Search

Epithelial ovarian carcinoma (EOC) accounts for approximately 90% of all cases of ovarian cancer, which remains a leading cause of gynecologic cancer mortality in women worldwide. (1,2) Late-stage diagnosis of [...], * Context.--Folate receptor-[alpha] (FR[alpha], encoded by the FOLR1 gene) is overexpressed in several solid tumor types, including epithelial ovarian cancer (EOC), making it an attractive biomarker and target for FR[alpha]-based therapy in ovarian cancer. Objective.--To describe the development, analytic verification, and clinical performance of the VENTANA FOLR1 Assay (Ventana Medical Systems Inc) in EOC. Design.--We used industry standard studies to establish the analytic verification of the VENTANA FOLR1 Assay. Furthermore, the VENTANA FOLR1 Assay was used in the ImmunoGen Inc-sponsored SORAYA study to select patients for treatment with mirvetuximab soravtansine (MIRV) in platinum-resistant EOC. Results.--The VENTANA FOLR1 Assay is highly reproducible, demonstrated by a greater than 98% overall percent agreement (OPA) for repeatability and intermediate precision studies, greater than 93% OPA for interreader and greater than 96% for intrareader studies, and greater than 90% OPA across all observations in the interlaboratory reproducibility study. The performance of the VENTANA FOLR1 Assay in the SORAYA study was evaluated by the overall staining acceptability rate, which was calculated using the number of patient specimens that were tested with the VENTANA FOLR1 Assay that had an evaluable result. In the SORAYA trial, data in patients who received MIRV demonstrated clinically meaningful efficacy, and the overall staining acceptability rate of the assay was 98.4%, demonstrating that the VENTANA FOLR1 Assay is safe and effective for selecting patients who may benefit from MIRV. Together, these data showed that the assay is highly reliable, consistently producing evaluable results in the clinical setting. Conclusions.--The VENTANA FOLR1 Assay is a robust and reproducible assay for detecting FR[alpha] expression and identifying a patient population that derived clinically meaningful benefit from MIRV in the SORAYA study. (Arch Pathol Lab Med. 2024;148:1226-1233; doi: 10.5858/arpa.2023-0149-OA)

The investigation of the coordination chemistry of rare-earth metal complexes with cyanide ligands led to the isolation and crystallographic characterization of the Ln III cyano-tri-phenyl-borate complexes di-chlorido-(cyano-tri-phenyl-borato-κN)tetra-kis-(tetra-hydro-furan-κO)lanthanide(III), [LnCl2(C19H15BN)(C4H8O)4] [lanthanide (Ln) = dysprosium (Dy) and yttrium Y)] from reactions of LnCl3, KCN, and NaBPh4. Attempts to independently synthesize the tetra-ethyl-ammonium salt of (NCBPh3)- from BPh3 and [NEt4][CN] in THF yielded crystals of the phenyl-substituted cyclic borate, tetra-ethyl-aza-nium 2,2,4,6-tetra-phenyl-1,3,5,2λ4,4,6-trioxatriborinan-2-ide, C8H20N+·C24H20B3O3 - or [NEt4][B3(μ-O)3(C6H5)4]. The mechanochemical reaction of BPh3 and [NEt4][CN] without solvent produced crystals of tetra-ethyl-aza-nium cyano-diphenyl-λ4-boranyl di-phenyl-borinate, C8H20N+·C25H20B2NO- or [NEt4][NCBPh2(μ-O)BPh2]. Reaction of BPh3 and KCN in THF in the presence of 2.2.2-cryptand (crypt) led to a crystal of bis-[(2.2.2-cryptand)potassium] 2,2,4,6-tetra-phenyl-1,3,5,2λ4,4,6-trioxatriborinan-2-ide cyano-methyl-diphenyl-borate tetra-hydro-furan disolvate, 2C18H36KN2O6 +·C24H20B3O3 -·C14H13BN-·2C4H8O or [K(crypt)]2[B3(μ-O)3(C6H5)4][NCBPh2Me]·2THF. The [NCBPh2(μ-O)BPh2]1- and (NCBPh2Me)1- anions have not been structurally characterized previously. The structure of 1-Y was refined as a two-component twin with occupancy factors 0.513 (1) and 0.487 (1). In 4, one solvent mol-ecule was disordered and included using multiple components with partial site-occupancy factors.

The complexes [Cp'2Ln(μ-CH3)]2, (Cp' = C5H4SiMe3; Ln = Y, Tb, Dy) were reduced to determine if these methyl-bridged complexes would form mixed valent 4f n 5d1 Ln(II)/4f n Ln(III) compounds or bimetallic 4f n 5d1 Ln(II) compounds containing 5d1-5d1 metal-metal bonds upon reduction. Reaction of the known bridged-chloride complexes, [Cp'2Ln(μ-Cl)]2, 1-Ln (Ln = Y, Tb, Dy), with MeLi forms the bridged-methyl complexes [Cp'2Ln(μ-CH3)]2, 2-Ln, which were crystallographically characterized for Tb and Dy. KC8 reduction of 2-Ln in the presence of 2.2.2-cryptand produced 3-Y, 3-Tb, and 3-Dy, which exhibited intense dark colors and broad absorbance peaks around 400 nm with molar extinction coefficients of 1700, 2300, and 1800 M-1 cm-1, respectively, which are characteristics of Ln(II) ions. The dark maroon 3-Y product had an axial electron paramagnetic resonance spectrum at 77 K (g 1 = 1.99, A 1 = 17.9 G; g 2 = 2.00, A 2 = 17.7 G) and a two-line isotropic spectrum at 273 K (g = 1.99, A = 18.4 G), which indicates that an Y(II) ion is present. Although these results are indicative of Ln(II) ions present in the solution, crystallographic evidence was not obtained to establish the structure of these complexes.

Simple Summary: This study explored the current practices in the real world for grade 2 glioma, an uncommon primary brain cancer. Leveraging the prospective BRAIN registry, this study demonstrates that whilst sequential radiotherapy and chemotherapy improve progression-free survival in high-risk grade 2 glioma, the majority of patients are observed following surgery. In high-risk patients who are observed, 61% remain progression-free at 12 months, with 10% being progression-free at 5 years. This clinically meaningful progression-free survival suggests that validated biomarkers beyond the usual definition of high-risk are required to better inform patient management. Factors contributing to decision-making are underway. Background: Grade-2 gliomas (G2-glioma) are uncommon. In 2016, RTOG9802 established the addition of chemotherapy after radiation (CRT) as a new standard of care for patients with high-risk G2-glioma, defined as subtotal resection or age ≥40 yrs. Here, we report current practices using real-world data. Methods: Patients diagnosed with G2-glioma from 1 January 2016 to 31 December 2022 were identified in BRAIN, a prospective clinical registry collecting data on patients with brain tumours. High- and low-risk were defined as per RTOG9802. Two time periods, January 2016–December 2019 (TP1) and January 2020–December 2022 (TP2), were defined. Survival was estimated using the Kaplan–Meier method. Results: 224 patients were identified. Overall, 38 (17%) were low-risk, with 35 (91%) observed without further treatment. A total of 186 (83%) were high-risk, with 96 (52%) observed, 63 (34%) receiving CRT, and 19 (10%) receiving radiation. Over time, CRT use increased (TP1 vs. TP2: 22% vs. 36%, p = 0.004), and the rate of biopsy (TP1 vs. TP2: 35% vs. 20%, p = 0.02) and radiotherapy alone (TP1 vs. TP2: 14% vs. 4%, p = 0.01) decreased. Median progression-free survival (PFS) was significantly longer in high-risk patients who received CRT (NR) over observation (39 months) (HR 0.49, p = 0.007). In high-risk patients who were observed, 59 (61%) were progression-free at 12 months and 10 (10%) at 5 years. OS data remains immature. Conclusion: Congruent with RTOG9802, real-world BRAIN data shows CRT is associated with improved PFS compared to observation in high-risk G2-glioma. Whilst CRT use has increased over time, observation after surgery remains the most common strategy, with some high-risk patients achieving clinically meaningful PFS. Validated biomarkers are urgently required to better inform patient management. [ABSTRACT FROM AUTHOR]

The investigation of the coordination chemistry of rare-earth metal complexes with cyanide ligands led to the isolation and crystallographic characterization of the LnIII cyanotriphenylborate complexes dichlorido(cyanotriphenylborato- N)tetrakis(tetrahydrofuran-kO)lanthanide(III), [LnCl2(C19H15BN)(C4H8O)4] [lanthanide (Ln) = dysprosium (Dy) and yttrium Y)] from reactions of LnCl3, KCN, and NaBPh4. Attempts to independently synthesize the tetraethylammonium salt of (NCBPh3) from BPh3 and [NEt4][CN] in THF yielded crystals of the phenyl-substituted cyclic borate, tetraethylazanium 2,2,4,6- tetraphenyl-1,3,5,2-4,4,6-trioxatriborinan-2-ide, C8H20N+C24H20B3O3 or [NEt4][B3(-O)3(C6H5)4]. The mechanochemical reaction of BPh3 and [NEt4][CN] without solvent produced crystals of tetraethylazanium cyanodiphenyl- 4-boranyl diphenylborinate, C8H20N+C25H20B2NO or [NEt4][NCBPh2(-O)BPh2]. Reaction of BPh3 and KCN in THF in the presence of 2.2.2-cryptand (crypt) led to a crystal of bis[(2.2.2-cryptand)potassium] 2,2,4,6-tetraphenyl-1,3,5,2-4,4,6-trioxatriborinan-2-ide cyanomethyldiphenylborate tetrahydrofuran disolvate, 2C18H36KN2O6 + C24H20B3O3- C14H13BN-2C4H8O or [K(crypt)]2[B3(-O)3(C6H5)4][NCBPh2Me]-2THF. The [NCBPh2(-O)BPh2]1 and (NCBPh2Me)1 anions have not been structurally characterized previously. The structure of 1-Y was refined as a two-component twin with occupancy factors 0.513 (1) and 0.487 (1). In 4, one solvent molecule was disordered and included using multiple components with partial siteoccupancy factors. [ABSTRACT FROM AUTHOR]

The investigation of the coordination chemistry of rare-earth metal complexes with cyanide ligands led to the isolation and crystallographic characterization of the LnIII cyanotriphenylborate complexes dichlorido(cyanotriphenylborato- N)tetrakis(tetrahydrofuran-kO)lanthanide(III), [LnCl2(C19H15BN)(C4H8O)4] [lanthanide (Ln) = dysprosium (Dy) and yttrium Y)] from reactions of LnCl3, KCN, and NaBPh4. Attempts to independently synthesize the tetraethylammonium salt of (NCBPh3) from BPh3 and [NEt4][CN] in THF yielded crystals of the phenyl-substituted cyclic borate, tetraethylazanium 2,2,4,6- tetraphenyl-1,3,5,2-4,4,6-trioxatriborinan-2-ide, C8H20N+C24H20B3O3 or [NEt4][B3(-O)3(C6H5)4]. The mechanochemical reaction of BPh3 and [NEt4][CN] without solvent produced crystals of tetraethylazanium cyanodiphenyl- 4-boranyl diphenylborinate, C8H20N+C25H20B2NO or [NEt4][NCBPh2(-O)BPh2]. Reaction of BPh3 and KCN in THF in the presence of 2.2.2-cryptand (crypt) led to a crystal of bis[(2.2.2-cryptand)potassium] 2,2,4,6-tetraphenyl-1,3,5,2-4,4,6-trioxatriborinan-2-ide cyanomethyldiphenylborate tetrahydrofuran disolvate, 2C18H36KN2O6 + C24H20B3O3- C14H13BN-2C4H8O or [K(crypt)]2[B3(-O)3(C6H5)4][NCBPh2Me]-2THF. The [NCBPh2(-O)BPh2]1 and (NCBPh2Me)1 anions have not been structurally characterized previously. The structure of 1-Y was refined as a two-component twin with occupancy factors 0.513 (1) and 0.487 (1). In 4, one solvent molecule was disordered and included using multiple components with partial siteoccupancy factors. [ABSTRACT FROM AUTHOR]

Attempts to synthesize the base-free dication [(C5Me5)2Th]2+ by reaction of the bis(allyl) complex (C5Me5)2Th(C3H5)2 with 2 equiv of [Et3NH][BPh4] in benzene yielded a cationic phenyl complex that, in the presence of THF, crystallized from toluene as [(C5Me5)2Th(C6H5)(THF)][BPh4]. The reaction of the dimethyl complex (C5Me5)2ThMe2 with [Et3NH][BPh4] in toluene in the presence of nitriles RCN generates cations of the formula [(C5Me5)2Th(NCR)5][BPh4]2 (R = Me, Ph) in 40-55% crystalline yield. The molecular structures reveal the first examples of thorium cyclopentadienyl metallocene complexes with parallel rings. [ABSTRACT FROM AUTHOR]

Competing Interests: Both authors are employees of Roche Diagnostic Solutions. Mason owns stock in Roche Diagnostic.

The reduction of a bimetallic yttrium ansa -metallocene hydride was examined to explore the possible formation of Y-Y bonds with 4d 1 Y(II) ions. The precursor [Cp An Y(μ-H)(THF)] 2 (Cp An = Me 2 Si[C 5 H 3 (SiMe 3 )-3] 2 ) was synthesized by hydrogenolysis of the allyl complex Cp An Y(η 3 -C 3 H 5 )(THF), which was prepared from (C 3 H 5 )MgCl and [Cp An Y(μ-Cl)] 2 . Treatment of [Cp An Y(μ-H)(THF)] 2 with excess KC 8 in the presence of one equivalent of 2.2.2-cryptand (crypt) generates an intensely colored red-brown product crystallographically identified as [K(crypt)][(μ-Cp An )Y(μ-H)] 2 . The two rings of each Cp An ligand in the reduced anion [(μ-Cp An )Y(μ-H)] 2 1- are attached to two yttrium centers in a "flyover" configuration. The 3.3992(6) and 3.4022(7) Å Y···Y distances between the equivalent metal centers within two crystallographically independent complexes are the shortest Y···Y distances observed to date. Ultraviolet-visible (UV-visible)/near infrared (IR) and electron paramagnetic resonance (EPR) spectroscopy support the presence of Y(II), and theoretical analysis describes the singly occupied molecular orbital (SOMO) as an Y-Y bonding orbital composed of metal 4d orbitals mixed with metallocene ligand orbitals. A dysprosium analogue, [K(18-crown-6)(THF) 2 ][(μ-Cp An )Dy(μ-H)] 2 , was also synthesized, crystallographically characterized, and studied by variable temperature magnetic susceptibility. The magnetic data are best modeled with the presence of one 4f 9 Dy(III) center and one 4f 9 (5d z 2 ) 1 Dy(II) center with no coupling between them. CASSCF calculations are consistent with magnetic measurements supporting the absence of coupling between the Dy centers.

The complexes [Cp' 2 Ln(μ-CH 3 )] 2 , (Cp' = C 5 H 4 SiMe 3 ; Ln = Y, Tb, Dy) were reduced to determine if these methyl-bridged complexes would form mixed valent 4f n 5d 1 Ln(II)/4f n Ln(III) compounds or bimetallic 4f n 5d 1 Ln(II) compounds containing 5d 1 -5d 1 metal-metal bonds upon reduction. Reaction of the known bridged-chloride complexes, [Cp' 2 Ln(μ-Cl)] 2 , 1-Ln (Ln = Y, Tb, Dy), with MeLi forms the bridged-methyl complexes [Cp' 2 Ln(μ-CH 3 )] 2 , 2-Ln , which were crystallographically characterized for Tb and Dy. KC 8 reduction of 2-Ln in the presence of 2.2.2-cryptand produced 3-Y , 3-Tb , and 3-Dy , which exhibited intense dark colors and broad absorbance peaks around 400 nm with molar extinction coefficients of 1700, 2300, and 1800 M -1 cm -1 , respectively, which are characteristics of Ln(II) ions. The dark maroon 3-Y product had an axial electron paramagnetic resonance spectrum at 77 K ( g 1 = 1.99, A 1 = 17.9 G; g 2 = 2.00, A 2 = 17.7 G) and a two-line isotropic spectrum at 273 K ( g = 1.99, A = 18.4 G), which indicates that an Y(II) ion is present. Although these results are indicative of Ln(II) ions present in the solution, crystallographic evidence was not obtained to establish the structure of these complexes., Competing Interests: The authors declare no competing financial interest.