The accuracy of breast MRI radiomic methodologies in predicting pathological complete response to neoadjuvant chemotherapy: A systematic review and network meta-analysis.

BACKGROUND: Achieving pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) improves survival outcomes for breast cancer patients. Currently, conventional histopathological biomarkers predicting such responses are inconsistent. Studies investigating radiomic texture analysis from breast magnetic resonance imaging (MRI) to predict pCR have varied radiomic protocols introducing heterogeneity between results. Thus, the efficacy of radiomic profiles compared to conventional strategies to predict pCR are inconclusive. PURPOSE: Comparing the predictive accuracy of different breast MRI radiomic protocols to identify the optimal strategy in predicting pCR to NAC. MATERIAL AND METHODS: A systematic review and network meta-analysis was performed according to PRISMA guidelines. Four databases were searched up to October 4th, 2021. Nine predictive strategies were compared, including conventional biomarker parameters, MRI radiomic analysis conducted before, during, or after NAC, combination strategies and nomographic methodology. RESULTS: 14 studies included radiomic data from 2,722 breast cancers, of which 994 were used in validation cohorts. All MRI derived radiomic features improved predictive accuracy when compared to biomarkers, except for pre-NAC MRI radiomics (odds ratio [OR]: 0.00; 95 % CI: -0.07-0.08). During-NAC and post-NAC MRI improved predictive accuracy compared to Pre-NAC MRI (OR: 0.14, 95 % CI: 0.02-0.26) and (OR: 0.26, 95 % CI: 0.07-0.45) respectively. Combining multiple MRIs did not improve predictive performance compared to Mid- or Post-NAC MRIs individually. CONCLUSION: Radiomic analysis of breast MRIs improve identification of patients likely to achieve a pCR to NAC. Post-NAC MRI are the most accurate imaging method to extrapolate radiomic data to predict pCR.

Optimal reconstructive strategies in the setting of post-mastectomy radiotherapy - A systematic review and network meta-analysis.

BACKGROUND: A third of breast cancer patients require mastectomy. In some high-risk cases postmastectomy radiotherapy (PMRT) is indicated, threatening reconstructive complications. Several PMRT and reconstruction combinations are used. Autologous flap (AF) reconstruction may be immediate (AF→PMRT), delayed-immediate with tissue expander (TE [TE→PMRT→AF]) or delayed (PMRT→AF). Implant-based breast reconstruction (IBBR) includes immediate TE followed by PMRT and conversion to permanent implant (PI [TE→PMRT→PI]), delayed TE insertion (PMRT→TE→PI), and prosthetic implant conversion prior to PMRT (TE→PI→PMRT). AIM: Perform a network metanalysis (NMA) assessing optimal sequencing of PMRT and reconstructive type. METHODS: A systematic review and NMA was performed according to PRISMA-NMA guidelines. NMA was conducted using R packages netmeta and Shiny. RESULTS: 16 studies from 4182 identified, involving 2322 reconstructions over three decades, met predefined inclusion criteria. Studies demonstrated moderate heterogeneity. Multiple comparisons combining direct and indirect evidence established AF-PMRT as the optimal approach to avoid reconstructive failure, compared with IBBR strategies (versus PMRT→TE→PI; OR [odds ratio] 0.10, CrI [95% credible interval] 0.02 to 0.55; versus TE→PMRT→PI; OR 0.13, CrI 0.02 to 0.75; versus TE→PI→PMRT OR 0.24, CrI 0.05 to 1.05). PMRT→AF best avoided infection, demonstrating significant improvement versus PMRT→TE→PI alone (OR 0.12, CrI 0.02 to 0.88). Subgroup analysis of IBBR found TE→PI→PMRT reduced failure rates (OR 0.35, CrI 0.15-0.81) compared to other IBBR strategies but increased capsular contracture. CONCLUSION: Immediate AF reconstruction is associated with reduced failure in the setting of PMRT. However, optimal reconstructive strategy depends on patient, surgeon and institutional factors. If IBBR is chosen, complication rates decrease if performed prior to PMRT. PROSPERO REGISTRATION: CRD 42020157077.

Health-related quality of life measured by the UW-QoL--reference values from a general dental practice.

The objective of this study was to obtain age and sex-specific reference values for the University of Washington head and neck cancer questionnaire version 4 (UW-QoLv4) and to compare this with patients with oral and oropharyngeal cancer. Cross-sectional reference data was collected from 372 patients in six local general dental practices, 349 of whom presented for routine appointments. Quota sampling was used to collect data for similar numbers of patients by gender by four age bands (40-49, 50-59, 60-69, 70-79 yr). The longitudinal sample consisted of 450 consecutive patients undergoing primary surgery for previously untreated oral and oropharyngeal squamous cell carcinoma presenting to the Regional Maxillofacial Unit Liverpool, between the years 1995 and 2002. At baseline the key differences were anxiety, pain, swallowing, chewing, and mood. At 1yr there were big differences in all domains with deterioration in the oral cancer group. The difference was least notable in pain, shoulder, mood and anxiety. Reference data from a non-cancer population is very important when considering UW-QoL domains as an outcome parameter in clinical trials and also when discussing health-related quality of life outcomes with patients and their families.

Long-term effects of BIBN-99, a selective muscarinic M2 receptor antagonist, on improving spatial memory performance in aged cognitively impaired rats.

Aged Long-Evans rats were screened for spatial memory deficits using the Morris water maze task. Rats found to have impaired performance on the task (aged-impaired, AI) were then treated with a selective muscarinic M2 receptor antagonist, 5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxopentyl)ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (BIBN-99; 0.5 mg/kg, s.c.), for 3 successive days while receiving additional water maze training. BIBN-99 significantly improved performance in the task during the 3 days of drug treatment. Treatment was then ceased for the remainder of the study and rats were tested again in the water maze on days 10, 17, and 24. Compared to vehicle-treated rats, enhanced performance was observed in the AI rats that had previously been treated with BIBN-99. These results indicate that BIBN-99 enhances spatial learning in AI animals and that enhanced (or long-term) memory persists in the absence of the drug. In a second experiment, a 2-month delay was imposed in between the original water maze screening and the drug treatment regime. Again, BIBN-99 significantly improved performance in AI rats. This latter study suggests that reference memory does not decay, even in an AI animal that had displayed poor learning following original water maze screening. Together, these studies help provide further insight into possible mechanism(s) of reference memory and its potential clinical usefulness.

Assessing adult ADHD using a self-report symptom checklist.

The self-ratings of DSM-IV ADHD symptoms by adults reporting a previous ADHD diagnosis were contrasted with ratings by controls matched for age and sex. Adults previously diagnosed with ADHD endorsed significantly more symptoms of inattention and of hyperactivity-impulsivity. Specifically, 13 of the 18 DSM-IV ADHD symptoms were endorsed more frequently by the group previously diagnosed with ADHD than by the control group. Predictive power analysis showed that persons endorsing ADHD symptoms were highly likely to have reported a prior ADHD diagnosis. Finally, the data suggested that the DSM-IV diagnostic criteria of 6 symptoms of inattention or 6 symptoms of hyperactivity-impulsivity could be appropriately applied during adult ADHD assessment.

(R)-, (S)-, and racemic fluoxetine N-demethylation by human cytochrome P450 enzymes.

Fluoxetine is one of the most widely prescribed selective serotonin reuptake inhibitors (SSRIs) that is marketed worldwide. However, details of its human hepatic metabolism have been speculative and incomplete, possibly due to the sensitivity of analytical techniques and selectivity of specific in vitro probes and reagents used. Studies with (R)-, (S)-, and racemic fluoxetine were undertaken to determine the stereospecific nature of its metabolism and estimate intrinsic clearance contributions of each CYP for fluoxetine N-demethylation. Measurable fluoxetine N-demethylase activity was catalyzed by CYP1A2, -2B6, -2C9, -2C19, -2D6, -3A4, and -3A5. All enzymes catalyzed this reaction for both enantiomers and the racemate, and intrinsic clearance values were similar for the enantiomers for all CYP enzymes except CYP2C9, which demonstrated stereoselectivity for R- over the S-enantiomer. Scaling the intrinsic clearance values for the individual CYP enzymes to estimate contributions of each in human liver microsomes suggested that CYP2D6, CYP2C9, and CYP3A4 contribute the greatest amount of fluoxetine N-demethylation in human liver microsomes. These data were corroborated with the examination of the effects of CYP-specific inhibitors quinidine (CYP2D6), sulfaphenazole (CYP2C9), and ketoconazole (CYP3A4) on fluoxetine N-demethylation in pooled human liver microsomes. Together, these findings suggest a significant role for the polymorphically expressed CYP2D6 in fluoxetine clearance and are consistent with reports on the clinical pharmacokinetics of fluoxetine.

Metabolism of CP-195,543, a leukotriene B4 receptor antagonist, in the Long-Evans rat and Cynomolgus monkey.

1. The fate of [14C]CP-195,543, a novel leukotriene B4 receptor antagonist, was studied following oral administration to the Long-Evans rat and Cynomolgus monkey. 2. Most of the radioactivity was primarily excreted in the faeces, and urine was a minor route of excretion. 3. CP-195,543 was extensively metabolized in the two species, primarily by two metabolic pathways: glucuronidation of unchanged CP-195,543 and oxidative metabolism, presumably by cytochrome P450. 4. The sites of glucuronidation were the carboxylic acid moiety and the hydroxy group. The ester glucuronide was the predominant glucuronide conjugate detected in the rat, whereas the monkey generated the ether as well as the ester glucuronide. 5. The structures of oxidative metabolites were elucidated using mass spectrometry (in the positive- and negative-ion mode) and 1H-NMR. The sites of hydroxylation were the benzylic group and the 3-position of the benzopyran ring. 6. This study has indicated that CP-195,543 was mainly eliminated by Phase II metabolism in both species.

Characterization of polar urinary metabolites by ionspray tandem mass spectrometry following dansylation.

The present report illustrates the application of dansyl chloride coupled with ion spray tandem mass spectrometry (IS-MS/MS) in identifying polar urinary metabolites. In the course of the metabolism studies of a drug that is currently in development, the urine from rats and dogs was collected following oral administration of radiolabelled compound. Urinary metabolic profiles of the rat and dog indicated the presence of four major peaks and one major peak, respectively, in the radiochromatogram. Since all attempts to identify the peaks by conventional MS/MS techniques failed, the metabolites were isolated by fraction collection and dansylated. Derivatization of the metabolites resulted in the formation of more hydrophobic, readily ionizable species which were more sensitive in IS-MS/MS analysis than the underivatized metabolites. Examination of the molecular ions and the product ion mass spectra of these derivatives revealed the structures of all the urinary metabolites. The metabolites in the rat and the dog were 4-hydroxyphenylpiperazine glucuronide (M1), 1,4-dihydroxyphenyl glucuronide (M2), 1,4-dihydroxyphenyl sulfate (M3) and phenylpiperazine (M4). Thus, derivatization with dansyl chloride in conjunction with tandem mass spectrometry is a useful tool in identifying polar urinary metabolites.

Metabolism of droloxifene in the CD-1 mouse, Fischer-344 rat and cynomolgus monkey.

1. The fate of [14C]droloxifene, a novel non-steroidal anti-oestrogen, was studied following oral administration to the CD-1 mouse, F-344 rat and Cynomolgus monkey. 2. Most of the radioactivity was primarily excreted in the faeces and urine was the minor route of excretion. 3. Droloxifene was extensively metabolized in all three species, primarily by two metabolic pathways; glucuronidation of unchanged droloxifene and oxidative metabolism, presumably by cytochrome P450. 4. In mouse, oxidative metabolism followed by conjugation played a significant role in the elimination of droloxifene. An unusual diglucuronide of 4-hydroxydroloxifene was also identified in this species. 5. In rat, glucuronidation and oxidative metabolism were significant, whereas in monkey glucuronidation of droloxifene was the predominant pathway of elimination.

Health plans and state tort liability.

In 1997, Texas enacted legislation expanding state tort liability to health plans. The following article discusses major provisions of the Texas health plan liability law, as well as a recent lawsuit asserting that the statute is preempted by the Employee Retirement Income Security Act and the Federal Employees Health Benefits Act.

Managed care organizations' arrangements with nurse practitioners: a Connecticut perspective.

Executives in more than 50% of managed care organizations (MCOs) in New York and Connecticut were interviewed for information on the roles, participation, and listing of NPs as primary care providers. MCO executives are highly satisfied with their primary care provider NPs, particularly in women's health and geriatrics, secondary to spending more time teaching and explaining procedures than physicians. Among both health care professionals and the general public there is an overall lack of current knowledge and/or confusion about NPs and their practice. Eighty-two percent of executives in MCOs thought their organization should encourage the use of NPs as primary care providers. Beginning in the early 1960s, advanced practice nursing has shown steady growth. Research has found that NPs provide cost-effective, quality-driven patient care (Brown & Grimes, 1995; Cohen & Juszczak, 1997; Frampton & Wall, 1994; Hardy & Evans, 1995). Many thought health care reform would lead to an expansion of advanced practice nurses (APNs) and other nonphysician providers as primary care providers (Aiken & Salmon, 1994). Funding for and enrollment in graduate nursing programs rose nationwide (American Association of Colleges of Nursing, 1996). Anecdotal reports indicated that NPs were not included in MCO primary care provider panels. The purpose of this study was to explore MCO arrangements with nurse practitioners and the factors that influence them.

Managed care organizations' arrangements with nurse practitioners.

Thirty-four of 67 MCOs in New York and Connecticut responded to requests for information on the roles, participation, and listing of nurse practitioners as primary care providers or in other capacities. MCO executives report a high degree of satisfaction with NPs who serve as their primary care providers, especially in women's health and geriatrics, as they spend more time teaching and explaining procedures than physicians. Ongoing lack of up-to-date information and/or confusion about the scope of NP practice exists among both health care professionals and the public. Perceived differences in the scope of care provided by NPs was related to state regulations, physician practice patterns, and availability of primary care physicians. Eighty-five percent of MCO executives thought their organizations should encourage the use of NPs.

Validation of the General Neuropsychological Deficit Scale with nondisabled, learning-disabled, and head-injured young adults.

This study examines the validity of Reitan and Wolfson's General Neuropsychological Deficit Scale (GNDS). The GNDS differentiated nondisabled, learning-disabled, and head-injured young adults matched for FSIQ with greater accuracy than Halstead's Impairment Index.

Construct validity of neuropsychological tests of conceptual and attentional abilities.

In a mixed sample of community-living adults, this study examined the construct validity of five neuropsychological tests: Category Test (CAT), Wisconsin Card Sorting Test (WCST), Paced Auditory Serial Addition Task (PASAT), Visual Search and Attention Test (VSAT) and Trail Making Test: Part B (TMT-B). Principal components analyses showed that PASAT, VSAT, and TMT-B defined an attention factor and that CAT and WCST defined a conceptual factor. The results were discussed in terms of common interpretations of these procedures as well as in terms of Mirsky's (1989) components of attention.

Bioequivalence of two methotrexate formulations in psoriatic and cancer patients.

OBJECTIVE: To compare the bioequivalence of a generic methotrexate (MTX) tablet (Mylan) with that of a brand-name (Lederle) product. DESIGN: A single-dose, randomized, crossover study. SETTING: Clinical Research Center (CRC) at a university hospital. PATIENTS: Men and women who had a diagnosis of malignancy or psoriasis who were at least 21 years old. METHODOLOGY: Two overnight study periods were scheduled at the CRC at least one week, but not more than two weeks apart. Each period consisted of a 10-hour fast prior to and 4 hours following oral MTX 15 mg administered as six 2.5-mg tablets. Blood samples were collected over 48 hours. Plasma MTX concentrations were determined using an HPLC assay. Area under the curve from zero to infinity (AUC0-infinity) was calculated by the log-trapezoidal method. RESULTS: Twenty-two patients (21 psoriasis, 1 colon cancer) aged 23-61 years completed both study periods. Mean values for peak concentration, time to peak concentration, and AUC0-infinity were 0.80 mumol/L, 1.2 hours, and 3.0 mumol.h/L, respectively, for Mylan's MTX tablets and 0.81 mumol/L, 1.4 hours, 3.0 mumol.h/L, respectively, for Lederle's MTX. Normalization for weight or body surface area did not affect interpatient variability. Relative bioavailability of generic MTX was 99.2 percent. Rate and extent of absorption were not significantly different and the confidence intervals were within the range of 80-120 percent required by the Food and Drug Administration. CONCLUSIONS: Mylan's MTX tablet is bioequivalent to Lederle's product.

Characterization of two forms of cationic peroxidase from cultured peanut cells.

Two forms of cationic peroxidase from peanut cells were differentiated by concanavalin A affinity chromatography. They differed in molecular mass as well as concanavalin A binding, leading to the initial suggestion that they represented two isozymes of peroxidase. However, similar values for the specific activity, Soret absorption, calcium content, and peptide molecular mass were observed for each of the forms. Therefore, the binding and nonbinding fractions most likely represent two molecular forms of cationic peanut peroxidase, rather than two distinct cationic isozymes. The difference between these two forms is discussed in terms of glycosylation. Through the amino acid sequence analysis of the formic acid treated peptide, the cationic isozyme has been shown to be identical in amino acid sequence to the cDNA clone PNC1.