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Current Oncology (Toronto, Ont.) May 2022Glioblastomas with multiple foci at presentation (mGBMs) account for 2-35% of all GBMs. mGBMs have limited existing data and no standardized treatment. This study aims... (Review)
Review
Glioblastomas with multiple foci at presentation (mGBMs) account for 2-35% of all GBMs. mGBMs have limited existing data and no standardized treatment. This study aims to determine their incidence, demographic and clinical features, outcome, and prognostic factors in terms of overall survival. We performed a monocentric retrospective study, reviewing patients treated at the Istituto Oncologico Veneto. Inclusion criteria were: new diagnosis of GBM and presence of multiple lesions on pre-treatment MRI. ECOG PS was used to evaluate clinical condition, RANO criteria for radiological assessment, and CTCAE v5.0 for treatment-related adverse events. The incidence of newly diagnosed mGBM was 7.2% and the study population consisted of 98 patients. Median age was 63 years, M:F ratio of 1.8:1, and a surgical approach was undertaken in 73 patients (mostly partial resection). MGMT was methylated in 47.5%, and 82 patients received active oncological treatment (65.9% radiotherapy plus temozolomide (RT + TMZ)). The disease control rate with RT + TMZ was 63%. Median OS of the entire study population was 10.2 months (95% CI 6.6-13.8), and median PFS was 4.2 months (95% CI 3.2-5.2). The ECOG PS, the extent of resection, and the RT + TMZ were significant prognostic factors in the univariate analysis for OS, but only the RT + TMZ was a significant independent OS predictor in the multivariate analysis (HR = 3.1, 95% IC 1.3-7.7, = 0.014). The incidence of mGBM is not rare. RT + TMZ is confirmed to be an independent prognostic factor for survival and a safe and effective treatment. When feasible, RT + TMZ should be considered as a possible first-line treatment. The role of the extent of resection is still unclear.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Dacarbazine; Humans; Middle Aged; Retrospective Studies; Temozolomide
PubMed: 35621670
DOI: 10.3390/curroncol29050280 -
Genes Jun 2023The inhibition of histone deacetylases (HDACs) holds promise as a potential anti-cancer therapy as histone and non-histone protein acetylation is frequently disrupted in...
The inhibition of histone deacetylases (HDACs) holds promise as a potential anti-cancer therapy as histone and non-histone protein acetylation is frequently disrupted in cancer, leading to cancer initiation and progression. Additionally, the use of a histone deacetylase inhibitor (HDACi) such as the class I HDAC inhibitor-valproic acid (VPA) has been shown to enhance the effectiveness of DNA-damaging factors, such as cisplatin or radiation. In this study, we found that the use of VPA in combination with talazoparib (BMN-673-PARP1 inhibitor-PARPi) and/or Dacarbazine (DTIC-alkylating agent) resulted in an increased rate of DNA double strand breaks (DSBs) and reduced survival (while not affecting primary melanocytes) and the proliferation of melanoma cells. Furthermore, the pharmacological inhibition of class I HDACs sensitizes melanoma cells to apoptosis following exposure to DTIC and BMN-673. In addition, the inhibition of HDACs causes the sensitization of melanoma cells to DTIV and BMN-673 in melanoma xenografts in vivo. At the mRNA and protein level, the histone deacetylase inhibitor downregulated RAD51 and FANCD2. This study aims to demonstrate that combining an HDACi, alkylating agent and PARPi could potentially enhance the treatment of melanoma, which is commonly recognized as being among the most aggressive malignant tumors. The findings presented here point to a scenario in which HDACs, via enhancing the HR-dependent repair of DSBs created during the processing of DNA lesions, are essential nodes in the resistance of malignant melanoma cells to methylating agent-based therapies.
Topics: Humans; Histone Deacetylase Inhibitors; Valproic Acid; Poly(ADP-ribose) Polymerase Inhibitors; Dacarbazine; Histone Deacetylases; Antineoplastic Agents; Melanoma; DNA; Alkylating Agents
PubMed: 37372475
DOI: 10.3390/genes14061295 -
JCI Insight Jul 2023Glioblastomas (GBM) are aggressive tumors that lack effective treatments. Here, we show that the Rho family guanine nucleotide exchange factor Syx promotes GBM cell...
Glioblastomas (GBM) are aggressive tumors that lack effective treatments. Here, we show that the Rho family guanine nucleotide exchange factor Syx promotes GBM cell growth both in vitro and in orthotopic xenografts derived from patients with GBM. Growth defects upon Syx depletion are attributed to prolonged mitosis, increased DNA damage, G2/M cell cycle arrest, and cell apoptosis, mediated by altered mRNA and protein expression of various cell cycle regulators. These effects are phenocopied by depletion of the Rho downstream effector Dia1 and are due, at least in part, to increased phosphorylation, cytoplasmic retention, and reduced activity of the YAP/TAZ transcriptional coactivators. Furthermore, targeting Syx signaling cooperates with radiation treatment and temozolomide (TMZ) to decrease viability in GBM cells, irrespective of their inherent response to TMZ. The data indicate that a Syx-RhoA-Dia1-YAP/TAZ signaling axis regulates cell cycle progression, DNA damage, and therapy resistance in GBM and argue for its targeting for cancer treatment.
Topics: Humans; Glioblastoma; Cell Line, Tumor; Signal Transduction; Temozolomide; DNA Damage; Cell Division
PubMed: 37427593
DOI: 10.1172/jci.insight.157491 -
Cancer Medicine Mar 2023Melanoma is a highly heterogeneous malignant tumor that exhibits various forms of drug resistance. Recently, reversal transition of cancer cells to the G phase of the...
BACKGROUND
Melanoma is a highly heterogeneous malignant tumor that exhibits various forms of drug resistance. Recently, reversal transition of cancer cells to the G phase of the cell cycle under the influence of therapeutic drugs has been identified as an event associated with tumor dissemination. In the present study, we investigated the ability of chemotherapeutic agent dacarbazine to induce a transition of melanoma cells to the G phase as a mechanism of chemoresistance.
METHODS
We used the flow cytometry to analyze cell distribution within cell cycle phases after dacarbazine treatment as well as to identifyG -positive cells population. Transcriptome profiling was provided to determine genes associated with dacarbazine resistance. We evaluated the activity of β-galactosidase in cells treated with dacarbazine by substrate hydrolysis. Cell adhesion strength was measured by centrifugal assay application with subsequent staining of adhesive cells with Ki-67 monoclonal antibodies. Ability of melanoma cells to metabolize dacarbazine was determined by expressional analysis of CYP1A1, CYP1A2, CYP2E1 followed by CYP1A1 protein level evaluation by the ELISA method.
RESULTS
The present study determined that dacarbazine treatment of melanoma cells could induce an increase in the percentage of cells in G phase without alterations of β-galactosidase positive cells which corresponded to the fraction of the senescent cells. Transcriptomic profiling of cells under dacarbazine induction of G -positive cells percentage revealed that 'VEGFA-VEGFR2 signaling pathway' and 'Cell cycle' signaling were mostly enriched by dysregulated genes. 'Focal adhesion' signaling was also found to be triggered by dacarbazine. In melanoma cells treated with dacarbazine, an increase in G -positive cells among adherent cells was found.
CONCLUSIONS
Dacarbazine induces the alteration in a percentage of melanoma cells residing in G phase of a cell cycle. The altered adhesive phenotype of cancer cells under transition in the G phase may refer to a specific intercellular communication pattern of quiescent/senescent cancer cells.
Topics: Humans; Cell Line, Tumor; Melanoma; Dacarbazine; Cell Cycle; Cell Division
PubMed: 36533319
DOI: 10.1002/cam4.5510 -
Current Opinion in Oncology Sep 2021Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare B cell-derived malignancy. This review aims at providing an overview of recent developments in the... (Review)
Review
PURPOSE OF REVIEW
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare B cell-derived malignancy. This review aims at providing an overview of recent developments in the management of NLPHL.
RECENT FINDINGS
Patients with stage IA NLPHL without risk factors have excellent outcomes. The 8-year progression-free survival (PFS) is roughly 90% and the 8-year overall survival (OS) close to 100% after limited-field radiotherapy (RT) alone. Individuals presenting with early stages other than stage IA without risk factors and intermediate stages have 10-year PFS rates in excess of 70% and 10-year OS rates exceeding 90% when treated with 2 and 4 cycles of ABVD, respectively, followed by consolidation RT. In advanced NLPHL, different protocols such as BEACOPP, ABVD, and R-CHOP have been evaluated retrospectively. However, the optimal approach is undefined. Patients with relapsed NLPHL mostly receive single-agent anti-CD20 antibody treatment or conventional chemotherapy. High-dose chemotherapy and autologous stem cell transplantation are restricted to high-risk patients. NLPHL recurrence is salvaged successfully in the majority of cases.
SUMMARY
Patients with NLPHL have a very good prognosis. Treatment differs from classical Hodgkin lymphoma in some situations.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Dacarbazine; Doxorubicin; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Lymphocytes; Retrospective Studies; Transplantation, Autologous; Vinblastine
PubMed: 34224482
DOI: 10.1097/CCO.0000000000000774 -
British Journal of Cancer Oct 2023Patient-derived glioma stem-like cells (GSCs) have become the gold-standard in neuro-oncological research; however, it remains to be established whether loss of in situ...
BACKGROUND
Patient-derived glioma stem-like cells (GSCs) have become the gold-standard in neuro-oncological research; however, it remains to be established whether loss of in situ microenvironment affects the clinically-predictive value of this model. We implemented a GSC monolayer system to investigate in situ-in vitro molecular correspondence and the relationship between in vitro and patient response to temozolomide (TMZ).
METHODS
DNA/RNA-sequencing was performed on 56 glioblastoma tissues and 19 derived GSC cultures. Sensitivity to TMZ was screened across 66 GSC cultures. Viability readouts were related to clinical parameters of corresponding patients and whole-transcriptome data.
RESULTS
Tumour DNA and RNA sequences revealed strong similarity to corresponding GSCs despite loss of neuronal and immune interactions. In vitro TMZ screening yielded three response categories which significantly correlated with patient survival, therewith providing more specific prediction than the binary MGMT marker. Transcriptome analysis identified 121 genes related to TMZ sensitivity of which 21were validated in external datasets.
CONCLUSION
GSCs retain patient-unique hallmark gene expressions despite loss of their natural environment. Drug screening using GSCs predicted patient response to TMZ more specifically than MGMT status, while transcriptome analysis identified potential biomarkers for this response. GSC drug screening therefore provides a tool to improve drug development and precision medicine for glioblastoma.
Topics: Humans; Temozolomide; Glioblastoma; Dacarbazine; Drug Evaluation, Preclinical; Glioma; Biomarkers; DNA; Brain Neoplasms; Drug Resistance, Neoplasm; Antineoplastic Agents, Alkylating; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37620410
DOI: 10.1038/s41416-023-02402-y -
Current Pharmaceutical Design 2022Temozolomide (TMZ) is an imidazotetrazine prodrug used to treat glioblastoma multiforme. Its physicochemical properties and small size confer the ability to cross the... (Review)
Review
Temozolomide (TMZ) is an imidazotetrazine prodrug used to treat glioblastoma multiforme. Its physicochemical properties and small size confer the ability to cross the blood-brain barrier. The antitumor activity depends on pH-dependent hydrolysis of the methyldiazonium cation, which is capable of methylating purine bases (O6-guanine; N7-guanine, and N3-adenine) and causing DNA damage and cell death. TMZ is more stable in acidic media (pH ≤ 5.0) than in basic media (pH ≥ 7.0) due to the protonated form that minimizes the catalytic process. Due to this, TMZ has high oral bioavailability, but it has a half-life of 1.8 h and low brain distribution (17.8%), requiring a repeated dosing regimen that limits its efficacy and increases adverse events. Drug delivery Nanosystems (DDNs) improve the physicochemical properties of TMZ and may provide controlled and targeted delivery. Therefore, DDNs can increase the efficacy and safety of TMZ. In this context, to ensure the efficiency of DDNs, analytical methods are used to evaluate TMZ pharmacokinetic parameters, encapsulation efficiency, and the release profile of DDNs. Among the methods, high-performance liquid chromatography is the most used due to its detection sensitivity in complex matrices such as tissues and plasma. Micellar electrokinetic chromatography features fast analysis and no sample pretreatment. Spectrophotometric methods are still used to determine encapsulation efficiency due to their low cost, despite their low sensitivity. This review summarizes the physicochemical and pharmacological properties of free TMZ and TMZ-loaded DDNs. In addition, this review addresses the main analytical methods employed to characterize TMZ in different matrices.
Topics: Brain Neoplasms; Cell Line, Tumor; Glioblastoma; Guanine; Humans; Temozolomide
PubMed: 35658888
DOI: 10.2174/1381612828666220603152918 -
Melanoma Research Aug 2020We observed several cases of hypotension associated with high-dose dacarbazine. We conducted a retrospective observational analysis of all patients treated with...
We observed several cases of hypotension associated with high-dose dacarbazine. We conducted a retrospective observational analysis of all patients treated with high-dose dacarbazine from January 2018 to August 2019 in Oscar Lambret Center, Lille, France. In our study, a total of 23 patients in outpatient care were analyzed, they underwent 57 treatment cycles. We observed 8 episodes of hypotension in 7 of the 23 consecutive treated patients (30.4%). We discuss herein several hypotheses explaining dacarbazine-induced hypotension. Dacarbazine high dose and administration methods seem to be the main causes of hypotension adverse events. Administration methods include administration duration, which should be above 2 hours, concomitant hydration with 500 ml 0.9% sodium chloride, and UV-resistant pump tube downstream the administration tree.
Topics: Acute Disease; Antineoplastic Agents, Alkylating; Dacarbazine; Female; Humans; Hypotension; Male; Retrospective Studies
PubMed: 32141965
DOI: 10.1097/CMR.0000000000000659 -
Scientific Reports Oct 2022The aim of the study was to assess the predictive value of interim FDG-PET/CT (iPET) in patients with Hodgkin's lymphoma (HL) treated with Adriamycin, bleomycin,...
The aim of the study was to assess the predictive value of interim FDG-PET/CT (iPET) in patients with Hodgkin's lymphoma (HL) treated with Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy. A total of 245 consecutive patients with de novo HL between 12/2013 and 12/2017 were evaluated retrospectively. All patients were treated with upfront ABVD, performed PET/CT scans at baseline, after 2 cycles (interim PET, iPET2) or 4 cycles (iPET4) and at the end of therapy, and followed up for at least 6 months after therapy. The response status on iPET was defined according to the standard five-point Deauville scores (DS) as follows: complete metabolic response (CMR, DS 1-3) and non-complete metabolic response (nCMR) (DS 4 and 5). End-of-treatment (EoT) response was assessed by FDG-PET/CT and if needed biopsy confirmation of PET-positive findings. The association between iPET and EoT response was investigated using logistic regression analysis. Survival analysis was performed using the Cox regression hazard model and Kaplan-Meier methods. Sixty-nine patients underwent iPET-2 and 176 iPET-4. No association was found between the timing of iPET and iPET response status (P-value = 0.71). Two hundred and one patients (82%) had iPET-CMR and 44 (18%) iPET -nCMR. iPET was strongly associated with EoT response status: 194/201 (96 .5%) of iPET-CMR had a complete response at the EoT while only 21/44 (47.7%) of patients with iPET-nCMR presented a complete response at EoT (P-value < 0.0001). The median follow-up was 32 months (range 6-81). Patients with iPET-CMR presented a better outcome with 91% 3 y event-free-survival (EFS) and 95% 3 y overall survival (OS) than those with iPET-nCMR (41 and 86%, respectively, P-value < 0.0001). In multivariable analyses, iPET retained an independent prognostic factor of EFS and OS (P-value < 0.0001 and P-value = 0.002, respectively). iPET is highly predictive of outcome of HL patients treated with ABVD and allows to tailor therapy to the individual patient.
Topics: Humans; Hodgkin Disease; Fluorodeoxyglucose F18; Positron Emission Tomography Computed Tomography; Vinblastine; Antineoplastic Combined Chemotherapy Protocols; Retrospective Studies; Dacarbazine; Bleomycin; Doxorubicin; Positron-Emission Tomography
PubMed: 36271128
DOI: 10.1038/s41598-022-22032-3 -
Scandinavian Journal of Clinical and... Dec 2023The aim of this study was to develop a robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying dacarbazine levels in the plasma of...
The aim of this study was to develop a robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying dacarbazine levels in the plasma of advanced melanoma patients, followed by an assessment of its analytical capabilities. The research encompassed the design of a high-performance liquid chromatography (HPLC) system, with the quantitative analysis performed using the multiple reaction monitoring (MRM) techniques and specific ion transition: 181.0 > 152.5 for dacarbazine and 187.1 > 158.6 for the internal standard (IS), dacarbazine-D6. The validation of the method involved an evaluation of parameters including linearity, detection limit, precision, and accuracy. Notably, the linear range extended from 10 to 1,000 µg/L for dacarbazine, and the method exhibited a detection limit of 10 µg/L. The method's precision, indicated by within-run and between-run coefficients of variation (CV), both being ≤4.2% and ≤8.3%, respectively. Furthermore, the accuracy of measurements, ranging from 86.1% to 99.4%, underscored the method's reliability. In clinical application, the dacarbazine levels of healthy control ( = 20) were 0.6 ± 0.02 μg/L; 770.9 ± 203.2 μg/mL in early-stage-melanoma patients ( = 22), and 588.7 ± 153.2 μg/mL in advanced melanoma patients ( = 25). The results serve as clinical evidence showing that long-term dacarbazine treatment affects the metabolism of dacarbazine.
Topics: Humans; Chromatography, Liquid; Melanoma; Tandem Mass Spectrometry; Dacarbazine; Reproducibility of Results; Chromatography, High Pressure Liquid
PubMed: 38145313
DOI: 10.1080/00365513.2023.2297356