Indoximod-based chemo-immunotherapy for pediatric brain tumors: A first-in-children phase I trial.

BACKGROUND: Recurrent brain tumors are the leading cause of cancer death in children. Indoleamine 2,3-dioxygenase (IDO) is a targetable metabolic checkpoint that, in preclinical models, inhibits anti-tumor immunity following chemotherapy. METHODS: We conducted a phase I trial (NCT02502708) of the oral IDO-pathway inhibitor indoximod in children with recurrent brain tumors or newly diagnosed diffuse intrinsic pontine glioma (DIPG). Separate dose-finding arms were performed for indoximod in combination with oral temozolomide (200 mg/m2/day x 5 days in 28-day cycles), or with palliative conformal radiation. Blood samples were collected at baseline and monthly for single-cell RNA-sequencing with paired single-cell T cell receptor sequencing. RESULTS: Eighty-one patients were treated with indoximod-based combination therapy. Median follow-up was 52 months (range 39-77 months). Maximum tolerated dose was not reached, and the pediatric dose of indoximod was determined as 19.2 mg/kg/dose, twice daily. Median overall survival was 13.3 months (n = 68, range 0.2-62.7) for all patients with recurrent disease and 14.4 months (n = 13, range 4.7-29.7) for DIPG. The subset of n = 26 patients who showed evidence of objective response (even a partial or mixed response) had over 3-fold longer median OS (25.2 months, range 5.4-61.9, p = 0.006) compared to n = 37 nonresponders (7.3 months, range 0.2-62.7). Four patients remain free of active disease longer than 36 months. Single-cell sequencing confirmed emergence of new circulating CD8 T cell clonotypes with late effector phenotype. CONCLUSIONS: Indoximod was well tolerated and could be safely combined with chemotherapy and radiation. Encouraging preliminary evidence of efficacy supports advancing to Phase II/III trials for pediatric brain tumors.

Evaluation of commercial devices for patient specific QA of stereotactic radiotherapy plans.

Stereotactic radiotherapy (SRT) methods have become common for the treatment of small tumors in various parts of the body. Small field dosimetry has a unique set of challenges when it comes to the pre-treatment validation of a radiotherapy plan that involves film dosimetry or high-resolution detectors. Comparison of commercial quality assurance (QA) devices to the film dosimetry method for pre-treatment evaluation of stereotactic radiosurgery (SRS), fractionated SRT, and stereotactic body radiation therapy treatment plans have been evaluated in this study. Forty stereotactic QA plans were measured using EBT-XD film, IBA Matrixx Resolution, SNC ArcCHECK, Varian aS1200 EPID, SNC SRS MapCHECK, and IBA myQA SRS. The results of the commercial devices are compared to the EBT-XD film dosimetry results for each gamma criteria. Treatment plan characteristics such as modulation factor and target volume were investigated for correlation with the passing rates. It was found that all detectors have greater than 95% passing rates at 3%/3 mm. Passing rates decrease rapidly for ArcCHECK and the Matrixx as criteria became more strict. In contrast, EBT-XD film, SNC SRS MapCHECK, and IBA myQA SRS passing rates do not decline as rapidly when compared to Matrix Resolution, ArcCHECK, and the EPID. EBT-XD film, SNC SRS MapCHECK, and IBA myQA SRS maintain greater than 90% passing rate at 2%/1 mm and greater than 80% at 1%/1 mm. Additionally, the ability of these devices to detect changes in dose distribution due to MLC positioning errors was investigated. Ten VMAT SBRT/SRS treatment plans were created with 6 MV FFF or 10 MV FFF beam energies using Eclipse 15.6. A MATLAB script was used to create two MLC positioning error scenarios from the original treatment plan. It was found that errors in MLC positioning were most reliably detected at 2%/1 mm for high-resolution detectors and that lower-resolution detectors did not consistently detect MLC positioning errors.

Development of omega-3 rich eggs through dietary flaxseed and bio-evaluation in metabolic syndrome.

An egg is a nutrient-dense food that contains protein, fats, vitamins, and minerals. It is proven that the consumption of eggs influences serum lipid concentration. Therefore, a study was conducted to investigate the effect of normal and omega-3 eggs on serum lipids profiles. Lipids were extracted from egg yolks and analyzed for fatty acids content. The present research is a crossover study design in which 20 participants were recruited randomly, and all subjects received three treatments: no eggs, omega-3 eggs, and normal eggs. However, fasting blood was drawn at baseline and the end of each diet period and analyzed for serum lipids, blood glucose, and insulin level. Omega-3 egg treatment showed reduction in the serum total cholesterol by 16.57 mg/dl (p < .001), triglyceride by 17.48 mg/dl, and increase in HDL cholesterol concentration by 0.48 mg/dl (p < .001) as compared to no-egg. A significant (p < .05) reduction in blood pressure by 8.34/8.67 mm/Hg and insulin level was observed due to omega-3 egg consumption which indicates that omega-3 fatty acids improve insulin sensitivity. On the other hand, regular egg intake elevates serum total cholesterol and triglycerides concentration but decreases blood pressure. It was concluded that omega-3-enriched egg consumption had a positive effect on the serum lipid profile and blood pressure of patients with metabolic syndrome as compared to normal eggs.

Quantitative cone-beam CT imaging in radiation therapy using planning CT as a prior: first patient studies.

PURPOSE: Quantitative cone-beam CT (CBCT) imaging is on increasing demand for high-performance image guided radiation therapy (IGRT). However, the current CBCT has poor image qualities mainly due to scatter contamination. Its current clinical application is therefore limited to patient setup based on only bony structures. To improve CBCT imaging for quantitative use, we recently proposed a correction method using planning CT (pCT) as the prior knowledge. Promising phantom results have been obtained on a tabletop CBCT system, using a correction scheme with rigid registration and without iterations. More challenges arise in clinical implementations of our method, especially because patients have large organ deformation in different scans. In this paper, we propose an improved framework to extend our method from bench to bedside by including several new components. METHODS: The basic principle of our correction algorithm is to estimate the primary signals of CBCT projections via forward projection on the pCT image, and then to obtain the low-frequency errors in CBCT raw projections by subtracting the estimated primary signals and low-pass filtering. We improve the algorithm by using deformable registration to minimize the geometry difference between the pCT and the CBCT images. Since the registration performance relies on the accuracy of the CBCT image, we design an optional iterative scheme to update the CBCT image used in the registration. Large correction errors result from the mismatched objects in the pCT and the CBCT scans. Another optional step of gas pocket and couch matching is added into the framework to reduce these effects. RESULTS: The proposed method is evaluated on four prostate patients, of which two cases are presented in detail to investigate the method performance for a large variety of patient geometry in clinical practice. The first patient has small anatomical changes from the planning to the treatment room. Our algorithm works well even without the optional iterations and the gas pocket and couch matching. The image correction on the second patient is more challenging due to the effects of gas pockets and attenuating couch. The improved framework with all new components is used to fully evaluate the correction performance. The enhanced image quality has been evaluated using mean CT number and spatial nonuniformity (SNU) error as well as contrast improvement factor. If the pCT image is considered as the ground truth, on the four patients, the overall mean CT number error is reduced from over 300 HU to below 16 HU in the selected regions of interest (ROIs), and the SNU error is suppressed from over 18% to below 2%. The average soft-tissue contrast is improved by an average factor of 2.6. CONCLUSIONS: We further improve our pCT-based CBCT correction algorithm for clinical use. Superior correction performance has been demonstrated on four patient studies. By providing quantitative CBCT images, our approach significantly increases the accuracy of advanced CBCT-based clinical applications for IGRT.

Regioselective carbon-carbon bond cleavage in the oxidation of cyclopropenylcarbinols.

The strained double bond of cyclopropenylcarbinols undergoes a facile oxidation reaction to lead to unsaturated carbonyl derivatives. The distribution of the formed products depends on the relative stability of carbon-centered radical species, and the Sharpless kinetic resolution leads to enantiomerically pure Baylis-Hillman enal adducts.

Recent advances in carbocupration of α-heterosubstituted alkynes.

Carbocupration of alpha-heterosubstituted alkynes leads to the formation of stereodefined functionalized vinyl copper species as single isomer. Recent advances in the field show that a simple pre-association of the organometallic derivative with an additional polar functional group in the vicinity of the reaction center may completely change the stereochemical outcome of the reaction. Representative examples are given in this mini-review.

Enols and thioenols of substituted cyanomonothiocarbonylmalonamides: structures, enolization vs. thioenolization, equilibria and conformations.

Condensation of organic isothiocyanates with cyanoacetamides gave 24 N- and N'-substituted cyanomonothiocarbonylmalonamides in different tautomeric ratios i.e., amide-thioamides (TMA)R3NHCSCH(CN)CONR1R2 (12), thioamide-enols of amides (E) R3NHCSC(CN)=C(OH)NR1R2 (11)or amide-thioenols (TE) R3NHC(SH)=C(CN)CONR1R2 (13). The equilibrium constants (K(thioenol) =[TE]/[TMA] and K(enol) = [E]/[TMA]) in solution depend on R1, R2, R3 and the solvent. The %(E + TE)for NR1R2 increases in the order NMe2 < NHMe < NH2. The (K(thioenol) + K(enol)) in various solvents follows the order CCl4 > CDCl3 > C6D6 > THF-d8 > (CD3)2CO > CD3CN > DMF-d7 > DMSO-d6. The delta(OH) values are 16.46-17.43 and the delta(SH) values are 3.87-5.26 ppm in non polar solvents, e.g.,CDCl3 and 6.34-6.97 ppm in THF-d8 and CD3CN. An intramolecular O-H...O hydrogen bond leads to the preferred Z-configuration of the enols, and an N-H...O bond stabilizes the thioenols' preferred E-configuration with a non-bonded SH in solution. X-Ray crystallography revealed that systems with high %(E + TE) in solution mostly display the enols 11 in the solid state and systems with lower %(E +TE) in solution display structure 12. The differences in delta(OH), delta(NH), K(enol) and crystallographic data for analogous enol and thioenol systems are compared.

A rich array of reactions of Cyanomonothiocarbonylmalonamides RNHCSCH(CN)CONHR' and their Thioenols RNHC(SH)=C(CN)CONHR'1.

The thioenols derived from cyanomonothiocarbonylmalonamides and a cyanodithiocarbonylmalonamide were found to be very reactive species. They react under a variety of conditions such as crystallization, reaction with several carbonyl compounds, and reactions with another thioenol molecule to give a variety of products, mostly heterocycles, including substituted 2,3-dihydroisothiazole-3-ones and 3-thione, 2-substituted methylenethiazoles, 3,4-dihydro-1,3-thiazine-4-ones and 4-thiones, divinyl sulfides, a 1,2-dithiolane radical, and a 3,7-diaza[3.3.0]bicyclooctane derivative. Mechanisms suggested for these reactions include radical mechanisms, nucleophilic substitutions, and condensations.

Oxa-ene reaction of enols of amides with 4-phenyl-1,2,4-triazoline-3,5-dione.

The reaction of 16 enols of amides with 4-phenyl-1,2,4-triazoline-1,3-dione gave open chain adducts rather than the [2 + 2] cycloadducts with a hemiaminal moiety, both in solid state and in solution. This assignment is based on X-ray crystallography, (1)H and (13)C NMR data, and IR spectra. The suggested mechanism involves hydroxyl proton loss in a formal oxa-ene reaction. Mechanistic details and a possible alternative are discussed.

Enols of substituted cyanomalonamides.

Twenty open-chain mono-, di-, and trialkyl and aryl-N-substituted cyanomalonamides R2R1NCOCH(CN)CONHR3 were prepared. In solution, signals for both amide and a single enol are mostly observed, despite the potential for E and Z isomeric enols. The equilibrium (KEnol) values between the amides and the enols were determined in different solvents by NMR spectra. They decrease on increasing the polarity of the solvent in the order CDCl3 approximately C6D6>THF-d8>(CD3)2CO>CD3CN>DMF-d7>DMSO-d6. For the R1R2NCOCH(CN)CONHR3 system when R1=R2=H, Me or R1=H, R2=Me, KEnol for R3 follows the order: C6F5>Ph>or=An>or= i-Pr>or= t-Bu, and for R1, R2:H, H>Me, H>Me, Me in all solvents. A unique feature is the appreciable % enol in DMSO-d6 when R1=R2=H, in contrast with enol systems with other electron-withdrawing groups (EWGs). Calculations (B3LYP/6-31G**) corroborate the higher KEnol values for less alkyl-substituted systems, showing that in the most stable conformer when R1=H, R2=R3=Me the N-hydrogens are closer to the CN group. The order of promoting substituents for enol of amide formation is CONH2>CO2CH2CF3>CO2Me>CONHMe. The solid-state structures of the isolated species, determined by X-ray crystallography, were either amides or enols, and a higher KEnol(CDCl3) value does not ensure a solid enol structure. In no system were both solid species isolated. The X-ray structures of the enols were temperature-dependent. In most cases, the difference between the O-H and O...H bond lengths at low temperature were appreciable, but they become closer at the higher temperature. Similar tendency for either the C=C/C-C or the C-O/C=O bonds was observed. This is ascribed to a hydrogen shift between two regioisomeric enols in an asymmetric double-well potential, which becomes faster at a higher temperature. Calculations show that the enol structures are nonsymmetrical, resembling the lower temperature structures, even when they are chemically symmetrical, but the energy differences between the two regioisomers are <1 kcal. The hydrogen bonds in the enol moiety are strong, with O...O distances <2.45 A, and are resonance-assisted hydrogen bonds. IR spectra in solution and the solid state qualitatively corroborate the NMR and X-ray structure determination.

The first example of isomeric solid amide and its enol.

[Structure: see text] The first example of a crystalline amide and its tautomeric enol was obtained for the amide MeNHCSCH(CN)CONHMe (8) and its enol MeNHCSC(CN)=C(OH)NHMe (9). Their X-ray structures were determined, and their structural features resemble those of other related amides and enols. No other example of a similar pair was obtained. In solution, both 8 and 9 and a small percentage of the isomeric enol of thioamide MeNHCOC(CN)=C(SH)NHMe (10) were obtained in solvent-dependent compositions, which are rapidly established.

Substituted 2-methylene-1,3-oxazolidines, -1,3-thiazolidines, -1,3-benzothiazines, -1,3-oxazines, and substituted imidazopyrimidinediones from Cl(CH2)nNCO and Cl(CH2)nNCS and active methylene compounds.

The reaction of omega-chloroalkyl isocyanates Cl(CH2)nNCO (n = 2 (2), 3 (4)) and isothiocyanate Cl(CH2)2NCS (3) with active methylene compounds CH2YY' 1 in the presence of Et3N or Na give 2-YY'-methylene-1,3-oxazolidines, (E,Z)-1,3-thiazolidines, and 1,3-oxazines from 2, 3, and 4, respectively. 2-(Chloromethyl)phenyl isocyanate 8 gives with 1 the corresponding benzo-oxazines. Ethyl 2-isothiocyanatobenzoate 10 gives the corresponding benzothiazolinone, whereas the analogous isocyanate 12 gives noncyclic enols. Ethoxycarbonyl isothiocyanate 14 gives an open-chain thioenol or an enol-thioamide. The cyanoamides CH2(CN)CONHR, R = H, Me, CHPh2, give with Et3N and 2 the bicyclic imidazopyrimidinediones 16, derived from two molecules of 2, but with their preformed Na salt they give the 1,3-oxazolidines. Reaction of cyanoacetamide with 3 in the presence of Na gave a tricyclic triaza(thia)indacene, derived from two molecules of 3. A reaction mechanism involving an initial attack of the anion 1- on the N=C=X (X = O, S) moiety gives an anion 18, which cyclizes intramolecularly and after tautomerization gives the mono-ring heterocycle. With the cyanoamides, the N- site of the ambident ion 18 attacks another molecule of 2 giving the anion 20, which by intramolecular attack on the CN, followed by expulsion of the Cl- gives the bicyclic 16 after tautomerization.

Enols of amides activated by the 2,2,2-trichloroethoxycarbonyl group.

Reaction of isocyanates XNCO (X = Ar, i-Pr, t-Bu) with CH(2)(Y)CO(2)CH(2)CCl(3) (Y = CO(2)Me, CO(2)CH(2)CCl(3), CN) gave 15 amides XNHCOCH(Y)CO(2)CH(2)CCl(3) (6) or enols of amides XNHC(OH)=C(Y)CO(2)CH(2)CCl(3) (5) systems. The amide/enol ratios in solution depend strongly on the substituent Y and the solvent and mildly on the substituent X. The percentage of enol for group Y increases according to Y = CN > CO(2)CH(2)CCl(3) > CO(2)Me and decreases with the solvent according to CCl(4) > C(6)D(6) > CDCl(3) > THF-d(8) > CD(3)CN > DMSO-d(6). With the most acidic systems (Y = CN) amide/enol exchange is observed in moderately polar solvents and ionization to the conjugate base is observed in DMSO-d(6). The solid-state structure of the compound with Y = CN, X = i-Pr was found to be that of the enol. The reasons for the stability of the enols were discussed in terms of polar and resonance effects. Intramolecular hydrogen bonds result in a very low delta(OH) and contribute to the stability of the enols and are responsible for the higher percentage of the E-isomers when Y = CO(2)Me and the Z-isomers when Y = CN. The differences in delta(OH), delta(NH), K(enol), and E/Z enol ratios from the analogues with CF(3) instead of CCl(3) are discussed.