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European Journal of Cancer (Oxford,... Apr 2024The Health outcomes and Understanding of MyelomA multi-National Study (HUMANS) was a large-scale, retrospective study conducted across Denmark, Finland and Sweden using...
AIM
The Health outcomes and Understanding of MyelomA multi-National Study (HUMANS) was a large-scale, retrospective study conducted across Denmark, Finland and Sweden using linked data from national registries. We describe the characteristics, treatment patterns and clinical outcomes for patients with newly diagnosed multiple myeloma (NDMM) over 2010-2018.
METHODS
Patients with NDMM who received MM-specific, first-line treatments, were categorised by treatment (autologous stem cell transplantation [ASCT] or a combination chemotherapy regimen based on bortezomib, lenalidomide or melphalan-prednisolone-thalidomide).
RESULTS
11,023 patients received treatment over 2010-2018. Time between diagnosis and treatment was shortest in Denmark (0.9 months), then Sweden (2.9 months) and Finland (4.6 months). Around one third of patients underwent ASCT. Lenalidomide-based regimens were prescribed to 23-28% of patients in Denmark and Finland, versus 12% in Sweden. Patients receiving lenalidomide had the longest wait for treatment, from 3.2 months (Denmark) to 12.1 months (Sweden). Treatment persistence was highest among patients receiving melphalan-prednisolone-thalidomide (7-8 months) in Finland and Sweden and lowest among those receiving bortezomib (3.5 months) in Finland. Overall survival (OS) was longest among patients with ASCT (7-10 years). Among patients receiving chemotherapy, OS (from diagnosis/treatment initiation), varied between cohorts. In a sensitivity analysis excluding patients with smouldering MM, OS decreased for all; for patients receiving bortezomib or lenalidomide, OS from diagnosis was 40-49 and 27-54 months, respectively.
CONCLUSIONS
This population-based study of patients with NDMM receiving first-line MM-specific treatment, provides real-world data on treatment patterns and outcomes to complement data from randomised clinical trials.
Topics: Humans; Multiple Myeloma; Lenalidomide; Bortezomib; Thalidomide; Hematopoietic Stem Cell Transplantation; Melphalan; Finland; Retrospective Studies; Sweden; Dexamethasone; Transplantation, Autologous; Antineoplastic Combined Chemotherapy Protocols; Prednisolone; Registries; Denmark
PubMed: 38377776
DOI: 10.1016/j.ejca.2024.113921 -
Cancer Medicine Jan 2024High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains an effective treatment for non-Hodgkin lymphoma (NHL). The limited availability of...
BACKGROUND
High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains an effective treatment for non-Hodgkin lymphoma (NHL). The limited availability of carmustine has prompted the exploration of novel alternative conditioning regimens. This study aimed to compare the efficacy and safety profile of GBM/GBC (gemcitabine, busulfan, and melphalan or cyclophosphamide) conditioning compared with the standard BEAM/BEAC regimens (carmustine, etoposide, cytarabine, and melphalan or cyclophosphamide) for ASCT in patients with NHL.
METHODS
A retrospective analysis was conducted on 231 NHL patients, who underwent ASCT from October 2010 to October 2021 at the Institute of Hematology & Blood Disease Hospital, including both first-line and salvage settings. This resulted in the inclusion of 112 patients in the GBM/GBC arm and 92 in the BEAM/BEAC arm. Propensity score matching was employed to validate the results.
RESULTS
Disease subtype distribution was similar between the GBM/GBC and BEAM/BEAC groups, with diffuse large B-cell lymphoma being the most common (58.9% vs. 58.7%), followed by PTCL (17.0% vs. 18.5%) and MCL (14.3% vs. 14.1%). At 3 months post-ASCT, complete response (CR) rates were comparable (GBM/GBC 93.5% vs. BEAM/BEAC 91.1%; p = 0.607). The 4-year progression-free survival (78.4% vs. 82.3%; p = 0.455) and 4-year overall survival (88.1% vs. 87.7%; p = 0.575) were also similar. Both groups exhibited low non-relapse mortality at 4 years (GBM/GBC 1.8% vs. BEAM/BEAC 3.5%; p = 0.790) with no transplant-related mortalities reported. The GBM/GBC cohort demonstrated a higher incidence of grade 3/4 oral mucositis and hepatic toxicity, whereas the BEAM/BEAC group had more frequent cases of bacteremia or sepsis (13 cases vs. 5 in GBM/GBC).
CONCLUSIONS
The GBM/GBC regimen is effective and well-tolerated, offering outcomes that are highly comparable to those in NHL patients conditioned with BEAM/BEAC, as demonstrated in a prognostically matched cohort.
Topics: Humans; Carmustine; Gemcitabine; Hematopoietic Stem Cell Transplantation; Melphalan; Retrospective Studies; Transplantation, Autologous; Lymphoma, Non-Hodgkin; Cyclophosphamide; Etoposide; Cytarabine; Antineoplastic Combined Chemotherapy Protocols; Transplantation Conditioning
PubMed: 38348996
DOI: 10.1002/cam4.6965 -
Cells Jan 2024Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) utilizes angiotensin-converting enzyme 2 (ACE2) as its main receptor for cell entry. We bioengineered a...
Soluble Angiotensin-Converting Enzyme 2 Protein Improves Survival and Lowers Viral Titers in Lethal Mouse Model of Severe Acute Respiratory Syndrome Coronavirus Type 2 Infection with the Delta Variant.
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) utilizes angiotensin-converting enzyme 2 (ACE2) as its main receptor for cell entry. We bioengineered a soluble ACE2 protein termed ACE2 618-DDC-ABD that has increased binding to SARS-CoV-2 and prolonged duration of action. Here, we investigated the protective effect of this protein when administered intranasally to k18-hACE2 mice infected with the aggressive SARS-CoV-2 Delta variant. k18-hACE2 mice were infected with the SARS-CoV-2 Delta variant by inoculation of a lethal dose (2 × 10 PFU). ACE2 618-DDC-ABD (10 mg/kg) or PBS was administered intranasally six hours prior and 24 and 48 h post-viral inoculation. All animals in the PBS control group succumbed to the disease on day seven post-infection (0% survival), whereas, in contrast, there was only one casualty in the group that received ACE2 618-DDC-ABD (90% survival). Mice in the ACE2 618-DDC-ABD group had minimal disease as assessed using a clinical score and stable weight, and both brain and lung viral titers were markedly reduced. These findings demonstrate the efficacy of a bioengineered soluble ACE2 decoy with an extended duration of action in protecting against the aggressive Delta SARS-CoV-2 variant. Together with previous work, these findings underline the universal protective potential against current and future emerging SARS-CoV-2 variants.
Topics: Humans; Mice; Animals; Angiotensin-Converting Enzyme 2; Peptidyl-Dipeptidase A; COVID-19; SARS-CoV-2; gamma-Globulins; Melphalan
PubMed: 38334597
DOI: 10.3390/cells13030203 -
Cancer Treatment Reviews Mar 2024Patients with high-risk or metastatic Ewing sarcoma (ES) and rhabdomyosarcoma (RMS) have a guarded prognosis. High-dose chemotherapy (HDT) with autologous stem cell... (Review)
Review
High-dose chemotherapy for Ewing sarcoma and Rhabdomyosarcoma: A systematic review by the Australia and New Zealand sarcoma association clinical practice guidelines working party.
INTRODUCTION
Patients with high-risk or metastatic Ewing sarcoma (ES) and rhabdomyosarcoma (RMS) have a guarded prognosis. High-dose chemotherapy (HDT) with autologous stem cell transplant (ASCT) has been evaluated as a treatment option to improve outcomes. However, survival benefits remain unclear, and treatment is associated with severe toxicities.
METHODS
A systematic review was conducted, using the population, intervention, comparison outcome (PICO) model, to evaluate whether utilization of HDT/ASCT impacts the outcome of patients with ES and RMS compared to standard chemotherapy alone, as part of first line treatment or in the relapse setting. Medline, Embase and Cochrane Central were queried for publications from 1990 to October 2022 that evaluated event-free survival (EFS), overall survival (OS), and toxicities. Each study was screened by two independent reviewers for suitability. A qualitative synthesis of the results was performed.
RESULTS
Of 1,172 unique studies screened, 41 studies were eligible for inclusion with 29 studies considering ES, 10 studies considering RMS and 2 studies considering both. In ES patients with high-risk localised disease who received HDT/ASCT after VIDE chemotherapy, consolidation with melphalan-based HDT/ASCT as first line therapy conveyed an EFS and OS benefit over standard chemotherapy consolidation. Efficacy of HDT/ASCT using a VDC/IE backbone, which is now standard care, has not been established. Survival benefits are not confirmed for ES patients with metastatic disease at initial diagnosis. For relapsed/refractory ES, four retrospective studies report improvement in outcomes with HDT/ASCT with the greatest evidence in patients who demonstrate a treatment response before HDT, and in patients under the age of 14. In RMS, there is no proven survival benefit of HDT/ASCT in primary localised, metastatic or relapsed disease.
CONCLUSION
Prospective randomised trials are required to determine the utility of HDT/ASCT in ES and RMS. Selected patients with relapsed ES could be considered for HDT/ASCT.
Topics: Humans; Sarcoma, Ewing; Combined Modality Therapy; Antineoplastic Combined Chemotherapy Protocols; Retrospective Studies; Prospective Studies; New Zealand; Neoplasm Recurrence, Local; Rhabdomyosarcoma; Transplantation, Autologous; Treatment Outcome; Hematopoietic Stem Cell Transplantation
PubMed: 38325070
DOI: 10.1016/j.ctrv.2024.102694 -
Virology Apr 2024Here we investigated the virulence properties of a unique cell-adapted SARS-CoV-2 mutant showing a ten-amino acid deletion encompassing the furin cleavage site of the...
Here we investigated the virulence properties of a unique cell-adapted SARS-CoV-2 mutant showing a ten-amino acid deletion encompassing the furin cleavage site of the spike protein (ΔSPRAARSVAS; Δ680-689-B.1) in comparison to its parental strain (wt-B.1) and two Delta variants (AY.122 and AY.21) of concern. After intranasal inoculation, transgenic K18-hACE2 mice were monitored for 14 days for weight change, lethality, and clinical score; oral swabs were daily collected and tested for the presence of N protein subgenomic RNA. At 3 and 7 dpi mice were also sacrificed and organs collected for molecular, histopathological, and immune response profile investigations. The Δ680-689-B.1-infected mice exhibited reduced shedding, lower virulence at the lung level, and milder pulmonary lesions. In the lung, infection with Δ680-689-B.1 was associated with a significant lower expression of some cytokines at 3 dpi (IL-4, IL-27, and IL-28) and 7 dpi (IL-4, IL-27, IL-28, IFN-γ and IL-1α).
Topics: Mice; Animals; Furin; COVID-19; Interleukin-27; Interleukin-4; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Virulence; Mice, Transgenic; Disease Models, Animal; gamma-Globulins; Melphalan
PubMed: 38324940
DOI: 10.1016/j.virol.2024.109997 -
Frontiers in Pharmacology 2024Oral cancer is a severe health problem that accounts for an alarmingly high number of fatalities worldwide. (L.) Dunal has been extensively studied against various...
Oral cancer is a severe health problem that accounts for an alarmingly high number of fatalities worldwide. (L.) Dunal has been extensively studied against various tumor cell lines from different body organs, rarely from the oral cavity. We thus investigated the cytotoxicity of fruits (W-F) and roots (W-R) hydromethanolic extracts and their chromatographic fractions against oral squamous cell carcinoma (OSCC) cell lines [Ca9-22 (derived from gingiva), HSC-2, HSC-3, and HSC-4 (derived from tongue)] and three normal oral mesenchymal cells [human gingival fibroblast (HGF), human periodontal ligament fibroblast (HPLF), and human pulp cells (HPC)] in comparison to standard drugs. The root polar ethyl acetate (W-R EtOAc) and butanol (W-R BuOH) fractions exhibited the strongest cytotoxicity against the Ca9-22 cell line (CC = 51.8 and 40.1 μg/mL, respectively), which is relatively the same effect as 5-FU at CC = 69.4 μM and melphalan at CC = 36.3 μM on the same cancer cell line. Flow cytometric analysis revealed changes in morphology as well as in the cell cycle profile of the W-R EtOAc and W-R BuOH-treated oral cancer Ca9-22 cells compared to the untreated control. The W-R EtOAc (125 μg/mL) exerted morphological changes and induced subG accumulation, suggesting apoptotic cell death. A UHPLC MS/MS analysis of the extract enabled the identification of 26 compounds, mainly alkaloids, withanolides, withanosides, and flavonoids. Pharmacophore-based inverse virtual screening proposed that BRD3 and CDK2 are the cancer-relevant targets for the annotated withanolides D () and O (), and the flavonoid kaempferol (). Molecular modeling studies highlighted the BRD3 and CDK2 as the most probable oncogenic targets of anticancer activity of these molecules. These findings highlight 's potential as an affordable source of therapeutic agents for a range of oral malignancies.
PubMed: 38303989
DOI: 10.3389/fphar.2024.1325272 -
Haematologica Jun 2024The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data are limited regarding factors predicting survival in BCOR-mutated...
The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data are limited regarding factors predicting survival in BCOR-mutated (mBCOR) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We evaluated 138 patients with mBCOR myeloid disorders, of which 36 (26.1%) had AML and 63 (45.6%) had MDS. Sixty-six (47.8%) patients had a normal karyotype while 18 (13%) patients had complex karyotype. BCOR-mutated MDS/AML were highly associated with RUNX1 and U2AF1 co-mutations. In contrast, TP53 mutation was infrequently seen with mBCOR MDS. Patients with an isolated BCOR mutation had similar survival compared to those with high-risk co-mutations by European LeukemiaNet (ELN) 2022 criteria (median OS 1.16 vs. 1.27 years, P=0.46). Complex karyotype adversely impacted survival among mBCOR AML/MDS (HR 4.12, P<0.001), while allogeneic stem cell transplant (alloSCT) improved survival (HR 0.38, P=0.04). However, RUNX1 co-mutation was associated with an increased risk of post-alloSCT relapse (HR 88.0, P=0.02), whereas melphalan-based conditioning was associated with a decreased relapse risk (HR 0.02, P=0.01). We conclude that mBCOR is a high-risk feature across MDS/AML, and that alloSCT improves survival in this population.
Topics: Humans; Male; Female; Repressor Proteins; Mutation; Middle Aged; Aged; Adult; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Proto-Oncogene Proteins; Aged, 80 and over; Core Binding Factor Alpha 2 Subunit; Prognosis; Young Adult; Hematopoietic Stem Cell Transplantation; Adolescent
PubMed: 38299584
DOI: 10.3324/haematol.2023.284185 -
Bone Marrow Transplantation Apr 2024Bortezomib (Vel)- Melphalan 200 mg/m2 (Mel200) (Vel-Mel) has been utilised to intensify conditioning in autologous hematopoietic stem cell transplantation (AHCT) for...
In the era of Bortezomib-based Induction, intensification of Melphalan-based conditioning with Bortezomib does not improve Survival Outcomes in newly diagnosed Multiple Myeloma: a study from the Chronic Malignancies Working Party of the EBMT.
Bortezomib (Vel)- Melphalan 200 mg/m2 (Mel200) (Vel-Mel) has been utilised to intensify conditioning in autologous hematopoietic stem cell transplantation (AHCT) for multiple myeloma (MM). This EBMT registry-based study compared Vel-Mel with Mel200 during upfront AHCT. Between 2010 and 2017, MM patients who received Vel-Mel (n = 292) conditioning were compared with 4,096 Mel200 patients in the same 58 centres. Pre-AHCT, compared to Mel200 patients, Vel-Mel patients had similar International Staging System (ISS) scores and cytogenetic risk profiles; a similar proportion had received bortezomib-based induction (85% and 87.3%, respectively) though they were younger with a better performance status. Vel-Mel patients were more likely to achieve CR post-induction (40.6% vs 20.3%, p < 0.001) and by day 100 of AHCT (CR/VGPR: 70.2 % vs. 57.2%, p < 0.001). There was no difference in 3-year PFS (49% vs 46%, p = 0.06) or early post-AHCT mortality. In multivariable analysis, Vel-Mel associated with inferior PFS (HR: 1.69 (1.27-2.25, p < 0.001) and OS (HR:1.46 (1.14-1.86,p = 0.002), similar to negative effects on PFS of advanced ISS (HR:1.56 (1.33-1.83, p < 0.001), high-risk cytogenetics (HR:1.43(1.18-1.74, p < 0.001) and poor post-induction response(<=PR)(HR: 1.43(1.25-1.62, p < 0.001) Overall, despite superior pre- and post-AHCT responses, there was no improvement in PFS or OS following Vel-Mel. This data supports the findings of the smaller prospective IFM study.
Topics: Humans; Multiple Myeloma; Bortezomib; Melphalan; Prospective Studies; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38297040
DOI: 10.1038/s41409-023-02160-8 -
American Journal of Ophthalmology Case... Mar 2024To report the successful treatment of persistent retinoblastoma vitreous seeding with 6 cycles of intra-arterial chemotherapy and 15 cycles of intravitreal chemotherapy...
PURPOSE
To report the successful treatment of persistent retinoblastoma vitreous seeding with 6 cycles of intra-arterial chemotherapy and 15 cycles of intravitreal chemotherapy injections.
OBSERVATIONS
A three-year-old female presented to the ocular oncology clinic with Group D retinoblastoma with severe vitreous seeding. The patient received 3 cycles of intra-arterial chemotherapy (melphalan, topotecan, and carboplatin) and 15 cycles of intravitreal chemotherapy (melphalan and combined melphalan/topotecan). Complete tumor regression and resolution of vitreous seeding was achieved. The best corrected visual acuity in the affected eye was 20/50.
CONCLUSIONS AND IMPORTANCE
Intravitreal chemotherapy for retinoblastoma vitreous seeding is often restricted to 8 treatment cycles. Patients who do not respond after 8 cycles face salvage therapy with radiation or enucleation. This is a case in which prolonged intravitreal chemotherapy delivery was well tolerated and resulted in sustained tumor remission, with useful visual acuity in the treated eye.
PubMed: 38283770
DOI: 10.1016/j.ajoc.2023.101987 -
Indian Journal of Cancer Oct 2023High-dose chemotherapy with melphalan, followed by autologous hematopoietic stem cell transplantation (AHCT) remains the standard of care for consolidation therapy of... (Review)
Review
Bortezomib-based induction therapy followed by autologous hematopoietic cell transplantation in newly diagnosed multiple myeloma patients: A single-center experience and review of Indian literature.
INTRODUCTION
High-dose chemotherapy with melphalan, followed by autologous hematopoietic stem cell transplantation (AHCT) remains the standard of care for consolidation therapy of fit patients with newly diagnosed multiple myeloma (NDMM), for more than 20 years now.
MATERIAL AND METHODS
This is a retrospective study of NDMM patients who underwent AHCT at our center from 2011 to 2018. Data was undertaken using the hospital electronic medical records (EMR).
RESULTS
Among transplant eligible patients (which were 764), 78 patients (10.2%) underwent AHCT. The predominant stage in the study cohort was International Scoring System (ISS)-III (55%), and IgG-kappa (44%) was the commonest subtype of multiple myeloma (MM). Light chain myeloma was found in 23.5% of patients. Pretransplant, 42%, 48%, and 10% patients were in more than very good partial response (>VGPR), very good partial response (VGPR), and partial response (PR), respectively. The median duration of follow-up was 57.2 months (range: 12.1-120.2 months). The entire cohort's 5-year overall survival (OS) and progression-free survival (PFS) were 89.1% and 41.8%, respectively.
CONCLUSION
Bortezomib based triplet induction regimens were effective and well tolerated in this retrospective analysis of Indian patients. We observed that AHCT effectively achieves deep and durable remission in MM.
Topics: Humans; Bortezomib; Hematopoietic Stem Cell Transplantation; Induction Chemotherapy; Multiple Myeloma; Retrospective Studies
PubMed: 38258869
DOI: 10.4103/ijc.ijc_78_22