Relationship of cell proliferation (Ki-67) to (99m)Tc-(V)DMSA uptake in breast cancer

INTRODUCTION: The aim of the present study was to identify the relationships between the uptake of radiotracers – namely pentavalent dimercaptosuccinic acid [(V)DMSA] and sestamibi (MIBI) – and the following parameters in primary breast cancer: steroid receptor concentrations (i.e. estrogen receptor [ER] and progesterone receptor [PR]), Ki-67 expression, tumor size, tumor grade, age, and levels of expression of p53 and c-erbB-2. In addition, by multivariate regression analysis, we further isolated those factors with independent associations with (V)DMSA and/or MIBI uptake in primary breast cancer. METHODS: Thirty-four patients with histologically confirmed breast carcinoma underwent preoperative scintimammography with technetium-99m ((99m)Tc)-(V)DMSA and/or (99m)Tc-MIBI in consecutive sessions 10 and 60 min after administration of 925–1110 MBq of each radiotracer. The tumor-to-background ratio was calculated and correlated with the presence of ER, PR, Ki-67, tumor size, tumor grade, p53, and c-erbB-2. ER, PR, p53, and c-erbB-2 were determined immunohistochemically. The analysis included tumor-to-background ratio of (V)DMSA and MIBI uptake as dependent and all of the other parameters as independent variables. RESULTS: Correlation was positive between Ki-67 and (V)DMSA (r = 0.37 at 10 min, P = 0.038; r = 0.42 at 60 min, P = 0.018) and inverse between PR and (V)DMSA uptake (r = -0.46 at 10 min, P = 0.010; r = -0.51 at 60 min, P = 0.003). Multivariate regression analysis demonstrated a positive correlation between Ki-67 and (V)DMSA at 60 min (P = 0.045). Ki-67 was not significantly correlated with MIBI uptake, whereas tumor size was positively correlated with MIBI uptake at 60 min both in univariate (r = 0.45, P = 0.027) and multivariate analysis (P = 0.024). Negative correlations were observed between (V)DMSA uptake and ER, as well as between ER/PR and MIBI uptake, but these were not significant. CONCLUSION: Ki-67 appears to represent the major independent factor affecting (V)DMSA uptake in breast cancer. Tumor size was the only independent parameter influencing MIBI uptake in breast cancer. (V)DMSA appears to have an advantage over MIBI in that it can be used to visualize tumors with intense proliferative activity, and thus it can identify those tumors that are more aggressive

Reduced uptake of the proliferation-seeking radiotracer technetium-99m-labelled pentavalent dimercaptosuccinic acid in a 47-year-old woman with severe breast epithelial hyperplasia taking ibuprofen: a case report

<p>Abstract</p> <p>Introduction</p> <p>Recent studies have reported a risk reduction in the progression of benign breast disease to breast carcinoma through COX-2 pathways.</p> <p>Case presentation</p> <p>We present a case of severe epithelial hyperplasia in a 47-year-old woman with increased breast density submitted to scintimammography by the proliferation-imaging tracer Technetium-99m-labelled pentavalent dimercaptosuccinic acid, before and after an oral ibuprofen treatment for 4 weeks. The radiotracer uptake after ibuprofen intake was significantly reduced, both visually and by semi-quantitative analysis, based on a calculation of lesion-to-background ratios.</p> <p>Conclusion</p> <p>In proliferating breast lesions, scintigraphically displayed reduction in Technetium-99m-labelled pentavalent dimercaptosuccinic acid uptake may indicate inhibition by ibuprofen in the pathway of malignant epithelial cell transformation.</p

Imaging in situ breast carcinoma (with or without an invasive component) with technetium-99m pentavalent dimercaptosuccinic acid and technetium-99m 2-methoxy isobutyl isonitrile scintimammography

INTRODUCTION: The aim of the study was to retrospectively define specific features of the technetium-99m pentavalent dimercaptosuccinic acid ((99m)Tc-(V)DMSA) and technetium-99m 2-methoxy isobutyl isonitrile ((99m)Tc-Sestamibi [(99m)Tc-MIBI]) distribution in ductal breast carcinoma in situ and lobular breast carcinoma in situ (DCIS/LCIS), in relation to mammographic, histological and immunohistochemical parameters. MATERIALS AND METHODS: One hundred and two patients with suspicious palpation or mammographic findings were submitted preoperatively to scintimammography (a total of 72 patients with (99m)Tc-(V)DMSA and a total of 75 patients with (99m)Tc-Sestamibi, 45 patients receiving both radiotracers). Images were acquired at 10 min and 60 min, and were evaluated for a pattern of diffuse radiotracer accumulation. The tumor-to-background ratios were correlated (T-pair test) with mammographic, histological and immunohistochemical characteristics. RESULTS: Histology confirmed malignancy in 46/102 patients: 20/46 patients had DCIS/LCIS, with or without coexistent invasive lesions, and 26/46 patients had isolated invasive carcinomas. Diffuse (99m)Tc-(V)DMSA accumulation was noticed in 18/19 cases and (99m)Tc-Sestamibi in 6/13 DCIS/LCIS cases. Epithelial hyperplasia demonstrated a similar accumulation pattern. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value for each tracer were calculated. Solely for (99m)Tc-(V)DMSA, the tumor-to-background ratio was significantly higher at 60 min than at 10 min and the diffuse uptake was significantly associated with suspicious microcalcifications, with the cell proliferation index ≥ 40% and with c-erbB-2 ≥ 10%. CONCLUSION: (99m)Tc-(V)DMSA showed high sensitivity and (99m)Tc-Sestamibi showed high specificity in detecting in situ breast carcinoma ((99m)Tc-(V)DMSA especially in cases with increased cell proliferation), and these radiotracers could provide clinicians with preoperative information not always obtainable by mammography

Rapid scale-up of COVID-19 training for frontline health workers in 11 African countries

Background The global spread of the SARS-CoV-2 virus highlights both the importance of frontline healthcare workers (HCW) in pandemic response and their heightened vulnerability during infectious disease outbreaks. Adequate preparation, including the development of human resources for health (HRH) is essential to an effective response. ICAP at Columbia University (ICAP) partnered with Resolve to Save Lives and MOHs to design an emergency training initiative for frontline HCW in 11 African countries, using a competency-based backward-design approach and tailoring training delivery and health facility selection based on country context, location and known COVID-19 community transmission. Methods Pre- and post-test assessments were conducted on participants completing the COVID-19 training. Parametric and non-parametric methods were used to examine average individual-level changes from pre- to post-test, and compare performance between countries, cadres, sex and facility types. A post-evaluation online training survey using Qualtrics was distributed to assess participants’ satisfaction and explore training relevance and impact on their ability to address COVID-19 in their facilities and communities. Results A total of 8797 HCW at 945 health facilities were trained between June 2020 and October 2020. Training duration ranged from 1 to 8 days (median: 3 days) and consisted of in person, virtual or self guided training. Of the 8105 (92%) HCW working at health facilities, the majority (62%) worked at secondary level facilities as these were the HF targeted for COVID-19 patients. Paired pre- and post-test results were available for 2370 (25%) trainees, and 1768 (18%) participants completed the post-evaluation training survey. On average, participants increased their pre- to post-test scores by 15 percentage points (95% CI 0.14, 0.15). While confidence in their ability to manage COVID-19 was high following the training, respondents reported that lack of access to testing kits (55%) and PPE (50%), limited space in the facility to isolate patients (45%), and understaffing (39%) were major barriers. Conclusion Ongoing investment in health systems and focused attention to health workforce capacity building is critical to outbreak response. Successful implementation of an emergency response training such as this short-term IPC training initiative in response to the COVID-19 pandemic, requires speed, rigor and flexibility of its design and delivery while building on pre-existing systems, resources, and partnerships

The Impact of HIV Infection and CD4 Cell Count on the Performance of an Interferon Gamma Release Assay in Patients with Pulmonary Tuberculosis

BACKGROUND:The performance of the tuberculosis specific Interferon Gamma Release Assays (IGRAs) has not been sufficiently documented in tuberculosis- and HIV-endemic settings. This study evaluated the sensitivity of the QuantiFERON TB-Gold In-Tube (QFT-IT) in patients with culture confirmed pulmonary tuberculosis (PTB) in a TB- and HIV-endemic population and the effect of HIV-infection and CD4 cell count on test performance. METHODOLOGY/PRINCIPAL FINDINGS:161 patients with sputum culture confirmed PTB were subjected to HIV- and QFT-IT testing and measurement of CD4 cell count. The QFT-IT was positive in 74% (119/161; 95% CI: 67-81%). Sensitivity was higher in HIV-negative (75/93) than in HIV-positive (44/68) patients (81% vs. 65%, p = 0.02) and increased with CD4 cell count in HIV-positive patients (test for trend p = 0.03). 23 patients (14%) had an indeterminate result and this proportion decreased with increasing CD4 cell count in HIV-positive patients (test for trend p = 0.03). Low CD4 cell count (<300 cells/microl) did not account for all QFT-IT indeterminate nor all negative results. Sensitivity when excluding indeterminate results was 86% (95% CI: 81-92%) and did not differ between HIV-negative and HIV-positive patients (88 vs. 83%, p = 0.39). CONCLUSIONS/SIGNIFICANCE:Sensitivity of the QFT-IT for diagnosing active PTB infection was reasonable when excluding indeterminate results and in HIV-negative patients. However, since the test missed more than 10% of patients, its potential as a rule-out test for active TB disease is limited. Furthermore, test performance is impaired by low CD4 cell count in HIV-positive patients and possibly by other factors as well in both HIV-positive and HIV-negative patients. This might limit the potential of the test in populations where HIV-infection is prevalent

Mavoglurant in Fragile X Syndrome:Results of two open-label, extension trials in adults and adolescents

Fragile X syndrome (FXS) is the most common monogenic cause of inherited intellectual and developmental disabilities. Mavoglurant, a selective metabotropic glutamate receptor subtype-5 antagonist, has shown positive neuronal and behavioral effects in preclinical studies, but failed to demonstrate any behavioral benefits in two 12-week, randomized, placebo-controlled, double-blind, phase IIb studies in adults and adolescents with FXS. Here we report the long-term safety (primary endpoint) and efficacy (secondary endpoint) results of the open-label extensions. Adolescent (n = 119, aged 12-19 years) and adult (n = 148, aged 18-45 years) participants received up to 100 mg bid mavoglurant for up to 34 months. Both extension studies were terminated prematurely due to lack of proven efficacy in the core studies. Mavoglurant was well tolerated with no new safety signal. Five percent of adults and 16.9 percent of adolescents discontinued treatment due to adverse events. Gradual and consistent behavioral improvements as measured by the ABC-C &lt;sub&gt;FX&lt;/sub&gt; scale were observed, which were numerically superior to those seen in the placebo arm of the core studies. These two extension studies confirm the long-term safety of mavoglurant in FXS, but further investigations are required to determine whether and under which conditions the significant preclinical results obtained with mGluR5 inhibition can translate to humans

Multiple ecosystem services from field margin vegetation for ecological sustainability in agriculture: scientific evidence and knowledge gaps

Background: Field margin and non-crop vegetation in agricultural systems are potential ecosystem services providers because they offer semi-natural habitats for both below and above ground animal groups such as soil organisms, small mammals, birds and arthropods that are service supplying units. They are considered as a target area for enhancing farm biodiversity. Methodology: To explore the multiple potential benefits of these semi-natural habitats and to identify research trends and knowledge gaps globally, a review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 235 publications from the year 2000 to 2016 in the Scopus and Web of Science databases were reviewed. Results: The literature showed an increasing trend in the number of published articles over time with European studies leading in the proportion of studies conducted, followed by North America, Asia, South America, Africa and Australia. Several functional groups of organisms were studied from field margin and non-crop vegetation around agricultural lands including natural enemies (37%), insect pests (22%), birds (17%), pollinators (16%), soil macro fauna (4%) and small mammals (4%). Ecosystem services derived from the field margin included natural pest regulation, pollination, nutrient cycling and reduced offsite erosion. Some field margin plants were reported to host detrimental crop pests, a major ecosystem dis-service, potentially leading to increased pest infestation in the field. Conclusion: The majority of studies revealed the importance of field margin and non-crop vegetation around arable fields in enhancing ecosystem biodiversity. Promotion of field margin plants that selectively enhance the population of beneficial organisms would support sustainable food security rather than simply boosting plant diversity. Our analyses also highlight that agro-ecological studies remain largely overlooked in some regions

Spectroscopy and dynamics of complexes of the hydroxyl radical with methane and nitrogen

The CH4 + OH → CH3 + H2O reaction coordinate has been probed by stabilizing complexes of CH4 and OH reactants in a shallow well in the entrance channel to the hydrogen abstraction reaction. These entrance channel complexes have been activated via the OH fundamental and overtone stretching transitions (νOH, 2ν OH) as well as the symmetric and asymmetric stretching modes of CH 4 (ν1, ν3) using infrared and/or stimulated Raman excitation. Vibrational excitation provides enough energy to surmount the relatively low barrier to reaction or, alternatively, to break the weak intermolecular bond, thereby initiating reactive and/or inelastic scattering processes between the CH4 and OH partners within the CH4-OH. The complexes were first identified via electronic spectroscopy in the OH A 2Σ+-X 2Π (1,0) and (0,0) regions. A cut off in laser-induced fluorescence above the OH A 2Σ+ (v ′ = 1) + CH4 asymptote as well as an onset of fluorescence above the OH A 2Σ+ (v ′ = 0) + CH4 asymptote permitted determination of the ground state binding energy. An IR-UV double resonance technique was utilized to obtain rotationally resolved infrared spectra of CH4 OH in the OH fundamental and overtone stretching regions as well as infrared spectra of the CH4-OD isotopomer in the OD overtone region. Pure OH stretching bands along with combination bands involving the simultaneous excitation of OH stretch and intermolecular bending motion were identified. The infrared spectra of CH4-OH in the pure OH stretching regions are consistent with a C3v geometry where the OH radical lies along the intermolecular axis and points toward CH4. This orientation is in accord with electronic structure calculations performed by Lendvay. The pure OD overtone spectrum of CH4-OD is analogous to that of CH4-OH. Homogeneous lifetime broadening of spectral features indicates rapid decay via vibrational predissociation and/or chemical reaction. The infrared spectrum of CH4-OD exhibits less extensive homogeneous lifetime broadening. Vibrational spectra of CH4-OH in the CH4 stretching regions indicate that the CH4 partner undergoes nearly free internal rotation within the complex. Stimulated Raman excitation of OH in the ν 1 symmetric stretching region reveals two blended Q-branch features attributed to different nuclear spin states of CH4. Infrared excitation in the ν3 asymmetric stretching region results in an enormously broad spectrum that extends 40 cm−1. CH4-OH undergoes a multitude of allowed transitions in this region associated with the rovibrational transitions of CH4. The ν1 and ν 3 spectra exhibit extensive homogeneous broadening due to rapid decay via vibrational predissociation and/or chemical reaction. A rotationally resolved infrared spectrum of OD-N2 has been observed in the OD overtone region. The pure OD overtone band of OD-N 2 as well as combination bands involving simultaneous OD stretch and intermolecular geared bending excitation were characterized. Direct time-resolved measurements yield a 150 ± 16 ns lifetime for OD-N2 upon OD overtone excitation. A decrease in lifetime was observed upon excitation of the lower energy geared bending state. The OD (v = 1) fragments from vibrational predissociation of OD-N2 are produced with high rotational excitation in accord with a vibrational to rotational and/or translational energy transfer mechanism

ELECTRONIC EXCITATION SPECTROSCOPY OF THE OH-CO REACTANT COMPLEX

Author Institution: University of Pennsylvania; Department of Chemistry, University of PennsylvaniaThe electronic excitation spectrum of the OH-CO reactant complex in the OH A-X (1,0) spectral region has been investigated using a fluorescence depletion technique. This technique combines infrared overtone excitation of OH-CO at $1.4 \mu m$ with ultraviolet excitation of OH-CO between 275 and 300 nm, which induces a fluorescence signal. When the IR and UV transitions originate from a common ground state, the IR excitation reduces the ground state population and causes a depletion in the UV laser induced fluorescence signal. Scanning only the IR laser yields a rotationally resolved infrared spectrum of the pure OH overtone band of OH-CO at $6941.8 cm^{-1}$, while tuning only the UV laser results in a broad and relatively unstructured electronic spectrum for OH-CO spanning from 33500 to $36000 cm^{-1}$. The electronic spectrum peaks around $34600 cm^{-1}$ and exhibits a secondary shoulder near $35300 cm^{-1}$. The breadth and position of the electronic spectrum reflect the Franck-Condon window on the $OH A^{2}\Sigma^{+} (v^{\prime} = 1) + CO$ excited state potential. The lack of observable structure in the electronic spectrum is attributed to extensive homogeneous line broadening, most likely arising from rapid electronic quenching of OH $A^{2}\Sigma^{+}$ by the CO partner. The electronic excitation spectrum observed for the OH-CO will also be compared with analogous spectra obtained for complexes of OH with other partners