Search Results (104)

Bioactive natural products (NPs) may play a critical role in cancer progression by targeting nucleic acids and a wide array of proteins, including enzymes. Furthermore, a large number of derivatives (NPDs), including semi-synthetic products and pharmacophores from NPs, have been developed to enhance the solubility and stability of NPs. Acute myeloid leukemia (AML) is a poor-prognosis hematologic malignancy characterized by the clonal accumulation in the blood and bone marrow of myeloid progenitors with high proliferative capacity, survival and propagation abilities. A number of potential pathways and targets have been identified for development in AML, and include, but are not limited to, Fms-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenases resulting from genetic mutations, BCL2 family members, various signaling kinases and histone deacetylases, as well as tumor-associated antigens (such as CD13, CD33, P-gp). By targeting nucleic acids, FLT3 or CD33, several FDA-approved NPs and NPDs (i.e., cytarabine, anthracyclines, midostaurin, melphalan and calicheamicin linked to anti-CD33) are the major agents of upfront treatment of AML. However, the effective treatment of the disease remains challenging, in part due to the heterogeneity of the disease but also to the involvement of the bone marrow microenvironment and the immune system in favoring leukemic stem cell persistence. This review summarizes the current state of the art, and provides a summary of selected NPs/NPDs which are either entering or have been investigated in preclinical and clinical trials, alone or in combination with current chemotherapy. With multifaceted actions, these biomolecules may target all hallmarks of AML, including multidrug resistance and deregulated metabolism. Full article

Background/Objectives: Melphalan-based percutaneous hepatic perfusion (M-PHP) became approved in 2023 for treatment of liver-dominant metastatic uveal melanoma (mUM). Patients with liver-dominant mUM have a poor overall survival (OS) ≤ 12 months; however, the reported OS benefit from M-PHP varies in clinical trials from 9.6 to 27.4 months and remains uncertain. Here, we report the OS outcome after 10 years’ experience with M-PHP treatment of patients with liver-dominant mUM. Methods: A total of 38 consecutive patients (19 women, median age 57.7 years) with liver-dominant mUM underwent 99 M-PHP procedures (median: 2.6 M-PHP/patient) between April 2014 and March 2024 at our institution. OS outcomes were retrospectively analyzed using Kaplan–Meier methods and Cox proportional hazard models. Results: Median OS was 29.1 months after first M-PHP treatment (median follow-up: 25.8 months). The estimated percentage of patients surviving at 1, 2, and 3 years was 79.5%, 53.2%, and 28.5%, respectively. Each additional M-PHP cycle was associated with about 40% reduction in the risk of death (hazard ratio = 0.414). Median OS was numerically improved by 8.4 months with ≥3 versus ≤2 cycles of M-PHP administered (29.8 versus 21.4 months, p = 0.058). No treatment-related deaths occurred. Conclusions: This study found a clinically meaningful OS benefit in M-PHP-treated patients with liver-dominant mUM, reaching nearly 2.5-year median OS with ≥3 M-PHP cycles administered. This finding supports the need to account for the institutional volume and experience with the M-PHP procedure in both clinical practice and research, and may provide an OS reference for estimating OS gains in the evolving therapeutic landscape for mUM patients. Full article

Background: Limited real-world data (RWD) may provide important information regarding diagnostic and treatment patterns in patients (pts) with AL Amyloidosis. The aim was to analyze the characteristics, treatment approach and clinical outcome of patients in the real-world settings. Materials and Methods: RWD of 60 pts diagnosed with AL amyloidosis were analyzed. Advanced cardiac involvement, Mayo Clinical Stage (CS) IIIa and IIIb, and Revised-Mayo CS III and IV, has been found in 26.7%, and 16.7%, or 33.3% and 16.7%, respectively. Bortezomib (Bz)-based regimens were applied in 36 pts (60%), and alkylating-based regimens in 24 pts (40%). In 8 pts (13.3%) treated initially with CyBorD induction, high-dose therapy with Melphalan and autologous stem cell transplantation (HDT + ASCT) was applied as the first line of treatment. Results: The overall response rate (ORR, ≥partial response) was achieved in 40 pts (70%). Patients treated with Bz-based induction followed by HDT + ASCT achieved significantly better hematologic (p = 0.001), cardiac (p = 0.004) and renal response rates (p = 0.002) in comparison to CyBorD or Alk-based regimens alone. There was no difference in PFS between those groups (p = 0.733), but patients treated with CyBorD + HDT + ASCT had significantly durable OS (p = 0.039). Univariate analysis pointed out the predictive influence of cardiac involvement (Mayo CS and Revised Mayo CS), ASCT eligibility, and hematologic, cardiac, renal and composite response rates. Conclusions: Advanced cardiac involvement and cardiac and hematologic response still retain adverse prognostic impact on the clinical outcome. Bz-based combinations significantly improved the survival of patients with AL amyloidosis, regardless of HDT + ASCT treatment. Full article

The DNA Damage Response (DDR) network is an essential machinery for maintaining genomic integrity, with DDR defects being implicated in cancer initiation, progression, and treatment resistance. Moreover, oxidative stress, an imbalance between reactive oxygen species production and antioxidant defense, can significantly impact cell viability, leading to cell death or survival. Herein, we tested the hypothesis that DDR-related signals and redox status measured in multiple myeloma (MM) cell lines correlate with the sensitivity to genotoxic insults. At baseline and following irradiation with Ultraviolet C (UVC; 50 J/m²) or treatment with melphalan (100 μg/mL for 5 min) DDR-related parameters, redox status expressed as GSH/GSSG ratio and apurinic/apyrimidinic sites were evaluated in a panel of eleven human MM cell lines and one healthy B lymphoblastoid cell line. We found that MM cell lines with increased apoptosis rates displayed significantly higher levels of endogenous/baseline DNA damage, reduced GSH/GSSG ratio, augmented apurinic/apyrimidinic lesions, decreased nucleotide excision repair and interstrand crosslinks repair capacities, and highly condensed chromatin structure. Taken together, these findings demonstrate that DDR-related parameters and redox status correlate with the sensitivity of MM cells to DNA-damaging agents, specifically melphalan, and, if further validated, may be exploited as novel sensitive/effective biomarkers. Full article

Background/Objectives: Hematological toxicities (i.e., neutropenia, thrombocytopenia, and anemia), are common chemotherapy complications and may be exacerbated by renal or hepatic impairment due to altered drug exposure. This study assessed the association between renal and hepatic impairment and hematologic toxicities during chemotherapy in routine clinical practice. Methods: A single-center retrospective cohort study using the Utrecht Patient Oriented Database (UPOD) identified all chemotherapy administrations at the University Medical Centre Utrecht between 2011 and 2024. Regimens administered in ≥10 patients and ≥5 renally (GFR < 60 mL/min) or hepatically (bilirubin or AST > 1× ULN) impaired patients were included in descriptive analyses. Cox proportional hazards models estimated associations between organ impairment and grade ≥ 3 hematologic toxicities for regimens with ≥10 events per toxicity endpoint. Results: Overall, 4489 patients were included in renal analyses and 6218 in hepatic analyses, with smaller endpoint-specific subgroups for survival analyses. Renal impairment was associated with grade ≥ 3 neutropenia (HR: 1.43 [95% CI: 1.18–1.73]), thrombocytopenia (HR: 1.46 [95% CI: 1.15–1.86], and anemia (HR: 1.66 [1.27–2.16]). Hepatic impairment was similarly associated with neutropenia (HR: 1.25 [95% CI: 1.11–1.40]), thrombocytopenia (HR: 1.33 [95% CI: 1.13–1.57]), and anemia (HR: 1.62 [95% CI: 1.34–1.95]). Cyclophosphamide (pro-drug) regimens showed higher toxicity risk in renally impaired patients and reduced risk in hepatically impaired patients. Etoposide, melphalan and methotrexate were associated with increased toxicity in hepatically impaired patients. Conclusions: Renal and hepatic impairment significantly increase chemotherapy-induced hematologic toxicity. Several high-risk chemotherapy regimens were identified; however, larger multi-center datasets are needed to refine dosing guidance based on renal and hepatic function. Full article

Background/Objectives: Despite significant advancements in cancer treatment outcomes, side effects, such as gastrointestinal mucositis (GIM), continue to impair patients’ quality of life. The recent literature suggests L-citrulline as a novel treatment for GIM. However, no in vitro model to study the potential for L-citrulline as a treatment for GIM is currently available, and the effect of L-citrulline on the gut microbiota remains unclear. This study aims to propose a suitable in vitro model to study the effect of L-citrulline on the gut microbiota and to determine whether it can mitigate GIM. Methods: The CaCo-2 and T84 cell lines were cultured using cell impedance assays and treated with different doses of methotrexate and melphalan to select an appropriate model for L-citrulline research. The selected model was further used to investigate the impact of L-citrulline on gut microbiota cultured using microbial culture assays containing YCFAG. Results: Neither CaCo-2 nor T84 cells treated with methotrexate were suitable models for our study due to varying responses to treatment. T84 cells treated with 100 μg/mL melphalan demonstrated a consistent response, making them a suitable model for in vitro research on treatments for GIM. The use of L-citrulline demonstrated potential protective effects, as melphalan-treated enterocytes showed less cellular damage in its presence and slightly reduced enteroaggregative E. coli growth. Conclusions: L-Citrulline supplementation reduced epithelial cell injury due to melphalan, suggesting therapeutic potential. Further testing is required to determine its efficacy in vivo and clarify the mechanisms underlying this potential benefit. Full article

This report presents the case of a seven-year-old West Highland White Terrier diagnosed with relapsed and refractory multiple myeloma (MM), managed using multiple treatment approaches, including conventional chemotherapy (melphalan, vincristine, doxorubicin, and dexamethasone), radiation therapy (RT), and novel agents such as the selective inhibitor of nuclear export (verdinexor), proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), and tyrosine kinase inhibitors (TKIs; toceranib and sorafenib). Treatment response was monitored using serum globulin concentration and imaging studies. Verdinexor achieved the longest period of stable remission with minimal toxicity post-RT. Bortezomib + dexamethasone was effective in controlling hyperglobulinemia at doses ≥ 1.45 mg/m², although cumulative hematologic and gastrointestinal toxicity limited its prolonged use. Second-line proteasome inhibitors and TKIs demonstrated limited efficacy. Despite initial therapeutic response, the patient’s condition deteriorated due to persistent hyperglobulinemia and hyperviscosity syndrome. The absence of advanced supportive options, including plasmapheresis, contributed to a fatal outcome. This case highlights the potential utility of novel therapies such as verdinexor and bortezomib in managing refractory canine MM. Timely intervention, individualized dosing, and supportive care are essential for optimizing treatment outcomes. Further research is required to define effective combinations and integrate advanced care options, including stem cell transplantation and targeted antibody therapies, in veterinary MM. Full article

Background/Objectives: This prospective study investigated the impact of high-dose chemotherapy and autologous stem cell transplantation (ASCT) on anti-COVID-19 antibody levels in previously vaccinated multiple myeloma (MM) patients with confirmed antibody response (AR). Methods: All patients underwent at least a two-dose regimen mRNA vaccination and later received a high-dose melphalan conditioning regimen and ASCT. Results: Fourteen MM patients with confirmed AR underwent a total of nineteen ASCT reinfusions; their median age was 55 (34–67). The study found a significant and progressive decrease in antibody levels after ASCT, from 311 BAU/mL at baseline to 276 BAU/mL and 188 BAU/mL after one and three months, respectively, with a median anti-COVID-19 antibody level reduction of 39% (range 16–66%) that was statistically significant (p = 0.014) using the Friedman test. However, the third “booster” vaccination post-ASCT improved the humoral response at six months in nine patients (50% response rate) and corrected, at least in part, the negative impact of high-dose chemotherapy (p = 0.597). Despite the antibody decline, three patients who contracted COVID-19 after ASCT experienced mild, outpatient-managed infections, suggesting sufficient immune response. Furthermore, booster doses increased the proportion of high-responders (AR > 500 BAU/mL) post-ASCT from 22% to 55% (5/9 patients) at three and six months, respectively. Conclusions: The study concludes that ASCT negatively affects the humoral response, but booster vaccination can improve it, and residual antibodies may prevent severe COVID-19 in these vulnerable patients. Full article

Background: Intra-arterial chemotherapy (IAC) is increasingly useful for treating intraocular retinoblastoma (Rb). It offers targeted delivery of chemotherapy with reduced systemic exposure. In this study, we evaluate management outcomes and identify predictive factors for globe salvage following IAC in children with Rb. Methods: This retrospective study included 20 eyes of 20 melphalan-based IAC-treated patients (67 sessions) between 2015 and 2023 in a tertiary cancer center (King Hussein Cancer Center) in Jordan. Data collection included patients’ demographics, tumor staging, eye salvage, complications, and survival, followed by statistical comparisons between eye salvage rates and clinical factors. Results: The median age of IAC initiation was 38 months (range: 6–78 months). IAC was used as a primary treatment in 35% (7/20) of eyes and as a secondary treatment following systemic chemotherapy in 65% (13/20) of eyes. Nineteen (95%) eyes showed initial tumor regression, 15 (75%) eyes showed short term tumor control, and long-term eye salvage was achieved in 11 (55%) eyes. Poor prognostic factors for eye salvage included advanced tumor stage (Group D/E: 43% salvage rate vs. Group C: 83%; p = 0.047), vitreous seeding at the time of IAC (38% with seeding vs. 75% without; p = 0.046), use of IAC as a secondary rather than a primary treatment (46% vs. 71%; p = 0.047), and the need for >3 IAC cycles (20% success with >3 cycles vs. 67% with ≤3 cycles; p = 0.034). Complications were notable: systemic adverse effects were seen in five (25%) patients, including neutropenia (20%) and bronchospasm (6%). Procedure-related complications were seen with 22% of injections, including failure of the procedure (7%), ophthalmic artery spasm (6%), and intra-procedural stroke (3%). Five (25%) eyes developed ocular complications, including vitreous hemorrhage (15%), retinal detachment (10%), optic atrophy (10%), and retinal or choroidal ischemia (10%). Notably, all infants under 12 months of age (4/4) developed complications, including the two events of stroke. At a median follow-up of 60 months, eye salvage was achieved in 11 (55%) eyes, and none of the 9 (45%) enucleated eyes showed high-risk pathological features. There was no orbital recurrence, and one (5%) child developed CNS metastasis and passed away. Conclusion: IAC achieves long-term globe salvage in 55% of Rb cases; however, outcomes are poorer with Group D/E tumors, vitreous seeds, prior IVC failure, or requiring >3 IAC cycles. While reducing systemic chemotherapy toxicity, IAC carries significant risks of vision- and life-threatening complications. Infants and single-eyed patients require particularly cautious consideration. Though IAC remains crucial for globe preservation, optimal implementation demands improved patient selection criteria, multicenter collaboration, and long-term outcome studies to maximize safety and efficacy. Full article

Background: Uveal melanoma (UM) is a relatively rare malignancy, yet it remains the most common primary intraocular cancer in adults. Several risk factors have been identified, including light iris color, fair skin tone, and cutaneous freckles. Methods: The aim of this article was an overview of the treatment methods for uveal melanoma, with a particular focus on emerging therapies such as tebentafusp and da-rovasertib. The research method was a review of the latest literature. Results: Genetic studies have uncovered key mutations in GNAQ and GNA11, which significantly contribute to UM pathogenesis. Treatment selection depends on tumor location and disease stage. In localized disease, radiotherapy—especially brachytherapy—is commonly used and generally effective. However, the prognosis worsens significantly once distant metastases, most often to the liver, develop, as no standard systemic therapy has demonstrated high efficacy in this setting. Recent years have seen the emergence of promising therapies, including tebentafusp, which stimulates immune responses against gp100-expressing melanoma cells, and darovasertib, a potent PKC inhibitor that targets MAPK pathway activation driven by GNAQ/GNA11 mutations. Both agents have shown encouraging tolerability; tebentafusp has demonstrated clinical benefit in Phase II and III trials, while darovasertib is still under investigation. Additionally, melphalan-based liver-directed therapy, particularly via hepatic arterial infusion (approved by the FDA), has shown potential in controlling liver-dominant disease in metastatic UM. This localized approach may provide significant benefit for patients with limited extrahepatic spread. Conclusions: Future research should focus on optimizing these novel strategies—tebentafusp, darovasertib, melphalan, and combination therapies—and on expanding our understanding of UM’s molecular drivers to enable the development of more effective, personalized treatments. Full article

Background/Objectives: Effective anti-inflammatory treatment for COVID-19 is necessary. It was shown that ultra-low doses (100-fold lower than therapeutic ones) of alkylating drug melphalan (MEL) interact with cytokine cell receptors without DNA damage. A method of treating severe COVID-19 with ultra-low doses of MEL inhalations was proposed. The objective was to study the efficacy and safety of MEL inhalations for COVID-19 pneumonia treatment. Methods: An open-label comparative study (NCT04380376) with 120 patients divided into two groups was conducted. The control group (CG) received standard treatment, and the melphalan group (MG) also received seven daily 0.1 mg MEL inhalations. Changes in clinical improvement, inflammatory markers, and CT lung scan data were primary and secondary endpoints. Results: Patients in the MG showed significantly better clinical outcomes compared to the CG, with improvements in dyspnea according to the WHO Ordinal Scale of Clinical Improvement and the modified Borg Scale, CT scans, and inflammatory markers. No adverse effects (including irritant and bronchoconstrictor effects) possibly related to MEL were reported. Conclusions: This study demonstrated the efficacy of incorporating ultra-low-dose MEL inhalations into the therapeutic regimen for patients with COVID-19-associated pneumonia. This conclusion is supported by a statistically significant improvement in clinical outcomes, as assessed by the OSCI, a more rapid reduction in the severity of dyspnea, and a marked anti-inflammatory effect, evidenced by a faster decline in C-reactive protein levels. No adverse effects were observed with the proposed treatment method. Further large-scale randomized clinical trials are warranted to validate these findings and to evaluate the potential for the implementation of ultra-low-dose MEL inhalation in clinical practice. Full article

Background: Cerebral intra-arterial chemotherapy (CIAC) has been demonstrated to achieve tumoricidal concentrations in cerebral tumour cells that are otherwise unachievable due to the presence of the blood–brain barrier. In this study, we sought to analyze the safety of CIAC in a cohort of patients treated at the Centre intégré universitaire de santé et de services sociaux de l’Estrie—Centre hospitalier universitaire de Sherbrooke (CIUSSS-CHUS). Methods: Treatments consisted of monthly CIAC. A neurological examination and neuroimaging study (MRI) were performed before every treatment. The files of patients enrolled in our CIAC programme were reviewed. Adverse events were analyzed and categorized. Results: Overall, 2991 CIAC procedures were performed in 642 patients. Pathologies were as follows: malignant gliomas (68.7%), cerebral metastasis (17.6%), and cerebral lymphomas (13.7%). Perfusion vessels were as follows: 80% internal carotid artery and 20% vertebral artery. The chemotherapeutic agents used were carboplatin (86.4%), methotrexate (28.5%), melphalan (28.6%), and liposomal doxorubicin (2.8%). Osmotic blood–brain barrier disruption (BBBD) was induced in 30.5% of treatments. Symptomatic vascular adverse events occurred during 27 procedures (0.9%) in 26 patients (4%). Namely, 23 strokes, one carotid artery occlusion (responsible for one of the strokes), and two intratumoral and one subdural hemorrhage. The absolute risk of stroke was 1.3% and 0.5% for CIAC with or without BBBD, respectively. The use of the vertebral artery significantly increased the risk of stroke. Drug infusion-related seizures occurred in 2.5% of patients; 83.8% were associated with methotrexate and 16.2% with carboplatin. Conclusions: CIAC is a safe procedure with a 0.9% overall rate of symptomatic complications (stroke, carotid occlusion, subdural hemorrhage or intratumoral bleeding—n = 27/2991) on a treatment basis, mainly consisting of strokes (85%, n = 23), with a modified NIH Stroke Scale score of 4.1 ± 3.3. Full article

Introduction: The growing body of evidence around sexual and gender dimorphism in medicine, particularly in oncology, has highlighted differences in treatment response, outcomes, and side effects between males and females. Differences in drug metabolism, distribution, and elimination, influenced by factors like body composition and enzyme expression, contribute to these variations. Methods: We retrospectively analyzed data of 112 multiple myeloma (MM) patients treated with first-line high-dose chemotherapy (HDCT) with treosulfan and melphalan (TreoMel) followed by autologous stem cell transplantation (ASCT) at a single academic center between January 2020 and August 2022. We assessed response rate, progression-free survival (PFS), overall survival (OS), and toxicities in relation to gender and treosulfan exposure. Results: Our analysis revealed significant gender-specific differences in treosulfan exposure. Females had higher peak levels (343.8 vs. 309.0 mg/L, p = 0.0011) and area under the curve (AUC) (869.9 vs. 830.5 mg*h/L, p = 0.0427) compared to males. Higher treosulfan exposure was associated with increased mortality in females but not in males. Females with treosulfan AUC > 900 mg*h/L had significantly shorter overall survival, while PFS was unaffected by treosulfan exposure. Conclusion: Our study demonstrates that female patients undergoing TreoMel HDCT have higher treosulfan exposure than males and that females with higher levels are at increased risk for toxicity and adverse outcomes. These data suggest that higher treosulfan doses do not confer a benefit in terms of better outcomes for females. Therefore, exploring lower treosulfan doses for female MM patients undergoing TreoMel HDCT may be warranted to mitigate toxicity and improve outcomes. Full article

Background: This real-life study aimed to investigate the possible impact of D-VTd induction therapy on hematopoietic engraftment after autologous stem cell transplantation (auto-SCT). Methods: Sixty consecutive NDMM patients received four cycles of induction therapy with D-VTd. The conditioning regimen consisted of melphalan 200 mg/m². These patients were compared with a historical control group of 80 patients who received four cycles of VTd as induction therapy. Results: The median days to reach neutrophil and platelet engraftment significantly differed between patients treated with D-VTd (11 and 13 days, respectively) and VTd (10 and 12 days). Univariate Cox analyses show that patients treated with D-VTd had a hazard ratio of neutrophil engraftment that was 42% significantly lower than those in the VTd arm (HR: 0.58, p = 0.002), and a multivariate model confirmed this result. Patients treated with D-VTd developed FN more frequently. Univariate and multivariate logistic regressions revealed an association between D-VTd and FN. Delayed engraftment did not correlate with more extended hospitalization. No patients died in the first six months after transplantation. Conclusions: Our real-life study showed that a four-drug induction therapy containing DARA does not impact transplant safety outcomes. Full article

Real-world evidence on the impact of monoclonal antibodies as first-line treatment in Spain is limited. This observational, retrospective and prospective, multicenter, descriptive study included 117 transplant-ineligible newly diagnosed multiple myeloma (TIE-NDMM) patients divided into Group A, who received no daratumumab standard regimens, and the DVMP group (daratumumab, bortezomib, melphalan, and prednisone treatment). More than 90% of the patients in Group A received bortezomib, lenalidomide, or a combination of them. The median follow-up time for Group A was 38.2 months in comparison to 25.8 months for the DVMP group (p < 0.0001). The rate of DVMP patients that experienced disease progression or death from any cause was 36.8%, compared to 67.3% of Group A patients at 36 months of follow-up. The DVMP group had a higher 36-month progression-free survival (PFS) rate (52.9% vs. 31.7%). During the retrospective period, 73.0% of patients reported adverse drug reactions, while in the prospective period, 40.5% experienced adverse events, with no clinical differences between groups. The study supports the use of daratumumab regimens in frontline therapy based on real-world data. The findings provide valuable insights into the clinical outcomes of daratumumab therapy, which can help physicians make informed decisions regarding the optimal treatment approach for this patient population. Full article