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AIM: To evaluate the effect of sodium picosulfate/magnesium citrate (SPMC) and 3 L split-dose polyethylene glycol (PEG) with or without dimethicone on bowel preparation before colonoscopy. METHODS: In this multicenter, prospective, randomized, controlled study conducted from April 2021 to December 2021, consecutive adult patients scheduled for colonoscopy were prospectively randomized into four groups: SPMC, SPMC plus dimethicone, 3 L PEG, and 3 L PEG plus dimethicone. Primary endpoint was colon cleansing based on Boston Bowel Preparation Scale (BBPS). Secondary endpoints were bubble score, time to cecal intubation, adenoma detection rate (ADR), patient safety and compliance, and adverse events. RESULTS: We enrolled 223 and 291 patients in SPMC and 3 L PEG group, respectively. The proportion with acceptable bowel cleansing, total BBPS score and cecal intubation time were similar in all four subgroups (p > 0.05). Patient-reported acceptability and tolerability was significantly greater in SPMC than 3 L PEG group (p < 0.001); adverse events were significantly lower in SPMC than latter group (p < 0.001). ADR in both groups was greater than 30%. CONCLUSION: SPMC had significantly higher acceptability and tolerability than 3 L PEG, however, was similar in terms of bowel-cleansing effect and cecal intubation time and hence can be used before colonoscopy preparation.
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Catárticos , Citratos , Colonoscopía , Compuestos Organometálicos , Picolinas , Polietilenglicoles , Humanos , Colonoscopía/métodos , Femenino , Masculino , Catárticos/administración & dosificación , Catárticos/efectos adversos , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , China , Estudios Prospectivos , Adulto , Citratos/administración & dosificación , Citratos/efectos adversos , Picolinas/administración & dosificación , Picolinas/efectos adversos , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/efectos adversos , Anciano , Ácido Cítrico/administración & dosificación , Ácido Cítrico/efectos adversos , Adenoma/diagnóstico , Cooperación del Paciente/estadística & datos numéricosRESUMEN
BACKGROUND: There are currently no standard first-line treatment options for patients with higher grade 2-3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) treatment. METHODS: NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous 177Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (177Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting. FINDINGS: Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the 177Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7-13·8) in the control group and 22·8 months (19·4-not estimated) in the 177Lu-Dotatate group (stratified hazard ratio 0·276 [0·182-0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the 177Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period. INTERPRETATION: First-line 177Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177Lu-Dotatate should be considered a new standard of care in first-line therapy in this population. FUNDING: Advanced Accelerator Applications, a Novartis Company.
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Neoplasias Intestinales , Tumores Neuroendocrinos , Octreótido , Compuestos Organometálicos , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Octreótido/uso terapéutico , Octreótido/administración & dosificación , Octreótido/análogos & derivados , Octreótido/efectos adversos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Masculino , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/mortalidad , Femenino , Persona de Mediana Edad , Compuestos Organometálicos/uso terapéutico , Compuestos Organometálicos/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Neoplasias Gástricas/mortalidad , Anciano , Neoplasias Intestinales/tratamiento farmacológico , Neoplasias Intestinales/patología , Neoplasias Intestinales/radioterapia , Neoplasias Intestinales/mortalidad , Adulto , Radiofármacos/uso terapéutico , Resultado del Tratamiento , Clasificación del Tumor , Supervivencia sin ProgresiónRESUMEN
PURPOSE: This study aimed to develop a user-friendly prediction formula for dose rate adjustment after initial 177Lu-Dotatate therapy from a prospective observational study of patients. MATERIALS AND METHODS: This study included consenting patients in a prospective observational study who underwent their first treatment in four cycles of 177Lu-Dotatate treatment at our hospital between January 2022 and February 2024. All patients received 7.4 GBq of 177Lu-Dotatate. The prediction formula was derived from the regression analysis of tumor-related factors and renal function. Creatinine clearance was estimated using the Cockcroft-Gault equation in this study for renal function. RESULTS: Among the 13 patients (seven males, six females, median age: 59 years), logarithmically transformed total tumor volume (cc) and maximum tumor diameter (mm) of primary tumors or metastases showed strong correlations (p < 0.001, R2 = 0.897). As such, the maximum tumor diameter was used as the tumor parameter in the prediction formula. Additionally, maximum tumor diameter and creatinine clearance showed strong (p < 0.001, R2 = 0.768) and moderate (p = 0.013, R2 = 445) correlations, respectively, with the ratio of the dose rate 5.5-h post-administration to the dose rate immediately post-administration (%) at 1 m from the body surface. The resulting formula, 51.4 + 0.360 × maximum tumor diameter (mm) - 0.212 × creatinine clearance (ml/min), demonstrated an extremely strong correlation (p < 0.001, R2 = 0.937). CONCLUSION: The present study showed that the maximum tumor diameter and renal function affected the declining the dose rate of patients surface after 177Lu-Dotatate, which can inform post-administration dose rate management and potentially facilitate outpatient treatment in Japan.
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Octreótido , Compuestos Organometálicos , Humanos , Masculino , Femenino , Persona de Mediana Edad , Compuestos Organometálicos/uso terapéutico , Compuestos Organometálicos/administración & dosificación , Octreótido/análogos & derivados , Octreótido/uso terapéutico , Octreótido/administración & dosificación , Estudios Prospectivos , Anciano , Japón , Adulto , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/diagnóstico por imagen , Carga Tumoral , Radiofármacos/uso terapéutico , Riñón/diagnóstico por imagen , Riñón/patología , Pruebas de Función Renal/métodos , Dosificación RadioterapéuticaRESUMEN
Chloraluminium phthalocyanine (ClAlPc) has potential therapeutic effect for the treatment of cancer; however, the molecule is lipophilic and may present self-aggregation which limits its clinical success. Thus, nanocarriers like liposomes can improve ClAlPc solubility, reduce off-site toxicity and increase circulation time. For this purpose, developing suitable liposomes requires the evaluation of different lipid compositions. Herein, we aimed to develop liposomes containing soy phosphatidylcholine (SPC), 1,2-distearoyl-sn-glycero- 3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPEPEG2000), cholesterol and oleic acid loaded with ClAlPc using the surface response methodology and the Box-Behnken design. Liposomes with particle size from 110.93 to 374.97 nm and PdI from 0.265 to 0.468 were obtained. The optimized formulation resulted in 69.09 % of ClAlPc encapsulated, with particle size and polydispersity index, respectively, at 153.20 nm and 0.309, providing stability and aggregation control. Atomic force microscopy revealed vesicles in a spherical or almost spherical shape, while the analyzes by Differential Scanning Calorimetry (DSC), Powder X-ray Diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR) suggested that the drug was adequately incorporated into the lipid bilayer of liposomes, in its amorphous state or molecularly dispersed. In vitro studies conducted in breast cancer cells (4T1) showed that liposome improved phototoxicity compared to the ClAlPc solution. ClAlPc-loaded liposomes also enhanced the production of ROS 3-fold compared to the ClAlPc solution. Finally, confocal microscopy and flow cytometry demonstrated the ability of the liposomes to enter cells and deliver the fluorescent ClAlPc photosensitizer with dose and time-dependent effects. Thus, this work showed that Box-Behnken factorial design was an effective strategy for optimizing formulation development. The obtained ClAlPc liposomes can be applied for photodynamic therapy in breast cancer cells.
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Neoplasias de la Mama , Indoles , Liposomas , Compuestos Organometálicos , Tamaño de la Partícula , Fotoquimioterapia , Fármacos Fotosensibilizantes , Fotoquimioterapia/métodos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Indoles/química , Indoles/administración & dosificación , Femenino , Compuestos Organometálicos/química , Compuestos Organometálicos/administración & dosificación , Humanos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/farmacología , Línea Celular Tumoral , Polietilenglicoles/química , Fosfatidiletanolaminas/química , Fosfatidilcolinas/química , Colesterol/química , Ácido Oléico/químicaRESUMEN
Peptide receptor radionucleotide therapy (PRRT) with 177Lu-dotatate is widely used for the treatment of patients with neuroendocrine tumors (NETs). We analyzed data from 104 patients with NETs treated with 177Lu -dotatate at a US academic center between December 2017 and October 2020 to better understand patterns of long-term efficacy, safety, and toxicity in the real-world setting. 177Lu-dotatate (200 mCi) was administered every eight weeks for four doses. The most common sites of primary disease were small intestine NETs (n = 49, 47%), pancreatic NETs (n = 32, 31%), and lung NETs (n = 7, 7%). Twenty-seven percent had Ki-67 <3%, 49% had Ki-67 between 3-20%, and 13.5% had Ki-67 >20%. The cohort had been pretreated with a median of two prior lines of treatment. Forty percent had received prior liver-directed treatment. Seventy-four percent of patients completed all four doses of treatment. The objective response rate was 18%. The median time-to-treatment failure/death was significantly longer for small-bowel NETs when compared to pancreatic NETs (37.3 months vs. 13.2 months, p = 0.001). In a multivariate model, Ki-67, primary site, and liver tumor burden ≥50% were found to independently predict time-to-treatment failure/death. Around 40% of patients experienced adverse events of ≥grade 3 severity. Treatment-related adverse events leading to discontinuation of therapy happened in 10% of patients. Preexisting mesenteric/peritoneal disease was present in 33 patients; seven of these patients developed bowel-related toxicities including two grade 5 events. We also report two cases of delayed-onset minimal change nephrotic syndrome, which occurred 14 and 27 months after the last dose of PRRT. Lastly, we describe six patients who developed rapid tumor progression in the liver leading to terminal liver failure within 7.3 months from the start of PRRT, and identify potential risk factors associated with this occurrence, which will need further study.
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Tumores Neuroendocrinos , Octreótido , Receptores de Péptidos , Humanos , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Anciano , Octreótido/análogos & derivados , Octreótido/uso terapéutico , Octreótido/efectos adversos , Octreótido/administración & dosificación , Receptores de Péptidos/metabolismo , Adulto , Resultado del Tratamiento , Compuestos Organometálicos/uso terapéutico , Compuestos Organometálicos/efectos adversos , Compuestos Organometálicos/administración & dosificación , Anciano de 80 o más Años , Radiofármacos/uso terapéutico , Radiofármacos/efectos adversos , Radiofármacos/administración & dosificación , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/patología , Estudios RetrospectivosRESUMEN
BACKGROUND: This study examined the experiences of owners of dogs with leishmaniosis who treated their dogs with daily subcutaneous meglumine antimoniate injections. The owners' perceived ease of administering the injections, the occurrence of problems and the effects on the owners and on the dogâowner bond were evaluated. METHODS: Dogs prescribed meglumine antimoniate as a treatment for leishmaniosis were identified using the database of the veterinary pharmacy of the Faculty of Veterinary Medicine, Utrecht University. An online questionnaire was sent to the owners of these dogs to evaluate the perceived ease of administering the injections, the occurrence of problems and the effects on the owner and the dog-owner bond. RESULTS: Responses were received from 64 dog owners. Most respondents (78%) reported that administering the injections was not difficult. Pain or the development of nodules at the injection site was reported in 50% and 40% of the dogs, respectively. Polyuria was reported in 44% of the dogs. Some owners reported that administering the injections had a negative impact on their psychological wellbeing (20%), and some would have liked more veterinary support (11%). LIMITATIONS: Some questions were answered by a limited number of people, and their responses may not be representative. CONCLUSION: Dog owners remain highly motivated to persevere with meglumine antimoniate treatment and are willing to administer the injections themselves. The availability of active support when needed during the therapy cycle may further improve their acceptance of and confidence in giving the injections.
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Antiprotozoarios , Enfermedades de los Perros , Leishmaniasis , Antimoniato de Meglumina , Perros , Animales , Antimoniato de Meglumina/uso terapéutico , Antimoniato de Meglumina/administración & dosificación , Enfermedades de los Perros/tratamiento farmacológico , Leishmaniasis/veterinaria , Leishmaniasis/tratamiento farmacológico , Encuestas y Cuestionarios , Humanos , Masculino , Antiprotozoarios/uso terapéutico , Antiprotozoarios/administración & dosificación , Femenino , Propiedad , Meglumina/uso terapéutico , Meglumina/administración & dosificación , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/uso terapéutico , Inyecciones Subcutáneas/veterinariaRESUMEN
BACKGROUND: Tooth discoloration is a common concern in antimicrobial photodynamic therapy (aPDT) using various photosensitizers (PS). Toluidine Blue (TB), Methylene Blue (MB), Phthalocyanine (Pc), and 2-mercaptopyridine-substituted zinc phthalocyanine (TM-ZnPc) are among those studied, but their relative impacts on tooth discoloration remain unclear. AIM: This study aimed to compare the effects of TB, MB, Pc, and TM-ZnPc in aPDT on tooth discoloration, utilizing a controlled experimental setup. MATERIALS AND METHODS: The study comprised seventy-five single-rooted incisors with root canals. Following meticulous preparation, a standardized area on the crown surface was designated for examination, and precise measurements of the initial tooth colors were recorded. Samples were randomly divided into five groups: Negative control, MB, TM, Pc, and TM-ZnPc. Photoactivation was performed using LED light, and color measurements were taken at multiple time points up to 90 days. Data were converted to Lab* color values of the CIE Lab* color system (International Commission on Illumination, Vienna, Austria), and ΔE values were calculated. Statistical analysis was performed using Two-way ANOVA and Post-Hoc Tukey tests (p < 0.05). RESULTS: At day 7 and 30, TM-ZnPc and Pc caused less discoloration compared to MB and TB. TM-ZnPc caused more tooth discoloration compared to Pc (p < 0.05). Compared to baseline, MB and TM-ZnPc caused more tooth discoloration at 30 days and TB caused more tooth discoloration at 90 days (p < 0.05). No significant difference was observed in terms of tooth discoloration at all periods evaluated after Pc application (p > 0.05). All photosensitizers tested in the study caused tooth coloration. CONCLUSION: All PS induced clinically detectable tooth discoloration, with TB and MB causing more significant discoloration compared to Pc and TM-ZnPc at certain time points. TM-ZnPc and Pc demonstrated more stable coloration levels over time, suggesting their potential reliability in aPDT applications. This study highlights the importance of selecting appropriate PS to minimize tooth discoloration in aPDT, with Pc showing promise in this regard.
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Isoindoles , Azul de Metileno , Fotoquimioterapia , Fármacos Fotosensibilizantes , Espectrofotometría , Cloruro de Tolonio , Decoloración de Dientes , Fotoquimioterapia/métodos , Fotoquimioterapia/efectos adversos , Fármacos Fotosensibilizantes/administración & dosificación , Humanos , Decoloración de Dientes/inducido químicamente , Azul de Metileno/administración & dosificación , Compuestos de Zinc , Indoles/efectos adversos , Indoles/administración & dosificación , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/efectos adversosRESUMEN
Prolonged warm ischemic is the main cause discarding donated organs after cardiac death. Here, we identified that prolonged warm ischemic time induced disseminated intravascular coagulation and severe capillary vasospasm after cardiac death of rat kidneys. Additionally, we found a significant accumulation of fibrinogen in a hypoxic cell culture of human umbilical vein epithelial cells and in isolated kidneys exposed to prolonged warm ischemic following flushing out of blood. However, pre-flushing the kidney with snake venom plasmin in a 90-minute warm ischemic model maximized removal of micro thrombi and facilitated the delivery of oxygen and therapeutic agents. Application of carbon monoxide-releasing CORM-401 during ex vivo hypothermic oxygenated perfusion achieved multipath protective effects in prolonged warm ischemic kidneys. This led to significant improvements in perfusion parameters, restoration of the microcirculation, amelioration of mitochondrial injury, oxidative stress, and apoptosis. This benefit resulted in significantly prolonged warm ischemic kidney recipient survival rates of 70%, compared with none in those receiving ex vivo hypothermic oxygenated perfusion alone. Significantly, ex vivo hypothermic oxygenated perfusion combined with cytoprotective carbon monoxide releasing CORM-401 treatment meaningfully protected the donated kidney after cardiac death from ischemia-reperfusion injury by reducing inflammation, oxidative stress, apoptosis, and pathological damage. Thus, our study suggests a new combination treatment strategy to potentially expand the donor pool by increasing use of organs after cardiac death and salvaging prolonged warm ischemic kidneys.
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Trasplante de Riñón , Riñón , Preservación de Órganos , Compuestos Organometálicos , Perfusión , Isquemia Tibia , Animales , Isquemia Tibia/efectos adversos , Riñón/irrigación sanguínea , Riñón/patología , Riñón/efectos de los fármacos , Perfusión/métodos , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Humanos , Preservación de Órganos/métodos , Masculino , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/farmacología , Daño por Reperfusión/prevención & control , Daño por Reperfusión/etiología , Daño por Reperfusión/patología , Ratas , Oxígeno/metabolismo , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Microcirculación/efectos de los fármacos , Factores de Tiempo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacosRESUMEN
Israel is endemic for Old-World cutaneous leishmaniasis. The most common species is Leishmania major. However, the available treatment options are limited. This study's objective was to compare the authors' experience with different antimony intralesional treatments of Leishmania major cutaneous leishmaniasis. A retrospective evaluation was undertaken for cases of Leishmania major cutaneous leishmaniasis treated by pentavalent antimony in a university-affiliated medical centre in Israel. The previous treatment of intralesional sodium stibogluconate (Pentostam®) was compared with the current treatment of meglumine antimoniate (Glucantime®). One hundred cases of cutaneous leishmaniasis were treated during the study period, of whom 33 were treated with intralesional sodium stibogluconate and 67 were treated with intralesional meglumine antimoniate. The patients were 78 males and 22 females, mean age 24 (range 10-67) and there was a total of 354 skin lesions. Within 3 months from treatment, 91% (30/33) of the intralesional sodium stibogluconate group and 88% (59/67) of the intralesional meglumine antimoniate group had complete healing of the cutaneous lesions after an average of 3 treatment cycles (non-statistically significant). In conclusion, the 2 different medications have the same efficacy and safety for treating cutaneous leishmaniasis. Pentavalent antimoniate intralesional infiltration treatment is safe, effective, and well tolerated with minimal side effects for Old-World cutaneous leishmaniasis.
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Gluconato de Sodio Antimonio , Antiprotozoarios , Inyecciones Intralesiones , Leishmania major , Leishmaniasis Cutánea , Antimoniato de Meglumina , Humanos , Antimoniato de Meglumina/administración & dosificación , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Cutánea/parasitología , Leishmaniasis Cutánea/diagnóstico , Femenino , Masculino , Gluconato de Sodio Antimonio/administración & dosificación , Estudios Retrospectivos , Adulto , Antiprotozoarios/administración & dosificación , Antiprotozoarios/efectos adversos , Persona de Mediana Edad , Leishmania major/efectos de los fármacos , Anciano , Adulto Joven , Adolescente , Resultado del Tratamiento , Niño , Factores de Tiempo , Israel , Meglumina/administración & dosificación , Compuestos Organometálicos/administración & dosificaciónRESUMEN
Displaying antibodies on carrier surfaces facilitates precise targeting and delivery of drugs to diseased cells. Here, we report the synthesis of antibody-lipid conjugates (ALCs) through site-selective acetylation of Lys 248 in human Immunoglobulin G (IgG) and the development of antibody-functionalized red blood cells (immunoRBC) for targeted drug delivery. ImmunoRBC with the HER2-selective antibody trastuzumab displayed on the surface (called Tras-RBC) was constructed following a three-step procedure. First, a peptide-guided, proximity-induced reaction transferred an azidoacetyl group to the ε-amino group of Lys 248 in the Fc domain. Second, the azide-modified IgG was subsequently conjugated with dibenzocyclooctyne (DBCO)-functionalized lipids via strain-promoted azide-alkyne cycloaddition (SPAAC) to result in ALCs. Third, the lipid portion of ALCs was then inserted into the cell membranes, and IgGs were displayed on red blood cells (RBCs) to construct immunoRBCs. We then loaded Tras-RBC with a photosensitizer (PS), Zinc phthalocyanine (ZnPc), to selectively target HER2-overexpressing cells, release ZnPc into cancer cells following photolysis, and induce photodynamic cytotoxicity in the cancer cells. This work showcases assembling immunoRBCs following site-selective lipid conjugation on therapeutic antibodies and the targeted introduction of PS into cancer cells. This method could apply to the surface functionalization of other membrane-bound vesicles or lipid nanoparticles for antibody-directed drug delivery.
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Sistemas de Liberación de Medicamentos , Eritrocitos , Indoles , Isoindoles , Lípidos , Trastuzumab , Humanos , Eritrocitos/efectos de los fármacos , Trastuzumab/química , Trastuzumab/administración & dosificación , Lípidos/química , Indoles/química , Indoles/administración & dosificación , Compuestos de Zinc , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/química , Compuestos Organometálicos/química , Compuestos Organometálicos/administración & dosificación , Receptor ErbB-2/inmunología , Inmunoconjugados/química , Inmunoconjugados/administración & dosificación , Inmunoglobulina G/química , Línea Celular Tumoral , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/química , Azidas/químicaRESUMEN
Contrast enhanced pulmonary vein magnetic resonance angiography (PV CE-MRA) has value in atrial ablation pre-procedural planning. We aimed to provide high fidelity, ECG gated PV CE-MRA accelerated by variable density Cartesian sampling (VD-CASPR) with image navigator (iNAV) respiratory motion correction acquired in under 4 min. We describe its use in part during the global iodinated contrast shortage. VD-CASPR/iNAV framework was applied to ECG-gated inversion and saturation recovery gradient recalled echo PV CE-MRA in 65 patients (66 exams) using .15 mmol/kg Gadobutrol. Image quality was assessed by three physicians, and anatomical segmentation quality by two technologists. Left atrial SNR and left atrial/myocardial CNR were measured. 12 patients had CTA within 6 months of MRA. Two readers assessed PV ostial measurements versus CTA for intermodality/interobserver agreement. Inter-rater/intermodality reliability, reproducibility of ostial measurements, SNR/CNR, image, and anatomical segmentation quality was compared. The mean acquisition time was 3.58 ± 0.60 min. Of 35 PV pre-ablation datasets (34 patients), mean anatomical segmentation quality score was 3.66 ± 0.54 and 3.63 ± 0.55 as rated by technologists 1 and 2, respectively (p = 0.7113). Good/excellent anatomical segmentation quality (grade 3/4) was seen in 97% of exams. Each rated one exam as moderate quality (grade 2). 95% received a majority image quality score of good/excellent by three physicians. Ostial PV measurements correlated moderate to excellently with CTA (ICCs range 0.52-0.86). No difference in SNR was observed between IR and SR. High quality PV CE-MRA is possible in under 4 min using iNAV bolus timing/motion correction and VD-CASPR.
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Medios de Contraste , Interpretación de Imagen Asistida por Computador , Angiografía por Resonancia Magnética , Variaciones Dependientes del Observador , Compuestos Organometálicos , Valor Predictivo de las Pruebas , Venas Pulmonares , Humanos , Venas Pulmonares/diagnóstico por imagen , Venas Pulmonares/cirugía , Venas Pulmonares/fisiopatología , Masculino , Femenino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Medios de Contraste/administración & dosificación , Compuestos Organometálicos/administración & dosificación , Anciano , Técnicas de Imagen Sincronizada Cardíacas , Fibrilación Atrial/cirugía , Fibrilación Atrial/diagnóstico por imagen , Fibrilación Atrial/fisiopatología , Ablación por Catéter , ElectrocardiografíaRESUMEN
BACKGROUND: Automatic myocardial scar segmentation from late gadolinium enhancement (LGE) images using neural networks promises an alternative to time-consuming and observer-dependent semi-automatic approaches. However, alterations in data acquisition, reconstruction as well as post-processing may compromise network performance. The objective of the present work was to systematically assess network performance degradation due to a mismatch of point-spread function between training and testing data. METHODS: Thirty-six high-resolution (0.7×0.7×2.0 mm3) LGE k-space datasets were acquired post-mortem in porcine models of myocardial infarction. The in-plane point-spread function and hence in-plane resolution Δx was retrospectively degraded using k-space lowpass filtering, while field-of-view and matrix size were kept constant. Manual segmentation of the left ventricle (LV) and healthy remote myocardium was performed to quantify location and area (% of myocardium) of scar by thresholding (≥ SD5 above remote). Three standard U-Nets were trained on training resolutions Δxtrain = 0.7, 1.2 and 1.7 mm to predict endo- and epicardial borders of LV myocardium and scar. The scar prediction of the three networks for varying test resolutions (Δxtest = 0.7 to 1.7 mm) was compared against the reference SD5 thresholding at 0.7 mm. Finally, a fourth network trained on a combination of resolutions (Δxtrain = 0.7 to 1.7 mm) was tested. RESULTS: The prediction of relative scar areas showed the highest precision when the resolution of the test data was identical to or close to the resolution used during training. The median fractional scar errors and precisions (IQR) from networks trained and tested on the same resolution were 0.0 percentage points (p.p.) (1.24 - 1.45), and - 0.5 - 0.0 p.p. (2.00 - 3.25) for networks trained and tested on the most differing resolutions, respectively. Deploying the network trained on multiple resolutions resulted in reduced resolution dependency with median scar errors and IQRs of 0.0 p.p. (1.24 - 1.69) for all investigated test resolutions. CONCLUSION: A mismatch of the imaging point-spread function between training and test data can lead to degradation of scar segmentation when using current U-Net architectures as demonstrated on LGE porcine myocardial infarction data. Training networks on multi-resolution data can alleviate the resolution dependency.
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Cicatriz , Medios de Contraste , Modelos Animales de Enfermedad , Interpretación de Imagen Asistida por Computador , Infarto del Miocardio , Miocardio , Valor Predictivo de las Pruebas , Sus scrofa , Animales , Medios de Contraste/administración & dosificación , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/patología , Cicatriz/diagnóstico por imagen , Cicatriz/patología , Cicatriz/fisiopatología , Miocardio/patología , Reproducibilidad de los Resultados , Redes Neurales de la Computación , Automatización , Compuestos Organometálicos/administración & dosificación , Imagen por Resonancia Cinemagnética , Aprendizaje Profundo , Imagen por Resonancia Magnética , Conjuntos de Datos como AsuntoRESUMEN
BACKGROUND: Despite an increased interest in visualizing the lymphatic vessels with magnetic resonance lymphangiography (MRL), little literature is available describing their appearance in nonlymphedematous individuals. To determine lymphatic abnormalities, an understanding of how healthy lymphatic vessels appear and behave needs to be established. Therefore, in this study, MRL of individuals without a history of lymphatic disease was performed. METHODS: A total of 25 individuals (15 women) underwent MRL of their lower limbs using a 3.0 T Philips magnetic resonance imaging scanner (Philips Medical Systems). The first nine participants were recruited to establish the concentration of gadolinium-based contrast agent (GBCA) to administer, with the remainder imaged before and after interdigital forefoot GBCA injections at the optimized dose. Outcomes, including lymphatic vessel diameter, tortuosity, and frequency of drainage via particular drainage routes, were recorded. RESULTS: Healthy lymphatic vessels following the anteromedial pathway were routinely observed in post-contrast T1-weighted images (average tortuosity, 1.09 ± 0.03), with an average of 2.16 ± 0.93 lymphatic vessels with a diameter of 2.47 ± 0.50 mm crossing the anterior ankle. In six limbs, vessels following the anterolateral pathways were observed. No vessels traversing the posterior of the legs were seen. In a subset of 10 vessels, the lymphatic signal, measured at the ankle, peaked 29 minutes, 50 seconds ± 9 minutes, 29 seconds after GBCA administration. No lymphatic vessels were observed in T2-weighted images. CONCLUSIONS: Contrast-enhanced MRL reliably depicts the lymphatic vessels in the legs of healthy controls. Following interdigital contrast injection, anteromedial drainage appears dominant. Quantitative measures related to lymphatic vessel size, tortuosity, and drainage rate are readily obtainable and could be beneficial for detecting even subtle lymphatic impairment.
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Medios de Contraste , Vasos Linfáticos , Linfografía , Imagen por Resonancia Magnética , Valor Predictivo de las Pruebas , Humanos , Femenino , Masculino , Medios de Contraste/administración & dosificación , Adulto , Linfografía/métodos , Vasos Linfáticos/diagnóstico por imagen , Adulto Joven , Persona de Mediana Edad , Compuestos Organometálicos/administración & dosificación , Extremidad Inferior/irrigación sanguínea , Extremidad Inferior/diagnóstico por imagen , Voluntarios Sanos , Gadolinio DTPA/administración & dosificación , Meglumina/administración & dosificación , Meglumina/análogos & derivadosRESUMEN
BACKGROUND: The presence of myocardial scar is associated with poor prognosis in several underlying diseases. Late-gadolinium-enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging reveals clinically silent "unrecognized myocardial scar" (UMS), but the etiology of UMS often remains unclear. This population-based CMR study evaluated prevalence, localization, patterns, and risk factors of UMS. METHODS: The study population consisted of 1064 consecutive Hamburg City Health Study participants without a history of coronary heart disease or myocarditis. UMS was assessed by standard-phase-sensitive-inversion-recovery LGE CMR. RESULTS: Median age was 66 [quartiles 59, 71] years and 37% (388/1064) were females. UMS was detected in 244 (23%) participants. Twenty-five participants (10%) had ischemic, and 217 participants (89%) had non-ischemic scar patterns, predominantly involving the basal inferolateral left-ventricular (LV) myocardium (75%). Two participants (1%) had coincident ischemic and non-ischemic scar. The presence of any UMS was independently associated with LV ejection fraction (odds ratios (OR) per standard deviation (SD) 0.77 (confidence interval (CI) 0.65-0.90), p = 0.002) and LV mass (OR per SD 1.54 (CI 1.31-1.82), p < 0.001). Ischemic UMS was independently associated with LV ejection fraction (OR per SD 0.58 (CI 0.39-0.86), p = 0.007), LV mass (OR per SD 1.74 (CI 1.25-2.45), p = 0.001), and diabetes (OR 4.91 (CI 1.66-13.03), p = 0.002). Non-ischemic UMS was only independently associated with LV mass (OR per SD 1.44 (CI 1.24-1.69), p < 0.001). CONCLUSION: UMS, in particular with a non-ischemic pattern, is frequent in individuals without known cardiac disease and predominantly involves the basal inferolateral LV myocardium. Presence of UMS is independently associated with a lower LVEF, a higher LV mass, and a history of diabetes.
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Cicatriz , Medios de Contraste , Imagen por Resonancia Cinemagnética , Miocardio , Valor Predictivo de las Pruebas , Volumen Sistólico , Función Ventricular Izquierda , Humanos , Femenino , Masculino , Persona de Mediana Edad , Medios de Contraste/administración & dosificación , Cicatriz/diagnóstico por imagen , Cicatriz/fisiopatología , Cicatriz/etiología , Cicatriz/patología , Anciano , Miocardio/patología , Factores de Riesgo , Prevalencia , Alemania/epidemiología , Compuestos Organometálicos/administración & dosificación , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/fisiopatología , Cardiomiopatías/patología , Estudios Transversales , Estudios Prospectivos , Isquemia Miocárdica/diagnóstico por imagen , Isquemia Miocárdica/fisiopatología , Enfermedades AsintomáticasRESUMEN
OBJECTIVES: Especially patients with aortic aneurysms and multiple computed tomography angiographies (CTA) might show medical conditions which oppose the use of iodine-based contrast agents. CTA using monoenergetic reconstructions from dual layer CT and gadolinium (Gd-)based contrast agents might be a feasible alternative in these patients. Therefore, the purpose of this study was to evaluate the feasibility of clinical spectral CTA with a Gd-based contrast agent in patients with aortic aneurysms. METHODS: Twenty-one consecutive scans in 15 patients with and without endovascular aneurysm repair showing contraindications for iodine-based contrast agents were examined using clinical routine doses (0.2 mmol/kg) of Gd-based contrast agent with spectral CT. Monoenergetic reconstructions of the spectral data set were computed. RESULTS: There was a significant increase in the intravascular attenuation of the aorta between pre- and post-contrast images for the MonoE40 images in the thoracic and the abdominal aorta (p < 0.001 for both). Additionally, the ratio between pre- and post-contrast images was significantly higher in the MonoE40 images as compared to the conventional images with a factor of 6.5 ± 4.5 vs. 2.4 ± 0.5 in the thoracic aorta (p = 0.003) and 4.1 ± 1.8 vs. 1.9 ± 0.5 in the abdominal aorta (p < 0.001). CONCLUSIONS: To conclude, our study showed that Gd-CTA is a valid and reliable alternative for diagnostic imaging of the aorta for clinical applications. Monoenergetic reconstructions of computed tomography angiographies using gadolinium based contrast agents may be a useful alternative in patients with aortic aneurysms and contraindications for iodine based contrast agents.
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Aortografía , Angiografía por Tomografía Computarizada , Medios de Contraste , Estudios de Factibilidad , Valor Predictivo de las Pruebas , Humanos , Medios de Contraste/administración & dosificación , Femenino , Anciano , Masculino , Persona de Mediana Edad , Aortografía/métodos , Compuestos Organometálicos/administración & dosificación , Anciano de 80 o más Años , Aorta Abdominal/diagnóstico por imagen , Aneurisma de la Aorta Abdominal/diagnóstico por imagen , Interpretación de Imagen Radiográfica Asistida por Computador , Aorta Torácica/diagnóstico por imagen , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Aneurisma de la Aorta Torácica/cirugía , Reproducibilidad de los Resultados , Aneurisma de la Aorta/diagnóstico por imagen , Estudios RetrospectivosRESUMEN
BACKGROUND: Helicobacter pylori (H. pylori) is strongly associated with peptic ulcer disease and gastric cancer. We evaluated two triple therapy regimens comprising esomeprazole, high dose bismuth, and different doses of amoxicillin for first-line H. pylori eradication. MATERIALS AND METHODS: Two hundred patients with dyspepsia and naive H. pylori infection were randomly assigned into two groups (n = 100). Both groups were treated for 14 days similarly with esomeprazole (40 mg, twice daily) and bismuth subcitrate (240 mg, three times daily), but the dose of amoxicillin was varied between Groups A (750 mg) and B (1000 mg) three times daily. Treatment compliance and side effect were evaluated following the therapies and after 8 weeks, a negative test of stool H. pylori antigen confirmed eradication. RESULTS: The two groups were comparable with respect to sex and age. According to intention to treat analysis, eradication rates were 80% (95% CI: 77.2%-82.8%) and 90% (95% CI: 84.1%-95.9%) in A and B groups, respectively (p = 0.22). Per-protocol eradication rates were 87% (95% CI: 80.4%-93.6%) and 92.8% (95% CI: 87.7%-97.9%), respectively (p = 0.23). Severe adverse effects were 3% and 2%, respectively (p = 0.34). CONCLUSION: High dose esomeprazole, amoxicillin and bismuth achieved 92.8% cure rates per protocol in a country with a high background rate of resistance. Additional studies are needed to ascertain whether this therapy can be further improved. Until then, it can be recommended as a first-line H. pylori eradication in north of Iran.
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Amoxicilina , Esomeprazol , Infecciones por Helicobacter , Helicobacter pylori , Compuestos Organometálicos , Humanos , Amoxicilina/administración & dosificación , Antibacterianos/administración & dosificación , Quimioterapia Combinada/efectos adversos , Esomeprazol/administración & dosificación , Infecciones por Helicobacter/tratamiento farmacológico , Irán , Compuestos Organometálicos/administración & dosificación , Proyectos Piloto , Masculino , FemeninoRESUMEN
Molecular Imaging is entering the most fruitful, exciting period in its history with many new agents under development, and several reaching the clinic in recent years. While it is unusual for just one laboratory to take an agent from initial discovery through to full clinical approval the steps along the way are important to understand for all interested participants even if one is not involved in the entire process. Here, we provide an overview of these processes beginning at discovery and preclinical validation of a new molecular imaging agent and using as an exemplar a low molecular weight disease-specific targeted positron emission tomography (PET) agent. Compared to standard drug development requirements, molecular imaging agents may benefit from a regulatory standpoint from their low mass administered doses, they nonetheless still need to go through a series of well-defined steps before they can be considered for Phase 1 human testing. After outlining the discovery and preclinical validation approaches, we will also discuss the nuances of Phase 1, Phase 2 and Phase 3 studies that may culminate in an FDA general use approval. Finally, some post-approval aspects of novel molecular imaging agents are considered.
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Aprobación de Drogas , Desarrollo de Medicamentos/métodos , Imagen Molecular/métodos , Octreótido/análogos & derivados , Compuestos Organometálicos/administración & dosificación , Tomografía de Emisión de Positrones/métodos , Ensayos Clínicos como Asunto/organización & administración , Humanos , Peso Molecular , Octreótido/administración & dosificación , Octreótido/efectos adversos , Compuestos Organometálicos/efectos adversos , Estados Unidos , United States Food and Drug AdministrationRESUMEN
INTRODUCTION: an adequate bowel preparation is essential for good mucosal inspection during colonoscopy. This study aims to compare the efficacy of two validated oral lavage solutions for colonoscopy preparation in African patients. METHODS: a prospective observational study of patients undergoing colonoscopy in a referral endoscopy facility in Port Harcourt, Nigeria, using sodium picosulfate magnesium citrate (SPMC) and 4L split-dose polyethylene glycol (PEG). Variables collated were sociodemographic, primary indication, comorbidities, Aronchick bowel preparation scale, polyp/adenoma detection, caecal intubation and outcome. Statistical analysis was performed using IBM SPSS version 20. RESULTS: one hundred and twenty-four patients received PEG prior to colonoscopy and SPMC in 175 patients. The age range was from 22 to 92 years; mean age of 53.8 ± 14.2 years for PEG group and 55.3 ± 13.2 years for SPMC group (p=0.361). There were 215 males and 84 females. An excellent/good bowel preparation scale was recorded in 77 (62%) PEG group and 130 (74.3%) for SPMC group (p=0.592). PEG was predominantly used in the early years of endoscopists practice with the odds ratio (OR) of no polyp detection in the PEG vs SPMC groups as 1.64 (confidence interval CI 1.06-2.55) versus 0.76 (CI 0.62-0.92), respectively (p=0.016). For no adenoma detection, OR was 4.18 (CI 1.12-15.60) versus OR 0.63 (CI 0.52-0.75), respectively (p=0.012). CONCLUSION: there is similar efficacy profile using either split volume PEG or SPMC prior to colonoscopy in these African patients. Polyp and adenoma detection rates are highly dependent on the expertise of the endoscopist.
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Catárticos/administración & dosificación , Citratos/administración & dosificación , Colonoscopía/métodos , Compuestos Organometálicos/administración & dosificación , Picolinas/administración & dosificación , Polietilenglicoles/administración & dosificación , Adenoma/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/diagnóstico , Pólipos del Colon/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nigeria , Estudios Prospectivos , Adulto JovenRESUMEN
To quantify the urinary bladder wall T1 relaxation time (T1) before and after the instillation contrast mixture in rats previously subjected to water avoidance stress (WAS) and/or acute exposure to protamine sulfate (PS). Female Wistar rats were randomized to receive either sham (control) or 1 h of WAS for ten consecutive days before the evaluation of nocturnal urination pattern in metabolic cages. T1 mapping of urinary bladder wall at 9.4 T was performed pre- and post- instillation of 4 mM Gadobutrol in a mixture with 5 mM Ferumoxytol. Subsequently, either T1 mapping was repeated after brief intravesical PS exposure or the animals were sacrificed for histology and analyzing the mucosal levels of mRNA. Compared to the control group, WAS exposure decreased the single void urine volume and shortened the post-contrast T1 relaxation time of mucosa- used to compute relatively higher ingress of instilled Gadobutrol. Compromised permeability in WAS group was corroborated by the urothelial denudation, edema and ZO-1 downregulation. PS exposure doubled the baseline ingress of Gadobutrol in both groups. These findings confirm that psychological stress compromises the paracellular permeability of bladder mucosa and its non-invasive assay with MRI was validated by PS exposure.
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Cistitis Intersticial/fisiopatología , Vejiga Urinaria/diagnóstico por imagen , Urotelio/patología , Administración Intravesical , Animales , Cistitis Intersticial/diagnóstico por imagen , Modelos Animales de Enfermedad , Femenino , Imagen por Resonancia Magnética , Membrana Mucosa , Compuestos Organometálicos/administración & dosificación , Permeabilidad , Protaminas/farmacología , Ratas Wistar , Estrés PsicológicoRESUMEN
Zinc pyrithione (ZnPT) is an anti-fungal drug delivered as a microparticle to skin epithelia. It is one of the most widely used ingredients worldwide in medicated shampoo for treating dandruff and seborrheic dermatitis (SD), a disorder with symptoms that include skin flaking, erythema and pruritus. SD is a multi-factorial disease driven by microbiol dysbiosis, primarily involving Malassezia yeast. Anti-fungal activity of ZnPT depends on the cutaneous availability of bioactive monomeric molecular species, occurring upon particle dissolution. The success of ZnPT as a topical therapeutic is underscored by the way it balances treatment efficacy with formulation safety. This review demonstrates how ZnPT achieves this balance, by integrating the current understanding of SD pathogenesis with an up-to-date analysis of ZnPT pharmacology, therapeutics and toxicology. ZnPT has anti-fungal activity with an average in vitro minimum inhibitory concentration of 10-15 ppm against the most abundant scalp skin Malassezia species (Malassezia globosa and Malassezia restrica). Efficacy is dependent on the targeted delivery of ZnPT to the skin sites where these yeasts reside, including the scalp surface and hair follicle infundibulum. Imaging and quantitative analysis tools have been fundamental for critically evaluating the therapeutic performance and safety of topical ZnPT formulations. Toxicologic investigations have focused on understanding the risk of local and systemic adverse effects following exposure from percutaneous penetration. Future research is expected to yield further advances in ZnPT formulations for SD and also include re-purposing towards a range of other dermatologic applications, which is likely to have significant clinical impact.