Current and Potential Roles of Ferroptosis in Bladder Cancer

Ferroptosis,a type of regulated cell death driven by iron-dependent lipid peroxidation,is mainly initiated by extramitochondrial lipid peroxidation due to the accumulation of iron-dependent reactive oxygen species.Ferroptosis is a prevalent and primitive form of cell death.Numerous cellular metabolic processes regulate ferroptosis,including redox homeostasis,iron regulation,mitochondrial activity,amino acid metabolism,lipid metabolism,and various disease-related signaling pathways.Ferroptosis plays a pivotal role in cancer therapy,particularly in the eradication of aggressive malignancies resistant to conventional treatments.Multiple studies have explored the connection between ferroptosis and bladder cancer,focusing on its incidence and treatment outcomes.Several biomolecules and tumor-associated signaling pathways,such as p53,heat shock protein 1,nuclear receptor coactivator 4,RAS-RAF-MEK,phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin,and the Hippo-tafazzin signaling system,exert a moderating influence on ferroptosis in bladder cancer.Ferroptosis inducers,including erastin,artemisinin,conjugated polymer nanoparticles,and quinazolinyl-arylurea derivatives,hold promise for enhancing the effectiveness of conventional anticancer medications in bladder cancer treatment.Combining conventional therapeutic drugs and treatment methods related to ferroptosis offers a promising approach for the treatment of bladder cancer.In this review,we analyze the research on ferroptosis to augment the efficacy of bladder cancer treatment.

Circulating tumor DNA and its role in detection, prognosis and therapeutics of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is considered the fifth most prevalent cancer among all types of cancers and has the third most morbidity value. It has the most frequent duplication time and a high recurrence rate. Recently, the most unique technique used is liquid biopsies, which carry many markers;the most prominent is circulating tumor DNA(ctDNA). Varied methods are used to investigate ctDNA, including various forms of polymerase chain reaction(PCR) [emulsion PCR(ePCR), digital PCR(dPCR), and bead, emulsion, amplification, magnetic(BEAMing) PCR]. Hence ctDNA is being recognized as a potential biomarker that permits early cancer detection,treatment monitoring, and predictive data on tumor burden are subjective to therapy or surgery. Numerous ctDNA biomarkers have been investigated based on their alterations such as 1) single nucleotide variations(either insertion or deletion of a nucleotide) markers including TP53, KRAS, and CCND1;2) copy number variations which include markers such as CDK6, EFGR, MYC and BRAF;3) DNA methylation(RASSF1A, SEPT9, KMT2C and CCNA2);4) homozygous mutation includes ctDNA markers as CDKN2A, AXIN1;and 5) gain or loss of function of the genes, particularly for HCC. Various researchers have conducted many studies and gotten fruitful results.Still, there are some drawbacks to ctDNA namely low quantity, fragment heterogeneity, less stability, limited mutant copies and standards, and differential sensitivity. However, plenty of investigations demonstrate ctDNA's significance as a polyvalent biomarker for cancer and can be viewed as a future diagnostic, prognostic and therapeutic agent. This article overviews many conditions in genetic changes linked to the onset and development of HCC, such as dysregulated signaling pathways, somatic mutations, single-nucleotide polymorphisms, and genomic instability. Additionally, efforts are also made to develop treatments for HCC that are molecularly targeted and to unravel some of the genetic pathways that facilitate its early identification.

Insomnia Burden among Informal Caregivers of Hospitalized Lung Cancer Patients and Its Influencing Factors

Objective This study aimed to reveal the insomnia burden and relevant influencing factors among informal caregivers(ICs)of hospitalized patients with lung cancer.Methods A cross-sectional study on ICs of hospitalized patients with lung cancer was conducted from December 31,2020 to December 31,2021.ICs’burden was assessed using the Caregiver Reaction Assessment(CRA),Hospital Anxiety and Depression Scale(HADS),and Insomnia Severity Index(ISI).Linear and logistic regression models were used to identify the influencing factors.Results Among 289 ICs of hospitalized patients with lung cancer,83(28.72%),53(18.34%),and 14(4.84%)ICs experienced mild,moderate,and severe insomnia,respectively.The scores concerning self-esteem,lack of family support,financial problems,disturbed schedule,and health problems were 4.32±0.53,2.24±0.79,2.84±1.14,3.63±0.77,and 2.44±0.95,respectively.ICs with higher Activities of Daily Living Scale(ADLS)scores were associated with a lower risk of insomnia,with an odd ratio(OR)and 95%confidence interval(CI)of 0.940(0.898–0.983).Among the ICs,female gender(OR=2.597),alcohol consumption(OR=3.745),underlying medical conditions(OR=11.765),long-term caregiving experience(OR=37.037),and higher monthly expenses(OR=5.714)were associated with a high risk of insomnia.Conclusion Of the hospitalized patients with lung cancer,51.9%experienced insomnia.Patients’ADL,ICs gender,alcohol consumption,underlying medical conditions,caregiving duration,and monthly expenses were influencing factors.Therefore,prompt screening and early intervention for ICs of patients with lung cancer is necessary.

Unusual gastric and pancreatic metastatic renal cell carcinoma presentation 10 years after surgery and immunotherapy: A case report and a review of literature

Renal cell carcinoma （RCC） is the most common renal tumor, accounting for 2%-3% of all malignancies. Though RCC is known to spread hematogenously, isolated RCC metastasis to the stomach is a rare event. In this article, we describe the clinical course of a patient who developed a pancreatic recurrence of RCC and 1 year later a gastric recurrence of RCC treated 10 years ago with a resection and interleukin-2 （IL-2）. Accumulating evidence indicates that metastatic involvement of the pancreas and stomach should be suspected in any patient with a history of RCC who presents with gastrointestinal symptoms even 10 years after RCC resection and immunotherapy.

Clinical observation of continuously subcutaneous-pumped octreotide infusion in palliative treatment of malignant bowel obstruction

Objective： The aim of the study was to observe the effectiveness of continuously subcutaneous-pumped octreotide infusion in palliative treatment of malignant bowel obstruction （MBO）. Methods： Clinical data were retrospectively analyzed in 26 carcinoma patients complicated with MBO, in the Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, China, from March 2007 to April 2009. All 26 carcinoma patients with MBO were divided into no groups： the controlling group （CG, routine therapy, 15 patients） and the octreotide group （OG, 11 patients）. The octreotide group received routine therapy combined with octreotide （0.3 mg/d） by 24 hours continuously subcutaneous octreotide infusion. The changes of curative effectiveness related to symptoms, the times of recovering exsufflation and defecation, the average drain of gastrointestinal drainage tube, the duration of gastrointestinal drainage tube and the rate of extubation, were observed and compared between the two groups. Results： After treatment, remarkable changing rates of MBO related symptoms were 81.8% （9/11） in OG, and 46.7% （7/15） in CG （P 〈 0.05）. The 78% of SG and 30% of CG recovered the exsufflation and defecation, and the mean times they needed were 3.2 d and 5.8 d, respectively （P 〈 0.05）. The durations of gastrointestinal drainage tube of OG and CG were （5 ± 1.2） d and （10 ±2.3） d, respectively, and the rates of extubation were 54.5% and 20%, respectively. The improvement rate in the octreotide group was better than that in the controlling group and the difference was significant （72.7% and 26.7%, P 〈 0.05）. Conclusion; The administration of octreotide in combination with routine treatment can be very effective in the treatment of MBO. It can relieve the symptoms of MBO effectively and improve the quality of life of the end-stage patients. It has provided one kind of new treating thought and method for treatment of malignant bowel obstruction.

Polycomb response element-binding sites in the MDR of CLL: Potential tumor suppressor regulation

Chronic lymphocytic leukemia [CLL] is the most common adult leukemia and is heterogeneous in clinical presentation. CLL cases present with various chromosomal aberrations, including 11q23, 14q32, 17p, and trisomy 12, with the most common abnormality being deletion of 13q14 [1]. Although monoallelic deletion of 13q14 is common, there is a subset of patients who have complete nullisomy at 13q14, a locus that has been hypothesized to contribute to CLL pa thogenesis [2] due to loss of tumor suppressors [DLEU and miR-15a/16-1]. We hypothesized that deletion of both copies of 13q14 would lead to uncontrollable proliferation of CLL cells and a poor prognosis. We examined our 13q14 nullisomy for survival, treatment-free survival, lymphocyte doubling time, and the presence of lymphadenopathy. Furthermore, we compared the gene expression profiles between patients with 13q14 monosomy, nullisomy, or normal karyotype. Our results suggest that patients with 13q nullisomy have a higher incidence of bulky lymphadenopathy [16.6% compared to 10% of monosomy patients], a higher frequency of lymphocyte doubling time [27.7% compared to 7.4% of monosomy patients], and a higher rate of needing treatment [50% compared to 18.5% of monosomy patients]. We observed deletion of DLEU1 and HTR2A, consistent with a gene dosage effect, and observed PRE-binding sites on DLEU1. Patients with homozygous deletion of 13q14 had a worse prognosis compared to heterozygotes. Lastly, the DLEU1 locus is a possible “second hit” loss for CLL progression.

UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil

AIM:To evaluate effects of UDP-glucuronosyltransferase1A1(UGT1A1) and thymidylate synthetase(TS) gene polymorphisms on irinotecan in metastatic colorectal cancer(mCRC).METHODS:Two irinotecan-and fluorouracil-based regimens,FOLFIRI and IFL,were selected as second-line therapy for 138 Chinese mCRC patients.Genomic DNA was extracted from peripheral blood samples before treatment.UGT1A1 and TS gene polymorphisms were determined by direct sequencing and restriction fragment length polymorphism,respectively.Gene polymorphisms of UGT1A1*28,UGT1A1*6 and promoter enhancer region of TS were analyzed.The relationship between genetic polymorphisms and clinical outcome,that is,response,toxicity and survival were assessed.Pharmacokinetic analyses were performed in a subgroup patients based on different UGT1A1 genotypes.Plasma concentration of irinotecan and its active metabolite SN-38 and inactive metabolite SN-38G were determined by high performance liquid chromatography.Differences in irinotecan and its metabolites between UGT1A1 gene variants were compared.RESULTS:One hundred and eight patients received the FOLFIRI regimen,29 the IFL regimen,and one irinotecan monotherapy.One hundred and thirty patients were eligible for toxicity and 111 for efficacy evaluation.One hundred and thirty-six patients were tested for UGT1A1*28 and *6 genotypes and 125 for promoter enhancer region of TS.Patients showed a higher frequency of wild-type UGT1A1*28(TA6/6) compared with a Caucasian population(69.9% vs 45.2%).No significant difference was found between response rates and UGT1A1 genotype,although wild-type showed lower response rates compared with other variants(17.9% vs 24.2% for UGT1A1*28,15.7% vs 26.8% for UGT1A1*6).When TS was considered,the subgroup with homozygous UGT1A1*28(TA7/7) and non-3RG genotypes showed the highest response rate(33.3%),while wild-type UGT1A1*28(TA6/6) with non-3RG only had a 13.6% response rate,but no significant difference was found.Logistic regression showed treatment duration was closely linked to clinical response.In toxicity comparison,UGT1A1*28 TA6/6 was associated with lower incidence of grade 2-4 diarrhea(27.8% vs 100%),and significantly reduced the risk of grade 4 neutropenia compared with TA7/7(7.8% vs 37.5%).Wild-type UGT1A1*6(G/G) tended to have a lower incidence of grade 3/4 diarrhea vs homozygous mutant(A/A) genotype(13.0% vs 40.0%).Taking UGT1A1 and TS genotypes together,lower incidence of grade 2-4 diarrhea was found in patients with non-3RG TS genotypes,when TA6/6 was compared with TA7/7(35.3% vs 100.0%).No significant association with time to progression(TTP) and overall survival(OS) was observed with either UGT1A1 or TS gene polymorphisms,although slightly longer TTP and OS were found with UGT1A1*28(TA6/6).Irinotecan PK was investigated in 34 patients,which showed high area under concentration curve(AUC) of irinotecan and SN-38,but low AUC ratio(SN-38G /SN-38) in those patients with UGT1A1*28 TA7/7.CONCLUSION:A distinct distribution pattern of UGT1A1 genotypes in Chinese patients might contribute to relatively low toxicity associated with irinotecan and 5-fluorouracil in mCRC patients.

Sequential chemotherapy and icotinib as first-line treatment for advanced epidermal growth factor receptor-mutated non-small cell lung cancer

BACKGROUND Icotinib could have potential effect and tolerability when used sequentially with chemotherapy for advanced epidermal growth factor receptor(EGFR)-mutated non-small cell lung cancer(NSCLC).AIM To evaluate the efficacy and safety of chemotherapy followed by icotinib maintenance therapy as first-line treatment for advanced EGFR-mutated NSCLC.METHODS This multicenter,open-label,pilot randomized controlled trial enrolled 68 EGFRmutated stage IIIB/IV NSCLC patients randomized 2:3 to the icotinib alone and chemotherapy+icotinib groups.RESULTS The median progression-free survival in the icotinib alone and chemotherapy+icotinib groups was 8.0 mo(95%CI:3.84-11.63)and 13.4 mo(95%CI:10.18-16.33),respectively(P=0.0249).No significant differences were found in the curative effect when considering different cycles of chemotherapy or chemotherapy regimen(all P>0.05).CONCLUSION A sequential combination of chemotherapy and EGFR-tyrosine kinase inhibitor is feasible for stage IV EGFR-mutated NSCLC patients.

An open-labeled, randomized, multicenter phase Ⅱa study of gambogic acid injection for advanced malignant tumors

Background Gambogic acid is a pure active compound isolated from the traditional Chinese medicinal plant gamboge （Garcinia morella Desv.）. Based on the preliminary results of a phase I study, this phase Ila study compared the efficacy and safety of different dosage schedules of gambogic acid in patients with advanced malignant tumors. Methods Patients with advanced or metastases cancer who had not received any effective routine conventional treatment or who had failed to respond to the existing conventional treatment were randomly assigned to receive either 45 mg/m2 gambogic acid intravenously from Days 1 to 5 of a 2-week cycle （Group A）, or 45 mg/m2 every other day for a total of five times during a 2-week cycle （Group B）. The primary endpoint was objective response rate （ORR）. Results Twenty-one patients assigned to Group A and 26 to Group B were included in the final analysis. The ORRs were 14.3% in Group A and 0% in Group B. It was not possible to analyze the significant difference because one of the values was zero. The disease control rates （DCRs） were 76.2% in Group A and 61.5% in Group B （P=0.0456）. The observed adverse reactions were mostly Grades I and II, and occurred in most patients after administration of the trial drug. There was no significant difference in the incidence of adverse reactions between the two arms. Conclusions The preliminary results of this phase Ila exploratory study suggest that gambogic acid has a favorable safety profile when administered at 45 mg/m2. The DCR was greater in patients receiving gambogic acid on Days 1-5 of a 2-week cycle, but the incidence of adverse reactions was similar irrespective of the administration schedule.

Therapeutic utility of Lung-MAP:ushering into an era of genomic and biomarker-driven clinical trials

demonstrated us The Lung Cancer Master Protocol(Lung-MAP;SI400)in a detailed manner.The authors introduced us screening registrations,assignments,and sub-study registrations carefully.Unlike conventional clinical trials,Lung-MAP study is a biomarker-driven umbrella trial testing the effect of different drugs on different mutations for squamous cell lung cancer(LUSC)(Fig.la).It is known that LUSC is intimately associated with tobacco exposure and could possibly amount to a high tumor mutation burden.2 Different subtypes of LUSC have been defined according to comprehensive analyses of genomic alterations.

Ligustrazine as a salvage agent for patients with relapsed or refractory non-Hodgkin＇s lymphoma

Background The prognosis is poor for patients with relapsed or refractory non-Hodgkin＇s lymphoma （NHL）. The main reason for poor prognosis is multidrug resistance （MDR）, for which the main phenotype is overexpression of P-glycoprotein （P-gp）. This study explored the efficacy of ligustrazine as a salvage agent in patients with relapsed or refractory NHL, and the relationship to P-gp expression. Methods Sixty patients were randomized to a reversal agent group, receiving ligustrazine plus chemotherapy, and a control group, receiving chemotherapy alone. Flow cytometry was performed to evaluate P-gp expression. Results In the 56 patients we were able to evaluate, there was no statistically significant difference in progression-free survival （PFS） in the two groups （P=0.0651）, but the reversal agent group had a higher overall response rate （ORR） than did the control group （P=0.048）. Forty-one of 56 patients had P-gp（＋） tumor cells. Among these patients, six of eighteen patients in the reversal agent group and in the control group had complete remission or complete remission/unconfirmed （CR＋CRu） reflecting a significant advantage in the reversal agent group （P=0.048）. Patients with P-gp（＋） tumor cells in the reversal agent group had a higher overall response rate （ORR） than did the control group （11/18 vs. 6/23, P=0.024）. Kaplan-Meier Survival curve and log-rank test demonstrated that patients with P-gp（＋） tumor cells in the reversal agent group had longer progression-free survival than did the control group （P=0.0464）. A small number of patients who received ligustrazine had a decrease in blood pressure. Conclusion Ligustrazine as a salvage agent in combination with chemotherapy can elevate response rate, prolong PFS with manageable toxicity, and correlate with P-gp expression in relapsed or refractory NHL.

Tracheal glomus tumor： two cases with bronchoscopic intervention

Glomus tumors are neoplasms derived from specialized cells of glomus bodies surrounding arteriovenous anastomoses.Although most of them are benign,aggressive cases have been described.Glomus tumors can be found throughout the body but are most highly concentrated in the digits,palms,and soles of the feet.It is rare in lung and trachea and the optimal therapy has not been thoroughly described.

Dynamic single-cell mapping unveils Epstein-Barr virusimprinted T-cell exhaustion and on-treatment response

Epstein-Barr virus(EBV)-associated gastric cancer(GC)manifests an intriguing immunotherapy response.However,the cellular basis for EBV-imprinted tumour immunity and on-treatment response remains undefined.This study aimed to finely characterize the dynamic tumour immune contexture of human EBV(+)GC treated with immunochemotherapy by longitudinal scRNA-seg and paired scTCR/BCR-seq.EBV(+)GC exhibits an inflamed-immune phenotype with increased T-cell and B-cell infiltration.