GEM (1000 mg/m2; days 1, 8, and 15 every 4 weeks for 6 months). The primary endpoint was relapse‐free survival (RFS) and the secondary endpoints were OS and treatment completion. Results Between November 2010 and August 2013, 53 patients who underwent complete resection were enrolled, including 30, 20, and 3 patients who underwent pancreaticoduodenectomies and distal and total pancreatectomies, respectively. In total, 51 (96.2%) patients underwent R0 resection, of whom 3, 2, 12, 35, 0, and 1 had stages IA, IB, IIA, IIB, III, and IV cancer, respectively, and 47 (88.7%) patients completed PI4W. The median RFS was 22.0 months (1‐, 3‐, 5, and 10 years RFS: 64.9%, 38.1%, 38.1%, and 38.1%, respectively), whereas the median OS was 32.0 months (1‐, 3‐, 5, and 10 years OS:86.6%, 47.2%, 44.4%, and 44.4%, respectively). Conclusion Treatment with PI4W followed by GEM for 6 months after surgery may be beneficial in patients undergoing curative resection of pancreatic cancer.

Abstract Background Pancreatic cancer (PC) first‐line therapy often consists of polychemotherapy regimens, but choosing a second‐line therapy after disease progression, especially following first‐line FOLFIRINOX, remains a clinical challenge. This study presents results from a large, multicenter, retrospective analysis of Italian patients with metastatic PC (mPC) treated with Nab‐paclitaxel/Gemcitabine (AG) as second or later line of treatment. Main objective of the study is to identify prognostic factors that could inform treatment decisions. Methods The study included 160 mPC patients treated with AG in 17 Italian institutions. AG was administered according to labelling dose, until disease progression, unacceptable toxicity or patient refusal. Variations in schedules, dose modifications, supportive measures, and response evaluation were determined by individual clinicians' practice. Results AG was well‐tolerated and exhibited promising clinical activity. The overall response rate (ORR) and the disease control rate (DCR) were 22.5% and 45.6%, respectively. Median progression‐free survival (PFS) and overall survival (OS) were 3.9 and 6.8 months, respectively. Among the patients who received AG as a second‐line therapy (n = 111, 66.9%), median PFS and OS were 4.2 and 7.4 months, respectively. Notably, in the 76 patients (68%) receiving AG after first‐line FOLFIRINOX, an ORR of 19.7% and a DCR of 46.0% were observed, resulting in a median PFS of 3.5 and median OS of 5.7 months. The study identified specific clinical or laboratory parameters (LDH, NLR, fasting serum glucose, liver metastases, ECOG PS, and first‐line PFS) as independent prognostic factors at multivariate level. These factors were used to create a prognostic nomogram that divided patients into three risk classes, helping to predict second‐line OS and PFS. Conclusions This study represents the largest real‐world population of mPC patients treated with AG as a second or later line of therapy. It supports the feasibility of this regimen following first‐line FOLFIRINOX, particularly in patients with specific clinical and laboratory characteristics who derived prolonged benefit from first‐line therapy.

Abstract Purpose Whether the addition of tislelizumab to gemcitabine and cisplatin (GC) chemotherapy increases the incidence of myelosuppression has not been well established. This study identified the risk factors for the development of myelosuppression in patients with urothelial carcinoma (UC) after receiving GC chemotherapy with or without tislelizumab. Materials and Methods We enrolled 192 UC patients who received GC with or without tislelizumab at the Affiliated Hospital of Xuzhou Medical University between July 2014 and November 2022. Patient baseline characteristics were included in the statistical analyses after adjusting for previously reported risk factors affecting survival using propensity score matching (1:1). Binary logistic regression analysis was used to identify the risk factors associated with posttreatment myelosuppression. Results A total of 192 patients were enrolled, of whom 96 were treated with tislelizumab plus gemcitabine and cisplatin (T + GC) and 96 with GC alone. The incidence of leukopenia, anemia, and thrombocytopenia of any grade was 50.0%, 70.8%, and 42.7%, respectively, in the T + GC group and 41.7%, 72.9%, and 20.8%, respectively, in the GC group. In multivariate analysis, patients aged over 70 years (OR = 2.486, 95% CI: 1.067–5.792, p = 0.035) and those who received T + GC (OR = 3.119, 95% CI: 1.576–6.173, p = 0.001) were more likely to develop thrombocytopenia. Patients aged over 70 years (OR = 3.213, 95% CI: 1.254–8.237, p = 0.015) were more likely to develop anemia, and patients with renal insufficiency (OR = 2.105, 95% CI: 1.035–4.280, p = 0.040) were more likely to develop leukopenia. Eventually, 99 (51.6%) patients with UC successfully completed all the treatment cycles. Conclusions This study demonstrates that the addition of tislelizumab to GC chemotherapy led to a considerable increase in the occurrence of thrombocytopenia, whereas no significant changes were observed regarding anemia or leukopenia. It is crucial to fully inform patients at increased risk for myelosuppression of potential risks and closely monitor changes in their blood routines.

Abstract Aim To investigate the relationship between chemoresistance in pancreatic cancer patients receiving postoperative gemcitabine adjuvant therapy and specific clinical/pathological characteristics, as well as its impact on patient prognosis. Methods From June 2018 to June 2021, clinical and pathological data of 148 pancreatic cancer patients were collected, and 101 patients were followed up for tumor recurrence/metastasis and survival status. The correlation between chemoresistance and specific clinical/pathological characteristics or patient prognosis was retrospectively analyzed. Results Of the 148 patients, 78 were in the chemoresistance group and 70 in the non‐chemoresistance group. Univariate analysis showed that the development of chemoresistance may be related to patient age, combined diabetes, preoperative CA19‐9 level, tumor size, AJCC stage, vascular invasion, and positive lymph node ratio. Furthermore, subsequent multivariate analysis incorporating these variables indicated that tumor size may be a key factor influencing chemoresistance (p 3 cm). Conclusions Patients with pancreatic cancer receiving postoperative gemcitabine adjuvant therapy are more likely to develop chemoresistance when their tumor sizes are larger (diameter >3 cm). Development of chemoresistance exacerbates the prognosis of patients with pancreatic cancer, and larger tumor size is also a risk factor for poor prognosis in these patients.

Abstract Introduction Gemcitabine (GEM) is often used to treat pancreatic cancer. Many anti‐cancer drugs induce cancer cell death, but some cells survive after cell cycle arrest. Such a response to DNA damage is termed cellular senescence. Certain drugs, including the Bcl‐2‐family inhibitor ABT‐263, kill senescent cells; this is termed senolysis. In this study, we examined the therapeutic benefits of ABT‐263 in GEM‐induced senescence of human pancreatic cancer cells. Methods and Results Of four pancreatic cancer cell lines (PANC‐1, AsPC‐1, CFPAC‐1, and PANC10.05), GEM induced senescent features in PANC‐1 and AsPC‐1 cells, including increases in the cell sizes and expression levels of mRNAs encoding interleukin (IL)‐6/IL‐8 and induction of β‐galactosidase. Successive treatment with GEM and ABT‐263 triggered apoptosis in PANC‐1 and AsPC‐1 cells and suppressed colony formation significantly. Senolysis of GEM‐induced senescent pancreatic cancer cells by ABT‐263 was triggered by a Bcl‐xL inhibitor, but not by a Bcl‐2 inhibitor, suggesting a central role for Bcl‐xL in senolysis. In a xenograft mouse model, combined treatment with GEM and ABT‐737 (an ABT‐263 analog exhibiting the same specificity) suppressed in vivo growth of AsPC‐1 significantly. Conclusion Together, our results indicate that sequential treatment with GEM and senolytic drugs effectively kill human pancreatic cancer cells.

Abstract Purpose Gemcitabine, cisplatin, and S‐1 chemotherapy was superior to gemcitabine and cisplatin chemotherapy for progression‐free survival and overall survival for unresectable and recurrent biliary tract cancer in a randomized phase III trial (KHBO1401). This study aimed to evaluate the outcome of conversion surgery after chemotherapy in biliary tract cancer patients (ancillary study, KHBO1401‐3C). Methods A total of 246 patients were enrolled in KHBO1401. We compared progression‐free and overall survivals between the conversion surgery and non‐conversion surgery groups. Results Eight patients (3.3%) underwent conversion surgery with chemotherapy, seven of whom were diagnosed with unresectable disease and one with recurrence. Six and two patients received gemcitabine, cisplatin, and S‐1 chemotherapy as well as gemcitabine and cisplatin chemotherapy, respectively. Three patients in the conversion surgery group who received gemcitabine, cisplatin, and S‐1 chemotherapy showed no disease progression and survived without postoperative chemotherapy. Preoperative carbohydrate antigen 19‐9 (CA19‐9) level was a prognostic factor for conversion surgery. After correcting for immortal time bias, 1‐year progression‐free survival rates in the conversion surgery and non‐conversion surgery groups were 50.0% and 19.0%, respectively (hazard ratio 0.343, 95% confidence interval 0.286–0.843, p = 0.0092). One‐year overall survival rates in the conversion surgery and non‐conversion surgery groups were 87.5% and 56.0%, respectively (hazard ratio 0.222, 95% confidence interval 0.226–0.877, p = 0.0197). Conclusions Conversion surgery might be an option for the treatment of unresectable and recurrent biliary tract cancer in patients with normal preoperative CA19‐9 level.

Abstract Background Nab‐paclitaxel plus gemcitabine is a standard treatment for metastatic/locally advanced pancreatic cancer. The effectiveness of neoadjuvant therapy with nab‐paclitaxel plus gemcitabine (GnP‐NAT) in patients with borderline resectable pancreatic cancer (BRPC) remains unclear. Patients and Methods This single‐arm phase II trial included 61 patients with BRPC that were treated with two cycles of GnP‐NAT, (nab‐paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2), on days 1, 8, and 15 over a 4‐week period, which comprised one cycle. The primary endpoint was overall survival time. In the absence of disease progression, patients underwent planned pancreatectomy. Results Median overall survival, the primary endpoint, was 25.2 months, and the median recurrence‐free survival was 12.3 months. The overall rate of grade 3/4 events was 73.8%. One patient, who had a history of radiation therapy for past esophageal cancer, died from exacerbation via pneumonia. The overall resection rate was 73.8% (n = 45), and the R0 resection rate was 63.9% (n = 39). Overall, postoperative complications were found in 19 patients (42%) with 24 events, and nine patients (20%) with nine events ≥ grade IIIa, based on Dindo's classification. Conclusions This protocol treatment is thought to be a feasible, safe, and promising treatment regimen, but we caution against its use in patients with a history of interstitial lung disease and/or prior pulmonary irradiation. The survival data from this study suggest the need for further investigations of GnP‐NAT efficacy in patients with BRPC, as well as prospective evaluation of adverse events. Clinical Trial Registration UMIN Clinical Trials Registry, UMIN000024154 and ClinicalTrials.gov, NCT02926183.

Abstract Background and Aim A multicenter, open‐label randomized Phase II trial was conducted to determine whether low‐dose gemcitabine plus nab‐paclitaxel (GnP) could improve tolerability and show equivalent efficacy to the standard‐dose GnP for elderly patients with metastatic pancreatic cancer. Methods Consecutive patients aged ≥65 years with metastatic pancreatic cancer who presented at one of four Japanese referral centers between November 2016 and January 2021 were enrolled. The 60 patients were randomly assigned to low‐ or standard‐dose groups with a 1:1 ratio. Patients in the low‐dose GnP group received gemcitabine at a dose of 250 mg/m2 and nab‐paclitaxel at 125 mg/m2. Results Low‐dose GnP significantly decreased the rate of cases requiring dose reduction (16.7% vs 63.3%). The response rate (36.7% vs 33.3%) and progression‐free survival (7.3 vs 8 months) were comparable between the low‐ and standard‐dose groups as determined by independent review. The difference in the median overall survival between the two groups was not significant (7.9 vs 12 months). The proportion of patients with hematologic and non‐hematologic treatment‐related adverse events was comparable between the two groups. Conclusion Low‐dose GnP had an equivalent efficacy to conventional therapy; however, it did not reduce adverse events.

Abstract Background Pancreatic cancer is mostly diagnosed in an advanced stage and treated with systemic therapy with palliative intent. Nowadays, the doublet chemotherapy of Gemcitabine and nab‐paclitaxel (Gem‐Nab) is one of the most frequently used regimens worldwide, but is not ubiquitarily available or reimbursed. Therefore, we compared the clinical efficacy of Gem‐Nab to a historical control of patients treated with gemcitabine and oxaliplatin (Gem‐Ox) at our tertiary cancer center, which was the standard treatment prior to the introduction of FOLFIRINOX. Methods This single‐center retrospective real world study includes 121 patients diagnosed with locally advanced or primary metastatic pancreatic adenocarcinoma who were treated with chemotherapy doublet, with either Gem‐Nab or Gem‐Ox in palliative first‐line. Survival rates were analyzed using the Kaplan–Meier method, and comparisons were made with log‐rank tests. Gem‐Ox was considered as standard first line therapy at our institution for patients who were deemed fit for doublet chemotherapy between the years 2006 to 2012. These patients were compared to a cohort of patients treated with the new standard first‐line therapy of Gem‐Nab between 2013 and 2020. Results A total of 554 patients with pancreatic cancer of all stages were screened, and 73 patients treated with Gem‐Nab and 48 patients treated with Gem‐Ox in the palliative first‐line setting were identified and included in this analysis. Patients receiving Gem‐Ox had a statistically significantly better performance score (ECOG PS) when compared to the Gem‐Nab group (Odds ratio (OR) 0.28, 95% CI 0.12–0.65, p = 0.005), more often suffered from locally advanced than metastatic disease (OR 3.10, 95% CI 1.27–7.91, p = 0.019) and were younger in age (OR 0.95, 95% CI 0.91–0.99, p = 0.013). Median overall survival (OS) of the whole study cohort was 10.3 months (95% CI 8.5–11.6). No statistically significant difference in OS could be observed between the Gem‐Nab and the Gem‐Ox cohort (median OS: 8.9 months (95% CI 6.4–13.5) versus 10.9 months (95% CI 9.5–13.87, p = 0.794, HR 1.27, 95% CI 0.85–1.91)). Median progression‐free survival (PFS) was 6.8 months in the entire cohort (95% CI 4.9–8.4). No statistically significant difference in PFS could be observed between the Gem‐Nab and the Gem‐Ox cohort (median PFS: 5.8 months (95% CI 4.3–8.2) versus 7.9 months (95% CI 5.4–9.5) p = 0.536, HR 1.11, 95% CI 0.74–1.67). Zero‐truncated negative binomial regressions on OS and PFS adjusting for gender, age, performance status (ECOG PS), and CA19‐9 levels yielded no significant difference between Gem‐Nab or Gem‐Ox. Conclusion From our analysis, we could evidence no difference in outcome parameters in this retrospective analysis despite the worse prognostic pattern for GemOX. Therefore, we suggest Gem‐Ox as potential first line treatment option for inoperable locally advanced or metastatic pancreatic cancer, especially if Gem‐Nab is not available.

Introduction Prostatic stromal sarcoma is an extremely rare malignancy of the prostate with a poor prognosis. Case presentation A 65‐year‐old man presented with dyschezia, and computed tomography showed a large prostate mass. The diagnosis was prostate stromal sarcoma by transrectal needle biopsy. Magnetic resonance imaging suggested rectal infiltration. The patient underwent 4 courses of neoadjuvant chemotherapy with gemcitabine and docetaxel hydrate followed by total pelvic exenteration. Conclusion No recurrence has occurred at 5 years after the surgery. This is the first report of complete resection in prostate stromal sarcoma after neoadjuvant chemotherapy with gemcitabine and docetaxel hydrate.

Abstract Background Neoadjuvant treatment with nab‐paclitaxel and gemcitabine for potentially operable pancreatic adenocarcinoma has not been well studied in a prospective interventional trial and could down‐stage tumors to achieve negative surgical margins. Methods A single‐arm, open‐label phase 2 trial (NCT02427841) enrolled patients with pancreatic adenocarcinoma deemed to be borderline resectable or clinically node‐positive from March 17, 2016 to October 5, 2019. Patients received preoperative gemcitabine 1000 mg/m2 and nab‐paclitaxel 125 mg/m2 on Days 1, 8, 15, every 28 days for two cycles followed by chemoradiation with 50.4 Gy intensity‐modulated radiation over 28 fractions with concurrent fluoropyrimidine chemotherapy. After definitive resection, patients received four additional cycles of gemcitabine and nab‐paclitaxel. The primary endpoint was R0 resection rate. Other endpoints included treatment completion rate, resection rate, radiographic response rate, survival, and adverse events. Results Nineteen patients were enrolled, with the majority having head of pancreas primary tumors, both arterial and venous vasculature involvement, and clinically positive nodes on imaging. Among them, 11 (58%) underwent definitive resection and eight of 19 (42%) achieved R0 resection. Disease progression and functional decline were primary reasons for deferring surgical resection after neoadjuvant treatment. Pathologic near‐complete response was observed in two of 11 (18%) resection specimens. Among the 19 patients, the 12‐month progression‐free survival was 58%, and 12‐month overall survival was 79%. Common adverse events were alopecia, nausea, vomiting, fatigue, myalgia, peripheral neuropathy, rash, and neutropenia. Conclusion Gemcitabine and nab‐paclitaxel followed by long‐course chemoradiation represents a feasible neoadjuvant treatment strategy for borderline resectable or node‐positive pancreatic cancer.

Abstract Background The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin‐bound (nab)‐paclitaxel (GemPac) necessitating the need for a more effective treatment strategy for this refractory disease. Previously, we have demonstrated that nuclear exporter protein exportin 1 (XPO1) is a valid therapeutic target in PDAC, and the selective inhibitor of nuclear export selinexor (Sel) synergistically enhances the efficacy of GemPac in pancreatic cancer cells, spheroids and patient‐derived tumours, and had promising activity in a phase I study. Methods Here, we investigated the impact of selinexor–gemcitabine–nab‐paclitaxel (Sel‐GemPac) combination on LSL‐KrasG12D/+; LSL‐Trp53R172H/+; Pdx1‐Cre (KPC) mouse model utilising digital spatial profiling (DSP) and single nuclear RNA sequencing (snRNAseq). Results Sel‐GemPac synergistically inhibited the growth of the KPC tumour‐derived cell line. The Sel‐GemPac combination reduced the 2D colony formation and 3D spheroid formation. In the KPC mouse model, at a sub‐maximum tolerated dose (sub‐MTD) , Sel‐GemPac enhanced the survival of treated mice compared to controls (p

Abstract The lethality and chemotherapy resistance of pancreatic cancer necessitates the urgent development of innovative strategies to improve patient outcomes. To address this issue, we designed a novel drug delivery system named GDMCN2,which uses iron‐based metal organic framework (Fe‐MOF) nanocages encased in a covalent organic framework (COF) and modified with the pancreatic cancer‐specific antibody, NRP2. After being targeted into tumor cells, GDMCN2 gradually release the sonosensitizer sinoporphyrin sodium (DVDMS) and chemotherapeutic gemcitabine (GEM) and simultaneously generated reactive oxygen species (ROS) under ultrasound (US) irradiation. This system can overcome gemcitabine resistance in pancreatic cancer and reduce its toxicity to non‐targeted cells and tissues. In a mechanistic cascade, the release of ROS activates the mitochondrial transition pore (MPTP), leading to the release of Ca2+ and induction of endoplasmic reticulum (ER) stress. Therefore, microtubule‐associated protein 1A/1B‐light chain 3 (LC3) is activated, promoting lysosomal autophagy. This process also induces autophagy‐dependent ferroptosis, aided by the upregulation of Nuclear Receptor Coactivator 4 (NCOA4). This mechanism increases the sensitivity of pancreatic cancer cells to chemotherapeutic drugs and increases mitochondrial and DNA damage. The findings demonstrate the potential of GDMCN2 nanocages as a new avenue for the development of cancer therapeutics.

Abstract Gemcitabine has shown clinical activity against angiosarcoma in small series, alone, or combined with taxanes. We aimed to evaluate its activity as a single‐agent in a larger series of patients with advanced angiosarcoma. We retrospectively reviewed the electronic medical records of consecutive adult patients with advanced angiosarcoma treated with single‐agent gemcitabine at our institutions from January 2010 to January 2021. Response was evaluated according to RECIST 1.1, and toxicity was graded according to NCI‐CTC v5.0. 42 patients were identified. 38 patients (90%) had received prior anthracyclines and weekly paclitaxel, and 9 (21%) had received pazopanib. The best tumor response was partial response (PR) in 16 patients (38%), or stable disease (10 patients, 24%). All 8 patients with cardiac angiosarcoma experienced a PR. Median PFS was 5.4 months (95%CI: 3.1–6.5), and median OS was 9.9 months (95%CI: 6.6–13.4). Single‐agent gemcitabine has clinically meaningful activity in advanced, heavily pre‐treated angiosarcoma.

Abstract Background Studies are trying to add immunotherapy to gemcitabine and cisplatin (GP) induction chemotherapy, the standard therapy, in nasopharyngeal carcinoma (NPC) patients with locoregionally advanced disease. However, how the immune system responds to GP remains unknown. Method We examined the dynamic changes of circulating immune cells and plasma cytokines in NPC patients administered with GP. Result After GP administration, immunosuppressive myeloid cells, including CD11b+CD14+ monocytes, CD33+ myeloid cells, CD33+CD11+ myeloid cells, total MDSCs (CD33+CD11+HLA‐DR−/low), monocytic MDSCs, and granulocytic MDSCs decreased significantly. The regulatory T cells and B cells, two important suppressive lymphocyte subpopulations, also decreased. On the other hand, the levels of CD3+ T cells, total B cells, central memory CD4+ T cells, and pro‐inflammatory cytokines (including Interleukin [IL]‐1β, IL‐6, IL‐2, IL‐5, and IL‐8) increased significantly after GP administration. Besides, GP chemotherapy did not weaken the cytotoxic activity and proliferative capacity of T cells. Conclusion Our results showed the immune modulation effect of GP induction chemotherapy in locoregionally advanced NPC, providing a solid basis for its combination with immunotherapy.

Resistance to gemcitabine is the main challenge of chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Hence, the development of a response signature to gemcitabine is essential for precision therapy of PDAC. However, existing quantitative signatures of gemcitabine are susceptible to batch effects and variations in sequencing platforms. Therefore, based on within‐sample relative expression ordering of pairwise genes, we developed a transcriptome‐based gemcitabine signature consisting of 28 gene pairs (28‐GPS) that could predict response to gemcitabine for PDAC at the individual level. The 28‐GPS was superior to previous quantitative signatures in terms of classification accuracy and prognostic performance. Resistant samples classified by 28‐GPS showed poorer overall survival, higher genomic instability, lower immune infiltration, higher metabolic level and higher‐fidelity DNA damage repair compared with sensitive samples. In addition, we found that gemcitabine combined with phosphoinositide 3‐kinase (PI3K) inhibitor may be an alternative treatment strategy for PDAC. Single‐cell analysis revealed that cancer cells in the same PDAC sample showed both the characteristics of sensitivity and resistance to gemcitabine, and the activation of the TGFβ signalling pathway could promote progression of PDAC. In brief, 28‐GPS could robustly determine whether PDAC is resistant or sensitive to gemcitabine, and may be an auxiliary tool for clinical treatment.

Abstract Herein, we report a case of a 73‐year‐old female patient diagnosed with cT4N0M1a lung adenocarcinoma with KRAS G12C mutation, PDL1

Somatic inactivation of p53 (TP53) mainly occurs as missense mutations that lead to the acquisition of neomorphic mutant protein forms. p53 mutants have been postulated to exert gain‐of‐function (GOF) effects, including promotion of metastasis and drug tolerance, which generally contribute to the acquisition of the lethal phenotype. Here, by integrating a p53R270H‐dependent transcriptomic analysis with chromatin accessibility (ATAC‐seq) profiling, we shed light on the molecular basis of a p53 mutant‐dependent drug‐tolerant phenotype in pancreatic cancer. p53R270H finely tunes chromatin accessibility in specific genomic loci, orchestrating a transcriptional programme that participates in phenotypic evolution of the cancer. We specifically focused on the p53R270H‐dependent regulation of the tyrosine kinase receptor macrophage‐stimulating protein receptor (MST1r). MST1r deregulation substantially impinged on drug response in the experimental model, recapitulating the p53R270H‐dependent phenotype, and strongly correlated with p53 mutant and aggressive phenotype in pancreatic cancer patients. As cellular plasticity in the final stages of the evolution of pancreatic cancer seems to predominantly originate from epigenetic mechanisms, we propose that mutant p53 participates in the acquisition of a lethal phenotype by fine‐tuning the chromatin landscape.

Abstract Background Lipusu is the first commercialized liposomal formulation of paclitaxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma (LSCC) in a small‐scale study. Here, we conducted a multicenter, randomized, phase 3 study to compare the efficacy and safety of cisplatin plus Lipusu (LP) versus cisplatin plus gemcitabine (GP) as first‐line treatment in locally advanced or metastatic LSCC. Methods Patients enrolled were aged between 18 to 75 years, had locally advanced (clinical stage IIIB, ineligible for concurrent chemoradiation or surgery) or metastatic (Stage IV) LSCC, had no previous systemic chemotherapy and at least one measurable lesion as per the Response Evaluation Criteria in Solid Tumors (version 1.1) before administration of the trial drug. The primary endpoint was progression‐free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profiles. To explore the possible predictive value of plasma cytokines for LP treatment, plasma samples were collected from the LP group at baseline and first efficacy evaluation time and were then subjected to analysis by 45‐Plex ProcartaPlex Panel 1 to detect the presence of 45 cytokines using the Luminex xMAP technology. The correlation between treatment outcomes and dynamic changes in the levels of cytokines were evaluated in preliminary analyses. Results The median duration of follow‐up was 15.4 months. 237 patients in the LP group and 253 patients in the GP group were included in the per protocol set (PPS). In the PPS, the median PFS was 5.2 months versus 5.5 months in the LP and GP group (hazard ratio [HR]: 1.03, P = 0.742) respectively. The median OS was 14.6 months versus 12.5 months in the LP and GP group (HR: 0.83, P = 0.215). The ORR (41.8% versus 45.9%, P = 0.412) and DCR (90.3% versus 88.1%, P = 0.443) were also similar between the LP and GP group. A significantly lower proportion of patients in the LP group experienced adverse events (AEs) leading to treatment interruptions (10.9% versus 26.4%, P < 0.001) or treatment termination (14.3% versus 23.1%, P = 0.011). The analysis of cytokine levels in the LP group showed that low baseline levels of 27 cytokines were associated with an increased ORR, and 15 cytokines were associated with improved PFS, with 14 cytokines, including TNF‐α, IFN‐γ, IL‐6, and IL‐8, demonstrating an overlapping trend. Conclusion The LP regimen demonstrated similar PFS, OS, ORR and DCR as the GP regimen for patients with locally advanced or metastatic LSCC but had more favorable toxicity profiles. The study also identified a spectrum of different cytokines that could be potentially associated with the clinical benefit in patients who received the LP regimen.

Background: In this single-arm, multicenter, phase 2 trial, the authors evaluated the efficacy and safety of avelumab plus gemcitabine in patients with leiomyosarcoma (LMS) who failed on first-line chemotherapy., Methods: Patients with advanced LMS received avelumab 10 mg/kg on days 1 and 15 (for up to 24 months) plus gemcitabine 1000 mg/m 2 on days 1, 8, and 15 of a 28-day cycle until they developed disease progression or intolerable toxicity. The primary end point was the objective response rate (ORR)., Results: In total, 38 patients were enrolled. Of these, 35 patients were evaluable, and the ORR was 20% (95% confidence interval; [CI], 8%-37%). The disease control rate was 71%, and the median duration of response was 21.8 months (range, 7.6 to ≥43.3 months). The median progression free-survival was 5.6 months (95% CI, 4.5-6.8 months), and the median overall survival was 27.5 months (95% CI, 20.4-34.6 months). Grade 3-4 adverse events occurred in 70% of patients, of which neutropenia was the most common (54%). Immune-mediated adverse events occurred in five patients (14%; hypothyroidism, n = 3; hepatitis, n = 2). Patients who had a higher density of tumor-infiltrating lymphocytes (greater than the median) exhibited better ORR (35% vs. 8%; p = .104), progression-free survival (median, 7.3 vs. 3.3 months; p = .024), and overall survival (median, not reached vs. 21.5 months; p = .027)., Conclusions: The combination of avelumab and gemcitabine demonstrated promising efficacy and manageable safety in patients with advanced LMS who progressed on first-line therapy. Tumor-infiltrating lymphocyte density may be an important factor in predicting the response to combining immunotherapy with chemotherapy., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Combined Immuno-chemotherapy consisting of gemcitabine, cisplatin and the programmed death-ligand one inhibitor durvalumab (GCD) is the new standard of care for patients with biliary tract cancers (BTC) based on positive results of the TOPAZ-1 study., Objective: We here evaluated the efficacy and safety of GCD for BTC in a German multicenter real-world patient cohort., Methods: Patients with BTC treated with GCD from 9 German centers were included. Clinicopathological baseline parameters, overall survival (OS), response rate and adverse events (AEs) were retrospectively analyzed. The prognostic impact was determined by Kaplan-Meier analyses and Cox regression models., Results: A total of 165 patients treated with GCD between 2021 and 2024 were included in the study. Median OS and median progression-free survival were 14 months (95% CI 10.3-17.7) and 8 months (95% CI 6.8-9.2), respectively. The best overall response rate was 28.5% and disease control rate was 65.5%. While extrahepatic and intrahepatic BTC showed similar outcomes, mOS was significantly shorter in patients with gall bladder cancer (GB-CA) with 9 months (95% CI 5.5-12.4; p = 0.02). In univariate analyses age ≥70 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥1, status post cholecystectomy, GB-CA and high baseline CRP values were significantly associated with OS. ECOG PS ≥ 1 and GB-CA remained independent prognostic factors for OS in multivariable cox regression analysis. AEs have been reported in 130 patients (78.8%), including 149 grade 3-4 AEs (25.5%). One patient died of severe infectious pneumonia. Immune-related (ir)AEs occurred in 17 patients (10.3%), including 9 grade 3-4 irAEs (2.2%), which led to treatment interruption in 4 patients., Conclusions: Immuno-chemotherapy in patients with BTC was feasible, effective and safe in a real-life scenario. Our results were comparable to the phase 3 clinical trial results (TOPAZ-1). Reduced efficacy was noted in patients with GB-CA and/or a reduced performance status that warrants further investigation., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: Genetic polymorphisms of molecules are known to cause individual differences in the therapeutic efficacy of anticancer drugs. However, to date, germline mutations (but not somatic mutations) for anticancer drugs have not been adequately studied. The objective of this study was to investigate the association between germline polymorphisms of gemcitabine metabolic and transporter genes with carbohydrate antigen 19-9 (CA 19-9) response (decrease ≥50% from the pretreatment level at 8 weeks) and overall survival (OS) in patients with metastatic pancreatic cancer who receive gemcitabine-based chemotherapy., Methods: This multicenter, prospective, observational study enrolled patients with metastatic pancreatic cancer patients who were receiving gemcitabine monotherapy or gemcitabine plus nanoparticle albumin-bound paclitaxel combination chemotherapy. Thirteen polymorphisms that may be involved in gemcitabine responsiveness were genotyped, and univariate and multivariate logistic regression analyses were used to determine the association of these genotypes with CA 19-9 response and OS. The significance level was set at 5%., Results: In total, 180 patients from 11 hospitals in Japan were registered, and 159 patients whose CA 19-9 response could be assessed were included in the final analysis. Patients who had a CA 19-9 response had significantly longer OS (372 vs. 241 days; p = .007). RRM1 2464A>G and RRM2 175T>G polymorphisms suggested a weak association with CA 19-9 response and OS, but it was not statistically significant. COX-2 -765G>C polymorphism did not significantly correlate with CA 19-9 response but was significantly associated with OS (hazard ratio, 2.031; p = .019)., Conclusions: Genetic polymorphisms from the pharmacokinetics of gemcitabine did not indicate a significant association with efficacy, but COX-2 polymorphisms involved in tumor cell proliferation might affect OS., (© 2024 American Cancer Society.)

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

Abstract A 72‐year‐old man, diagnosed with advanced lung squamous cell carcinoma, was administered of cisplatin plus gemcitabine with necitumumab, a human monoclonal antibody that binds to the epidermal growth factor receptor (EGFR), as a sixth‐line treatment. Tumor shrinkage was observed, but asymptomatic grade 4 hypomagnesemia occurred on day 8 of the second cycle. He received magnesium replenishment and hypomagnesemia recovered on day 40, but tumor progression was observed during the period of magnesium correction. Hypomagnesemia is known as a major adverse event of treatment with anti‐EGFR antibodies, but there have been no case reports of severe hypomagnesemia or its clinical course.

Abstract Background Expression of human equilibrative nucleoside transporter‐1 (hENT1) is reported to predict survival of gemcitabine (GEM)‐treated patients. However, predictive values of immunohistochemical hENT1 expression may differ according to the antibodies, 10D7G2 and SP120. Aim We aimed to investigate the concordance of immunohistochemical hENT1 expression between the two antibodies and prognosis. Methods The subjects of this study were totally 332 whose formalin‐fixed paraffin‐embedded specimens and/or unstained sections were obtained. The individual H‐scores and four classifications according to the staining intensity were applied for the evaluation of hENT1 expression by 10D7G2 and SP120, respectively. Results The highest concordance rate (79.8%) was obtained when the cut‐off between high and low hENT1 expression using SP120 was set between moderate and strong. There were no correlations of hENT1 mRNA level with H‐score (p = .258). Although the hENT1 mRNA level was significantly different among four classifications using SP120 (p = .011), there was no linear relationship among them. Multivariate analyses showed that adjuvant GEM was a significant predictor of the patients with low hENT1 expression using either 10D7G2 (Hazard ratio [HR] 2.39, p = .001) or SP120 (HR 1.84, p

Abstract Previously published digital autoradiography of 3H‐labeled capecitabine reveals a near‐uniform distribution of activity throughout a murine pancreatic model. This is in contrast both to 14C‐labeled gemcitabine, and established expectations, as the dense stroma of pancreatic cancer is understood to inhibit drug penetration. Capecitabine is a pro‐drug for 5 FU. The positioning of the radiolabel on capecitabine leaves open the possibility that much of the autoradiographic signal is generated by nontoxic compounds. Studies were performed on tumors derived via organoid culture from a murine KPC tumor. As before, we performed autoradiography comparing 3H capecitabine to the gemcitabine analog 18F‐FAC. The metabolism of capecitabine in this model was studied through LC–MS of tumor tissue. The autoradiographs confirmed that the 3H label from capecitabine was much more uniformly distributed through the tumor than the 18F from the gemcitabine analog. LC–MS revealed that approximately 75% of the molar mass of capecitabine had been converted into 5 FU or pre‐5 FU compounds. The remainder had been converted into nontoxic species. Therapeutically relevant capecitabine metabolites achieve a relatively even distribution in this pancreatic cancer model, in contrast to the gemcitabine analog 18F‐FAC. In a human xenograft model, (BxPC3), the 3H label from capecitabine was also uniformly spread across the tumor autoradiographs. However, at 2 h post‐administration the metabolism of capecitabine had proceeded further and the bulk of the agent was in the form of nontoxic species.

Abstract High‐dose chemotherapy and autologous stem cell transplantation (ASCT) are too toxic for elderly patients with relapsed or refractory diffuse large B‐cell lymphoma (DLBCL). Therefore, effective and tolerable regimens for elderly patients are urgently needed. The present phase II study assessed the efficacy and safety of dose‐adjusted therapy with gemcitabine, dexamethasone, cisplatin, and rituximab (GDP‐R) in this population. ASCT‐ineligible elderly patients with relapsed or refractory DLBCL received dose‐adjusted GDP‐R in each 28‐day cycle for up to six cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints were complete response (CR) rate, progression‐free survival (PFS), and safety. Thirty‐three patients were enrolled and received dose‐adjusted GDP‐R. The median age was 75 years (range: 68‐87 years). The ORR was 82.8% (90% confidence interval [CI], 67.1‐93.0%), with a CR rate of 58.6% (90% CI, 41.7‐74.1%). At a median follow‐up of 20.9 months, the 2‐year PFS rate was 46.8% (90% CI, 30.7‐61.5%) and the 2‐year overall survival rate was 63.2% (90% CI, 45.8‐76.3%). The most frequently observed grade 4 adverse events were neutropenia (63.6%), thrombocytopenia (57.6%), and lymphocytopenia (39.4%). Dose‐adjusted GDP‐R is a promising salvage regimen for ASCT‐ineligible elderly patients with relapsed DLBCL after rituximab‐containing chemotherapy and warrants further investigation.

Introduction Adrenocortical carcinoma is a rare malignant tumor with an unfavorable prognosis in the advanced stage for which second‐/third‐line chemotherapy is not well established. Case presentation A 34‐year‐old woman was referred to our institution for left adrenal tumor with multiple liver metastases and tumor thrombus extending to the inferior vena cava. According to her clinical diagnosis of adrenocortical carcinoma (T4N0M1, European Network for the Study of Adrenal Tumors stage IV), we resected the left adrenal tumor and tumor thrombus. Pathological examination confirmed the adrenocortical carcinoma diagnosis. After four courses of etoposide, doxorubicin, cisplatin, and mitotane therapy, the liver metastases progressed, and we started gemcitabine, capecitabine, and mitotane therapy as second‐line chemotherapy. After 7 months, significant shrinkage of the liver metastases was observed, and they remained stable over 16 months. Conclusion We reported a case of advanced adrenocortical carcinoma with significant shrinkage of liver metastases following gemcitabine, capecitabine, and mitotane therapy, with the effect maintained over 16 months.

As treatment options for patients with incurable metastatic castration‐resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK‐8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel‐resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo‐naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient‐derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339‐DOC and PC346C‐DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC.

Abstract Background Gemcitabine (GEM) plus nab‐paclitaxel (NabP) (GEM 1000 mg/m2 IV over 30 minutes + NabP 125 mg/m2 IV given days 1, 8, and 15 every 28 days) is one of the two standard of care combination therapies for metastatic pancreatic ductal adenocarcinoma (PDAC). Our cancer center has utilized GEM‐NabP given every two‐weeks due to tolerability and patient convenience. Here, we review the safety and efficacy of this modified regimen. Methods Metastatic PDAC patients (pts) who initiated front‐line or second‐line GEM‐NabP during 2013‐2017 were retrospectively reviewed. Primary objective was overall survival. Secondary objectives were disease control rate, progression‐free survival, and the incidence of dose delays and/or adjustments. Results From a total of 235 patients, 140 pts received GEM‐NabP front‐line while 95 pts received GEM‐NabP second‐line. Median dosing was 600 mg/m2 at fixed‐dose rate for GEM and 125 mg/m2 for NabP given predominantly (~90%) every two‐weeks. Eastern Cooperative Group performance status of 0 and 1 pts had front‐line OS of 12.7 and 9.6 months and when given second‐line had OS of 8 months and 7.3 months, respectively. ECOG 0 and 1 pts had front‐line progression‐free survival (PFS) of 5.3 months and 2.8 months and second‐line PFS was 3.5 months and 2.4 months, respectively. Treatment was well tolerated with limited dose modifications. Conclusion Our analysis revealed safety with every two‐week low dose GEM‐NabP while maintaining efficacy. Patient schedule convenience should factor into metastatic incurable malignancies. We suggest the use of every two‐week GEM‐NabP particularly in patients desiring a modified schedule.

Abstract Background In Ontario, FOLFIRINOX (FFX) and gemcitabine + nab‐paclitaxel (GnP) have been publicly funded for first‐line unresectable locally advanced pancreatic cancer (uLAPC) or metastatic pancreatic cancer (mPC) since April 2015. We examined the real‐world effectiveness and safety of FFX vs GnP for advanced pancreatic cancer, and in uLAPC and mPC. Methods Patients receiving first‐line FFX or GnP from April 2015 to March 2017 were identified in the New Drug Funding Program database. Baseline characteristics and outcomes were obtained through the Ontario Cancer Registry and other population‐based databases. Overall survival (OS) was assessed using Kaplan‐Meier and weighted Cox proportional hazard models, weighted by the inverse propensity score adjusting for baseline characteristics. Weighted odds ratio (OR) for hospitalization and emergency department visits (EDV) were estimated from weighted logistic regression models. Results For 1130 patients (632 FFX, 498 GnP), crude median OS was 9.6 and 6.1 months for FFX and GnP, respectively. Weighted OS was improved for FFX vs GnP (HR = 0.77, 0.70‐0.85). Less frequent EDV and hospitalization were observed in FFX (EDV: 67.8%; Hospitalization: 49.2%) than GnP (EDV: 77.7%; Hospitalization: 59.3%). More frequent febrile neutropenia‐related hospitalization was observed in FFX (5.8%) than GnP (3.3%). Risk of EDV and hospitalization were significantly lower for FFX vs GnP (EDV: OR = 0.68, P = .0001; Hospitalization: OR = 0.76, P = .002), whereas the risk of febrile neutropenia‐related hospitalization was significantly higher (OR = 2.12, P = .001). Outcomes for uLAPC and mPC were similar. Conclusion In the real world, FFX had longer OS, less frequent all‐cause EDV and all‐cause hospitalization, but more febrile neutropenia‐related hospitalization compared to GnP.

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

Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis and high mortality rates. Therefore, it is necessary to identify new targets and therapeutic strategies to improve the prognosis of patients with PDAC. Integrative therapies are increasingly being used to boost the efficacy of the known anticancer therapeutic approaches. Hence, this study aimed to evaluate the effects of a novel combination of different potential anticancer molecules, melatonin (MLT), cannabidiol (CBD), and oxygen-ozone (O 2 /O 3 ) to treat PDAC using in vitro and in vivo models of human PDAC. The effect of this combination was investigated in combination with gemcitabine (GEM), the most common chemotherapeutic drug used for PDAC treatment. The combination of MLT + CBD + O 2 /O 3 was more effective than the individual treatments in inhibiting PDAC cell viability and proliferation, inducing cell death, and modulating the RAS pathway protein levels. Moreover, different combinations of treatments reduced tumor mass in the PDAC mouse model, thus promoting the effect of GEM. In conclusion, a mixture of MLT + CBD + O 2 /O 3 could serve as a potential adjuvant therapeutic strategy for PDAC., (© 2024 The Author(s). Journal of Pineal Research published by John Wiley & Sons Ltd.)

Pancreatic cancer remains one of the most lethal malignant diseases. Gemcitabine-based chemotherapy is still one of the first-line systemic treatments, but chemoresistance occurs in the majority of patients. Recently, accumulated evidence has demonstrated the role of the tumour microenvironment in promoting chemoresistance. In the tumour microenvironment, pancreatic stellate cells (PSCs) are among the main cellular components, and extracellular vesicles (EVs) are common mediators of cell‒cell communication. In this study, we showed that SP1-transcribed miR-31-5p not only targeted LATS2 in pancreatic cancer cells but also regulated the Hippo pathway in PSCs through EV transfer. Consequently, PSCs synthesized and secreted protein acidic and rich in cysteins (SPARC), which was preferentially expressed in stromal cells, stimulating Extracellular Signal regulated kinase (ERK) signalling in pancreatic cancer cells. Therefore, pancreatic cancer cell survival and chemoresistance were improved due to both the intrinsic Hippo pathway regulated by miR-31-5p and external SPARC-induced ERK signalling. In mouse models, miR-31-5p overexpression in pancreatic cancer cells promoted the chemoresistance of coinjected xenografts. In a tissue microarray, pancreatic cancer patients with higher miR-31-5p expression had shorter overall survival. Therefore, miR-31-5p regulates the Hippo pathway in multiple cell types within the tumour microenvironment via EVs, ultimately contributing to the chemoresistance of pancreatic cancer cells., (© 2024 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

Recently, olsalazine a DNA hypomethylating agent was found to inhibit the growth of breast cancer cells. The present study was carried out to evaluate the effects of olsalazine pretreatment in the potentiation of chemosensitivity of gemcitabine for the treatment of hepatocellular carcinoma (HCC). In silico molecular docking was performed to analyze the interaction of olsalazine and gemcitabine with DNMT1 and DNA, respectively, using the AutoDock tools 1.5.6. Cytotoxicity of olsalazine, gemcitabine, and combination were measured on human HePG2 cells using MTT assay. Antiproliferative effects were assessed using animal model of N-nitrosodiethylamine and carbon tetrachloride-induced HCC. Treatment was initiated from 8th week of induction to 11th week and change in body weight, liver weight, and survival rate were measured. Following treatment, blood samples were collected for estimation serum biochemistry. Blood serum was used for the estimation of inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), C-reactive protein [CRP], lactate dehydrogenase (LDH), and P53 levels. Oxidative stress markers were measured in liver tissue homogenates. Histopathology and immunohistochemistry (IHC) were performed on liver sections to detect the morphological changes and P53 expression. Docking analysis revealed the interactions between olsalazine and DNMT1 with a binding energy score of -5.34 and gemcitabine and DNA with a binding energy score of -5.93. Olsalazine pretreatment potentiated the antiproliferative effect of gemcitabine in cell line study. In the group receiving olsalazine pretreatment showed significant reductions in relative liver weight and improved survival rate of gemcitabine treatment group. Serum biochemical markers: serum glutamate pyruvate transaminase, serum glutamic oxaloacetic transaminase, alkaline phosphatase, and bilirubin revealed improved liver functions. Olsalazine pretreatment also reduced the levels of inflammatory markers like CRP, LDH, TNF-α, and IL-6 and oxidative stress markers dose dependently. Histopathology and IHC showed improved liver morphology with potentiated the induction of P53 upon olsalazine pretreatment in combination with gemcitabine. In conclusion, sequential combination of olsalazine and gemcitabine improved the treatment outcomes during the progression of HCC., (© 2024 Wiley Periodicals LLC.)

Abstract Purpose Notch signaling dysregulation is implicated in the development of pancreatic adenocarcinoma (PDAC). Tarextumab is a fully human IgG2 antibody that inhibits Notch2/3 receptors. Patients and Methods Aphase 2, randomized, placebo‐controlled, multicenter trial evaluated the activity of tarextumab in combination with nab‐paclitaxel and gemcitabine in patients with metastatic PDAC. Patients were stratified based on ECOG performance score and Ca 19‐9 level and randomized 1:1 to nab‐paclitaxel, gemcitabine with either tarextumab or placebo. Based on preclinical and phase Ib results suggesting a positive correlation between Notch3 gene expression and tarextumab anti‐tumor activity, patients were also divided into subgroups of low, intermediate, and high Notch3 gene expression. Primary endpoint was overall survival (OS) in all and in patients with the three Notch3 gene expression subgroups (≥25th, ≥50% and ≥75% percentiles); secondary end points included progression‐free survival (PFS), 12‐month OS, overall response rate (ORR), and safety and biomarker investigation. Results Median OS was 6.4 months in the tarextumab group vs 7.9 months in the placebo group (HR = 1.34 [95% CI = 0.95, 1.89], P = .0985). No difference observed in OS in the Notch3 gene expression subgroups. PFS in the tarextumab‐treated group (3.7 months) was significantly shorter compared with the placebo group (5.5 months) (hazard ratio was 1.43 [95% CI = 1.01, 2.01]; P = .04). Grade 3 diarrhea and thrombocytopenia were more common in the tarextumab group. Conclusions The addition of tarextumab to nab‐paclitaxel and gemcitabine did not improve OS, PFS, or ORR in first‐line metastatic PDAC, and PFS was specifically statistically worse in the tarextumab‐treated patients. Clinical trial registry no NCT01647828.

Background Drug‐eluting beads bronchial arterial chemoembolization (DEB‐BACE) can embolize the tumor‐feeding artery and also be loaded with antitumor drugs, which can be released slowly into the local tumor environment. The effect of DEB‐BACE in patients with lung cancer remains unclear. We evaluated the efficacy and safety of DEB‐BACE with gemcitabine‐loaded CalliSpheres beads in patients with non‐small cell lung cancer (NSCLC). Methods From May 2017 to December 2018, six patients with NSCLC who were ineligible or refused to receive standard treatment underwent DEB‐BACE with gemcitabine‐loaded CalliSpheres beads. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression‐free survival (PFS), overall survival (OS), and quality of life. Safety was evaluated by the occurrences of adverse events and serious adverse events. Results All patients were treated with DEB‐BACE loaded with gemcitabine (800 mg) using CalliSpheres beads. Five patients also received transarterial infusion with nedaplatin (80–100 mg). Of the six patients, five underwent a second session of DEB‐BACE, with intervals of one month between the first and second session. The median follow‐up time was 16.5 months (7.0–23.0 months). ORR and disease control rate were 50.0% and 100.0%, 50.0% and 83.3%, 50.0% and 66.7% respectively at 2, 4, and 6 months after DEB‐BACE. One patient maintained a partial response and the other five had progressive disease, of whom two patients died and the other three remained alive receiving targeted therapy, radiotherapy, transarterial infusion or thermal ablation. The median PFS was 8.0 months (4–23 months), and the 6‐ and 12 month PFS rates were 66.7% and 16.7%, respectively. The median OS was 16.5 months (7–23 months), and the six and 12 month OS rates were 100.0% and 66.7%, respectively. Hemoptysis, cough and dyspnea disappeared after DEB‐BACE in four patients. Global quality of life, physical and emotional functioning were all significantly improved at two months (P

Abstract Background/Aim There is no standard salvage chemotherapy for metastatic periampullary adenocarcinoma and duodenal adenocarcinoma and the prognosis of those who fail oxaliplatin, irinotecan, and 5FU is dismal. We examined nanoparticle albumin‐bound paclitaxel (nab‐paclitaxel) as salvage therapy for these two malignancies. Methods Patients who failed oxaliplatin, irinotecan, and 5FU and whose archival tumors stained immunohistochemical (IHC) tumor positive for CK7 or MUC1 received nab‐paclitaxel and gemcitabine therapy with or without cisplatin. Results Three patients, 2 with metastatic ampullary adenocarcinoma and 1 with duodenal adenocarcinoma with positive IHC staining for CK7 or MUC1 who failed 2 lines of chemotherapy with oxaliplatin, irinotecan, and 5FU received nab‐paclitaxel and gemcitabine with or without cisplatin. All achieved excellent tumor response on CT scans with marked falls in tumor markers CA19‐9 and CEA as well as ≥1 year of progression‐free survival. All 3 have continued to survive 2‐3 years since diagnosed with stage 4 metastatic adenocarcinoma. Conclusions Nab‐paclitaxel plus gemcitabine with or without cisplatin should be investigated as a standard‐of‐care chemotherapy regimen for patients with ampullary adenocarcinoma and duodenal adenocarcinoma.

Abstract Extranodal natural killer/T‐cell lymphoma (ENKL), nasal‐type is a rare but highly aggressive disease with poor prognosis. Optimal treatment strategies for newly diagnosed localized ENKL have not been fully defined. Here we retrospectively analyzed 72 patients with newly diagnosed stage IE/IIE ENKL treated with gemcitabine, dexamethasone, and cisplatin (GDP) regimen chemotherapy with sandwiched radiotherapy in our department between May 2012 and September 2014. After 2 cycles of GDP induction chemotherapy, the complete response rate (CRR) and overall response rate (ORR) were 30.6% (22/72) and 91.7% (66/72). After whole treatment completion, the CRR and ORR were 81.9% (59/72) and 91.7% (66/72), respectively. With a median follow‐up of 57.8 months (Interquartile Range 54.0‐64.5 months), the 5‐year progression‐free survival rate was 70.9% (95% CI, 60.1% to 81.7%), and the 5‐year overall survival rate was 72.0% (95% CI, 61.6% to 82.4%), respectively. Patients with CRR after treatment had better prognosis than their counterparts. The major adverse events were myelosuppression, liver dysfunction, gemcitabine‐related skin rash, and digestive tract toxicities. Grade 3 to 4 neutropenia and thrombocytopenia were 18.0% (13/72) and 15.3% (11/72), respectively. No treatment related deaths were observed. It is concluded that the GDP regimen with sandwiched radiotherapy was an effective and well‐tolerated treatment for newly diagnosed stage IE/IIE ENKL, nasal‐type.

Abstract The standard of care for patients with locoregionally advanced nasopharyngeal carcinoma is concurrent platinum-based chemoradiotherapy. Existing literature have demonstrated that the addition of gemcitabine and cisplatin as induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma may have promising efficacy but were from phase 2 clinical trials. Stronger evidence-based data in forms of phase 3 clinical trial investigating the survival benefits of adding gemcitabine and cisplatin induction chemotherapy for such patients have been urgently warranted. In one of our recent studies published in the New England Journal of Medicine, “Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma”, 480 locoregionally advanced nasopharyngeal carcinoma patients from 12 hospitals across China were randomly assigned in a 1:1 ratio to receive either chemoradiotherapy alone or gemcitabine plus cisplatin and chemoradiotherapy. Our findings evinced that, as compared to chemoradiotherapy alone, the addition of induction chemotherapy comprising of gemcitabine plus cisplatin to concurrent cisplatin-radiotherapy to patients with locoregionally advanced nasopharyngeal carcinoma was safe, demonstrated improved recurrence-free survival, overall survival, and distant recurrence-free survival, and marginally superior locoregional recurrence-free survival.

Abstract Cancer therapy is increasingly shifting toward targeting the tumor immune microenvironment and influencing populations of tumor infiltrating lymphocytes. Breast cancer presents a unique challenge as tumors of the triple‐negative breast cancer subtype employ a multitude of immunosilencing mechanisms that promote immune evasion and rapid growth. Treatment of breast cancer with chemotherapeutics has been shown to induce underlying immunostimulatory responses that can be further amplified with the addition of immune‐modulating agents. Here, we investigate the effects of combining doxorubicin (DOX) and gemcitabine (GEM), two commonly used chemotherapeutics, with monophosphoryl lipid A (MPLA), a clinically used TLR4 adjuvant derived from liposaccharides. MPLA was incorporated into the lipid bilayer of liposomes loaded with a 1:1 molar ratio of DOX and GEM to create an intravenously administered treatment. In vivo studies indicated excellent efficacy of both GEM‐DOX liposomes and GEM‐DOX‐MPLA liposomes against 4T1 tumors. In vitro and in vivo results showed increased dendritic cell expression of CD86 in the presence of liposomes containing chemotherapeutics and MPLA. Despite this, a tumor rechallenge study indicated little effect on tumor growth upon rechallenge, indicating the lack of a long‐term immune response. GEM/DOX/MPLA‐L displayed remarkable control of the primary tumor growth and can be further explored for the treatment of triple‐negative breast cancer with other forms of immunotherapy.

Background and Purpose: Elevated fibroblast growth factor receptor (FGFR) activity correlates with pancreatic adenocarcinoma (PDAC) progression and poor prognosis. However, its potential as a therapeutic target remains largely unexplored., Experimental Approach: The mechanisms of action and therapeutic effects of selective pan-FGFR inhibitors (pan-FGFRi) were explored using in vitro and in vivo PDAC models ranging from gemcitabine-sensitive to highly gemcitabine-resistant (GemR). Gain-/loss-of-function investigations were employed to define the role of individual FGFRs in cell proliferation, migration, and treatment response and resistance., Results: The pan-FGFRi NVP-BGJ398 significantly inhibited cell proliferation, migration, and invasion, and downregulated key cell survival- and invasiveness markers in multiple PDAC cell lines. Gemcitabine is a standard-of-care for PDAC, but development of resistance to gemcitabine (GemR) compromises its efficacy. Acquired GemR was modelled experimentally by developing highly GemR cells using escalating gemcitabine exposure in vitro and in vivo. FGFRi treatment inhibited GemR cell proliferation, migration, GemR marker expression, and tumour progression. FGFR2 or FGFR3 loss-of-function by shRNA knockdown failed to decrease cell growth, whereas FGFR1 knockdown was lethal. FGFR1 overexpression promoted cell migration more than proliferation, and reduced FGFRi-mediated inhibition of proliferation and migration. Single-agent FGFRi suppressed the viability and growth of multiple patient-derived xenografts inversely with respect to FGFR1 expression, underscoring the influence of FGFR1-dependent tumour responses to FGFRi. Importantly, secondary data analysis showed that PDAC tumours expressed FGFR1 at lower levels than in normal pancreas tissue., Conclusions and Implications: Single-agent FGFR inhibitors mediate selective, molecularly-targeted suppression of PDAC proliferation, and their effects are greatest in PDAC tumours expressing low-to-moderate levels of FGFR1., (© 2023 British Pharmacological Society.)

Abstract Background Combination therapy with oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) chemotherapy drastically improves survival of advanced pancreatic cancer patients. However, the efficacy of FOLFIRINOX as a second-line treatment after gemcitabine failure has not been tested prospectively. We investigated the feasibility and safety of attenuated FOLFIRINOX in patients with gemcitabine-refractory advanced pancreatic cancer. Methods A multicenter phase II prospective open-label, single-arm study was conducted at 14 hospitals. Patients with histologically proven invasive ductal pancreatic adenocarcinoma, a measurable or evaluable lesion, Eastern Cooperative Oncology Group performance status 0 or 1, adequate organ function, and aged 19 years or older were eligible. Attenuated FOLFIRINOX consisted of oxaliplatin 65 mg/m2, irinotecan 135 mg/m2, and leucovorin 400 mg/m2 injected intravenously on day 1 and 5-fluorouracil 2000 mg/m2 continuously infused intravenously over 46 h on days 1–2, repeated every 2 weeks. The primary endpoint was progression-free survival from the initiation of FOLFIRINOX. Secondary endpoints were the objective response rate, disease control rate, overall survival, safety, and tolerability. We estimated overall survival and progression-free survival using the Kaplan–Meier methods. Results We enrolled 39 patients from 14 institutions. The objective response rate was 10.3%, while the disease control rate was 64.1%. The 6-month and 1-year overall survival rates were 59.0% and 15.4%, respectively. Median progression-free survival and overall survival were 3.8 months (95% confidence interval [CI] 1.5–6.0 months) and 8.5 months (95% CI 5.6–11.4 months), respectively. Grade 3 or 4 adverse events were neutropenia (41.0%), nausea (10.3%), anorexia (10.3%), anemia (7.7%), mucositis (7.7%), pneumonia/pleural effusion (5.1%), and fatigue (5.1%). One treatment-related death attributable to septic shock occurred. Conclusion Attenuated FOLFIRINOX may be promising as a second-line therapy for gemcitabine-refractory pancreatic cancer.

As an established anticancer drug, gemcitabine (GEM) is an effective systemic treatment for advanced pancreatic cancer (PC). However, little is known about the potential effectors that may modify tumour cell sensitivity towards GEM. Autophagy, as a physiological cellular mechanism, is involved in both cell survival and cell death. In this study, we found that exposure to GEM induced a significant increase in autophagy in a dose‐dependent manner in PANC‐1 and BxPC‐3 cells. Inhibition of autophagy by chloroquine (CQ) and ATG7 siRNA increased GEM‐induced cytotoxicity, and CQ was more effective than ATG7 siRNA. Moreover, CQ significantly enhanced GEM‐induced apoptosis, while ATG7 siRNA failed to show the similar effect. Subsequently, we identified a potential mechanism of this cooperative interaction by showing that GEM with CQ pretreatment markedly triggered reactive oxygen species (ROS) boost and then increased lysosomal membrane permeability. Consequently, cathepsins released from lysosome into the cytoplasm induced apoptosis. We showed that CQ could enhance PC cells response to GEM in xenograft models. In conclusion, our data showed that CQ sensitized PC cells to GEM through the lysosomal apoptotic pathway via ROS. Thus, CQ as a potential adjuvant to GEM might represent an attractive therapeutic strategy for PC treatment.