Metronomic chemotherapy in hematology: Lessons from preclinical and clinical studies to build a solid rationale for future schedules.

Metronomic chemotherapy (mCHEMO), based on frequent, regular administration of low, but pharmacologically active drug doses, optimizes antitumor efficacy by targeting multiple targets and reducing toxicity of antineoplastic drugs. This minireview will summarize preclinical and clinical studies on cytotoxic drugs given at weekly, daily, or at continuous metronomic schedules alone or in combination with novel targeted agents for hematological malignancies, including lymphoma, multiple myeloma, and leukemia. Most of the preclinical in vitro and in vivo studies have reported a significant benefit of both mCHEMO monotherapy and combinatorial regimens compared with chemotherapy at the maximum tolerated dose. However, the combination of mCHEMO with targeted drugs is still little explored in the hematologic clinical setting. Data obtained from preclinical studies on low dose metronomic chemotherapy in hematological malignancies clearly suggested the possibility to clinically investigate more tolerable and effective strategies for the treatment of patients with advanced hematological malignancies, or at least for those frail and elderly patients, who are not eligible or resistant to standard treatments.

Glioblastoma and Internal Carotid Artery Calcium Score: A Possible Novel Prognostic Partnership?

Purpose: Clinical evidence suggests an association between comorbidities and outcome in patients with glioblastoma (GBM). We hypothesised that the internal carotid artery (ICA) calcium score could represent a promising prognostic biomarker in a competing risk analysis in patients diagnosed with GBM. Methods: We validated the use of the ICA calcium score as a surrogate marker of the coronary calcium score in 32 patients with lung cancer. Subsequently, we assessed the impact of the ICA calcium score on overall survival in GBM patients treated with radio-chemotherapy. Results: We analysed 50 GBM patients. At the univariate analysis, methyl-guanine-methyltransferase gene (MGMT) promoter methylation (p = 0.048), gross total tumour resection (p = 0.017), and calcium score (p = 0.011) were significant prognostic predictors in patients with GBM. These three variables also maintained statistical significance in the multivariate analysis. Conclusions: the ICA calcium score could be a promising prognostic biomarker in GBM patients.

Metronomic Chemotherapy in Elderly Patients.

PURPOSE OF REVIEW: This review describes the most relevant studies found in the scientific literature regarding metronomic chemotherapy (MCT) in the geriatric oncology population to support its use as a feasible treatment of care in the frail elderly patients. RECENT FINDINGS: Recent years have seen a reevaluation of cancer chemotherapeutic drugs and MCT is an emerging schedule in phase II and III clinical trials. Ageing is one of the risk factors for the development of cancer, the incidence of whom increases dramatically in people who live longer. To date, standard oncological protocols involve chemotherapeutic drugs in short cycles of therapy at the maximum tolerated dose (MTD). Although these therapeutic regimens may be successful, they can cause important adverse drug reactions, especially in elderly or frail patients. MCT is a different modality of delivery of chemotherapeutic drugs (frequent low dose for prolonged time) and it looks at the overcoming of the limitations and disadvantages of MTD, in particular the toxicity aspect. We reviewed the experience of clinicians who have used MCT in clinical trials enrolling elderly patients with different cancer types.

Complete Remission of a Diffuse Large B-Cell Lymphoma in a Young Patient, with Severe Tuberous Sclerosis, Treated with Metronomic Chemotherapy and Ibrutinib: A Case Report.

Tuberous sclerosis (TS) is a rare autosomal dominant genetic multisystem disease caused by mutations in either the TSC1 or TSC2 gene and results in the growth of non-cancerous masses in several organs. Diffuse large B-cell lymphoma (DLBCL) is the predominant non-Hodgkin lymphoma in adolescents and young adults. Metronomic chemotherapy (mCHEMO) can be defined as the frequent, regular administration of drug doses able to maintain a low, but active, range of concentrations of chemotherapeutic drugs during prolonged periods of time. We present the case of a young woman with severe TS who developed DLBCL. She was treated consecutively with the mCHEMO schedule R-DEVEC (prednisone, vinorelbine, etoposide, cyclophosphamide, plus rituximab) and then ibrutinib, achieving an impressive long-lasting complete remission. In conclusion, alternative treatments could be necessary when comorbidities are present in patients, and mCHEMO can be a potential successful therapeutic approach in frail subjects.

Melanocortin receptor 4 as a new target in melanoma therapy: Anticancer activity of the inhibitor ML00253764 alone and in association with B-raf inhibitor vemurafenib.

The aim of our study is to investigate in vitro and in vivo MC4R as a novel target in melanoma using the selective antagonist ML00253764 (ML) alone and in combination with vemurafenib, a B-rafV600E inhibitor. The human melanoma B-raf mutated A-2058 and WM 266-4 cell lines were used. An MC4R null A-2058 cell line was generated using a CRISPR/Cas9 system. MC4R protein expression was analysed by western blotting, immunohistochemistry, and immunofluorescence. Proliferation and apoptotic assays were performed with ML00253764, whereas the synergism with vemurafenib was evaluated by the combination index (CI) and Loewe methods. ERK1/2 phosphorylation and BCL-XL expression were quantified by western blot. In vivo experiments were performed in Athymic Nude-Foxn1nu male mice, injecting subcutaneously melanoma cells, and treating animals with ML, vemurafenib and their concomitant combination. Comet and cytome assays were performed. Our results show that human melanoma cell lines A-2058 and WM 266-4, and melanoma human tissue, express functional MC4R receptors on their surface. MC4R receptors on melanoma cells can be inhibited by the selective antagonist ML, causing antiproliferative and proapoptotic activity through the inhibition of phosphorylation of ERK1/2 and a reduction of BCL-XL. The concomitant combination of vemurafenib and ML caused a synergistic effect on melanoma cells in vitro and inhibited in vivo tumor growth in a preclinical model, without causing mouse weight loss or genotoxicity. Our original research contributes to the landscape of pharmacological treatments for melanoma, providing MC4R antagonists as drugs that can be added to established therapies.

Discovery of a Potent Dual Inhibitor of Aromatase and Aldosterone Synthase.

Estrogen deficiency derived from inhibition of estrogen biosynthesis is a typical condition of postmenopausal women and breast cancer (BCs) patients undergoing antihormone therapy. The ensuing increase in aldosterone levels is considered to be the major cause for cardiovascular diseases (CVDs) affecting these patients. Since estrogen biosynthesis is regulated by aromatase (CYP19A1), and aldosterone biosynthesis is modulated by aldosterone synthase (CYP11B2), a dual inhibitor would allow the treatment of BC while reducing the cardiovascular risks typical of these patients. Moreover, this strategy would help overcome some of the disadvantages often observed in single-target or combination therapies. Following an in-depth analysis of a library of synthesized benzylimidazole derivatives, compound X21 was found to be a potent and selective dual inhibitor of aromatase and aldosterone synthase, with IC50 values of 2.3 and 29 nM, respectively. Remarkably, the compound showed high selectivity with respect to 11ß-hydroxylase (CYP11B1), as well as CYP3A4 and CYP1A2. When tested in cells, X21 showed potent antiproliferative activity against BC cell lines, particularly against the ER+ MCF-7 cells (IC50 of 0.26 ± 0.03 µM at 72 h), and a remarkable pro-apoptotic effect. In addition, the compound significantly inhibited mTOR phosphorylation at its IC50 concentration, thereby negatively modulating the PI3K/Akt/mTOR axis, which represents an escape for the dependency from ER signaling in BC cells. The compound was further investigated for cytotoxicity on normal cells and potential cardiotoxicity against hERG and Nav1.5 ion channels, demonstrating a safe biological profile. Overall, these assays demonstrated that the compound is potent and safe, thus constituting an excellent candidate for further evaluation.

Correction: Bocci et al. Remarkable Remission Rate and Long-Term Efficacy of Upfront Metronomic Chemotherapy in Elderly and Frail Patients, with Diffuse Large B-Cell Lymphoma. J. Clin. Med. 2022, 11, 7162.

In the original publication [...].

Philadelphia chromosome-negative myeloproliferative chronic neoplasms: is clonal hematopoiesis the main determinant of autoimmune and cardio-vascular manifestations?

In this article, we reviewed the possible mechanisms linking the clonal hematopoiesis of indeterminate potential (CHIP) to chronic myeloproliferative neoplasms (MPNs), autoimmune diseases (ADs), and cardiovascular diseases (CADs). CHIP is characterized by the presence of clonal mutations with an allelic frequency >2% in the peripheral blood without dysplasia, overt hematological neoplasms, or abnormalities in blood cell count. The prevalence may reach 20% of elderly healthy individuals and is considered a risk factor for myelodysplastic neoplasms and acute leukemia. In MPNs, CHIP is often associated with mutations such as JAK2V617F or DNMT3A, TET2, or ASXL1, which exhibit a 12.1- and 1.7-2-fold increase in CADs. Specifically, JAK2-mutated cells produce excessive cytokines and reactive oxygen species, leading to proinflammatory modifications in the bone marrow microenvironment. Consequently, the likelihood of experiencing thrombosis is influenced by the variant allele frequency (VAF) of the JAK2V617F mutation, which also appears to be correlated with anti-endothelial cell antibodies that sustain thrombosis. However, DNMT3A mutations induce pro-inflammatory T-cell polarization and activate the inflammasome complex, while TET2 downregulation leads to endothelial cell autophagy and inflammatory factor upregulation. As a result, in patients with TET2 and DNMT3A-related CHIP, the inflammasome hyperactivation represents a potential cause of CADs. CHIP also occurs in patients with large and small vessel vasculitis, while ADs are more frequently associated with MPNs. In these diseases, monocytes and neutrophils play a key role in the formation of neutrophil extracellular trap (NET) as well as anti-endothelial cell antibodies, resulting in a final procoagulant effect. ADs, such as systemic lupus erythematosus, psoriasis, and arthritis, are also characterized by an overexpression of the Rho-associated coiled-coil containing protein kinase 2 (ROCK2), a serine/threonine kinase that can hyperactivate the JAK-STAT pathway. Interestingly, hyperactivation of ROCK2 has also been observed in myeloid malignancies, where it promotes the growth and survival of leukemic cells. In summary, the presence of CHIP, with or without neoplasia, can be associated with autoimmune manifestations and thrombosis. In the presence of these manifestations, it is necessary to consider a "disease-modifying therapy" that may either reduce the clonal burden or inhibit the clonally activated JAK pathway.

Methadone dose escalation in patients with opioid use disorder and cancer as a strategy for controlling cancer-related pain: A case series.

OBJECTIVES: Opioid use disorder (OUD) and cancer gained attention as co-occurring diseases in the last 2 decades due to the possible relationship between opioid prescriptions for cancer pain and the risk of developing substance use disorder in cancer patients. However, little is known about patients previously diagnosed with OUD who develop cancer and how to manage both OUD symptoms and control pain. METHODS: The present case series deals with this subpopulation and proposes a dose escalation of methadone to control both the cancer-related pain and drug addiction symptoms. RESULTS: This approach is peculiar because methadone is not used as a first-line treatment in cancer pain management and is not often used as a second-line treatment as well. Our 4 patients experienced good clinical control of symptoms and no major adverse reactions. SIGNIFICANCE OF RESULTS: The subgroup of patients with OUD who develop cancer could be the perfect population to reconsider the use of methadone as a first-line treatment for cancer pain. Prospective studies are needed to evaluate the efficacy and safety of increasing doses of methadone in these patients to validate our clinical approach.

Non-pegylated liposomal doxorubicin in older adjuvant early breast cancer patients: cardiac safety analysis and final results of the COLTONE study.

AIMS: To explore the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) plus Cyclophosphamide (CTX) followed by weekly Paclitaxel, in elderly women (≥ 65 years) with high-risk breast cancer. Previously, we described no symptomatic cardiac events within the first 12 months from starting treatment. We now reported the updated results after a median follow-up 76 months. METHODS: The cardiac activity was evaluated with left ventricular ejection fraction (LVEF) echocardiograms assessments, before starting chemotherapy and every 6 months, until 30 months from baseline, then yearly for at least 5 years. RESULTS: Forty-seven women were recruited by two Units of Medical Oncology (Ethics Committee authorization CESM-AOUP, 3203/2011; EudraCT identification number: 2010-024067-41, for Pisa and Pontedera Hospitals). An episode of grade 3 CHF (NCI-CTCAE, version 3.0) occurred after 18 months the beginning of chemotherapy. The echocardiograms assessments were performed comparing the LVEF values of each patient evaluated at fixed period of time, compared to baseline. We observed a slight changed in terms of mean values at 48, 60, 72 and 84 months. At these time points, a statistically significant reduction of - 3.2%, - 4.6%, - 6.4% and - 7.1%, respectively, was observed. However, LVEF remained above 50% without translation in any relevant clinical signs. No other cardiac significant episodes were reported. To this analysis, in 13 patients (28%) occurred disease relapse and,  of them, 11 (23%) died due to metastatic disease. Eight patients died of cancer-unrelated causes. CONCLUSIONS: The combination including NPL-DOX in elderly patients revealed low rate of cardiac toxic effects. Comparative trials are encouraged.

The impact of survivorship bias in glioblastoma research.

Despite advances in the therapy of Central Nervous System (CNS) malignancies, treatment of glioblastoma (GB) poses significant challenges due to GB resistance and high recurrence rates following post-operative radio-chemotherapy. The majority of prognostic and predictive GB biomarkers are currently developed using tumour samples obtained through surgical interventions. However, the selection criteria adopted by different neurosurgeons to determine which cases are suitable for surgery make operated patients not representative of all GB cases. Particularly, geriatric and frail individuals are excluded from surgical consideration in some cancer centers. Such selection generates a survival (or selection) bias that introduces limitations, rendering the patients or data chosen for downstream analyses not representative of the entire community. In this review, we discuss the implication of survivorship bias on current and novel biomarkers for patient selection, stratification, therapy, and outcome analyses.

A 5-Year Study of Antiseizure Medications (ASMs) Monitoring in Patients with Neuropsychiatric Disorders in an Italian Clinical Center.

Despite receiving appropriate antiseizure medications (ASMs), a relevant percentage of neuropsychiatric patients do not benefit from this approach, and one reason is subtherapeutic ASMs plasma concentration (C(p)) due to improper drug adherence, interindividual pharmacokinetic differences, or metabolic interactions among different drugs. For these reasons, therapeutic drug monitoring (TDM) by measuring ASMs C(p) is an effective tool that improves pharmacological therapies in clinical practice. Based on these premises, in the present real-world study, we analyzed the C(p) of the most used ASMs in diverse medical conditions, which were assayed during the years 2018-2022 at the University Hospital of Pisa, including about 24,000 samples. This population was largely heterogeneous, and our database did not contain clinical information about the patients. The most used ASMs were Valproate (VPA: 54.5%) and Levetiracetam (LEV: 18.6%), followed by Oxcarbazepine (OxCBZ: 8.3%) and Carbamazepine (CBZ: 7.2%), whereas the associations LEV/VPA, Ethosuximide (ESM)/VPA, and CBZ/VPA were the most frequently proposed. In about 2/3 of assays, ASMs C(p) was in range, except for VPA, which was underdosed in almost half of the samples. Importantly, toxic levels of ASMs C(p) were found very rarely. For VPA, there was a decrease of mean C(p) across ages, from adolescents to older patients, while the C(p) of LEV, CBZ, OxCBZ, and Topiramate (TPM) showed a slight tendency to increase. When we compared females and males, we found that for VPA, the average age was higher for females, whereas women taking Lamotrigine (LTG) and OxCBZ were younger than men. Then, comparing ASMs used in neurologic and psychiatric disorders, based on the request form, it emerged that the mean C(p) of CBZ, OxCBZ, and LTG on samples collected in the Psychiatric Unit was lower compared to the Neurology and Child Neuropsychiatry Units. Finally, the ASMs subjected to multiple dosing starting from an initial subtherapeutic C(p) increased their level at different time points within a year, reaching the reference range for some of them. In conclusion, the present study suggests that TDM is widely applied to monitor ASMs C(p), finding many of them within the reference range, as a demonstration of its utility in clinical practice.

Valproate and lithium: Old drugs for new pharmacological approaches in brain tumors?

Beyond its use as an antiepileptic drug, over time valproate has been increasingly used for several other therapeutic applications. Among these, the antineoplastic effects of valproate have been assessed in several in vitro and in vivo preclinical studies, suggesting that this agent significantly inhibits cancer cell proliferation by modulating multiple signaling pathways. During the last years various clinical trials have tried to find out if valproate co-administration could enhance the antineoplastic activity of chemotherapy in glioblastoma patients and in patients suffering from brain metastases, demonstrating that the inclusion of valproate in the therapeutic schedule causes an improved median overall survival in some studies, but not in others. Thus, the effects of the use of concomitant valproate in brain cancer patients are still controversial. Similarly, lithium has been tested as an anticancer drug in several preclinical studies mainly using the unregistered formulation of lithium chloride salts. Although, there are no data showing that the anticancer effects of lithium chloride are superimposable to the registered lithium carbonate, this formulation has shown preclinical activity in glioblastoma and hepatocellular cancers. However, few but interesting clinical trials have been performed with lithium carbonate on a very small number of cancer patients. Based on published data, valproate could represent a potential complementary therapeutic approach to enhance the anticancer activity of brain cancer standard chemotherapy. Same advantageous characteristics are less convincing for lithium carbonate. Therefore, the planning of specific phase III studies is necessary to validate the repositioning of these drugs in present and future oncological research.

Discovery and Development of Tumor Angiogenesis Assays.

The angiogenesis process was described in its basic concepts in the works of the Scottish surgeon John Hunter and terminologically assessed in the early twentieth century. An aberrant angiogenesis is a prerequisite for cancer cells in solid tumors to grow and metastasize. The sprouting of new blood vessels is one of the major characteristics of cancer and represents a gateway for tumor cells to enter both the blood and lymphatic circulation systems. In vivo, ex vivo, and in vitro models of angiogenesis have provided essential tools for cancer research and antiangiogenic drug screening. Several in vivo studies have been performed to investigate the various steps of tumor angiogenesis and in vitro experiments contributed to dissecting the molecular bases of this phenomenon. Moreover, coculture of cancer and endothelial cells in 2D and 3D matrices have contributed to improve the recapitulation of the complex process of tumor angiogenesis, including the peculiar conditions of tumor microenvironment.

Remarkable Remission Rate and Long-Term Efficacy of Upfront Metronomic Chemotherapy in Elderly and Frail Patients, with Diffuse Large B-Cell Lymphoma.

The upfront treatment of very elderly and frail patients with diffuse large B-cell lymphoma (DLBCL) is still a matter of debate. Herein, we report results of the metronomic all-oral DEVEC [prednisolone/deltacortene®, vinorelbine (VNR), etoposide (ETO), cyclophosphamide] combined with i.v. rituximab (R). This schedule was administered as a first line therapy in 22 elderly/frail DLBCL subjects (median age = 84.5 years). In 17/22 (77%) patients, the Elderly-IPI-score was high. After a median follow-up of 24 months, 15 patients had died: seven (50%) for causes unrelated to DLBCL or its treatment, six (40%) for progression, and two (13%) for multiorgan failure. Six treatment-pertinent serious-adverse-events occurred. At the end of induction, 14/22 (64%) achieved complete remission; overall survival and event-free survival at 24 months were both 54% (95% CI = 32−72%), while the time to progression was 74% (95% CI = 48−88%). Furthermore, antiproliferative and proapoptotic assays were performed on DLBCL/OCI-LY3 cell-line using metronomic VNR and ETO and their combination. Both metronomic VNR and ETO had concentration-dependent antiproliferative (IC50 = 0.036 ± 0.01 nM and 7.9 ± 3.6 nM, respectively), and proapoptotic activities in DLBCL cells. Co-administration of the two drugs showed a strong synergism (combination index < 1 and dose reduction index > 1) against cell proliferation and survival. This low-dose schedule seems to compare favourably with intravenous-CHEMO protocols used in the same subset. Indeed, the high synergism shown by metronomic VRN+ETO in in vitro studies, explains the remarkable clinical responses and it allows significant dose reductions.

Metronomic Chemotherapy in Pediatric Oncology: From Preclinical Evidence to Clinical Studies.

Metronomic chemotherapy (MC) is the frequent, regular administration of drug doses designed to maintain a low, but active, range of concentrations of chemotherapeutic drugs, during prolonged periods of time without inducing excessive toxicities. To date, more than 400,000 children and adolescents under the age of 20 are diagnosed with cancer, per year, with 80% survival in most high-income countries, but less than 30% in low- and middle-income ones. In this review, we summarized the principal preclinical and clinical studies involving the use of MC in the most common pediatric tumors, with an overview of efficacy, toxicity, pharmacokinetic profile, and biomarkers. The best advantages of MC are low toxicity, oral administration and, thus, the feasibility of a more comfortable, home-based treatment, therefore improving the quality of life of the children themselves and of their parents and caregivers. Moreover, MC could represent a valid method to reduce the economic burden of anticancer therapy in the pediatric setting.

Predictive Power of Tissue and Circulating Biomarkers for the Severity of Biopsy-Validated Chronic Liver Diseases.

Background: Although liver biopsy remains the gold standard for the diagnosis and the monitoring of liver disease, non-invasive biomarkers have been recently suggested to predict liver disease severity, progression, and response to therapy. We investigated multiple tissue and circulating markers of angiogenesis in predicting the severity of biopsy-validated chronic liver diseases in patients with chronic hepatitis C virus (HCV) and in NAFLD/NASH patients. Methods: We studied samples from forty-six patients with HCV and/or NAFLD who underwent liver biopsy, liver ultrasonography, and liver stiffness measurement. Ishak and Brunt scores were calculated. Expression of selective genes and luminex analyses of 17 different circulating pro-angiogenic factors were performed. Results: The phenotype of NAFLD/NASH or HCV subjects was similar, except for insulin, which was expressed at higher levels in NAFLD/NASH patients. A Mann−Whitney test showed significant differences for the circulating levels of HB-EGF and for follistatin between HCV and NAFLD/NASH patients. In HCV patients, we found an inverse correlation between disease stage and BMP-9 and VEGF-A circulating levels, while in NASH/NAFLD direct correlations between stage and BMP-9 and VEGF-A circulating levels were noted. The K-means algorithm divided HCV and NASH/NAFLD patients in two clusters with significant differences between them. Logistic regression models showed a positive relationship with BMP-9 levels for NASH/NAFLD and with HB-EGF circulating concentrations for HCV. ROC analysis showed for BMP-9 > 1188 pg/mL a worse disease in NASH/NAFLD, whereas for HB-EGF < 61 pg/mL a higher severity of disease in HCV. Conclusion: Our data show that circulating biomarker profiles can identify the severity of chronic liver disease of NAFLD/NASH or HCV origin.

Early increase of plasma soluble VEGFR-2 is associated with clinical benefit from second-line treatment of paclitaxel and ramucirumab in advanced gastric cancer.

Ramucirumab plus paclitaxel is considered the standard of care in the second-line treatment of gastric carcinoma (GC). The aim of this study was to evaluate plasma vascular endothelial growth factor-A (VEGF-A), VEGF-D, and circulating soluble VEGF receptor-2 (sVEGFR-2) as possible markers of resistance or response to ramucirumab administered with paclitaxel in pretreated metastatic GC patients. Plasma samples were collected at different time points (on days 1 and 15 of the first 3 cycles, at best radiologic response and at disease progression). VEGF-A, VEGF-D and sVEGFR-2 were analysed by ELISA. Correlations of biomarker baseline levels or dynamic changes with outcome measures were assessed. Progression-free survival (PFS) was the primary endpoint of the study. Forty-one patients were enrolled. VEGF-A and VEGF-D, but not sVEGFR-2, values significantly increased during treatment compared to baseline (P < 0.001). A positive correlation between VEGF-A and sVEGFR-2 at cycle 2 was found (P=0.045). At univariate analysis, higher baseline levels of VEGF-A were associated with worse OS (P=0.015). Early increase of sVEGFR-2 levels after the first treatment cycle was the only factor associated with longer PFS (6.6 vs. 3.6 months, P=0.049) and OS (18.6 vs. 5.2 months, P=0.008). Significance of sVEGFR-2 early increase was retained at multivariate analysis for OS (HR 0.32; 95% CI 0.12-0.91; P=0.032). The reported results confirmed the prognostic role of baseline VEGF-A and, with the limitations of the limited sample size and the lack of a control arm, suggested that the early increase of sVEGFR-2 after 1 cycle of treatment could be a potential predictive biomarker of benefit from second-line ramucirumab plus paclitaxel in GC.

New antiproliferative agents derived from tricyclic 3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazine scaffold: Synthesis and pharmacological effects.

A series of novel 3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazine (BIT) derivatives were designed and synthesized. In vitro antiproliferative activity was detected toward two human colorectal adenocarcinoma cell lines (CaCo-2 and HT-29) and one human dermal microvascular endothelial cell line (HMVEC-d). The most active compounds, namely 2-4 and 8, were further investigated to clarify the mechanism behind their biological activity. Through immunofluorescence assay, we identified the target of these molecules to be the microtubule cytoskeleton with subsequent formation of dense microtubule accumulation, particularly at the periphery of the cancer cells, as observed in paclitaxel-treated cells. Overall, these results highlight BIT derivatives as robust and feasible candidates deserving to be further developed in the search for novel potent antiproliferative microtubule-targeting agents.

Old and New Systemic Immune-Inflammation Indexes Are Associated with Overall Survival of Glioblastoma Patients Treated with Radio-Chemotherapy.

Background. Systemic immunity and inflammation indexes (SI) derived from blood cells have gained increasing attention in clinical oncology as potential biomarkers that are associated with survival. Materials and methods. We tested 12 different SI using blood tests from patients with isocitrate dehydrogenase 1 and 2 wild-type glioblastomas, treated with radio-chemotherapy. The primary endpoint was their overall survival. Results. A total of 77 patients, comprising 43 males and 34 females, with a median age of 64 years (age range 26-84), who were treated between October 2010 and July 2020, were included in the present analysis (approved by a local ethics committee). In the univariate Cox regression analysis, all the indexes except two showed a statistically significant impact on OS. In the multivariate Cox regression analysis, neutrophil × platelet × leukocyte/(lymphocyte × monocyte) (NPW/LM) and neutrophil × platelet × monocyte/lymphocyte (NPM/L) maintained their statistically significant impact value. Conclusions. This univariate analysis confirms the potential of systemic inflammation indexes in patients with glioblastoma, while the multivariate analysis verifies the prognostic value of NPW/LM and NPM/L.