Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis.

BACKGROUND: In the primary analysis of the HER2CLIMB trial, tucatinib added to trastuzumab and capecitabine significantly improved overall survival (OS) and progression-free survival (PFS) in patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer. We report efficacy and safety outcomes, including the final OS and safety outcomes from follow-up in HER2CLIMB. PATIENTS AND METHODS: HER2CLIMB is a randomized, double-blind, placebo-controlled trial in patients with locally advanced or metastatic HER2+ breast cancer, including patients with brain metastases. Patients were randomized 2 : 1 to receive tucatinib or placebo, in combination with trastuzumab and capecitabine. After the primary analysis (median follow-up of 14 months), the protocol was amended to allow for unblinding sites to treatment assignment and cross-over from the placebo combination to the tucatinib combination. Protocol prespecified descriptive analyses of OS, PFS (by investigator assessment), and safety were carried out at ∼2 years from the last patient randomized. RESULTS: Six hundred and twelve patients enrolled in the HER2CLIMB trial. At a median OS follow-up of 29.6 months, median duration of OS was 24.7 months for the tucatinib combination group versus 19.2 months for the placebo combination group [hazard ratio (HR) for death: 0.73, 95% confidence interval (CI): 0.59-0.90, P = 0.004] and OS at 2 years was 51% and 40%, respectively. HRs for OS across prespecified subgroups were consistent with the HR for the overall study population. Median duration of PFS was 7.6 months for the tucatinib combination group versus 4.9 months for the placebo combination group (HR for progression or death: 0.57, 95% CI: 0.47-0.70, P < 0.00001) and PFS at 1 year was 29% and 14%, respectively. The tucatinib combination was well tolerated with a low rate of discontinuation due to adverse events. CONCLUSIONS: With additional follow-up, the tucatinib combination provided a clinically meaningful survival benefit for patients with HER2+ metastatic breast cancer.

Beyond Numbers - Recent Understanding of Emotional Needs of Persons Diagnosed with Cancer 2007-2018.

Epidemiology is a vital tool of public health. The usefulness of epidemiology is not only about numbers of persons' ill in the community but also to understand the associations, the presentation, identification of new syndromes, to map the historical trends, and calculate morbid risk. The emotional impact of the diagnosis of cancer is well-recognized. Indian cancer research relating to the psychosocial aspects has been largely limited to counting the numbers with psychiatric syndromes. The review covers 12 years of the Indian research in psycho-oncology to understand the different aspects of epidemiology. During the review period, there are growing number of epidemiological studies (29); psychiatric morbidity ranges from 41.7% to 46%; and prevalence rate ranges from 4.4% to 97.8% for anxiety and 1.2%-89.9% for depression; majority of the studies have used one-stage screening for assessment, which is not the ideal method of identifying mental disorders. The severity of the disorders is presented only in nine studies. Quality of life is the most common associated dimension of the studies. There is the absence of studies of posttraumatic growth, resilience, and spirituality. This review calls for greater rigor in the planning of studies of emotional impact, especially the use of two-stage method, longitudinal studies, studies of different types of cancer and in different stages, include additional measures such as disease burden, coping, resilience, spirituality, and the family/social factors to understand the emotional aspects of living with cancer. There is a need for describing the emotional aspects of living with cancer (lived-in experiences) beyond the clinical syndromes.

Clinicopathological and surgical factors associated with long-term survival in patients with HER2-positive metastatic breast cancer.

Trastuzumab-based treatment has dramatically improved the outcomes of HER2-positive (HER2+) metastatic breast cancer (MBC) patients, with some patients achieving prolonged survival times. In this study, we aim to identify factors that are associated with long-term survival. Patients with HER2+ MBC treated with anti-HER2 target therapy were identified. Patients were grouped according to overall survival (OS) and categorized as long-term survivors (LTS, OS ≥ 5 years), or non-long-term survivors (non-LTS, OS < 5 years). Descriptive statistics and multivariable logistic regression modeling were used. A sensitivity analysis was carried out, including only patients diagnosed before 2007; therefore, 5 years of potential follow-up was possible. 1063 patients with HER2+ MBC diagnosed between 1994 and 2012 and treated with anti-HER2 therapy were identified. Among them, 154 (14.5 %) patients were categorized as LTS (median OS 92.2 months). Among LTS, 63.4 % were HR-positive and 32 % had de novo stage IV disease. Hormone receptor positivity (OR) 1.69; 95 % CI 1.17-2.44), resection of metastases (OR 2.38; 95 % CI 1.53-3.69), and primary breast surgery in patients with de novo stage IV (OR 2.88; 95 % CI 1.47-5.66) were associated with improved long-term survival. Greater number of metastatic sites (≥3 vs. 1, OR 0.41; 95 % CI 0.23-0.72) and visceral metastases (OR 0.61; 95 % CI 0.4-0.91) were associated with poor survival. Hormone receptor positivity, low burden of disease, metastasis to soft and bone tissues, and surgical management with resection of the metastatic site and the primary tumor were associated with long-term survival in patients with MBC who received anti-HER2 treatment.

Spray-dried particles as pulmonary delivery system of anti-tubercular drugs: design, optimization, in vitro and in vivo evaluation.

Currently, one-third of the world's population is infected with tuberculosis (TB) mainly spread by inhalation of the tubercle bacilli, Mycobacterium tuberculosis. Patient non-compliance is the major reason for failure of anti-tubercular drugs (ATDs) chemotherapy due to multidrug administration for longer duration of time period. The main aim of current research study was to develop and characterize inhalable spray-dried particles for pulmonary delivery of ATDs, i.e., rifampicin (RIF) and isoniazid (INH). ATDs-loaded alginate particles were prepared by ionotropic gelation technique followed by spray drying and characterized on the basis of various evaluation parameters. Results showed that the optimized spray-dried particles were found to be spherical in shape with excellent flow properties. The drug release showed the biphasic pattern of release, i.e., initial burst (30-40% up to 4 h) followed by a sustained release pattern (90% up to 60 h). Optimized formulations exhibited lower cytotoxicity and excellent lung uptake up to 8 h. Optimized formulation also showed higher rate and extent of drug uptake by lungs due to preferential phagocytosis be macrophage. In future, alginate particles could be a promising carrier for targeted delivery of ATDs to alveolar macrophages for efficient management of TB.

An analysis of the association between prostate cancer risk loci, PSA levels, disease aggressiveness and disease-specific mortality.

BACKGROUND: Genome-wide association studies have identified multiple single-nucleotide polymorphsims (SNPs) associated with prostate cancer (PCa). Although these SNPs have been clearly associated with disease risk, their relationship with clinical outcomes is less clear. Our aim was to assess the frequency of known PCa susceptibility alleles within a single institution ascertainment and to correlate risk alleles with disease-specific outcomes. METHODS: We genotyped 1354 individuals treated for localised PCa between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to phenotypic data. We investigated associations between 61 SNPs and disease-specific end points using multivariable analysis and also determined if SNPs were associated with PSA at diagnosis. RESULTS: Seven SNPs showed associations on multivariable analysis (P<0.05), rs13385191 with both biochemical recurrence (BR) and castrate metastasis (CM), rs339331 (BR), rs1894292, rs17178655 and rs11067228 (CM), and rs11902236 and rs4857841 PCa-specific mortality. After applying a Bonferroni correction for number of SNPs (P<0.0008), the only persistent significant association was between rs17632542 (KLK3) and PSA levels at diagnosis (P=1.4 × 10(-5)). CONCLUSIONS: We confirmed that rs17632542 in KLK3 is associated with PSA at diagnosis. No significant association was seen between loci and disease-specific end points when accounting for multiple testing. This provides further evidence that known PCa risk SNPs do not predict likelihood of disease progression.

Synthesis and Evaluation of Substituted Poly(organophosphazenes) as a Novel Nanocarrier System for Combined Antimalarial Therapy of Primaquine and Dihydroartemisinin.

PURPOSE: The synthesis and evaluation of novel biodegradable poly(organophosphazenes) (3-6) namely poly[bis-(2-propoxy)]phosphazene (3) poly[bis(4-acetamidophenoxy)]phosphazene (4)poly[bis(4-formylphenoxy)]phosphazene (5) poly[bis(4-ethoxycarbonylanilino)]phosphazene (6) bearing various hydrophilic and hydrophobic side groups for their application as nonocarrier system for antimalarial drug delivery is described. METHODS: The characterization of polymers was carried out by IR, (1)H-NMR and (31)P-NMR. The molecular weights of these novel polyphosphazenes were determined using size exclusion chromatography with a Waters 515 HPLC Pump and a Waters 2414 refractive index detector. The degradation behavior was studied by 200 mg pellets of polymers in phosphate buffers pH 5.5, 6.8 and 7.4 at 37°C. The degradation process was monitored by changes of mass as function of time and surface morphology of polymer pellets. The developed combined drugs nanoparticles formulations were evaluated for antimalarial potential in P. berghei infected mice. RESULTS: These polymers exhibited hydrolytic degradability, which can afford applications to a variety of drug delivery systems. On the basis of these results, the synthesized polymers were employed as nanocarriers for targeted drug delivery of primaquine and dihydroartemisinin. The promising in vitro release of both the drugs from nanoparticles formulations provided an alternative therapeutic combination therapy regimen for the treatment of drug resistant malaria. The nanoparticles formulations tested in resistant strain of P. berghei infected mice showed 100% antimalarial activity. CONCLUSIONS: The developed nanocarrier system provides an alternative combination regimen for the treatment of resistant malaria.

Characterization of the effect of Cr(VI) on humoral innate immunity using Drosophila melanogaster.

With the advancement of human race, different anthropogenic activities have heaped the environment with chemicals that can cause alteration in the immune system of exposed organism. As a first line of barrier, the evolutionary conserved innate immunity is crucial for the health of an organism. However, there is paucity of information regarding in vivo assessment of the effect of environmental chemicals on innate immunity. Therefore, we examined the effect of a widely used environmental chemical, Cr(VI), on humoral innate immune response using Drosophila melanogaster. The adverse effect of Cr(VI) on host humoral response was characterized by decreased gene expression of antimicrobial peptides (AMPs) in the exposed organism. Concurrently, a significantly decreased transcription of humoral pathway receptors (Toll and PGRP) and triglyceride level along with inhibition of antioxidant enzyme activities were observed in exposed organism. This in turn weakened the immune response of exposed organism that was manifested by their reduced resistance against bacterial infection. In addition, overexpression of the components of humoral immunity particularly Diptericin benefits Drosophila from Cr(VI)-induced humoral immune-suppressive effect. To our knowledge, this is the first report regarding negative impact of an environmental chemical on humoral innate immune response of Drosophila along with subsequent protection by AMPs, which may provide novel insight into host-chemical interactions. Also, our data validate the utility and sensitivity of Drosophila as a model that could be used for screening the possible risk of environmental chemicals on innate immunity with minimum ethical concern that can be further extrapolated to higher organisms.

Comparative toxicity of carbaryl, carbofuran, cypermethrin and fenvalerate in Metaphire posthuma and Eisenia fetida -a possible mechanism.

To establish the use of Metaphire posthuma as a sensitive test model for ecotoxicological studies, acute toxicity testing of carbaryl, carbofuran, cypermethrin and fenvalerate on Eisenia fetida and Metaphire posthuma were carried out. Two different types of bioassays, contact filter paper toxicity and soil toxicity bioassays were used to determine LC50 values for these insecticides. Among the tested chemicals, carbofuran was the most toxic to both the earthworm species. In paper contact method, 72 h-LC50 values of carbofuran in M. posthuma and E. fetida were found to be 0.08 µg/cm(2) and 1.55 µg/cm(2) respectively while in soil test, 14-d LC50 values were 0.49 mg/kg and 21.15 mg/kg respectively. On comparing the toxicity data of these chemicals for both the earthworm species, M. posthuma was found to be more sensitive than E. fetida. Based on the acute toxicity data, the order of toxicity of insecticides in both the test procedures was carbofuran>cypermethrin>carbaryl>fenvalerate for M. posthuma whereas for E. fetida it was carbofuran>carbaryl>fenvalerate>cypermethrin. Morphological changes also appeared in the organisms exposed to these chemicals which were more pronounced in M. posthuma at lower concentrations than E. fetida in both the test procedures. The results of the present study advocates the use of M. posthuma for ecotoxicity studies, being a more sensitive and reliable model than E. fetida. Based on the data on partial atomic charges, structural features and spectroscopic studies on carbaryl and carbofuran, a possible mechanism of toxicity of carbamate insecticides in earthworm was proposed.

Formulation and characterization of intranasal mucoadhesive nanoparticulates and thermo-reversible gel of levodopa for brain delivery.

Levodopa is the drug of choice in the treatment of Parkinson's disease but it exhibits low oral bioavailability (30%) and very low brain uptake due to its extensive metabolism by aromatic amino acid decarboxylase in the peripheral circulation. Hence, levodopa is co-administered with carbidopa, a peripheral amino acid decarboxylase inhibitor. In an attempt to improve brain uptake and to avoid degradation of levodopa in peripheral circulation and the use of carbidopa in combination, nose to brain drug delivery of levodopa alone via the olfactory route and the trigeminal nerves has been investigated. Chitosan nanoparticles loaded with levodopa (CNL) were prepared and were incorporated in a thermo-reversible gel prepared using Pluronic PF127 (CNLPgel). The preparation of CNL and CNLPgel was optimized for formulation parameters such as chitosan:TPP ratio, drug load Pluronic concentration to obtain desired particle size of CNL, gelling temperature, gelling time and mucoadhesive strength of CNLPgel. Rheological studies indicated a change in the rheological behavior of plain pluronic gel from Newtonian system at 30 °C to pseudoplastic behavior at 35 °C on incorporation of CNL. In vitro release studies from CNL obeyed Higuchi kinetic model, whereas the drug release from CNLPgel followed the Hixson-Crowell model. In vivo studies indicated a maximum recovery of the drug in brain following intranasal administration of CNL suspension in saline closely followed by the drug dispersed in plain pluronic gel.

ER stress signalling through eIF2α and CHOP, but not IRE1α, attenuates adipogenesis in mice.

AIMS/HYPOTHESIS: Although obesity is associated with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in adipose tissue, it is not known how UPR signalling affects adipogenesis. To test whether signalling through protein kinase RNA-like ER kinase/eukaryotic initiation factor 2 alpha (PERK/eIF2α) or inositol-requiring enzyme 1 alpha/X-box binding protein 1 (IRE1α/XBP1) is required for adipogenesis, we studied the role of UPR signalling in adipocyte differentiation in vitro and in vivo in mice. METHODS: The role of UPR signalling in adipogenesis was investigated using 3T3-L1 cells and primary mouse embryonic fibroblasts (MEFs) by activation or inhibition of PERK-mediated phosphorylation of the eIF2α- and IRE1α-mediated splicing of Xbp1 mRNA. Body weight change, fat mass composition and adipocyte number and size were measured in wild-type and genetically engineered mice fed a control or high-fat diet (HFD). RESULTS: ER stress repressed adipocyte differentiation in 3T3-L1 cells. Impaired eIF2α phosphorylation enhanced adipocyte differentiation in MEFs, as well as in mice. In contrast, increased eIF2α phosphorylation reduced adipocyte differentiation in 3T3-L1 cells. Forced production of CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP), a downstream target of eIF2α phosphorylation, inhibited adipogenesis in 3T3-L1 cells. Mice with deletion of Chop (also known as Ddit3) (Chop (-/-)) gained more fat mass than wild-type mice on HFD. In addition, Chop deletion in genetically obese Lepr (db/db) mice increased body fat mass without altering adipocyte size. In contrast to the eIF2α-CHOP pathway, activation or deletion of Ire1a (also known as Ern1) did not alter adipocyte differentiation in 3T3-L1 cells. CONCLUSIONS/INTERPRETATION: These results demonstrate that eIF2α-CHOP suppresses adipogenesis and limits expansion of fat mass in vivo in mice, rendering this pathway a potential therapeutic target.

Determination of t,t-muconic acid in urine samples using a molecular imprinted polymer combined with simultaneous ethyl chloroformate derivatization and pre-concentration by dispersive liquid-liquid microextraction.

The present communication describes the preparation and evaluation of a molecularly imprinted polymer (MIP) as a solid-phase extraction (SPE) sorbent and simultaneous ethyl chloroformate (ECF) derivatization and pre-concentration by dispersive liquid-liquid microextraction (DLLME) for the analysis of t,t-muconic acid (t,t-MA) in urine samples using gas chromatography-mass spectrometry. The imprinting polymer was prepared using methacrylic acid as a functional monomer, ethylene glycol dimethacrylate as a cross-linker, 2,2-azobisisobutyronitrile as the initiator and t,t-MA as a template molecule. The imprinted polymer was evaluated for its use as a SPE sorbent by comparing both imprinted and non-imprinted polymers in terms of the recovery of t,t-MA from urine samples. Molecular modelling studies were performed in order to estimate the binding energy and efficiency of the MIP complex formed between the monomer and the t,t-MA. Various factors that can affect the extraction efficiency of MIP, such as the loading, washing and eluting conditions, were optimized; other factors that can affect the derivatization and DLLME pre-concentration were also optimized. MIP in combination with ECF derivatization and DLLME pre-concentration for t,t-MA exhibits good linearity, ranging from 0.125 to 2 µg mL(-1) (R(2) = 0.9971), with limit of detection of 0.037 µg mL(-1) and limit of quantification of 0.109 µg mL(-1). Intra- and inter-day precision was found to be <6%. The proposed method has been proven to be effective and sensitive for the selective pre-concentration and determination of t,t-MA in urine samples of cigarette smokers.

Transcriptomic analysis provides insights on hexavalent chromium induced DNA double strand breaks and their possible repair in midgut cells of Drosophila melanogaster larvae.

Hexavalent chromium [Cr(VI)] is a well known mutagen and carcinogen. Since genomic instability due to generation of double strand breaks (DSBs) is causally linked to carcinogenesis, we tested a hypothesis that Cr(VI) causes in vivo generation of DSBs and elicits DNA damage response. We fed repair proficient Drosophila melanogaster (Oregon R(+)) larvae Cr(VI) (20.0µg/ml) mixed food for 24 and 48h and observed a significant (p<0.05) induction of DSBs in their midgut cells after 48h using neutral Comet assay. Global gene expression profiling in Cr(VI)-exposed Oregon R(+) larvae unveiled mis-regulation of DSBs responsive repair genes both after 24 and 48h. In vivo generation of DSBs in exposed Drosophila was confirmed by an increased pH2Av immunostaining along with the activation of cell cycle regulation genes. Analysis of mis-regulated genes grouped under DSB response by GOEAST indicated the participation of non-homologous end joining (NHEJ) DSB repair pathway. We selected two strains, one mutant (ligIV) and another ku80-RNAi (knockdown of ku80), whose functions are essentially linked to NHEJ-DSB repair pathway. As a proof of principle, we compared the DSBs generation in larvae of these two strains with that of repair proficient Oregon R(+). Along with this, DSBs generation in spn-A and okr [essential genes in homologous recombination repair (HR) pathway] mutants was also tested for the possible involvement of HR-DSB repair. A significantly increased DSBs generation in the exposed ku80-RNAi and ligIV (mutant) larvae because of impaired repair, concomitant with an insignificant DSBs generation in okr and spn-A mutant larvae indicates an active participation of NHEJ repair pathway. The study, first of its kind to our knowledge, while providing evidences for in vivo generation of DSBs in Cr(VI) exposed Drosophila larvae, assumes significance for its relevance to higher organisms due to causal link between DSB generation and Cr(VI)-induced carcinogenesis.

Temporal distribution of fine particulates (PM2.5:PM10), potentially toxic metals, PAHs and Metal-bound carcinogenic risk in the population of Lucknow City, India.

Ubiquitous fine particulates can readily be bound to toxic metals and polycyclic aromatic hydrocarbons and are considered to be a great threat to human health. The purpose of this study was to assess the magnitude of air pollution risks to public health by determining four crucial parameters- inhalable particulates, metals in particulates and PAHs which are associated with PM10 in the air environment of Lucknow, India during 2007-09. The values of PM10 and PM2.5 ranged between 102.3-240.5 and 28.0-196.9 µg/m³ whilst the average PM10 was 1.7 times and PM was 1.5 times higher than their respective NAAQS of 100 and 60 µg/m³ respectively. The estimated relative death rate and hospital admissions for each increase in the PM10 levels of 10 µg/m³ ranged from 1.5-8% and from 3.9-8.0% (as per APHEA2 1990) respectively in persons > 65 yrs. Among the locations; AQ, AQ and AQ (with diversified activities and heavy traffic) recorded higher concentrations of both the particulate fractions than the AQ (residential area with low traffic). The average concentrations of Fe, Pb, Ni, Cu, Cr, Cd in PM10 were 219.4, 40.6, 35.1, 27.3, 22.2 and 16.2 ng/m³ and that in PM2.5 were 54.3, 33.9, 38.5, 29.4, 8.4, and 1.17 ng/m³ respectively Regression analysis revealed that correlation of metals with PM2.5 was stronger than PM. The ratio of metals adsorbed on surface of particles (PM2.5:PM10) reveals that PM2.5 has more affinity for Ni, Cu and Pb and PM10 for Cd, Fe and Cr. Health risk due to carcinogenic metals bound to respirable particulates was predicted by estimating excess cancer risk (ECR). The highest ECR value was estimated for Cr, 266.70 × 10⁻6, which was associated with PM10 and 100.92 × 10⁻6 which was associated with PM2.5, whereas lead has the lowest ECR value. Amongst PAHs, benzo(a)pyrene (51.96 ± 19.71 ng/m) was maximum in PM10 samples. Maximum concentrations of PM10, PM2.5, metals and PAHs were detected during winter, and the lowest was during monsoon. The higher prevalence of diseases among the population may be due to high concentration of particulates coated with toxic metals and PAHs present in air environment.

ACR Appropriateness Criteria® Dialysis Fistula Malfunction.

The creation and maintenance of a dialysis access is vital for the reduction of morbidity, mortality, and cost of treatment for end stage renal disease patients. One's longevity on dialysis is directly dependent upon the quality of dialysis. This quality hinges on the integrity and reliability of the access to the patient's vascular system. All methods of dialysis access will eventually result in dialysis dysfunction and failure. Arteriovenous access dysfunction includes 3 distinct classes of events, namely thrombotic flow-related complications or dysfunction, nonthrombotic flow-related complications or dysfunction, and infectious complications. The restoration of any form of arteriovenous access dysfunction may be supported by diagnostic imaging, clinical consultation, percutaneous interventional procedures, surgical management, or a combination of these methods. This document provides a rigorous evaluation of how variants of each form of dysfunction may be appraised and approached systematically. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Studies on urban drinking water quality in a tropical zone.

Anthropogenic activities associated with industrialization, agriculture and urbanization have led to the deterioration in water quality due to various contaminants. To assess the status of urban drinking water quality, samples were collected from the piped supplies as well as groundwater sources from different localities of residential, commercial and industrial areas of Lucknow City in a tropical zone of India during pre-monsoon for estimation of coliform and faecal coliform bacteria, organochlorine pesticides (OCPs) and heavy metals. Bacterial contamination was found to be more in the samples from commercial areas than residential and industrial areas. OCPs like α,γ-hexachlorocyclohexane and 1,1 p,p-DDE {dichloro-2, 2-bis(p-chlorophenyl) ethene)} were found to be present in most of the samples from study area. The total organochlorine pesticide levels were found to be within the European Union limit (0.5 µg/L) in most of the samples. Most of the heavy metals estimated in the samples were also found to be within the permissible limits as prescribed by World Health Organization for drinking water. Thus, these observations show that contamination of drinking water in urban areas may be mainly due to municipal, industrial and agricultural activities along with improper disposal of solid waste. This is an alarm to safety of public health and aquatic environment in tropics.

ACR Appropriateness Criteria® Management of Liver Cancer: 2022 Update.

The treatment and management of hepatic malignancies can be complex because it encompasses a variety of primary and metastatic malignancies and an assortment of local and systemic treatment options. When to use each of these treatments is critical to ensure the most appropriate care for patients. Interventional radiologists have a key role to play in the delivery of a variety of liver directed treatments including percutaneous ablation, transarterial embolization with bland embolic particles alone, transarterial chemoembolization (TACE) with injection of a chemotherapeutic emulsion, and transarterial radioembolization (TARE). Based on 9 clinical variants, the appropriateness of each treatment is described in this document. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Improved diagnostic accuracy of breast MRI through combined apparent diffusion coefficients and dynamic contrast-enhanced kinetics.

This study investigated the relationship between apparent diffusion coefficient (ADC) measures and dynamic contrast-enhanced magnetic resonance imaging (MRI) kinetics in breast lesions and evaluated the relative diagnostic value of each quantitative parameter. Seventy-seven women with 100 breast lesions (27 malignant and 73 benign) underwent both dynamic contrast-enhanced MRI and diffusion weighted MRI. Dynamic contrast-enhanced MRI kinetic parameters included peak initial enhancement, predominant delayed kinetic curve type (persistent, plateau, or washout), and worst delayed kinetic curve type (washout > plateau > persistent). Associations between ADC and dynamic contrast-enhanced MRI kinetic parameters and predictions of malignancy were evaluated. Results showed that ADC was significantly associated with predominant curve type (ADC was higher for lesions exhibiting predominantly persistent enhancement compared with those exhibiting predominantly washout or plateau, P = 0.006), but was not significantly associated with peak initial enhancement or worst curve type (P > 0.05). Univariate analysis showed significant differences between benign and malignant lesions in both ADC (P < 0.001) and worst curve (P = 0.003). In multivariate analysis, worst curve type and ADC were significant independent predictors of benign versus malignant outcome and in combination produced the highest area under the receiver operating characteristic curve (0.85 and 0.78 with 5-fold cross validation).

Application of ethyl chloroformate derivatization for solid-phase microextraction-gas chromatography-mass spectrometric determination of bisphenol-A in water and milk samples.

A simple and rapid analytical method based on in-matrix ethyl chloroformate (ECF) derivatization has been developed for the quantitative determination of bisphenol-A (BPA) in milk and water samples. The samples containing BPA were derivatised with ECF in the presence of pyridine for 20 s at room temperature, and the non-polar derivative thus formed was extracted using polydimethylsiloxane solid-phase microextraction (SPME) fibres with thicknesses of 100 µm followed by analysis using gas chromatography-mass spectrometry. Three alkyl chloroformates (methyl, ethyl and isobutyl chloroformate) were tested for optimum derivatisation yields, and ECF has been found to be optimum for the derivatisation of BPA. Several parameters such as amount of ECF, pyridine and reaction time as well as SPME parameters were studied and optimised in the present work. The limit of detection for BPA in milk and water samples was found to be 0.1 and 0.01 µg L(-1), respectively, with a signal-to-noise ratio of 3:1. The limit of quantitation for BPA in milk and water was found to be 0.38 and 0.052 µg L(-1), respectively, with a signal-to-noise ratio of 10:1. In conclusion, the method developed was found to be rapid, reliable and cost-effective in comparison to silylation and highly suitable for the routine analysis of BPA by various food and environmental laboratories.