Feasibility evaluation of novel AI-based deep-learning contouring algorithm for radiotherapy.

PURPOSE: To evaluate the clinical feasibility of the Siemens Healthineers AI-Rad Companion Organs RT VA30A (Organs-RT) auto-contouring algorithm for organs at risk (OARs) of the pelvis, thorax, and head and neck (H&N). METHODS: Computed tomography (CT) datasets from 30 patients (10 pelvis, 10 thorax, and 10 H&N) were collected. Four sets of OARs were generated on each scan, one set by Organs-RT and the others by three experienced users independently. A physician (expert) then evaluated each contour by assigning a score from the following scale: 1-Must Redo, 2-Major Edits, 3-Minor Edits, 4-Clinically usable. Using the highest-scored OAR from the human users as a reference, the contours generated by Organs-RT were evaluated via Dice Similarity Coefficient (DSC), Hausdorff Distance (HDD), Mean Distance to Agreement (mDTA), Volume comparison, and visual inspection. Additionally, each human user recorded the time to delineate each structure set and time-saving efficiency was measured. RESULTS: The average DSC obtained for the pelvic OARs ranged between (0.81 ± 0.06)Rectum and (0.94 ± 0.03)Bladder . (0.75 ± 0.09)Esophagus to ( 0.96 ± 0.02 ) Rt . Lung ${( {0.96 \pm 0.02} )}_{{\mathrm{Rt}}.{\mathrm{\ Lung}}}$ for the thoracic OARs and (0.66 ± 0.07)Lips to (0.83 ± 0.04)Brainstem for the H&N. The average HDD in cm for the pelvis cohort ranged between (0.95 ± 0.35)Bladder to (3.62 ± 2.50)Rectum , (0.42 ± 0.06)SpinalCord to (2.09 ± 2.00)Esophagus for the thoracic set and ( 0.53 ± 0.22 ) Cerv _ SpinalCord ${( {0.53 \pm 0.22} )}_{{\mathrm{Cerv}}\_{\mathrm{SpinalCord}}}$ to (1.50 ± 0.50)Mandible for the H&N region. The time-saving efficiency was 67% for H&N, 83% for pelvis, and 84% for thorax. 72.5%, 82%, and 50% of the pelvis, thorax, and H&N OARs were scored as clinically usable by the expert, respectively. CONCLUSIONS: The highest agreement registered between OARs generated by Organs-RT and their respective references was for the bladder, heart, lungs, and femoral heads, with an overall DSC≥0.92. The poorest agreement was for the rectum, esophagus, and lips, with an overall DSC⩽0.81. Nonetheless, Organs-RT serves as a reliable auto-contouring tool by minimizing overall contouring time and increasing time-saving efficiency in radiotherapy treatment planning.

Efficacious In Vitro and In Vivo Effects of Dihydrosphingosine-Ethambutol Analogues Against Susceptible and Multi-drug-resistant Mycobacterium tuberculosis.

BACKGROUND AND AIMS: Tuberculosis (TB) is a major worldwide health problem in part due to the lack of new drugs and the emergence of multidrug-resistant strains (MDR). The aim of this study was to select anti-tuberculosis drug candidates from a collection of 69 synthetic sphingosine-ethambutol analogues through in vitro and in vivo evaluations. METHODS: The 69 compounds were evaluated in vitro against two Mycobacterium tuberculosis strains, a drug susceptible (H37Rv) and a MDR clinical isolate (CIBIN-99). Four selected compounds, those that exhibited the highest potency in vitro, were tested in vivo using a model of progressive TB in BALB/c mice infected with the drug susceptible strain, either alone or combined with conventional chemotherapy, as well as in mice infected with the MDR strain. The acute toxicity was evaluated on male and female adult BALB/c mice. RESULTS: Ten of the evaluated compounds resulted more potent in vitro than ethambutol. The experimental compound 2b (2-aminopalmitol benzyl ether) was the most efficacious and also showed additive effects in combination with conventional chemotherapy. It did not exhibit toxicity (LD50 >2000 mg/kg). CONCLUSIONS: Compound 2b can be considered as a new drug candidate to continue its development against M. tuberculosis MDR strains.

In vitro and in vivo evaluation of 2-aminoalkanol and 1,2-alkanediamine derivatives against Strongyloides venezuelensis.

BACKGROUND: Strongyloidiasis is a parasitic disease widely present in tropical and subtropical areas. Strongyloides stercoralis represents the main species that infects human beings. Ivermectin is the current drug of choice; however, issues related with treatment failure in patients with diabetes or infected with T-lymphotropic virus-1 make the identification of new molecules for alternative treatment a priority. In the present study, the activity of sphingosine-related aminoalcohol and diamine were evaluated against Strongyloides venezuelensis third-stage larva (L3) cultures and experimental infections in mice. METHODS: The efficacy of each compound against L3 was assessed using both XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) assay and microscopic observation with concentrations ranging from 1 to 350 µM. Cytotoxicity was evaluated using J774.2 macrophage cell line and XTT assay. Lethal concentration 50 (LC50), selectivity index (SI) and structure-activity relationships were established. The activity compounds 4 (2-(ethylamino) hexadecan-1-ol), 6 (2-(butylamino) hexadecan-1-ol), 17 (tert-butyl N-(1-aminododecan-2-yl) carbamate) and 18 (tert-butyl N-(1-aminohexadecan-2-yl) carbamate) were further assessed against experimental S. venezuelensis infections in CD1 mice measuring reductions in the numbers of parthenogenetic females and egg passed in faeces. Mice were infected with 3,000 L3 and treated with 20 mg/kg/day for five days. RESULTS: In the screening study of 15 aminoalcohols [lauryl (n = 9); palmityl (n = 13); stearyl (n = 15) and alcohol derivatives], the presence of a palmitol chain was associated with the highest efficacy against L3 (LC50 31.9-39.1 µM). Alkylation of the 2-amino group with medium size fragments as ethyl or n-butyl showed the best larvicidal activity. The dialkylation did not improve efficacy. Aminoalcohols 4 and 6 showed the highest SI (1.5 and 1.6, respectively). With respect to diamine derivative compounds, a chain size of sixteen carbon atoms (palmitoyl chain, n = 13), and the alkylation of the 2-amino group with medium-sized fragments, were associated with the highest lethal activities. The presence of carbamoyl group in diamines 17 and 18 yielded high SI (1.7 and 1.4, respectively). Infected mice treated with aminoalcohol 6 showed reduction in parthenogenetic females (59 %) and eggs in faeces (51 %). CONCLUSIONS: These results support the potentiality of aminoalcohol and diamine sphingosine-related compounds as suitable prototypes for developing new promising drugs against strongyloidiasis.

Trypanocidal Activity of Long Chain Diamines and Aminoalcohols.

Thirteen aminoalcohols and eight diamines were obtained and tested against Trypanosoma cruzi epimastigotes strains MG, JEM and CL-B5 clone. Some of them were equal or more potent (1.0-6.6 times) than the reference compound nifurtimox. From them, three aminoalcohols and two diamines were selected for amastigotes assays. Compound 5 was as potent as the reference drug nifurtimox against amastigotes of the CL-B5 strain (IC50 = 0.6 µM), with a selectivity index of 54.

Mechanisms of action of substituted ß-amino alkanols on Leishmania donovani.

Leishmaniasis is the protozoan disease second in importance for human health, superseded only by malaria; however, the options for chemotherapeutic treatment are increasingly limited due to drug resistance and toxicity. Under this perspective, a quest for new chemical compounds is urgently needed. An N-substituted 2-aminoalkan-1-ol scaffold has been shown to be a versatile scaffold for antiparasitic activity. Knowledge about its mechanism of action is still rather limited. In this work, we endeavored to define the leishmanicidal profile of such ß-amino alkanol derivatives using a set of 15 N-mono- and disubstituted surrogates, tested on Leishmania donovani promastigotes and intracellular amastigotes. The best compound (compound 5), 2-ethylaminododecan-1-ol, had a 50% effective concentration (EC50) of 0.3 µM and a selectivity index of 72 for infected THP-1 cells and was selected for further elucidation of its leishmanicidal mechanism. It induced fast depletion of intracellular ATP content in promastigotes in the absence of vital dye intracellular entry, ruling out plasma membrane permeabilization as its origin. Confocal and transmission electron microscopy analyses showed that compound 5 induced severe mitochondrial swelling and vesiculation. Polarographic analysis using an oxygen electrode demonstrated that complex II of the respiratory chain (succinate reductase) was strongly inhibited by compound 5, identifying this complex as one of the primary targets. Furthermore, for other ß-amino alkanols whose structures differed subtly from that of compound 5, plasma membrane permeabilization or interference with membrane traffic was also observed. In all, N-substituted ß-amino alkanols were shown as appealing leishmanicidal candidates deserving further exploration.

Diamine and aminoalcohol derivatives active against Trypanosoma brucei.

Twenty compounds selected as representative members of three series of long-chain 1,2-diamines, 2-amino-1-alkanols and 1-amino-2-alkanols structurally related to dihydrosphingosin, were synthesized and tested in vitro for their ability to inhibit the sleeping sickness parasites Trypanosoma bruceirhodesiense and Trypanosoma brucei gambiense. Eight compounds showed EC(50) values in the submicromolar range, with selectivity indexes up to 39 related to the respective cytotoxicity values for Vero cells. The parasite phenotype detected after treatment with the most potent compounds showed irreversible cell morphology alterations of the flagellar pocket that lead to inhibition of cell growth and parasite death.