-
The British Journal of Ophthalmology Dec 2023To report long-term results of intracameral chemotherapy (ICC) for aqueous seeding (AS) in retinoblastoma.
AIMS
To report long-term results of intracameral chemotherapy (ICC) for aqueous seeding (AS) in retinoblastoma.
METHODS
Retrospective study including 20 patients with primary (n=4) or secondary non-iatrogenic (n=16) AS treated with ICC according to a previously described technique between 2011 and 2020 with at least 1-year follow-up.
RESULTS
AS control was initially achieved in all cases with a mean 5 injections of melphalan (n=13) or topotecan (n=7). Three eyes had an isolated AS relapse at a mean interval of 8 months after the first ICC course, which regressed with a second course of intracameral melphalan. Concomitant interciliary process seed implantation was treated with additional brachytherapy if sectorial (n=3) or proton therapy if annular (n=1). Other therapies including systemic, intra-arterial chemotherapy and/or focal treatments were given in 15 eyes to treat concomitant tumour sites. Eye preservation was achieved in 85% of the eyes (n=17/20) at a mean event-free follow-up of 45 months for aqueous disease, and 40 months for any other intraocular tumour activity. Three cases were enucleated due to refractory non-aqueous disease. All patients are alive without metastasis (mean follow-up of 48 months after first ICC). ICC-related intraocular toxicity included iris atrophy (n=5), cataract (n=4), posterior synechiae (n=2) and iris heterochromia (n=1). No patient suffered irreversible vision loss. Useful to normal vision was found in 82% of the cases (n=14/17).
CONCLUSION
ICC appears to be safe and efficient for AS without irreversible vision-threatening adverse effects. More data are needed to determine any superiority in efficiency/toxicity of topotecan versus melphalan.
Topics: Humans; Infant; Retinoblastoma; Retinal Neoplasms; Melphalan; Topotecan; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Vitreous Body; Neoplasm Seeding; Antineoplastic Agents, Alkylating
PubMed: 36379686
DOI: 10.1136/bjo-2022-322492 -
Acta Biomaterialia Feb 2024Mucosal vaccinations for respiratory pathogens provide effective protection as they stimulate localized cellular and humoral immunities at the site of infection....
Mucosal vaccinations for respiratory pathogens provide effective protection as they stimulate localized cellular and humoral immunities at the site of infection. Currently, the major limitation of intranasal vaccination is using effective adjuvants capable of withstanding the harsh environment imposed by the mucosa. Herein, we describe the efficacy of using a unique biopolymer, N-dihydrogalactochitosan (GC), as a nasal mucosal vaccine adjuvant against respiratory infections. Specifically, we mixed GC with recombinant SARS-CoV-2 trimeric spike (S) and nucleocapsid (NC) proteins to intranasally vaccinate K18-hACE2 transgenic mice, in comparison with Addavax (AV), an MF-59 equivalent. In contrast to AV, intranasal application of GC induces a robust, systemic antigen-specific antibody response and increases the number of T cells in the cervical lymph nodes. Moreover, GC+S+NC-vaccinated animals were largely resistant to the lethal SARS-CoV-2 challenge and experienced drastically reduced morbidity and mortality, with animal weights and behavior returning to normal 22 days post-infection. In contrast, animals intranasally vaccinated with AV+S+NC experienced severe weight loss, mortality, and respiratory distress, with none surviving beyond 6 days post-infection. Our findings demonstrate that GC can serve as a potent mucosal vaccine adjuvant against SARS-CoV-2 and potentially other respiratory viruses. STATEMENT OF SIGNIFICANCE: We demonstrated that a unique biopolymer, N-dihydrogalactochitosan (GC), was an effective nasal mucosal vaccine adjuvant against respiratory infections. Specifically, we mixed GC with recombinant SARS-CoV-2 trimeric spike (S) and nucleocapsid (NC) proteins to intranasally vaccinate K18-hACE2 transgenic mice, in comparison with Addavax (AV). In contrast to AV, GC induces a robust, systemic antigen-specific antibody response and increases the number of T cells in the cervical lymph nodes. About 90 % of the GC+S+NC-vaccinated animals survived the lethal SARS-CoV-2 challenge and remained healthy 22 days post-infection, while the AV+S+NC-vaccinated animals experienced severe weight loss and respiratory distress, and all died within 6 days post-infection. Our findings demonstrate that GC is a potent mucosal vaccine adjuvant against SARS-CoV-2 and potentially other respiratory viruses.
Topics: Mice; Animals; Viral Proteins; Adjuvants, Vaccine; Antibodies, Viral; Adjuvants, Immunologic; Influenza Vaccines; Recombinant Proteins; Respiratory Tract Infections; Mucous Membrane; Mice, Transgenic; Biopolymers; Respiratory Distress Syndrome; Weight Loss; Melphalan; Acetylglucosamine; Squalene; gamma-Globulins; Polysorbates
PubMed: 38160856
DOI: 10.1016/j.actbio.2023.12.039 -
Blood Cancer Journal Nov 2023
Topics: Humans; Hematopoietic Stem Cell Transplantation; Benchmarking; Transplantation, Autologous; Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Stem Cell Transplantation; Melphalan
PubMed: 37968258
DOI: 10.1038/s41408-023-00945-0 -
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 -
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 -
Biomedicine & Pharmacotherapy =... May 2024Retinoblastoma (RB) is a type of pediatric solid tumor in the fundus. The lack of precision therapies combined with the difficulty of delivering small interfering RNA...
Retinoblastoma (RB) is a type of pediatric solid tumor in the fundus. The lack of precision therapies combined with the difficulty of delivering small interfering RNA (siRNA) into the eyes means that there is currently no nucleic acid-based therapy for RB in clinical practice. Here, we reported on anti-GD2 and glutathione-responsive spherical nucleic acids (SNAs), loaded with siRNA and the inhibitor NVP-CGM097, which jointly blocked the oncogenic factor n in RB cells (Y79 and WERI-RB-1). The SNAs were formed through the self-assembly of bifunctional cholesterol amphiphiles containing aptamers that specifically targeted GD2-positive RB cells, allowing for the formation of an SNA with a dense DNA shell. The aptamer/siRNA component functioned both as a carrier and a payload, enhancing the specific recognition and delivery of both components and constituting an active agent for MDM2 regulation. Following SNA endocytosis by RB cells, siRNA and NVP-CGM097 were released from the SNA particles by glutathione, which synergistically blocked the MDM2-p53 pathway, increasing p53 protein content and inducing cell apoptosis. This study showed a potent antitumor effect following intravitreal injection of SNAs in Y79 tumor-bearing mice through clinical manifestation and tumor pathological analysis. In hematological analysis and hepatotoxicity assays, SNAs were safer for mice than melphalan, the favored drug for treating RB in clinical practice. Our results illustrated the potential of intravitreally injected SNAs as a precision medicine for treating RB.
Topics: Animals; Humans; Mice; Apoptosis; Aptamers, Nucleotide; Cell Line, Tumor; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Proto-Oncogene Proteins c-mdm2; Retinal Neoplasms; Retinoblastoma; RNA, Small Interfering; Xenograft Model Antitumor Assays; Mice, Inbred ICR; Female
PubMed: 38522240
DOI: 10.1016/j.biopha.2024.116437 -
Viruses Mar 2024The sudden emergence of SARS-CoV-2 demonstrates the need for new vaccines that rapidly protect in the case of an emergency. In this study, we developed a recombinant MVA...
The sudden emergence of SARS-CoV-2 demonstrates the need for new vaccines that rapidly protect in the case of an emergency. In this study, we developed a recombinant MVA vaccine co-expressing SARS-CoV-2 prefusion-stabilized spike protein (ST) and SARS-CoV-2 nucleoprotein (N, MVA-SARS-2-ST/N) as an approach to further improve vaccine-induced immunogenicity and efficacy. Single MVA-SARS-2-ST/N vaccination in K18-hACE2 mice induced robust protection against lethal respiratory SARS-CoV-2 challenge infection 28 days later. The protective outcome of MVA-SARS-2-ST/N vaccination correlated with the activation of SARS-CoV-2-neutralizing antibodies (nABs) and substantial amounts of SARS-CoV-2-specific T cells especially in the lung of MVA-SARS-2-ST/N-vaccinated mice. Emergency vaccination with MVA-SARS-2-ST/N just 2 days before lethal SARS-CoV-2 challenge infection resulted in a delayed onset of clinical disease outcome in these mice and increased titers of nAB or SARS-CoV-2-specific T cells in the spleen and lung. These data highlight the potential of a multivalent COVID-19 vaccine co-expressing S- and N-protein, which further contributes to the development of rapidly protective vaccination strategies against emerging pathogens.
Topics: Animals; Humans; Mice; SARS-CoV-2; COVID-19; COVID-19 Vaccines; Antibodies, Viral; Spike Glycoprotein, Coronavirus; Vaccination; Antibodies, Neutralizing; gamma-Globulins; Melphalan; Viral Vaccines; Vaccines, DNA
PubMed: 38543782
DOI: 10.3390/v16030417 -
Nature Communications Mar 2024Safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are crucial to fight against the coronavirus disease 2019 pandemic. Most...
Safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are crucial to fight against the coronavirus disease 2019 pandemic. Most vaccines are based on a mutated version of the Spike glycoprotein [K986P/V987P (S-2P)] with improved stability, yield and immunogenicity. However, S-2P is still produced at low levels. Here, we describe the V987H mutation that increases by two-fold the production of the recombinant Spike and the exposure of the receptor binding domain (RBD). S-V987H immunogenicity is similar to S-2P in mice and golden Syrian hamsters (GSH), and superior to a monomeric RBD. S-V987H immunization confer full protection against severe disease in K18-hACE2 mice and GSH upon SARS-CoV-2 challenge (D614G or B.1.351 variants). Furthermore, S-V987H immunized K18-hACE2 mice show a faster tissue viral clearance than RBD- or S-2P-vaccinated animals challenged with D614G, B.1.351 or Omicron BQ1.1 variants. Thus, S-V987H protein might be considered for future SARS-CoV-2 vaccines development.
Topics: Cricetinae; Animals; Humans; Mice; SARS-CoV-2; Mesocricetus; COVID-19 Vaccines; COVID-19; Spike Glycoprotein, Coronavirus; Immunization; Glycoproteins; Antibodies, Neutralizing; Antibodies, Viral; gamma-Globulins; Melphalan
PubMed: 38514609
DOI: 10.1038/s41467-024-46714-w -
Melanoma Research Apr 2024Recent studies indicate that melphalan percutaneous hepatic perfusion (M-PHP) for liver metastases from ocular melanoma (mUM) improves survival. Importantly, this...
BACKGROUND
Recent studies indicate that melphalan percutaneous hepatic perfusion (M-PHP) for liver metastases from ocular melanoma (mUM) improves survival. Importantly, this benefit must be carefully balanced with changes in a patient's quality of life (QoL). This study examines the QoL changes post-M-PHP.
METHODS
Retrospective analysis of the change in QoL using the Functional Assessment of Cancer Therapy-General (FACT-G) with mUM patients receiving M-PHP ( n = 20). The FACT-G scores, which comprise physical (PWB), social (SWB), emotional (EWB) and functional (FWB) wellbeing were measured pre-procedure and at day 1, day of discharge (mean = 2.4 days), 7, 14 and 28 days after M-PHP therapy. Wilcoxon signed-rank test gauged QoL domain changes.
RESULTS
Baseline FACT-G median (IQR) scores were 101.8 (21.8). QoL scoring significantly decreased immediately after the procedure [day 1; 85 (27.5); P = 0.002] and gradually improved over time. By day 28, QoL almost returned to pre-procedure levels [100.3 (13.8); P = 0.31]. Subscore analysis revealed that the initial drop in QoL at day 1 post-procedure was attributable to the PWB (28 vs. 24; P = 0.001) and FWB domains (26 vs. 18.5; P < 0.001). By day 28 there was a statistically significant improvement in EWB ( P = 0.01).
CONCLUSION
QoL following M-PHP decreases immediately after therapy and is not significantly different from baseline by the day of discharge. By day 28 there is improved emotional well-being. This study could help to optimize the time between treatment cycles when combined with toxicity data and blood count recovery.
Topics: Humans; Melanoma; Quality of Life; Melphalan; Retrospective Studies; Skin Neoplasms; Neoplasms, Second Primary; Perfusion; Uveal Neoplasms
PubMed: 38051786
DOI: 10.1097/CMR.0000000000000947 -
Supportive Care in Cancer : Official... Aug 2023Oral cryotherapy is an effective method to prevent oral mucositis (OM) induced by chemotherapeutic agents, such as melphalan (Mel). However, there is limited data about...
PURPOSE
Oral cryotherapy is an effective method to prevent oral mucositis (OM) induced by chemotherapeutic agents, such as melphalan (Mel). However, there is limited data about cryotherapy in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients; thus, the current study aimed to examine the efficacy of cryotherapy among allo-HSCT recipients treated with Mel-containing regimens.
METHODS
Medical records of 78 consecutive allo-HSCT recipients were retrospectively analyzed. Baseline characteristics and clinical courses between the patients who received cryotherapy (cryotherapy group, n = 42) and those who did not (control group, n = 36) were compared, especially focusing on methotrexate (MTX) use as a part of graft-versus-host disease (GVHD) prophylaxis.
RESULTS
Binary logistic regression analysis revealed that a higher dose of Mel (OR, 3.82; 95%CI, 1.085-13.46; P = 0.037) or MTX use (OR, 7.61; 95% CI, 2.41-23.97; P < 0.001) was associated with the incidence of OM. MTX use was also significantly associated with the duration of OM (β = 0.515; 95% CI, 9.712-21.636; P < 0.001). Among 31 patients without MTX use, cryotherapy was associated with a significant reduction of OM development (0% in the cryotherapy group vs 35% in the control group, P = 0.021). We did not find such an association in 47 patients with MTX use.
CONCLUSION
Cryotherapy was useful to prevent the incidence of OM in allo-HSCT recipients in the cases without MTX for GVHD prophylaxis.
Topics: Humans; Melphalan; Retrospective Studies; Hematopoietic Stem Cell Transplantation; Stomatitis; Methotrexate; Cryotherapy; Transplantation Conditioning; Graft vs Host Disease
PubMed: 37581845
DOI: 10.1007/s00520-023-07989-9