Nonheme FeIV═O Complexes Supported by Four Pentadentate Ligands: Reactivity toward H- and O- Atom Transfer Processes.

Four new pentadentate N5-donor ligands, [N-(1-methyl-2-imidazolyl)methyl-N-(2-pyridyl)-methyl-N-(bis-2-pyridylmethyl)-amine] (L1), [N-bis(1-methyl-2-imidazolyl)methyl-N-(bis-2-pyridylmethyl)amine] (L2), (N-(isoquinolin-3-ylmethyl)-1,1-di(pyridin-2-yl)-N-(pyridin-2-ylmethyl)methanamine (L3), and N,N-bis(isoquinolin-3-ylmethyl)-1,1-di(pyridin-2-yl)methanamine (L4), have been synthesized based on the N4Py ligand framework, where one or two pyridyl arms of the N4Py parent are replaced by (N-methyl)imidazolyl or N-(isoquinolin-3-ylmethyl) moieties. Using these four pentadentate ligands, the mononuclear complexes [FeII(CH3CN)(L1)]2+ (1a), [FeII(CH3CN)(L2)]2+ (2a), [FeII(CH3CN)(L3)]2+ (3a), and [FeII(CH3CN)(L4)]2+ (4a) have been synthesized and characterized. The half-wave potentials (E1/2) of the complexes become more positive in the order: 2a < 1a < 4a ≤ 3a ≤ [Fe(N4Py)(CH3CN)]2+. The order of redox potentials correlates well with the Fe-Namine distances observed by crystallography, which are 2a > 1a ≥ 4a > 3a ≥ [Fe(N4Py)(CH3CN)]2+. The corresponding ferryl complexes [FeIV(O)(L1)]2+ (1b), [FeIV(O)(L2)]2+ (2b), [FeIV(O)(L3)]2+ (3b), and [FeIV(O)(L4)]2+ (4b) were prepared by the reaction of the ferrous complexes with isopropyl 2-iodoxybenzoate (IBX ester) in acetonitrile. The greenish complexes 3b and 4b were also isolated in the solid state by the reaction of the ferrous complexes in CH3CN with ceric ammonium nitrate in water. Mössbauer spectroscopy and magnetic measurements (using superconducting quantum interference device) show that the four complexes 1b, 2b, 3b, and 4b are low-spin (S = 1) FeIV═O complexes. UV/vis spectra of the four FeIV═O complexes in acetonitrile show typical long-wavelength absorptions of around 700 nm, which are expected for FeIV═O complexes with N4Py-type ligands. The wavelengths of these absorptions decrease in the following order: 721 nm (2b) > 706 nm (1b) > 696 nm (4b) > 695 nm (3b) = 695 nm ([FeIV(O) (N4Py)]2+), indicating that the replacement of the pyridyl arms with (N-methyl) imidazolyl moieties makes L1 and L2 exert weaker ligand fields than the parent N4Py ligand, while the ligand field strengths of L3 and L4 are similar to the N4Py parent despite the replacement of the pyridyl arms with N-(isoquinolin-3-ylmethyl) moieties. Consequently, complexes 1b and 2b tend to be less stable than the parent [FeIV(O)(N4Py)]2+ complex: the half-life sequence at room temperature is 1.67 h (2b) < 16 h (1b) < 45 h (4b) < 63 h (3b) ≈ 60 h ([FeIV(O)(N4Py)]2+). Compared to the parent complex, 1b and 2b exhibit enhanced reactivity in both the oxidation of thioanisole in the oxygen atom transfer (OAT) reaction and the oxygenation of C-H bonds of aromatic and aliphatic substrates, presumed to occur via an oxygen rebound process. Furthermore, the second-order rate constants for hydrogen atom transfer (HAT) reactions affected by the ferryl complexes can be directly related to the C-H bond dissociation energies of a range of substrates that have been studied. Using either IBX ester or H2O2 as an oxidant, all four new FeII complexes display good performance in catalytic reactions involving both HAT and OAT reactions.

FDA Approval Summary: Atezolizumab as Adjuvant Treatment following Surgical Resection and Platinum-Based Chemotherapy for Stage II to IIIA NSCLC.

On October 15, 2021, the FDA approved atezolizumab as adjuvant therapy in patients with stage II to IIIA non-small cell lung cancer (NSCLC) whose tumors have programmed cell death ligand 1 (PD-L1) expression on ≥1% of tumor cells (TC), as detected by an FDA-approved test. The approval was based on results from the IMpower010 trial, in which 1,005 patients with NSCLC who had completed tumor resection and cisplatin-based adjuvant chemotherapy were randomly assigned 1:1 to receive atezolizumab for 16 cycles or best supportive care. The primary endpoint of disease-free survival (DFS) as assessed by investigator was tested hierarchically in the following analysis populations: stage II-IIIA NSCLC with PD-L1 expression on ≥1% of TCs (PD-L1 ≥ 1% TC); all randomly assigned patients with stage II-IIIA NSCLC; and the intent-to-treat population comprising all randomly assigned patients. At the prespecified interim DFS analysis, IMpower010 demonstrated a statistically significant and clinically meaningful improvement in DFS in the stage II-IIIA PD-L1 ≥ 1% TC analysis population, with an HR of 0.66 (95% confidence interval, 0.50-0.88; P = 0.004) favoring the atezolizumab arm. The safety profile of atezolizumab was generally consistent with known toxicities of anti-PD-(L) antibodies. The VENTANA PD-L1 (SP263) Assay (Ventana Medical Systems, Inc.) was contemporaneously approved as a companion diagnostic device to select patients with NSCLC who are PD-L1 ≥ 1% TC for adjuvant treatment with atezolizumab. Atezolizumab is the first immune checkpoint inhibitor approved by FDA for the adjuvant treatment of NSCLC.

Hydrogen-atom and oxygen-atom transfer reactivities of iron(IV)-oxo complexes of quinoline-substituted pentadentate ligands.

A series of iron(II) complexes with the general formula [FeII(L2-Qn)(L)]n+ (n = 1, L = F-, Cl-; n = 2, L = NCMe, H2O) have been isolated and characterized. The X-ray crystallographic data reveals that metal-ligand bond distances vary with varying ligand field strengths of the sixth ligand. While the complexes with fluoride, chloride and water as axial ligand are high spin, the acetonitrile-coordinated complex is in a mixed spin state. The steric bulk of the quinoline moieties forces the axial ligands to deviate from the Fe-Naxial axis. A higher deviation/tilt is noted for the high spin complexes, while the acetonitrile coordinated complex displays least deviation. This deviation from linearity is slightly less in the analogous low-spin iron(II) complex [FeII(L1-Qn)(NCMe)]2+ of the related asymmetric ligand L1-Qn due to the presence of only one sterically demanding quinoline moiety. The two iron(II)-acetonitrile complexes [FeII(L2-Qn)(NCMe)]2+ and [FeII(L1-Qn)(NCMe)]2+ generate the corresponding iron(IV)-oxo species with higher thermal stability of the species supported by the L1-Qn ligand. The crystallographic and spectroscopic data for [FeIV(O)(L1-Qn)](ClO4)2 bear resemblance to other crystallographically characterized S = 1 iron(IV)-oxo complexes. The hydrogen atom transfer (HAT) and oxygen atom transfer (OAT) reactivities of both the iron(IV)-oxo complexes were investigated, and a Box-Behnken multivariate optimization of the parameters for catalytic oxidation of cyclohexane by [FeII(L2-Qn)(NCMe)]2+ using hydrogen peroxide as the terminal oxidant is presented. An increase in the average Fe-N bond length in [FeII(L1-Qn)(NCMe)]2+ is also manifested in higher HAT and OAT rates relative to the other reported complexes of ligands based on the N4Py framework. The results reported here confirm that the steric influence of the ligand environment is of critical importance for the reactivity of iron(IV)-oxo complexes, but additional electronic factors must influence the reactivity of iron-oxo complexes of N4Py derivatives.

Subgroup Analyses in Oncology Trials: Regulatory Considerations and Case Examples.

Subgroup analyses are assessments of treatment effects based on certain patient characteristics out of the total study population and are important for interpretation of pivotal oncology trials. However, appropriate use of subgroup analyses results for regulatory decision-making and product labeling is challenging. Typically, drugs approved by the FDA are indicated for use in the total patient population studied; however, there are examples of restriction to a subgroup of patients despite positive study results in the entire study population and also extension of an indication to the entire study population despite positive results appearing primarily in one or more subgroups. In this article, we summarize key issues related to subgroup analyses in the benefit-risk assessment of cancer drugs and provide case examples to illustrate approaches that the FDA Oncology Center of Excellence has taken when considering the appropriate patient population for cancer drug approval. In general, if a subgroup is of interest, the subgroup analysis should be hypothesis-driven and have adequate sample size to demonstrate evidence of a treatment effect. In addition to statistical efficacy considerations, the decision on what subgroups to include in labeling relies on the pathophysiology of the disease, mechanistic justification, safety data, and external information available. The oncology drug review takes the totality of the data into consideration during the decision-making process to ensure the indication granted and product labeling appropriately reflect the scientific evidence to support patient population for whom the drug is safe and effective.

A 95-gene signature stratifies recurrence risk of invasive disease in ER-positive, HER2-negative, node-negative breast cancer with intermediate 21-gene signature recurrence scores.

PURPOSE: A subset of patients with intermediate 21-gene signature assay recurrence score may benefit from adjuvant chemoendocrine therapy, but a predictive strategy is needed to identify such patients. The 95-gene signature assay was tested to stratify patients with intermediate RS into high (95GC-H) and low (95GC-L) groups that were associated with invasive recurrence risk. METHODS: Patients with ER-positive, HER2-negative, node-negative breast cancer and RS 11-25 who underwent definitive surgery and adjuvant endocrine therapy without any cytotoxic agents were included. RNA was extracted from archived formalin-fixed, paraffin-embedded samples, and 95-gene signature was calculated. RESULTS: 206 patients had RS of 11-25 (95GC-L, N = 163; 95GC-H, N = 43). In Cox proportional hazards model, 95GC-H was significantly associated with shorter time to recurrence than was 95GC-L (HR 5.94; 95%CI 1.81-19.53; P = 0.005). The correlation between 95-gene signature and 21-gene signature assay scores was not strong (correlation coefficient r = 0.27), which might suggest that 95-gene signature reflects biological characteristics differing from what 21-gene signature shows. CONCLUSIONS: The 95-gene signature stratifies patients with ER-positive, HER2-negative, node-negative invasive breast cancer and intermediate RS of 11-25 into high and low groups that are associated with recurrence risk of invasive disease. Further retrospective analysis in the prospectively accrued TAILORx population is warranted to confirm that 95-gene signature can identify patients who would benefit from adjuvant chemoendocrine therapy.

FDA Approval Summary: Selumetinib for Plexiform Neurofibroma.

On April 10, 2020, the FDA approved selumetinib (KOSELUGO, AstraZeneca) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. Approval was based on demonstration of a durable overall response rate per Response Evaluation in Neurofibromatosis and Schwannomatosis criteria and supported by observed clinical improvements in plexiform neurofibroma-related symptoms and functional impairments in 50 pediatric patients with inoperable plexiform neurofibromas in a single-arm, multicenter trial. The overall reponse rate per NCI investigator assessment was 66% (95% confidence interval, 51-79) with at least 12 months of follow-up. The median duration of response was not reached, and 82% of responding patients experienced duration of response ≥12 months. Clinical outcome assessment endpoints provided supportive efficacy data. Risks of selumetinib are consistent with MAPK (MEK) inhibitor class effects, including ocular, cardiac, musculoskeletal, gastrointestinal, and dermatologic toxicities. Safety was assessed across a pooled database of 74 pediatric patients with plexiform neurofibromas and supported by adult and pediatric selumetinib clinical trial data in cancer indications. The benefit-risk assessment for selumetinib in patients with inoperable plexiform neurofibromas was considered favorable.

Development of novel alternative hair dyes to hazardous para-phenylenediamine.

Most of the permanent hair dye products contain p-phenylenediamine (PPD), a well-known skin sensitizer. PPD may cause cutaneous reactions and leads to allergic contact dermatitis (ACD), a condition with major medical and financial repercussions. Hair dye-induced ACD represents a growing concern both for consumers and the cosmetics industry. In this study we introduced novel side chains on the PPD molecule with the goal of overcoming the hazard potential of PPD. Our strategy relies on the replacement of the colorless PPD with new, larger and intrinsically colorled PPD derivatives to reduce dermal penetration and thus the skin sensitization potential. We synthesized two oligomers with bulky side-chains, which displayed 7-8 times lower cytotoxicity than PPD, a significantly weaker sensitization potential (22.0 % and 23.8 % versus 55.5 % for PPD) in the Direct Peptide Reactivity Assay, minimal cumulative penetration through excised skin and an intrinsic ability to colour and preserve the nuance when applied on bleached hair. The lower skin permeation and sensitizing potential are absolutely crucial and give a clear advantage of our products over other standards. These novel PPD hair dyes show significantly less hazard potential than PPD and may, upon further risk assessment studies, replace PPD in consumer care products.

Direct C-H bond halogenation and pseudohalogenation of hydrocarbons mediated by high-valent 3d metal-oxo species.

Late-stage direct functionalization of the C-H bond is synthetically desirable. Metalloenzymes having metal-oxo active sites are well known to selectively catalyze hydroxylation and halogenation reactions with high efficiency. This review highlights the recent developments in the field of direct C-H halogenation and pseudohalogenation reactions catalyzed by the functional models of metalloenzymes.

Semi-bridging σ-silyls as Z-type ligands.

The reactions of SiHPh(NCH2PPh2)2C6H4-1,2 with a range of zerovalent group 10 reagents afford the homoleptic bimetallic complexes [M2{µ-κ3-Si,P,P'-SiPh(CH2PPh2)2C6H4}2] (M = Ni, Pd, Pt) in which the M-M bond is unsymmetrically bridged by two σ-silyl groups. The asymmetry of the M2Si2 core increases from Ni through Pd to Pt and is consistent with a bonding description in which one metal acts as an electron pair donor to a trigonal bipyramidal 'Z-type' silicon centre, reminsicent of semi-bridging coordination by CO, carbynes and boryl ligands.

Structural Characterization of a Series of N5-Ligated MnIV -Oxo Species.

Analysis of extended X-ray absorption fine structure (EXAFS) data for the MnIV -oxo complexes [MnIV (O)(DMM N4py)]2+ , [MnIV (O)(2pyN2B)]2+ , and [MnIV (O)(2pyN2Q)]2+ (DMM N4py=N,N-bis(4-methoxy-3,5-dimethyl-2-pyridylmethyl)-N-bis(2-pyridyl)methylamine; 2pyN2B=(N-bis(1-methyl-2-benzimidazolyl)methyl-N-(bis-2-pyridylmethyl)amine, and 2pyN2Q=N,N-bis(2-pyridyl)-N,N-bis(2-quinolylmethyl)methanamine) afforded Mn=O and Mn-N bond lengths. The Mn=O distances for [MnIV (O)(DMM N4py)]2+ and [MnIV (O)(2pyN2B)]2+ are 1.72 and 1.70 Å, respectively. In contrast, the Mn=O distance for [MnIV (O)(2pyN2Q)]2+ was significantly longer (1.76 Å). We attribute this long distance to sample heterogeneity, which is reasonable given the reduced stability of [MnIV (O)(2pyN2Q)]2+ . The Mn=O distances for [MnIV (O)(DMM N4py)]2+ and [MnIV (O)(2pyN2B)]2+ could only be well-reproduced using DFT-derived models that included strong hydrogen-bonds between second-sphere solvent 2,2,2-trifluoroethanol molecules and the oxo ligand. These results suggest an important role for the 2,2,2-trifluoroethanol solvent in stabilizing MnIV -oxo adducts. The DFT methods were extended to investigate the structure of the putative [MnIV (O)(N4py)]2+ ⋅(HOTf)2 adduct. These computations suggest that a MnIV -hydroxo species is most consistent with the available experimental data.

Adaptive group-sequential design with population enrichment in phase 3 randomized controlled trials with two binary co-primary endpoints.

The use of co-primary endpoints in drug development allows investigators to capture an experimental intervention's multidimensional effect more comprehensively than a single primary endpoint. We propose the theoretical basis and development of an adaptive population enrichment design with co-primary endpoints, provide stage-wise boundary values for futility and efficacy, and discuss power under different efficacy configurations, subgroup prevalence, and analysis times using a pre-specified decision criterion. We considered a two-arm, two-stage, parallel group design where population enrichment occurs at the interim analysis by dropping any non-responsive subgroups. A test for efficacy is conducted only in the enriched population. Two binary endpoints are evaluated as co-primary endpoints. Our trial objective is to determine whether the experimental intervention is superior to the control intervention, with superiority required in both endpoints. We define the stopping boundary using alpha spending functions. Using a 0.025 significance level for each endpoint, we obtain the stage I threshold boundary values for futility and efficacy as -0.1040 and 2.2761, respectively, and the stage II boundary value for futility and efficacy is 2.2419. We show that in the presence of substantial heterogeneity of treatment effect, we gain more power to observe an effect in the subgroup where the benefits are greater. By allowing the dropping of non-responsive subgroups at an early stage, our design reduces the likelihood of obtaining false-negative results due to inclusion of the heterogeneous treatment effects of both subgroups, which would dilute the responsive subgroup's results.

MnIV-Oxo complex of a bis(benzimidazolyl)-containing N5 ligand reveals different reactivity trends for MnIV-oxo than FeIV-oxo species.

Using the pentadentate ligand (N-bis(1-methyl-2-benzimidazolyl)methyl-N-(bis-2-pyridylmethyl)amine, 2pyN2B), presenting two pyridyl and two (N-methyl)benzimidazolyl donor moieties in addition to a central tertiary amine, new MnII and MnIV-oxo complexes were generated and characterized. The [MnIV(O)(2pyN2B)]2+ complex showed spectroscopic signatures (i.e., electronic absorption band maxima and intensities, EPR signals, and Mn K-edge X-ray absorption edge and near-edge data) similar to those observed for other MnIV-oxo complexes with neutral, pentadentate N5 supporting ligands. The near-IR electronic absorption band maximum of [MnIV(O)(2pyN2B)]2+, as well as DFT-computed metric parameters, are consistent with the equatorial (N-methyl)benzimidazolyl ligands being stronger donors to the MnIV center than the pyridyl and quinolinyl ligands found in analogous MnIV-oxo complexes. The hydrogen- and oxygen-atom transfer reactivities of [MnIV(O)(2pyN2B)]2+ were assessed through reactions with hydrocarbons and thioanisole, respectively. When compared with related MnIV-oxo adducts, [MnIV(O)(2pyN2B)]2+ showed muted reactivity in hydrogen-atom transfer reactions with hydrocarbons. This result stands in contrast to observations for the analogous FeIV-oxo complexes, where [FeIV(O)(2pyN2B)]2+ was found to be one of the more reactive members of its class.

Medication Regimen Complexity and Low Adherence in Older Community-Dwelling Adults With Substantiated Self-Neglect.

OBJECTIVE: Determine whether medication regimen complexity predicts medication adherence levels in a sample of community-dwelling adults 65 years and older with Adult Protective Services-substantiated self-neglect. METHODS: A cross-sectional analysis of baseline data ( N = 31 participants) from a pilot intervention to increase medication adherence among the target group was performed. The Medication Regimen Complexity Index (MRCI) and the 8-item Morisky Medication Adherence Scale (MMAS-8)™ were the primary independent and dependent measures, respectively. A multivariable linear regression analysis, adjusting for potential confounders, was conducted to estimate the association between complexity and adherence. RESULTS: Regimen complexity was high (mean MRCI = 19.6) and adherence was low (mean MMAS = 5.1). Even after controlling for confounders, increased complexity was significantly associated with lower adherence. DISCUSSION: Older community-dwelling adults who self-neglect have complex medication regimens that contribute to low medication adherence. Medication regimen complexity may be a modifiable contributor to low adherence that can be targeted by future interventions to reduce self-neglect and its consequences.

Relationship between Hydrogen-Atom Transfer Driving Force and Reaction Rates for an Oxomanganese(IV) Adduct.

Hydrogen atom transfer (HAT) reactions by high-valent metal-oxo intermediates are important in both biological and synthetic systems. While the HAT reactivity of FeIV-oxo adducts has been extensively investigated, studies of analogous MnIV-oxo systems are less common. There are several recent reports of MnIV-oxo complexes, supported by neutral pentadentate ligands, capable of cleaving strong C-H bonds at rates approaching those of analogous FeIV-oxo species. In this study, we provide a thorough analysis of the HAT reactivity of one of these MnIV-oxo complexes, [MnIV(O)(2pyN2Q)]2+, which is supported by an N5 ligand with equatorial pyridine and quinoline donors. This complex is able to oxidize the strong C-H bonds of cyclohexane with rates exceeding those of FeIV-oxo complexes with similar ligands. In the presence of excess oxidant (iodosobenzene), cyclohexane oxidation by [MnIV(O)(2pyN2Q)]2+ is catalytic, albeit with modest turnover numbers. Because the rate of cyclohexane oxidation by [MnIV(O)(2pyN2Q)]2+ was faster than that predicted by a previously published Bells-Evans-Polanyi correlation, we expanded the scope of this relationship by determining HAT reaction rates for substrates with bond dissociation energies spanning 20 kcal/mol. This extensive analysis showed the expected correlation between reaction rate and the strength of the substrate C-H bond, albeit with a shallow slope. The implications of this result with regard to MnIV-oxo and FeIV-oxo reactivity are discussed.

Genetic Counseling Referral Rates in Long-Term Survivors of Triple-Negative Breast Cancer.

Background: Inherited BRCA gene mutations (pathogenic variants) cause 10% of breast cancers. BRCA pathogenic variants predispose carriers to triple-negative breast cancer (TNBC); around 30% of patients with TNBC carry BRCA pathogenic variants. The 2018 NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian recommend genetic counseling referrals for patients with TNBC diagnosed at age ≤60 years. This study sought to describe genetic counseling referral patterns among long-term TNBC survivors at The University of Texas MD Anderson Cancer Center. Methods: This single-institution retrospective analysis of female long-term (disease-free for ≥5 years) TNBC survivors sought to determine the rate of genetic counseling referral among patients diagnosed at age ≤60 years between 1992 and 2008. Patients who underwent treatment and surveillance visits at our institution and were followed until 2017 were included. We collected BRCA pathogenic variant status among tested patients. Descriptive statistical methods and a univariate analysis were used to identify patient characteristics associated with genetic counseling referral. Results: We identified 646 female long-term TNBC survivors with a median age at diagnosis of 47 years. Of these, 245 (38%) received a recommendation for a genetic counseling referral. Among those referred, 156 (64%) underwent genetic testing, and 35% of those tested had BRCA pathogenic variants. Interestingly, among those referred, 20% declined genetic testing. The rate of genetic referrals improved over time, from 25% among TNBC survivors whose last surveillance visit was between 2011 and 2013 to 100% among those whose last surveillance visit was between 2014 or later. Younger age and premenopausal status at diagnosis and a family history of breast or ovarian cancer were associated with an increased rate of referral for genetic counseling. Conclusions: Among long-term TNBC survivors, the rate of referral to genetic counseling increased over time, and among those tested, 35% carried a BRCA pathogenic variant. Survivorship care provides an excellent opportunity to refer eligible patients for genetic counseling.

Volatility and Chain Length Interplay of Primary Amines: Mechanistic Investigation on the Stability and Reversibility of Ammonia-Responsive Hybrid Perovskites.

Hybrid organic-inorganic perovskites possess promising signal transduction properties, which can be exploited in a variety of sensing applications. Interestingly, the highly polar nature of these materials, while being a bane in terms of stability, can be a boon for sensitivity when they are exposed to polar gases in a controlled atmosphere. However, signal transduction during sensing induces irreversible changes in the chemical and physical structure, which is one of the major lacuna preventing its utility in commercial applications. In the context of developing alkylammonium lead(II) iodide perovskite materials for sensing, here we address major issues such as reversibility of structure and properties, correlation between instability and properties of alkylamines, and relation between packing of alkyl chains inside the crystal lattice and the response time toward NH3 gas. The current investigation highlights that the vapor pressure of alkylamine formed in the presence of NH3 determines the reversibility and stability of the original perovskite lattice. In addition, close packing of alkyl chains inside the perovskite crystal lattice reduces the response toward NH3 gas. The mechanistic study addresses three important factors such as quick response, reversibility, and stability of perovskite materials in the presence of NH3 gas, which could lead to the design of stable and sensitive two-dimensional hybrid perovskite materials for developing sensors.

Determinants of Weight Gain During Adjuvant Endocrine Therapy and Association of Such Weight Gain With Recurrence in Long-term Breast Cancer Survivors.

BACKGROUND: Weight gain is a negative prognostic factor in breast cancer (BC) patients. The risk factors for weight gain during adjuvant endocrine therapy (ET) and the extent to which such weight gain is associated with disease recurrence remain unclear. PATIENTS AND METHODS: We retrospectively identified a cohort of women with a diagnosis of stage I-III, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC from January 1997 to August 2008, who had received initial treatment at the MD Anderson Cancer Center, had completed 5 years of ET, and had remained free of locoregional or distant relapse or contralateral BC for ≥ 5 years after diagnosis. The weight change at the end of 5 years of ET was measured as the percentage of the change in weight from the start of ET, with a weight gain of > 5% considered clinically significant. Multivariable logistic regression and Cox proportional hazards models were used to assess the determinants of such weight gain and the risk of recurrence after 5 years. RESULTS: Of 1282 long-term BC survivors, 432 (33.7%) had a weight gain of > 5% after 5 years of ET. Women who were premenopausal at diagnosis were 1.40 times more likely than women who were postmenopausal at diagnosis to have a weight gain of > 5%. Asian women had the lowest risk of gaining weight. The recurrence risks of patients who had gained weight and those who had not were not significantly different. CONCLUSION: Premenopausal BC patients had an increased risk of weight gain after 5 years of ET; however, BC patients with a weight gain of > 5% did not have an increased risk of disease recurrence.

Larval infestation in a common Pariah Kite Milvus migrans (Boddaert).

This paper describes a case of larval infestation in a common Pariah Kite Milvus migrans (Boddaert). Examination on the larvae revealed that the larvae were of the family Sarcophagidae (Diptera).

Inter-ligand electronic coupling mediated through a dimetal bridge: dependence on metal ions and ancillary ligands.

A series of Mo2, Ru2, Rh2 and Cu2 complexes with redox-active NP-R [2-(2-R)-1,8-naphthyridine; R = pyrazinyl (NP-pz, L1) and thiazolyl (NP-tz, L2)] ligands have been synthesized and characterized by X-ray crystallography and spectroscopic methods. Two NP-R ligands wrap the dimetal core by occupying four equatorial positions and two axial sites. The remaining four equatorial sites are engaged by bridging acetates in quadruply bonded cis-[Mo2(L1)2(OAc)2][BF4]2 (1), cis-[Mo2(L2)2(OAc)2][BF4]2 (1A), doubly bonded cis-[Ru2(L1)2(OAc)2][ClO4]2 (3), cis-[Ru2(L2)2(OAc)2][ClO4]2 (3A) and singly bonded trans-[Rh2(L1)2(OAc)2][BF4]2 (5) and trans-[Rh2(L2)2(OAc)2][BF4]2 (5A). Compounds cis-[Mo2(L1)2(CH3CN)4][BF4]4 (2), cis-[Mo2(L2)2(CH3CN)4][BF4]4 (2A), cis-[Ru2(L1)2(CO)4][OTf]2 (4) and cis-[Ru2(L2)2(CO)4][ClO4]2 (4A) contain acetonitriles or carbonyls as the ancillary ligands. The dicopper complexes trans-[Cu2(CH3CN)(L1)2][ClO4]2 (6) and trans-[Cu2(L2)2(ClO4)2] (6A) involve no bonding interaction between two Cu(i) units. Cyclic voltammogram studies reveal that two one-electron processes corresponding to each of the two ligands bound to the metal-metal bonded dimetal core result in four reversible one-electron reductions, with the exception of dirhodium(ii,ii) compounds 5 and 5A which show two one-electron reductions. The highest comproportionation constant (Kc) values are obtained for inter-valence complexes originating from the diruthenium(ii,ii) compounds 3 and 3A, whereas no electron delocalization is observed for dicopper(i,i) complexes 6 and 6A. The dimetal bridge and the ancillary ligands tune the degree of inter-ligand electronic coupling in these complexes. DFT calculations reveal a π*(NP)-δ*(M2)-π*(NP) orbital conduit for electron delocalization. For diruthenium(ii,ii) compounds 3 and 3A, an additional π*(NP)-π*(M2)-π*(NP) pathway is accessible contributing to high Kc values. The ancillary π-ligands (acetates and carbonyls) reduce the extent of the electron flow through π*(NP)-δ*(M2)-π*(NP) and thus lower the Kc values. The absence of metal-metal bond orbitals and the reduced metal-ligand covalency in dicopper(i,i) compounds are responsible for the lack of electron delocalization in these systems.

Outcomes in patients with early-stage breast cancer who underwent a 21-gene expression assay.

BACKGROUND: Invasive disease-free survival (IDFS) rates are excellent in patients with breast cancer (BC) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), axillary lymph node-negative (LN-) tumors with a 21-gene expression assay recurrence score (RS) of 0 to 10. However, to the authors' knowledge, the outcomes among patients with an RS of 11 to 25 who are treated with endocrine therapy alone are unknown. METHODS: In this retrospective single-institution study, the authors described the characteristics of patients with HR+, HER2-, LN- BC who underwent a 21-gene expression assay. In addition, among those individuals diagnosed between 2005 and 2011, we measured IDFS, recurrence-free survival, distant recurrence-free survival, and overall survival rates, focusing on patients with an RS of 11 to 25 by receipt of chemotherapy. The Kaplan-Meier method was used to estimate survival rates and multivariable Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals (95% CIs). RESULTS: Among 1424 patients, the RS distribution was 0 to 10 in 297 patients (21%), 11 to 25 in 894 patients (63%), and >25 in 233 patients (16%); of these, 1.7%, 15%, and 73.4% of patients, respectively, received chemotherapy. With a median follow-up of 58 months, those patients with an RS of 11 to 25 had an IDFS rate at 5 years of 92.6% (95% CI, 89.6%-94.7%), which was comparable between those who received chemotherapy and those who did not. The hazard ratios of the effect of chemotherapy were 1.64 for IDFS (95% CI, 0.73-3.71), 1.46 for recurrence-free survival (95% CI, 0.41-5.23), 1.25 for distant recurrence-free survival (95% CI, 0.32-4.92), and 2.19 for overall survival (95% CI, 0.44-11.0). CONCLUSIONS: The results of the current study demonstrate similar outcomes with or without chemotherapy in patients with HR+, HER2-, LN- BC who have an RS of 11 to 25, but a benefit from chemotherapy in this group cannot be ruled out. Cancer 2017;123:2422-31. © 2017 American Cancer Society.