Chemotherapy最新文献

Introduction: Abnormalities in splicing factors, such as mutations or deregulated expression, can lead to aberrant splicing of target genes, potentially contributing to the pathogenesis of acute myeloid leukemia (AML). Despite this, the precise mechanism underlying the abnormal alternative splicing (AS) induced by SRSF1, a splicing factor associated with poor AML prognosis, remains elusive.

Methods: Using strict splicing criteria, we globally screened for AS events in NPMc-positive and NPMc-negative AML samples from TCGA. An AS network associated with AML prognosis was then established. Functional assays, including CCK-8, flow cytometry, and Western blot, were conducted on K562 and THP-1 cells overexpressing SRSF1. Cell viability following 72-h Omipalisib treatment was also assessed. To explore the mechanism of SRSF1-induced AS, we created a BCL2L11 miniGene with a site-specific mutation at its branch point. The AS patterns of both wild-type and mutant miniGenes were analyzed following SRSF1 overexpression in HEK-293T, along with the subcellular localization of different spliceosomes.

Results: SRSF1 was significantly associated with AML prognosis. Notably, its expression was markedly upregulated in refractory AML patients compared to those with a favorable chemotherapy response. Overexpression of SRSF1 promoted THP-1 cell proliferation, suppressed apoptosis, and reduced sensitivity to Omipalisib. Mechanistically, SRSF1 recognized an aberrant branch point within the BCL2L11 intron, promoting the inclusion of a cryptic exon 3, which in turn led to apoptosis arrest.

Conclusion: Overexpression of SRSF1 and the resulting abnormal splicing of BCL2L11 are associated with drug resistance and poor prognosis in AML.

Introduction: The aim of this study was to compare the disease-free survival (DFS) and overall survival (OS) of patients who underwent interval cytoreductive surgery after 3-4 cycles or 6 cycles of neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian cancer patients.

Methods: Out of 219 patients with advanced epithelial ovarian cancer, 123 patients received 3-4 cycles and 96 patients received 6 cycles of platinum-based NACT. Afterward, laparotomy was performed for interval cytoreductive surgery.

Results: No statistically significant difference was found for DFS and OS of the patients who received 3-4 cycles and those who received 6 cycles of NACT (HR: 1.047, 95.0% CI [0.779-1.407]; p: 0.746 for DFS, and HR: 1.181, 95.0% CI [0.818-1.707]; p: 0.368 for OS). Evaluating 123 patients who received 3-4 cycles of NACT, 87 patients (70.7%) without macroscopic residual tumor after interval cytoreductive surgery had significantly longer DFS and OS compared to 36 patients (29.3%) with any residual tumor (HR: 1.830, 95.0% CI [1.194-2.806]; p: 0.003 for DFS, and HR: 1.946, 95.0% CI [1.166-3.250]; p: 0.009 for OS). 96 patients who received 6 courses of NACT were evaluated; 63 patients (65.6%) without macroscopic residual tumor after interval cytoreductive surgery had significantly longer DFS and OS than 33 patients (34.4%) with any residual tumor (HR: 1.716, 9 5.0% CI [1.092-2.697]; p: 0.010 for DFS, and HR: 1.921, 95.0% CI [1.125-3.282]; p: 0.013 for OS).

Conclusion: In patients with advanced ovarian cancer, there is no significant difference in DFS and OS between 3 and 4 cycles or 6 cycles of NACT. The most important factor determining survival is whether macroscopic residual tumor tissue remains after interval cytoreductive surgery following NACT.

Introduction: Gastric cancer is the fifth most common cancer and third leading cause of cancer-related death worldwide. There are three main ways to treat gastric cancer: surgical resection, radiation therapy, and drug therapy. Furthermore, combinations of two to three regimens can improve survival. However, the survival outcomes of chemotherapy in advanced gastric cancer patients are still unsatisfactory. Unfortunately, no widely useful biomarkers have been verified to predict the efficacy of chemotherapy for locally advanced gastric cancer.

Methods: An MTT assay was used to determine the cell viability after cisplatin or oxaliplatin treatment. Western blotting and immunohistochemistry were utilized to examine the secreted frizzled-related protein 4 (sFRP4) level and associated signaling pathways. Immunofluorescence staining was utilized to analyze the location of β-catenin. Colony formation and Transwell assays were used to analyze the functions related with cisplatin, oxaliplatin, and sFRP4.

Results: We have found that gastric cancer patients treated with combinations of 5-fluorouracil (5-FU) and cisplatin regimens have better survival rates than those treated with 5-FU-based chemotherapy alone. sFRP4 was selected as a potential target from stringent analysis and intersection of 5-FU and cisplatin resistance-related gene sets. sFRP4 was shown to be overexpressed in clinical gastric tumor tissues and positively correlated with a worse survival rate. In addition, sFRP4 and β-catenin were upregulated in cisplatin- and oxaliplatin-resistant gastric cancer cells compared to parental cells. Immunofluorescence staining and nuclear fractionation showed that β-catenin was translocated from the cytosol into the nucleus. Moreover, sFRP4 was detected in the conditioned medium of these resistant cells, which indicates that sFRP4 might have an extracellular role in chemotherapy resistance. Increased migration capacity and dysregulation of epithelial-mesenchymal transition-related markers, which might result from the dysregulation of sFRP4, were observed in cisplatin- and oxaliplatin-resistant gastric cancer cells.

Discussion/conclusion: In summary, sFRP4 might play a critical role in resistance to cisplatin and oxaliplatin, cell metastasis, and poor prognosis in gastric cancer via the Wnt-β-catenin pathway. Investigations of the molecular mechanism underlying sFRP4-modulated cancer progression and chemotherapeutic outcomes can provide additional therapeutic strategies for gastric cancer.

Background: Oral colonization and infections are frequently observed in patients during and soon after radiation therapy. Infective mucositis is a common side effect associated with cancer therapy, characterized by an inflammation of the oral mucous membranes with histological mucosal and submucosal changes. Ulcerative mucositis is responsible for significant pain, impairing the patient's nutritional intake and leading to local or systemic infections promoting mycosis due to several species of the genus Candida. According to international guidelines, treatment of candidiasis depends on the infection site and patient's condition.

Summary: Recently, several studies have shown the protective role of natural compounds counteracting the activity of Candida biofilms. The aim of this review was to discuss the antimicrobial activities of natural compounds in fungal infections, especially Candida spp., during and soon after radiotherapy. Indeed new molecules are being discovered and assessed for their capacity to control Candida spp. growth and, probably in the future, will be used to treat oral candidiasis, overall, during radiotherapy. This review reports several preliminary data about preclinical and clinical evidence of their efficacy in the prevention and/or treatment of mucositis due to radiotherapy with a brief description of the natural compounds with anti-Candida activities.

Key messages: The increase in the resistance to the available antifungal drugs related to Candida spp. infections increased as well as drug interactions, urging the development of innovative and more effective agents with antifungal action. Recent preclinical and clinical studies are identifying natural substances with anti-inflammatory and antifungal activity that could be tested in the prevention of candidiasis in patients undergoing radiotherapy. Further studies are needed to confirm these preliminary data.

Introduction: Sarcopenia has been associated with chronic diseases and cancer. The aim of this study was to evaluate sarcopenia in multiple myeloma patients undergoing autologous stem cell transplantation.

Methods: In 68 eligible patients, measurement of skeletal muscle area (cm2) on computed tomography scans at the level of the L3 vertebra (L3 SMI) was performed.

Results: 37 (54%) patients were categorized as sarcopenic: 26 males with L3 SMI values <52.4 cm2/m2, and 11 women with L3 SMI values <38.9 cm2/m2. The majority of sarcopenic patients included were older than 60 years (69%, p = 0.0005), with BMI <25 (75%; p = 0.0000). A significant association was found between sarcopenia and Sorror score value >1 (p = 0.02).

Conclusions: The Kaplan-Meier curve showed a median OS of 73.5 months for non-sarcopenic patients versus 86.5 months for sarcopenic patients, suggesting that sarcopenia is not an independent prognostic factor in this cohort of patients. Further prospective studies are needed to confirm these data.

Introduction: Antimicrobial resistance (AMR) is a serious health threat, and it has high priority among the European public health agenda. The development and implementation of the National Action Plans (NAPs) with a One-Health perspective to fight AMR was supported in 2017 by the European Union (EU) through a Joint Action on Antimicrobial Resistance and Healthcare Associated Infections (EU-JAMRAI). The Italian National Institute of Health (Istituto Superiore di Sanità), supported by the University of Udine, and the University of Foggia were among the 44 partners involved. This paper describes the results of EU-JAMRAI relevant to Italy and its impact on national policies.

Methods: The activities involved national and international experts who worked in groups, either in virtual or face-to-face meetings. Country-to-country visits were organized to assess and compare the national strategies to counteract AMR and to exchange best practices. In addition, qualitative research methods, particularly focus groups (FGs) and structured interviews, were carried out to collect information and opinions from the experts.

Results: The Italian team of experts from the Ministry of Health and the University of Foggia visited the Netherlands and hosted the Polish expert team in Italy. In two FG, stakeholders' opinions from different organizations were collected and analyzed to identify critical areas and provide recommendations to ensure implementation of the NAP and effective One-Health integration. In addition, attitudes of medical professionals toward antimicrobial stewardship were evaluated in a medium/large Italian hospital. Strengths were identified in the multidisciplinary approach and the hospital management's proactive involvement. As for the veterinary sector, Italy was among the 10 EU countries that did not have any national AMR surveillance in place for animal bacterial pathogens. Consequently, a European surveillance system was proposed with the adhesion of Italy. Regarding research and innovation to fight AMR and healthcare-associated infection, Italy worked with the other European partners to identify national research gaps and opportunities. As a result, recommendations were issued to the authorities to promote research and innovation with a One-Health approach.

Conclusions: The Italian participation in the EU JAMRAI provided experience and examples to the Italian government for implementing the NAP and planning the roadmap to fight AMR and helped point out the system's criticalities. It also supported the promotion of the One-Health integrated vision that was included in the updated NAP.

Introduction: Nosocomial meningitis may occur after procedures affecting the central nervous system or following traumatic injury. The causative infectious organism is commonly Staphylococcus aureus, a Gram-positive bacterium. The aim of the present study was to compare the effectiveness of two antibacterial agents, ceftobiprole and vancomycin, in an animal model of methicillin-resistant S. aureus (MRSA) meningitis.

Method: The strain of MRSA used was ATCC 43300. The animals were divided into three groups and infected intracisternally with MRSA. Controls received no antibiotherapy while the ceftobiprole group received 25 mg/kg and the vancomycin group received 20 mg/kg intravenously. Blood and cerebrospinal fluid (CSF) samples were collected at three time points. All animals were euthanized at 73 h after start of treatment.

Results: There was a significant difference (p < 0.05) between both treatment groups and the control animals at 24 h (drug trough) and 73 h (1 h after third dose) after start of treatment in terms of CSF bacterial levels. At 73 h, there was a significant difference in survival between the control group and the two treatment groups but no difference between the treated animal survival rates.

Conclusion: Intravenous treatment with ceftobiprole and vancomycin appears to be equally effective in a rabbit model of MRSA meningitis.

Introduction: Casiopeina III-ia (CasIII-ia) is a mixed chelate copper (II) compound capable of interacting with free radicals generated in the respiratory chain through redox reactions, producing toxic reactive oxygen species (ROS) that compromise the viability of cancer cells, bacteria and protozoa. Due to its remarkable effect on protozoa, this study evaluated the effect of CasIII-ia on Leishmania mexicana amastigotes and its potential use as a treatment for cutaneous leishmaniasis in the murine model.

Methods: We analyzed the leishmanicidal effect of CasIII-ia on L. mexicana amastigotes and on their survival in bone marrow-derived macrophages. Furthermore, we evaluated the production of ROS in treated parasites and the efficacy of CasIII-ia in the treatment of mice infected with L. mexicana.

Results: Our results show that CasIII-ia reduces parasite viability in a dose-dependent manner that correlates with increased ROS production. A decrease in the size of footpad lesions and in parasite loads was observed in infected mice treated with the intraperitoneal administration of CasIII-ia.

Conclusions: We propose CasIII-ia as a potential drug for the treatment of cutaneous leishmaniasis.

Introduction: The aim of the study was to conduct a systematic review to explore the therapeutic effect of transcatheter arterial chemoembolization (TACE) combined with portal vein embolization (PVE) for patients with hepatocellular carcinoma (HCC).

Methods: Chinese and English databases (PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang database, and VIP database) were searched from database inception to August 15, 2023. Studies comparing TACE combined with PVE versus TACE alone for patients with HCC were included. The degree of heterogeneity was assessed using I2 statistics and a Q test. The effect size was represented by risk ratio and mean difference (MD), and the effect size range was estimated using a 95% confidence interval (CI).

Results: Eight eligible studies were included in the systematic review, involving 689 participants. The results showed that the future liver residual (FLR) of patients treated with TACE combined with PVE was significantly higher than that of those treated with PVE alone (MD = 3.99%; 95% CI: 1.03-6.94). Furthermore, compared with PVE alone, TACE combined with PVE had a positive effect on disease-free survival (odds ratio [OR] = 2.16; 95% CI: 1.20-3.88), recurrence rate (OR = 0.79; 95% CI: 0.07-9.42), and complications (OR = 0.53; 95% CI: 0.30-0.96). There was no statistically significant impact on mortality with TACE combined with PVE treatment.

Conclusion: The combination of TACE with PVE can significantly reduce the FLR of patients with HCC, with higher disease-free survival, lower recurrence rate, and fewer complications.

Introduction: Mucormycosis presents a diagnostic challenge characterized by high morbidity and mortality rates due to its swift and pervasive nature, which leads to extensive tissue destruction and dissemination. Immunocompromised individuals, notably those with hematological malignancies, are at a heightened risk. First-line antifungal agents include liposomal amphotericin B (L-AMB), posaconazole, and isavuconazole (IVZ), which offer advantages, such as minimal drug interactions and a favorable safety profile. However, the necessity and efficacy of therapeutic drug monitoring (TDM) of IVZ remain unclear.

Case presentation: We report a successful case of IVZ therapy in a patient who was intolerant of L-AMB, highlighting the efficacy and pharmacokinetics of IVZ in treating pulmonary mucormycosis. Pharmacokinetic analysis revealed steady plasma IVZ concentrations, emphasizing the importance of monitoring IVZ levels, particularly in patients undergoing renal replacement therapy.

Conclusion: This case highlights the efficacy of IVZ therapy for mucormycosis and the potential utility of TDM in a specific patient population. Further research is needed to elucidate the optimal IVZ dosing and monitoring strategies to ensure safe and efficacious treatment.