ABSTRACT
Myeloma with extramedullary plasmacytomas not adjacent to bone (EMP) is associated with an extremely poor outcome compared with paraosseous plasmacytomas (PP) as current therapeutic approaches are unsatisfactory. The role of new molecules and in particular of monoclonal antibodies is under investigation. To determine whether daratumumab-based regimens are effective for myeloma with EMP, we report herein an initial multicenter observational analysis of 102 myeloma patients with EMP (n = 10) and PP (n = 25) at diagnosis and EMP (n = 28) and PP (n = 39) at relapse, treated with daratumumab-based regimens at 11 Haematological Centers in Italy.EMP and PP at diagnosis were associated with higher biochemical (90% vs. 96%, respectively) and instrumental ORR (86% vs. 83.3%, respectively), while at relapse, biochemical (74% vs. 73%) and instrumental (53% vs. 59%) ORR were lower. Median OS was inferior in EMP patients compared with patients with PP both at diagnosis (21.0 months vs. NR) (p = 0.005) and at relapse (32.0 vs. 40.0 months) (p = 0.428), although, during relapse, there was no statistically significant difference between the two groups. Surprisingly, at diagnosis, median TTP and median TTNT were not reached either in EMP patients or PP patients and during relapse there were no statistically significant differences in terms of median TTP (20 months for two groups), and median TTNT (24 months for PP patients vs. 22 months for EMP patients) between the two groups. Median TTR was 1 month in all populations.These promising results were documented even in the absence of local radiotherapy and in transplant-ineligible patients.
ABSTRACT
The ELOQUENT-3 trial demonstrated the superiority of the combination of elotuzumab, pomalidomide, and dexamethasone (EloPd) in terms of efficacy and safety, compared to Pd in relapsed/refractory multiple myeloma (RRMM), who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor. The present study is an 18-month follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloPd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 17.7 months, 213 patients (66.4%) experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 7.5 and 19.2 months, respectively. The updated multivariate analysis showed a significant reduction of PFS benefit magnitude both in advanced International Staging System (ISS) (II and III) stages and previous exposure to daratumumab cases. Instead, advanced ISS (II and III) stages and more than 2 previous lines of therapy maintained an independent prognostic impact on OS. Major adverse events included grade three-fourths neutropenia (24.9%), anemia (13.4%), lymphocytopenia (15.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 19.3% and 8.7%, respectively. A slight increase in the incidence of neutropenia and lymphocytopenia was registered with longer follow-up. In conclusion, our real-world study still confirms that EloPd is a safe and possible therapeutic choice for RRMM. Nevertheless, novel strategies are desirable for those patients exposed to daratumumab.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Dexamethasone , Multiple Myeloma , Thalidomide , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Multiple Myeloma/pathology , Male , Female , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Dexamethasone/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Middle Aged , Thalidomide/analogs & derivatives , Thalidomide/administration & dosage , Thalidomide/adverse effects , Thalidomide/therapeutic use , Retrospective Studies , Follow-Up Studies , Aged, 80 and over , Adult , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Drug Resistance, Neoplasm , Survival RateABSTRACT
In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved to have a superior clinical benefit over pomalidomide and dexamethasone with a manageable toxicity profile, leading to its approval for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. We report here a real-world experience of 200 cases of RRMM treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was two, with 51% of cases undergoing autologous stem cell transplant and 73% having been exposed to daratumumab. After a median follow-up of 9 months, 126 patients had stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate was 55.4%, a finding in line with the pivotal trial results. Regarding adverse events, the toxicity profile in our cohort was similar to that in the ELOQUENT-3 trial, with no significant differences between younger (<70 years) and older patients. The median progression-free survival was 7 months, which was shorter than that observed in ELOQUENT-3, probably because of the different clinical characteristics of the two cohorts. Interestingly, International Staging System stage III disease was associated with worse progression-free survival (hazard ratio=2.55). Finally, the median overall survival of our series was shorter than that observed in the ELOQUENT-3 trial (17.5 vs. 29.8 months). In conclusion, our real-world study confirms that EloPd is a safe and possible therapeutic choice for patients with RRMM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.
Subject(s)
Multiple Myeloma , Humans , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dexamethasone/therapeutic use , Lenalidomide/therapeutic use , Multiple Myeloma/diagnosis , Multiple Myeloma/drug therapy , Multiple Myeloma/etiology , Proteasome Inhibitors/therapeutic use , Retrospective Studies , Controlled Clinical Trials as TopicABSTRACT
Fluorescent core-shell silica nanoparticles are largely employed in nanomedicine and life science thanks to the many advantages they offer. Among these, the enhancement of the stability of the fluorescent signal upon fluorophore encapsulation into the silica matrix and the possibility to combine in a single vehicle multiple functionalities, physically separated in different compartments. In this work, we present a new approach to the Stöber method as a two-cycle protocol for the tailored synthesis of dual-color fluorescent core-shell silicon dioxide nanoparticles (SiO2 NPs) using two commercial dyes as model. To facilitate the colloidal stability, the nanoparticle surface was functionalized with biotin by two approaches. The biotinylated nanosystems were characterized by several analytical and advanced microscopy techniques including Fourier transform infrared (FT-IR) spectroscopy, dynamic light scattering (DLS), UV-vis, transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM). Moreover, advanced super-resolution based on structured illumination was used for the imaging of the double-fluorescent NPs, both on a substrate and in the cellular microenvironment, at nanometric resolution 100 nm, in view of their versatile potential employment in fluorescence optical nanoscopy as nanoscale calibration tools as well as in biomedical applications as biocompatible nanosystems for intracellular biosensing with high flexibility of use, being these nanoplatforms adaptable to the encapsulation of any couple of dyes with the desired function.
ABSTRACT
Cashew nut shell liquid (CNSL), obtained as a byproduct of the cashew industry, represents an important natural source of phenolic compounds, with important environmental benefits due to the large availability and low cost of the unique renewable starting material, that can be used as an alternative to synthetic substances in many industrial applications. The peculiarity of the functional groups of CNSL components, such as phenolic hydroxyl, the aromatic ring, acid functionality, and unsaturation(s) in the C15 alkyl side chain, permitted the design of interesting nanostructures. Cardanol (CA), anacardic acid (AA), and cardol (CD), opportunely isolated from CNSL, served as building blocks for generating an amazing class of nanomaterials with chemical, physical, and morphological properties that can be tuned in view of their applications, particularly focused on their bioactive properties.
Subject(s)
Antibodies, Monoclonal , Multiple Myeloma , Neoplasms, Plasma Cell , Humans , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bortezomib/therapeutic use , Dexamethasone/therapeutic use , Lenalidomide/therapeutic use , Multiple Myeloma/drug therapy , Retrospective Studies , Multicenter Studies as TopicABSTRACT
In this work, we developed a novel approach to purify [11C]Raclopride ([11C]RAC), an important positron emission tomography radiotracer, based on tailored shape-recognition polymers, with the aim to substitute single-pass HPLC purification with an in-flow trap & release process. Molecular imprinting technology (MIT) applied to solid phase extraction (MISPE) was investigated to develop a setting able to selectively extract [11C]RAC in a mixture containing a high amount of its precursor, (S)-O-Des-Methyl-Raclopride (DM-RAC). Two imprinted polymers selective for unlabeled RAC and DM-RAC were synthesized through a radical polymerization at 65 °C using methacrylic acid and trimethylolpropane trimethacrylate in the presence of template molecule (RAC or DM-RAC). The prepared polymer was characterized by scanning electron microscopy and Fourier transform infrared spectroscopy and tested in MISPE experiments. The polymers were used in testing conditions, revealing a high retention capacity of RAC-MISPE to retain RAC either in the presence of similar concentrations of RAC and DM-RAC precursor (96.9%, RSD 6.6%) and in the presence of a large excess of precursor (90%, RSD 4.6%) in the loading solution. Starting from these promising results, preliminary studies for selective purification of [11C]Raclopride using this RAC-MISPE were performed and, while generally confirming the selectivity capacity of the polymer, revealed challenging applicability to the current synthetic process, mainly due to high backpressures and long elution times.
ABSTRACT
Phenanthrene (PTH) and 9-phenanthrol (9-PTH) exhibited severe health threats and ecological hazards, for this reason, exploring a high-efficient removing strategy for PTH and 9-PTH could be considered of great urgency. Herein the 4,4'-biphenyldicarboxaldehyde m-phenylenediamine Schiff base magnetic polymer (magnetic BIPH-PHEN) was successfully fabricated via Schiff base polycondensation reaction and the subsequently one-pot embedded method. The mutual aromatic nucleus of BIPH-PHEN polymer and PTH/9-PTH could form π-π interaction, thus improving the capture ability, the embedded Fe3O4 nanoparticles provided the possibility for rapid separation. The physical and chemical properties of the magnetic BIPH-PHEN were systematically characterized. The removal rate of magnetic BIPH-PHEN towards PTH and 9-PTH was 85.65 % and 98.52 %, respectively (PTH or 9-PTH: 8 mg/L; Adsorbent: 0.2 g/L). The DFT calculations including energy calculations and electrostatic potential distribution analyzed the different bonding modes and proposed the most possible bonding modes in the adsorbent/adsorbate system. Moreover, the LUMO and HOMO orbits combined with energy gaps analysis proved the existence and specific types of the π-π interaction. The monolayer adsorption occurred on the homogeneous magnetic BIPH-PHEN surface, simultaneously the chemisorption was dominant. This work not only proposed new sights on assembling magnetic Schiff base polymer for removing polycyclic aromatic hydrocarbons, but also provided a deeper understanding of intramolecular interactions.
Subject(s)
Phenanthrenes , Polycyclic Aromatic Hydrocarbons , Adsorption , Density Functional Theory , Phenylenediamines , Polycyclic Aromatic Hydrocarbons/analysis , Polymers/chemistry , Schiff Bases/chemistry , Static ElectricityABSTRACT
The present study aimed to develop two survival risk scores (RS) for overall survival (OS, SRS KRd/EloRd ) and progression-free survival (PFS, PRS KRd/EloRd ) in 919 relapsed/refractory multiple myeloma (RRMM) patients who received carfilzomib, lenalidomide, and dexamethasone (KRd)/elotuzumab, lenalidomide, and dexamethasone (EloRd). The median OS was 35.4 months, with no significant difference between the KRd arm versus the EloRd arm. In the multivariate analysis, advanced ISS (HR = 1.31; P = 0.025), interval diagnosis-therapy (HR = 1.46; P = 0.001), number of previous lines of therapies (HR = 1.96; P < 0.0001), older age (HR = 1.72; P < 0.0001), and prior lenalidomide exposure (HR = 1.30; P = 0.026) remained independently associated with death. The median PFS was 20.3 months, with no difference between the two strategies. The multivariate model identified a significant progression/death risk increase for ISS III (HR = 1.37; P = 0.002), >3 previous lines of therapies (HR = 1.67; P < 0.0001), older age (HR = 1.64; P < 0.0001), and prior lenalidomide exposure (HR = 1.35; P = 0.003). Three risk SRS KRd/EloRd categories were generated: low-risk (134 cases, 16.5%), intermediate-risk (467 cases, 57.3%), and high-risk categories (213 cases, 26.2%). The 1- and 2-year OS probability rates were 92.3% and 83.8% for the low-risk (HR = 1, reference category), 81.1% and 60.6% (HR = 2.73; P < 0.0001) for the intermediate-risk, and 65.5% and 42.5% (HR = 4.91; P < 0.0001) for the high-risk groups, respectively. Notably, unlike the low-risk group, which did not cross the median timeline, the OS median values were 36.6 and 18.6 months for the intermediate- and high-risk cases, respectively. Similarly, three PRS KRd/EloRd risk categories were engendered. Based on such grouping, 338 (41.5%) cases were allocated in the low-, 248 (30.5%) in the intermediate-, and 228 (28.0%) in the high-risk groups. The 1- and 2-year PFS probability rates were 71.4% and 54.5% for the low-risk (HR = 1, reference category), 68.9% and 43.7% (HR = 1.95; P < 0.0001) for the intermediate-risk, and 48.0% and 27.1% (HR = 3.73; P < 0.0001) for the high-risk groups, respectively. The PFS median values were 29.0, 21.0, and 11.7 months for the low-, intermediate-, and high-risk cases. This analysis showed 2.7- and 4.9-fold increased risk of death for the intermediate- and high-risk cases treated with KRd/EloRd as salvage therapy. The combined progression/death risks of the two categories were increased 1.3- and 2.2-fold compared to the low-risk group. In conclusion, SRS KRd/EloRd and PRS KRd/EloRd may represent accessible and globally applicable models in daily clinical practice and ultimately represent a prognostic tool for RRMM patients who received KRd or EloRd.
ABSTRACT
In combination with lenalidomide and dexamethasone (KRd), Carfilzomib has been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) on ASPIRE trial. Efficacy and safety of the triplet are still the object of investigation by many groups to confirm ASPIRE results in the setting of RRMM treated in real-life who don't meet trial restrictive inclusion criteria. Therefore, we report a retrospective multicenter analysis of 600 RRMM patients treated with KRd between December 2015 and December 2018. The median age was 64 years (range 33-85), and the median number of previous therapies was two (range 1-11). After a median of 11 KRd cycles, the overall response rate was 79.9%. The median progression-free survival (PFS) was 22 months, and the 2-year probability of PFS was 47.6%. Creatinine clearance<30 ml/min, >1 line of previous therapy, and high-risk FISH were all associated with a poor prognosis in multivariate analysis. The median overall survival (OS) was 34.8 months; the 2-year probability of OS was 63.5%. At multivariate analysis, creatinine clearance<30 ml/min, >1 line of previous therapy, and high-risk FISH were significantly associated with poor prognosis. After a median follow-up of 16 months (range 1-50), 259 withdrew from therapy. The main discontinuation reason was progressive disease (81.8%). Seventy-four patients (12.3%) discontinued therapy for toxicity. The most frequent side effects were hematological (anemia 49.3%, neutropenia 42.7%, thrombocytopenia 42.5%) and cardiovascular (hypertension 14.5%, heart failure 2.5%, arrhythmias 3.6%). Our study confirms the safety and efficacy of KRd in the real-life setting of RRMM patients and encourages its use in clinical practice.
Subject(s)
Multiple Myeloma , Humans , Lenalidomide , Multiple Myeloma/drug therapy , Salvage Therapy , Retrospective Studies , Dexamethasone/adverse effectsABSTRACT
The combination of elotuzumab, lenalidomide, and dexamethasone (EloRd) enhanced the clinical benefit over Rd with a manageable toxicity profile in the ELOQUENT-2 trial, leading to its approval in relapsed/refractory multiple myeloma (RRMM). The present study is a 3-year follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloRd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 36 months (range 6-55), 236 patients experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 18.4 and 34 months, respectively. The updated multivariate analyses showed a significant reduction of PFS and OS benefit magnitude only in cases with International Staging System stage III. Major adverse events included grade 3/4 neutropenia (18.5%), anemia (15.4%), lymphocytopenia (12.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 33.9% and 18.9%, respectively. No new safety signals with longer follow-up have been observed. Of 319 patients, 245 (76.7%) reached at least a partial remission. A significantly lower response rate was found in patients previously exposed to lenalidomide. In conclusion, our study confirms that EloRd is a safe and effective regimen for RRMM patients, maintaining benefits across multiple unfavorable subgroups.
Subject(s)
Multiple Myeloma , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dexamethasone/adverse effects , Follow-Up Studies , Humans , Lenalidomide/therapeutic use , Retrospective Studies , Thalidomide/adverse effectsABSTRACT
The search for effective and less toxic drugs for the treatment of Cutaneous Leishmaniasis (CL) is desirable due to the emergence of resistant parasites. The present study shows the preparation, characterization and in vitro antileishmanial activity of green-based silver nanoparticles (AgNPs) with Cashew Nutshell Liquid (CNSL, main constituents: anacardic acid (AA) and cardol (CD). The synthesis of silver nanoparticles was achieved by reduction with sodium borohydride in the presence of anacardic acid or cardol under microwave irradiation (400 W, 60 °C, 5 min) resulting in AgAA and AgCD. In vitro assay showed opposite effects for AgAA and AgCD. While AgAA is highly toxic to macrophages (CC50 = 6.910 µg mL-1) and almost non-toxic for L.braziliensis (IC50 = 86.61 µg mL-1), AgCD results very selective toward killing the parasite (CC50 = 195.0 µg mL-1, IC50 = 11.54 µg mL-1). AA's higher polarity and conical shape easily promote cell lysis by increasing cell permeability, while CD has a protective effect: for that reason, AA and AgAA were not further used for tests. CD (EC50 = 2.906 µg mL-1) had higher ability to kill intracellular amastigotes than AgCD (EC50 = 16.00 µg mL-1), however, less intact cells were seen on isolated CD tests. In addition, considering that NO is one of the critical molecular species for the intracellular control of Leishmania, we used Griess colorimetric test to analyze the effect of treatment with AgCD and CD. Overall, the in vitro antileishmanial tests indicate that AgCD should be further explored as a promising non-toxic treatment for CL.
Subject(s)
Antiprotozoal Agents , Leishmaniasis, Cutaneous , Metal Nanoparticles , Anacardic Acids , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/therapeutic use , Humans , Leishmaniasis, Cutaneous/drug therapy , Resorcinols , Silver/pharmacologyABSTRACT
The lack of a randomized trial comparing carfilzomib (K) versus elotuzumab (Elo) associated with lenalidomide and dexamethasone (Rd) prompted us to assess the relative usefulness of one triplet over the other. Five independent retrospective cohorts of 883 relapsed/refractory multiple myeloma (RRMM) patients, including 300 EloRd and 583 KRd cases, outside clinical trials, entered this non-randomized comparison. KRd cohort accounted for a higher incidence of younger patients, cases with ≥3 lines of therapy, already exposed to lenalidomide, International Staging System (ISS) stage III, and abnormal lactic dehydrogenase (LDH) level compared with EloRd cohort. Moreover, cytogenetic risk categories, detected in roughly one-third of cases, were equally distributed between the two therapy arms. The probability of CR+VGPR response was significantly higher in KRd (n = 314, 53.9%) than in EloRd patients (n = 111, 37.0%). Likewise, the cumulative incidence function of CR+VGPR, taking into account the competitive risk of death, was significantly higher in KRd arm patients than those in the EloRd arm (p = .003). Moreover, KRd treatment significantly reduced the progression or death risk by 46% in an adjusted multivariate analysis (HR: 0.54, 95% CI 0.42-0.69, p < .0001). Finally, in an adjusted illness-progression/death model, the effect of KRd versus EloRd was of higher magnitude among those who achieved CR+VGPR (-39% hazard ratio reduction, p = .02) than among those who achieved < VGPR (-29% hazard ratio reduction, p = .007). With limitations characteristic to any retrospective analysis, this current clinical practice study's overall results demonstrated potential benefits of KRd therapy compared with EloRd. This observation may help the daily clinical practice.
Subject(s)
Multiple Myeloma , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dexamethasone , Humans , Lenalidomide , Multiple Myeloma/diagnosis , Multiple Myeloma/drug therapy , Oligopeptides , Retrospective Studies , Salvage TherapyABSTRACT
Molecular Imprinting Polymer (MIP) technology is a technique to design artificial receptors with a predetermined selectivity and specificity for a given analyte, which can be used as ideal materials in various application fields. In the last decades, MIP technology has gained much attention from the scientific world as summarized in several reviews with this topic. Furthermore, green synthesis in chemistry is nowadays one of the essential aspects to be taken into consideration in the development of novel products. In accordance with this feature, the MIP community more recently devoted considerable research and development efforts on eco-friendly processes. Among other materials, biomass waste, which is a big environmental problem because most of it is discarded, can represent a potential sustainable alternative source in green synthesis, which can be addressed to the production of high-value carbon-based materials with different applications. This review aims to focus and explore in detail the recent progress in the use of biomass waste for imprinted polymers preparation. Specifically, different types of biomass waste in MIP preparation will be exploited: chitosan, cellulose, activated carbon, carbon dots, cyclodextrins, and waste extracts, describing the approaches used in the synthesis of MIPs combined with biomass waste derivatives.
ABSTRACT
Disposable surgical face masks are usually used by medical/nurse staff but the current Covid-19 pandemic has caused their massive use by many people. Being worn closely attached to the people's face, they are continuously subjected to routine movements, i.e., facial expressions, breathing, and talking. These motional forces represent an unusual source of wasted mechanical energy that can be rather harvested by electromechanical transducers and exploited to power mask-integrated sensors. Typically, piezoelectric and triboelectric nanogenerators are exploited to this aim; however, most of the current devices are too thick or wide, not really conformable, and affected by humidity, which make them hardly embeddable in a mask, in contact with skin. Different from recent attempts to fabricate smart energy-harvesting cloth masks, in this work, a wearable energy harvester is rather enclosed in the mask and can be reused and not disposed. The device is a metal-free hybrid piezoelectric nanogenerator (hPENG) based on soft biocompatible materials. In particular, poly(vinylidene fluoride) (PVDF) membranes in the pure form and with a biobased plasticizer (cardanol oil, CA) are electrospun onto a laser-ablated polyimide flexible substrate attached on a skin-conformable elastomeric blend of poly(dimethylsiloxane) (PDMS) and Ecoflex. The multilayer structure of the device harnesses the piezoelectricity of the PVDF nanofibers and the friction triboelectric effects. The ultrasensitive mechanoelectrical transduction properties of the composite device are determined by the strong electrostatic behavior of the membranes and the plasticization effect of cardanol. In addition, encapsulation based on PVDF, PDMS, CA, and parylene C is used, allowing the hPENG to exhibit optimal reliability and resistance against the wet and warm atmosphere around the face mask. The proposed device reveals potential applications for the future development of smart masks with coupled energy-harvesting devices, allowing to use them not only for anti-infective protection but also to supply sensors or active antibacterial/viral devices.
Subject(s)
Biosensing Techniques/instrumentation , Electrochemistry/instrumentation , Masks , Conservation of Energy Resources/methods , HumansABSTRACT
Carfilzomib, lenalidomide, and dexamethasone (KRd) have been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) based on ASPIRE clinical trial. However, its effectiveness and safety profile in real clinical practice should be further assessed. We retrospectively evaluated 130 consecutive RRMM patients treated with KRd between December 2015 and August 2018, in 9 Hematology Departments of Rete Ematologica Pugliese (REP). The overall response rate (ORR) was 79%, with 37% complete response (CR). Treatment with KRd led to an improvement in response regardless of age, refractory disease, and number and type of previous therapies. After a median follow-up of 18 months, median PFS was 24 months and 2y-PFS was 54%. PFS was longer in patients achieving a very good partial response (VGPR) with median PFS of 32.4 months. The relapses after prior autologous transplant (ASCT) positively impact median PFS. Several baseline disease characteristics, such as III ISS scoring or elevated LDH, and prior exposure to lenalidomide were found to negatively impact PFS. Primary refractory or relapsed myeloma patients have been treated with KRd as bridge to ASCT with a great benefit. Thirty-four (83%) reached at least a partial response after KRd and 21 (61%) performed ASCT. In transplanted patients, median PFS was not reached and 2y-PFS was 100%. The treatment discontinuation rate due to adverse events (AEs) was 18%, most commonly for lenalidomide (11%). Overall, in 10% of patients, a KRd dose reduction was necessary at least once (2.5% for carfilzomib and 8% for lenalidomide). The most frequent AE was neutropenia (44%) and anemia (41%). Infections occurred in 14% of patients. Cardiovascular events occurred in 11% of patients. Elderly patients have tolerated therapy very well, without additional side effects compared to younger patients, except for cardiac impairment. Our analysis confirmed that KRd is effective in RRMM patients. It is well tolerated and applicable to the majority of patients outside clinical trials. A longer PFS was shown in patients achieving VGPR, in those lenalidomide naïve and in patients relapsing after previous ASCT. Previous ASCT should not hamper the option for KRd therapy. Accordingly, KRd should be used as bridge regimen to ASCT with remarkable improvement in response and PFS rates. Further clinical studies are needed.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Disease-Free Survival , Female , Humans , Lenalidomide/administration & dosage , Lenalidomide/adverse effects , Male , Middle Aged , Oligopeptides/administration & dosage , Oligopeptides/adverse effects , Recurrence , Survival RateABSTRACT
Cutaneous leishmaniasis (CL) is a neglected tropical disease (NTD), endemic mainly in low-income countries that lack adequate basic health care. The emergence of resistant parasites to pentavalent antimonials has led to the search for new treatments for CL. Photodynamic therapy (PDT) is a promising non-invasive and less toxic alternative for the treatment of CL. The present work describes the synthesis, characterization and photodynamic effect against CL of a new metalloporphyrin Pd (II) meso-tetra[4-(2-(3-n-pentadecylphenoxy)ethoxy]phenylporphyrin (PdP) derived from the cashew nut shell liquid (CNSL). The PdP complex presented a singlet oxygen quantum yield of 0.49, favoring a type II photochemical reaction. The results of the photodynamic experiment carried out with PdP on the promastigote forms of Leishmania braziliensis indicated a mortality percentage of 70 % of the cells when compared to the control after exposure to blue light (λ = 420 nm). Besides this, the metalloporphyrin PdP did not show considerable toxicity to macrophages, indicating the cell viability of the compound. Therefore, this metalloporphyrin derived from biomass represents an interesting alternative as a potential therapeutic drug for the treatment of CL through PDT, especially for patients with intolerance to the chemotherapeutic drugs currently available.
Subject(s)
Anacardium , Leishmania braziliensis , Leishmaniasis, Cutaneous , Photochemotherapy , Porphyrins , Humans , Leishmaniasis, Cutaneous/drug therapy , Nuts , Palladium/therapeutic use , Photochemotherapy/methods , Photosensitizing Agents/pharmacology , Photosensitizing Agents/therapeutic use , Porphyrins/pharmacology , Porphyrins/therapeutic useABSTRACT
The interaction between lanthanide diphthalocyanine complexes, LnPc2 (Ln = Nd, Sm, Eu, Gd, Yb, Lu; Pc = C32H16N8, phthalocyanine ligand) and trifluoroacetic acid (TFA) was investigated in benzene, and the stability of the resulting molecular system was assessed based on spectral (UV-Vis) and kinetic measurements. Structural Density Functional Theory (DFT) calculations provided interesting data regarding the nature of the bonding and allowed estimating the interaction energy between the LnPc2 and TFA species. Conjugates are created between the LnPc2 and TFA molecules via hydrogen bonds of moderate strength (>NââH··) at the meso- -bridges of the Pc moieties, which renders the sandwich system to flatten. Attachment of TFA is followed by rearrangement of electronic density within the chromophore system of the macrocycles manifested in considerable changes in their UV-Vis spectra and consequently the color of the studied solutions (from green to orange). The LnPc2@TFA conjugates including Nd, Sm, Eu, and Gd appeared evidently less photostable when exposed to UV radiation than the related mother compounds, whereas in the case of Yb and Lu derivatives some TFA-prompted stabilizing effect was noticed. The conjugates displayed the capacity for singlet oxygen generation in contrast to the LnPc2s itself. Photon upconversion through sensitized triplet-triplet annihilation was demonstrated by the TFA conjugates of Nd, Sm, Eu, and Gd.