-
Journal of Personalized Medicine Apr 2024Isolated limb hyperthermic-antiblastic perfusion (ILP) was the most effective local treatment for advanced in-transit melanoma, but the advent of modern effective...
BACKGROUND
Isolated limb hyperthermic-antiblastic perfusion (ILP) was the most effective local treatment for advanced in-transit melanoma, but the advent of modern effective immunotherapy (IT), such as immune checkpoint inhibitors, has changed the treatment landscape.
METHODS
This study evaluated the role of the association between ILP and IT in the treatment of locally advanced unresectable melanoma, particularly in relation to modern systemic therapies. We analyzed 187 consecutive patients who were treated with ILP (melphalan or melphalan associated with TNF-alpha) for advanced melanoma at the Veneto Institute of Oncology of Padua (Italy) and the Padua University Hospital (Italy) between June 1989 and September 2021. Overall survival (OS), disease-specific survival (DSS), local disease-free survival (local DFS) and distant disease-free survival (distant DFS) were evaluated. Local toxicity was classified according to the Wieberdink scale and surgical complications according to the Clavien-Dindo classification. Response to locoregional therapy was evaluated during follow-up according to the RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumor).
RESULTS
A total of 99 patients were treated with ILP and 88 with IT + ILP. The overall response rate was 67% in both groups. At 36 months, OS was 43% in the ILP group and 61% in the ILP + IT group ( = 0.02); DSS was 43% in the ILP group and 64% in the ILP + IT group ( = 0.02); local DFS was the 37% in ILP group and 53% in the ILP + IT group ( = 0.04); and distant DFS was 33% in the ILP group and 35% in the ILP + IT group ( = 0.40). Adjusting for age and lymph node involvement, receiving ILP + IT was associated with improved OS ( = 0.01) and DSS ( = 0.007) but not local DFS ( = 0.13) and distant DFS ( = 0.21).
CONCLUSIONS
Our findings confirm the synergy between ILP and IT. ILP remains a valuable loco-regional treatment option in the era of effective systemic treatments. Further studies are needed to establish the optimal combination of loco-regional and systemic treatments and address the best timing of this combination to obtain the highest local response rate.
PubMed: 38793023
DOI: 10.3390/jpm14050442 -
Cancers May 2024(1) Background: Treosulfan and melphalan (TreoMel)-based high-dose chemotherapy (HDCT) has shown promising safety and efficacy as a conditioning regimen for acute...
(1) Background: Treosulfan and melphalan (TreoMel)-based high-dose chemotherapy (HDCT) has shown promising safety and efficacy as a conditioning regimen for acute myeloid leukemia (AML) patients undergoing autologous stem cell transplantation (ASCT). However, despite intensive first-line induction treatment and upfront consolidation with HDCT and ASCT, AML relapse rates are still high, and further efforts are needed to improve patient outcomes. The aim of this study was to compare two melphalan dose schedules in regard to the safety of TreoMel HDCT and patient outcomes. (2) Methods: We retrospectively analyzed the safety and efficacy of two melphalan dose schedules combined with standard-dose treosulfan in AML patients undergoing HDCT and ASCT at the University Hospital of Bern, Switzerland, between August 2019 and August 2023. Patients received treosulfan 42 g/m combined with either melphalan 140 mg/m (TreoMel 140) or melphalan 200 mg/m (TreoMel 200). Co-primary endpoints were progression-free survival (PFS), overall survival (OS), as well as safety profile. (3) Results: We included a total of 51 AML patients: 31 (60.8%) received TreoMel 140 and 20 (39.2%) TreoMel 200. The patients' basal characteristics were comparable between both cohorts. No significant differences in the duration of hospitalization or the adverse event profile were identified. There were no statistically significant differences in relapse (0.45 vs. 0.30, = 0.381) and mortality rates (0.42 vs. 0.15, = 0.064) between the melphalan 140 mg/m and 200 mg/m cohorts, nor for PFS (HR: 0.81, 95% CI: 0.29-2.28, = 0.70) or OS (HR: 0.70, 95% CI: 0.19-2.57, = 0.59) for the TreoMel 140 vs. TreoMel 200 cohort. (4) Conclusions: A higher dose of melphalan (TreoMel 200) was well tolerated overall. No statistically significant differences for patient outcomes could be observed, possibly due to the relatively small patient cohort and the short follow-up. A longer follow-up and prospective randomized studies would be required to confirm the safety profile and clinical benefit.
PubMed: 38791965
DOI: 10.3390/cancers16101887 -
Cells May 2024Upfront high-dose therapy with melphalan (HDM) followed by autologous stem cell transplantation (ASCT) has established itself as a core treatment for newly diagnosed... (Review)
Review
Upfront high-dose therapy with melphalan (HDM) followed by autologous stem cell transplantation (ASCT) has established itself as a core treatment for newly diagnosed multiple myeloma (NDMM) patients in the past 30 years. Induction therapy, HDM-ASCT, and subsequent consolidation and maintenance therapy comprise the current fundamental framework for MM treatment. The introduction of anti-CD38 monoclonal antibodies such as daratumumab and isatuximab has changed the treatment paradigm for transplant-eligible NDMM patients in that quadruplets have become the new standard induction therapy. The treatment landscape of MM is undergoing a transformative shift with the introduction of potent new immunotherapies, such as chimeric antigen receptor (CAR)-T cells and bispecific antibodies (BsAbs), which are currently used in the relapsed/refractory setting (RRMM) and are already being tested in the NDMM. This review will focus on the incorporation of immunotherapy in the treatment scenario of NDMM patients eligible for ASCT.
Topics: Humans; Multiple Myeloma; Transplantation, Autologous; Immunotherapy; Hematopoietic Stem Cell Transplantation
PubMed: 38786075
DOI: 10.3390/cells13100853 -
ACS Omega May 2024Melphalan (Mel) is a potent alkylating agent utilized in chemotherapy treatments for a diverse range of malignancies. The need for its accurate and timely detection in...
Electrochemical Detection of Melphalan in Biological Fluids Using a g-CN@ND-COOH@MoSe Modified Electrode Complemented by Molecular Docking Studies with Cellular Tumor Antigen P53.
Melphalan (Mel) is a potent alkylating agent utilized in chemotherapy treatments for a diverse range of malignancies. The need for its accurate and timely detection in pharmaceutical preparations and biological samples is paramount to ensure optimized therapeutic efficacy and to monitor treatment progression. To address this critical need, our study introduced a cutting-edge electrochemical sensor. This device boasts a uniquely modified electrode crafted from graphitic carbon nitride (g-CN), decorated with activated nanodiamonds (ND-COOH) and molybdenum diselenide (MoSe), and specifically designed to detect Mel with unparalleled precision. Our rigorous testing employed advanced techniques such as cyclic voltammetry and differential pulse voltammetry. The outcomes were promising; the sensor consistently exhibited a linear response in the range of 0.5 to 12.5 μM. Even more impressively, the detection threshold was as low as 0.03 μM, highlighting its sensitivity. To further enhance our understanding of Mel's biological interactions, we turned to molecular docking studies. These studies primarily focused on Mel's interaction dynamics with the cellular tumor antigen P53, revealing a binding affinity of -5.0 kcal/mol. A fascinating observation was made when Mel was covalently conjugated with nanodiamond-COOH (ND-COOH). This conjugation resulted in a binding affinity that surged to -10.9 kcal/mol, clearly underscoring our sensor's superior detection capabilities. This observation also reinforced the wisdom behind incorporating ND-COOH in our electrode design. In conclusion, our sensor not only stands out in terms of sensitivity but also excels in selectivity and accuracy. By bridging electrochemical sensing with computational insights, our study illuminates Mel's intricate behavior, driving advancements in sensor technology and potentially revolutionizing cancer therapeutic strategies.
PubMed: 38764632
DOI: 10.1021/acsomega.4c00558 -
Cancers Apr 2024FAM46C is a well-established tumour suppressor with a role that is not completely defined or universally accepted. Although FAM46C expression is down-modulated in... (Review)
Review
FAM46C is a well-established tumour suppressor with a role that is not completely defined or universally accepted. Although FAM46C expression is down-modulated in several tumours, significant mutations in the gene are only found in multiple myeloma (MM). Consequently, its tumour suppressor activity has primarily been studied in the MM context. However, emerging evidence suggests that FAM46C is involved also in other cancer types, namely colorectal, prostate and gastric cancer and squamous cell and hepatocellular carcinoma, where FAM46C expression was found to be significantly reduced in tumoural versus non-tumoural tissues and where FAM46C was shown to possess anti-proliferative properties. Accordingly, FAM46C was recently proposed to function as a pan-cancer prognostic marker, bringing FAM46C under the spotlight and attracting growing interest from the scientific community in the pathways modulated by FAM46C and in its mechanistic activity. Here, we will provide the first comprehensive review regarding FAM46C by covering (1) the intracellular pathways regulated by FAM46C, namely the MAPK/ERK, PI3K/AKT, β-catenin and TGF-β/SMAD pathways; (2) the models regarding its mode of action, specifically the poly(A) polymerase, intracellular trafficking modulator and inhibitor of centriole duplication models, focusing on connections and interdependencies; (3) the regulation of FAM46C expression in different environments by interferons, IL-4, TLR engagement or transcriptional modulators; and, lastly, (4) how FAM46C expression levels associate with increased/decreased tumour cell sensitivity to anticancer agents, such as bortezomib, dexamethasone, lenalidomide, pomalidomide, doxorubicin, melphalan, SK1-I, docetaxel and norcantharidin.
PubMed: 38730656
DOI: 10.3390/cancers16091706 -
EJHaem Apr 2024Lenalidomide maintenance (LM) has shown benefit in progression-free survival (PFS) and overall survival (OS) in clinical trials. LM is the recommended standard of care...
Lenalidomide maintenance (LM) has shown benefit in progression-free survival (PFS) and overall survival (OS) in clinical trials. LM is the recommended standard of care in patients with newly diagnosed multiple myeloma (MM) after high-dose melphalan and autologous stem cell transplantation (HDM-ASCT). In Denmark, LM has been approved and publicly funded for all patients treated with HDM-ASCT since June 2019. Patients with newly diagnosed MM treated with their first HDM-ASCT between June 2019 and March 2022 were included and followed until data cut-off in June 2023. To compare outcomes, a historical pre-LM cohort from the Danish MM Registry, consisting of 364 MM patients treated with HDM-ASCT between June 2015 and June 2019, was used. Among 364 patients treated with HDM-ASCT after June 2019, 22.3% received consolidation therapy and 3.7% underwent tandem HDM-ASCT. During follow-up, 297 patients (81.6%) initiated maintenance therapy, with 277 (76.1%) receiving LM. Overall, 145 patients (52.3%) discontinued LM most commonly due to toxicity 75 (51.7%), with fatigue (30.7%), cytopenia (25.3%), and neuropathy (17.3%) being the main reasons. In a 6-month landmark analysis, early discontinuation did not negatively impact PFS or OS. The LM cohort had similar PFS, and OS compared to the pre-LM cohort. The 3-year PFS and OS rates in the LM cohort were 61% and 86%, respectively, while the pre-LM cohort had a 3-year PFS of 55% and a 3-year OS of 89%. In conclusion, the introduction of LM as a nationwide treatment option in Denmark did not lead to improved clinical outcomes.
PubMed: 38633122
DOI: 10.1002/jha2.881 -
Cancer Control : Journal of the Moffitt... 2024Percutaneous Hepatic Perfusion (PHP) is a liver directed regional therapy recently FDA approved for metastatic uveal melanoma to the liver involving percutaneous...
BACKGROUND
Percutaneous Hepatic Perfusion (PHP) is a liver directed regional therapy recently FDA approved for metastatic uveal melanoma to the liver involving percutaneous isolation of liver, saturation of the entire liver with high-dose chemotherapy and filtration extracorporeally though in line filters and veno-venous bypass. The procedure is associated with hemodynamic shifts requiring hemodynamic support and blood product resuscitation due to coagulopathy.
OBJECTIVE
To assess the cardiac safety and subsequent clinically significant sequalae of this therapy.
METHODS
Consecutive PHP procedures done at our center between 2010-2022 were assessed retrospectively. Cardiac risk factors, post procedural cardiac enzymes, electrocardiograms, and transthoracic echocardiograms along with 90-day cardiac outcomes were reviewed. All data were reviewed by cardio-oncologists at our institution.
RESULTS
Of 37 patients reviewed, mean age was 63 years and 57% were women. 132 procedures were performed with an average of 3.57 procedures per patient. 68.6% of patients had elevated troponin during at least 1 procedure. No patients were found to have acute coronary syndrome, heart failure, unstable arrhythmias, or cardiac death. No patients had notable echocardiographic changes. 10.8% of patients with positive troponin had asymptomatic transient electrocardiographic changes not meeting criteria for myocardial infarction. One patient had non-sustained ventricular tachycardiac intra-operatively which did not recur subsequently. Three patients died from non-cardiac causes within 90-days. There was no oncology treatment interruption, even in those with troponin elevation. In multivariable analysis, a history of hyperlipidemia was a predictor of postoperative troponin elevation. ( = .042).
CONCLUSION
Percutaneous Hepatic Perfusion is safe and associated with a transient, asymptomatic troponin elevation peri-operatively without major adverse cardiac events at 90 days. The observed troponin elevation is likely secondary to coronary demand-supply mismatch related to procedural hemodynamic shifts, hypotension, and anemia.
Topics: Humans; Female; Middle Aged; Male; Melphalan; Antineoplastic Agents, Alkylating; Retrospective Studies; Chemotherapy, Cancer, Regional Perfusion; Liver Neoplasms; Neoplasm Recurrence, Local; Perfusion; Melanoma; Uveal Neoplasms
PubMed: 38605434
DOI: 10.1177/10732748241246898 -
PloS One 2024Multiple myeloma (MM) is the second most prevalent hematologic malignancy which remains uncurable. Numerous drugs have been discovered to inhibit MM cells. Indisulam, an...
Multiple myeloma (MM) is the second most prevalent hematologic malignancy which remains uncurable. Numerous drugs have been discovered to inhibit MM cells. Indisulam, an aryl sulfonamide, has a potent anti-myeloma activity in vitro and in vivo. This study aims to explore the new mechanism of indisulam and investigate its potential use in combination with melphalan. We examined DNA damage in MM cells through various methods such as western blotting (WB), immunofluorescence, and comet assay. We also identified the role of topoisomerase IIα (TOP2A) using bioinformatic analyses. The impact of indisulam on the RNA and protein levels of TOP2A was investigated through qPCR and WB. Cell proliferation and apoptosis were assessed using CCK-8 assays, Annexin V/PI assays and WB. We predicted the synergistic effect of the combination treatment based on calculations performed on a website, and further explored the effect of indisulam in combination with melphalan on MM cell lines and xenografts. RNA sequencing data and basic experiments indicated that indisulam caused DNA damage and inhibited TOP2A expression by decreasing transcription and promoting degradation via the proteasome pathway. Functional experiments revealed that silencing TOP2A inhibited cell proliferation and induced apoptosis and DNA damage. Finally, Indisulam/melphalan combination treatment demonstrated a strong synergistic anti-tumor effect compared to single-agent treatments in vitro and in vivo. These findings suggest that combination therapies incorporating indisulam and melphalan have the potential to enhance treatment outcomes for MM.
Topics: Humans; Melphalan; Multiple Myeloma; Cell Line, Tumor; Sulfonamides
PubMed: 38593113
DOI: 10.1371/journal.pone.0299019 -
Cardiovascular and Interventional... Jun 2024Percutaneous hepatic perfusion with melphalan (M-PHP) is a minimally invasive therapy with proven efficacy in patients with uveal melanoma (UM) liver metastases. M-PHP...
PURPOSE
Percutaneous hepatic perfusion with melphalan (M-PHP) is a minimally invasive therapy with proven efficacy in patients with uveal melanoma (UM) liver metastases. M-PHP is associated with a short hospital admission time and limited systemic side effects. In this study, we assessed quality of life (QoL) in UM patients treated with M-PHP.
MATERIALS AND METHODS
A prospective, single-center study including 24 patients treated with M-PHP for UM metastases to the liver. QoL questionnaires were collected at baseline, on day 2/3 after M-PHP, and on day 7 and day 21 after M-PHP, according to study protocol. The results were scored according to EORTC-QLQ C30 global health status (GHS), functional scales, and symptom scales. The difference in scores at baseline and subsequent time points was analyzed with the Wilcoxon signed-rank test and multiple testing Bonferroni correction. Adverse events (AE) were registered up to 30 days after M-PHP according to CTCAE v5.0.
RESULTS
Twenty-four patients (14 males; median age 63.0 years) completed 96 questionnaires. Most scores on all scales declined on day 2/3 after M-PHP. On day 21 after M-PHP, 12 out of 15 scores returned to baseline, including median GHS scores. Three variables were significantly worse on day 21 compared to baseline: fatigue (6-33; p = 0.002), physical functioning (100 vs 86.7; p = 0.003), and role functioning (100 vs 66.7; p = 0.001). Grade 3/4 AEs consisted mainly of hematological complications, such as leukopenia and thrombopenia.
CONCLUSION
M-PHP causes fatigue and a decline in physical and role functioning in the 1st weeks after treatment, but GHS returns to baseline levels within 21 days. LEVEL OF EVIDENCE 3: Cohort study.
Topics: Humans; Male; Female; Uveal Neoplasms; Middle Aged; Prospective Studies; Quality of Life; Melanoma; Liver Neoplasms; Surveys and Questionnaires; Aged; Melphalan; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Adult; Treatment Outcome
PubMed: 38587534
DOI: 10.1007/s00270-024-03713-0 -
World Journal of Transplantation Mar 2024Conditioning regimens employed in autologous stem cell transplantation have been proven useful in various hematological disorders and underlying malig nancies; however,... (Review)
Review
Conditioning regimens employed in autologous stem cell transplantation have been proven useful in various hematological disorders and underlying malig nancies; however, despite being efficacious in various instances, negative consequences have also been recorded. Multiple conditioning regimens were extracted from various literature searches from databases like PubMed, Google scholar, EMBASE, and Cochrane. Conditioning regimens for each disease were compared by using various end points such as overall survival (OS), progression free survival (PFS), and leukemia free survival (LFS). Variables were presented on graphs and analyzed to conclude a more efficacious conditioning regimen. In multiple myeloma, the most effective regimen was high dose melphalan (MEL) given at a dose of 200/mg/m. The comparative results of acute myeloid leukemia were presented and the regimens that proved to be at an admirable position were busulfan (BU) + MEL regarding OS and BU + VP16 regarding LFS. In case of acute lymphoblastic leukemia (ALL), BU, fludarabine, and etoposide (BuFluVP) conferred good disease control not only with a paramount improvement in survival rate but also low risk of recurrence. However, for ALL, chimeric antigen receptor (CAR) T cell therapy was preferred in the context of better OS and LFS. With respect to Hodgkin's lymphoma, mitoxantrone (MITO)/MEL overtook carmustine, VP16, cytarabine, and MEL in view of PFS and regarding OS. Non-Hodgkin's lymphoma patients were administered MITO (60 mg/m) and MEL (180 mg/m) which showed promising results. Lastly, amyloidosis was considered, and the regimen that proved to be competent was MEL 200 (200 mg/m). This review article demonstrates a comparison between various conditioning regimens employed in different diseases.
PubMed: 38576761
DOI: 10.5500/wjt.v14.i1.87532