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Journal of Biomolecular Structure &... Apr 2024Despite considerable improvement in therapy and diagnosis, brain tumors remain a global public health concern. Among all brain tumors, 80% are due to Glioblastoma. The...
Despite considerable improvement in therapy and diagnosis, brain tumors remain a global public health concern. Among all brain tumors, 80% are due to Glioblastoma. The average survival rate of a patient once diagnosed with glioblastoma is 15 months. Lately, the role of peptidase enzymes, especially Neprilysin, a neutral endopeptidase, is gaining attention for its role in tumor growth regulation. Neprilysin expressions are positively correlated with several tumors including GBM and reduced expression of NEP protein is associated with the pathogenesis of multiple tumors. One of the main reasons for NEP protein downregulation is the action of Histone deacetylase (HDAC) enzymes, especially HDAC1. Additionally, studies have reported that increased levels of HDAC1 are responsible for downregulating NEP gene expression. Hence, HDAC1 inhibition can be a good target to elevate NEP levels, which can be a good therapeutic approach to GBM. This study utilizes the computational drug repurposing tool, Schrodinger Maestro to identify HDAC1 inhibitors from the ZINC15 database.1379 FDA-approved drugs from the ZINC15 database were screened through molecular docking. Based on docking score and ligand-protein interaction, the top ten molecules were selected which were then subjected to binding energy calculation and molecular dynamics (MD) simulations. The three most active drugs from the MD simulations- ZINC22010649 (Panobinostat), ZINC4392649 (Tasimelteon) and ZINC1673 (Melphalan), were tested on C6 and U87 MG glioblastoma cells for cytotoxicity and HDAC1 protein levels using western blot analysis. Among the three drugs, Panobinostat exhibited potent cytotoxic action and showed a significant reduction in the HDAC1 protein levels.Communicated by Ramaswamy H. Sarma.
PubMed: 38686917
DOI: 10.1080/07391102.2024.2335293 -
Bone Marrow Transplantation Apr 2024Acute kidney injury (AKI) is a complication related to important organ dysfunction during autologous stem cell transplantation (ASCT) in light chain (AL) amyloidosis....
Acute kidney injury (AKI) is a complication related to important organ dysfunction during autologous stem cell transplantation (ASCT) in light chain (AL) amyloidosis. This study aims to validate the risk factors of AKI during different periods of ASCT and the impact of AKI on long-term outcomes. 302 patients with AL amyloidosis and kidney involvement who underwent ASCT were included. The procedures from stem cell mobilization to 30 days after transplantation were categorized into four periods: Period 0 (stem cell mobilization and harvest), Period 1 (preparation), Period 2 (conditioning and transplantation), and Period 3 (engraftment). The incidence of AKI during ASCT was 27.15% (0.66% in Period 0, 6.62% in Period 1, 15.23% in Period 2, and 6.95% in Period 3). The major causes of AKI were capillary leak syndrome in Period 0, ganciclovir or sulfamethoxazole/trimethoprim in Period 1, high-dose melphalan in Period 2, and engraftment syndrome in Period 3. AKI in different periods had distinct risk factors and predictive models. AKI was a risk factor for both kidney survival and overall survival (OS). Even recovered AKI reduced 10-year kidney survival from 91.7% to 68.4% (p = 0.002) and 10-year OS from 91.1% to 77.7% (p = 0.005).
PubMed: 38658659
DOI: 10.1038/s41409-024-02292-5 -
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 -
American Journal of Ophthalmology Apr 2024To evaluate changes in retinal microvascular density and choroidal vascularity in patients with retinoblastoma (RB) after intra-arterial chemotherapy (IAC).
PURPOSE
To evaluate changes in retinal microvascular density and choroidal vascularity in patients with retinoblastoma (RB) after intra-arterial chemotherapy (IAC).
DESIGN
Retrospective clinical cohort study.
METHODS
This study included 12 unilateral RB eyes treated with IAC (RB tumor), 12 contralateral normal eyes (RB fellow), and 12 healthy controls. The macular retinal thickness and retinal microvascular structure, including the foveal avascular zone (FAZ) area, macular and peripapillary superficial vessel density (SVD), and deep vessel density (DVD), were measured by optical coherence tomography angiography (OCTA). The choroidal thickness (ChT) and choroidal vascularity, including total choroidal area (TCA), luminal area (LA), stromal area (SA), and choroidal vascularity index (CVI), were measured by spectral-domain optical coherence tomography (SD-OCT). A comparison among the 3 groups was conducted, and the correlations among the parameters were analyzed.
RESULTS
Among the 3 cohorts, the foveal retinal thickness, SVD, DVD, ChT, TCA, LA, SA, and CVI were significantly lower in RB tumor compared to RB fellow and the control eyes (all P < .01). There were no significant differences in the parameters between the contralateral and control eyes. The correlation analyses indicated a significant negative correlation between the total melphalan dose and foveal and parafoveal DVD, ChT, and LA.
CONCLUSIONS
The retinal microvascular density and choroidal vascularity were lower in unilateral RB treated with IAC, and seemed to be related to the total melphalan dose. There were no measurable changes in the contralateral eyes.
PubMed: 38615831
DOI: 10.1016/j.ajo.2024.04.007 -
Talanta Jul 2024Developing probes for simultaneous diagnosis and killing of cancer cells is crucial, yet challenging. This article presents the design and synthesis of a novel Rhodamine...
Developing probes for simultaneous diagnosis and killing of cancer cells is crucial, yet challenging. This article presents the design and synthesis of a novel Rhodamine B fluorescence probe. The design strategy involves utilizing an anticancer drug (Melphalan) to bind with a fluorescent group (HRhod-OH), forming HRhod-MeL, which is non-fluorescent. However, when exposed to the high levels of reactive oxygen species (ROS) of cancer cells, HRhod-MeL transforms into a red-emitting Photocage (Rhod-MeL), and selectively accumulates in the mitochondria of cancer cells, where, when activated with green light (556 nm), anti-cancer drugs released. The Photocage improve the efficacy of anti-cancer drugs and enables the precise diagnosis and killing of cancer cells. Therefore, the prepared Photocage can detect cancer cells and release anticancer drugs in situ, which provides a new method for the development of prodrugs.
Topics: Prodrugs; Humans; Antineoplastic Agents; Rhodamines; Drug Liberation; Fluorescent Dyes; Reactive Oxygen Species; Drug Design; Light; Cell Line, Tumor
PubMed: 38613948
DOI: 10.1016/j.talanta.2024.126002 -
ACS Biomaterials Science & Engineering May 2024Intratumoral injection of anticancer agents has limited efficacy and is not routinely used for most cancers. In this study, we aimed to improve the efficacy of...
Intratumoral injection of anticancer agents has limited efficacy and is not routinely used for most cancers. In this study, we aimed to improve the efficacy of intratumoral chemotherapy using a novel approach comprising peri-tumoral injection of sustained-release liposomal nanoparticles containing phenylephrine, which is a potent vasoconstrictor. Using a preclinical model of melanoma, we have previously shown that systemically administered (intravenous) phenylephrine could transiently shunt blood flow to the tumor at the time of drug delivery, which in turn improved antitumor responses. This approach was called dynamic control of tumor-associated vessels. Herein, we used liposomal phenylephrine nanoparticles as a "local" dynamic control strategy for the B16 melanoma. Local dynamic control was shown to increase the retention and exposure time of tumors to intratumorally injected chemotherapy (melphalan). C57BL/6 mice bearing B16 tumors were treated with intratumoral melphalan and peri-tumoral injection of sustained-release liposomal phenylephrine nanoparticles (i.e., the local dynamic control protocol). These mice had statistically significantly improved antitumor responses compared to melphalan alone ( = 0.0011), whereby 58.3% obtained long-term complete clinical response. Our novel approach of local dynamic control demonstrated significantly enhanced antitumor efficacy and is the subject of future clinical trials being designed by our group.
Topics: Animals; Phenylephrine; Liposomes; Nanoparticles; Mice, Inbred C57BL; Melanoma, Experimental; Mice; Antineoplastic Agents; Melphalan; Cell Line, Tumor; Melanoma
PubMed: 38613483
DOI: 10.1021/acsbiomaterials.4c00078 -
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 -
Pediatric Blood & Cancer Jun 2024Survival rates of patients with high-risk neuroblastoma are unacceptable. A time-intensified treatment strategy with delayed local treatment to control systemic diseases...
PURPOSE
Survival rates of patients with high-risk neuroblastoma are unacceptable. A time-intensified treatment strategy with delayed local treatment to control systemic diseases has been developed in Japan. We conducted a nationwide, prospective, single-arm clinical trial with delayed local treatment. This study evaluated the safety and efficacy of delayed surgery to increase treatment intensity.
PATIENTS AND METHODS
Seventy-five patients with high-risk neuroblastoma were enrolled in this study between May 2011 and September 2015. Delayed local treatment consisted of five courses of induction chemotherapy (cisplatin, pirarubicin, vincristine, and cyclophosphamide) and myeloablative high-dose chemotherapy (melphalan, etoposide, and carboplatin), followed by local tumor extirpation with surgery and irradiation. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), response rate, adverse events, and surgical complications.
RESULTS
Seventy-five patients were enrolled, and 64 were evaluable (stage 3, n = 8; stage 4, n = 56). The estimated 3-year PFS and OS rates (95% confidence interval [CI]) were 44.4% [31.8%-56.3%] and 80.7% [68.5%-88.5%], resspectively. The response rate of INRC after completion of the treatment protocol was 66% (42/64; 95% CI: 53%-77%; 23 CR [complete response], 10 VGPR [very good partial response], and nine PR [partial response]). None of the patients died during the protocol treatment or within 30 days of completion. Grade 4 adverse effects, excluding hematological adverse effects, occurred in 48% of patients [31/64; 95% CI: 36%-61%]. Major Surgical complications were observed in 25% of patients [13/51; 95% CI: 14%-40%].
CONCLUSION
This study indicates that delayed local treatment is feasible and shows promising efficacy, suggesting that this treatment should be considered further in a comparative study of high-risk neuroblastoma.
Topics: Humans; Neuroblastoma; Female; Male; Child, Preschool; Infant; Child; Antineoplastic Combined Chemotherapy Protocols; Japan; Prospective Studies; Survival Rate; Adolescent; Induction Chemotherapy; Etoposide; Follow-Up Studies; Vincristine; Combined Modality Therapy; Cyclophosphamide; Prognosis; Doxorubicin; Melphalan; Cisplatin
PubMed: 38577760
DOI: 10.1002/pbc.30976