Citations

Context.— Guidelines for HER2 testing in breast cancer have changed over time, from the US Food and Drug Administration guideline to the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines published in 2007, 2013, and 2018. Objective.— To investigate the change in assignment of HER2 status in breast cancers with equivocal (2+) immunohistochemistry (IHC) results by fluorescence in situ hybridization (FISH) following implementation of the ASCO/CAP 2018 guideline. Design.— The study included 3556 invasive breast cancers that were HER2 equivocal (2+) by IHC and were submitted to our FISH laboratory after July 2018. Reflex testing (with repeat IHC staining) was performed on certain categories of FISH results known as groups 2, 3, and 4. Concomitant review of IHC and FISH was performed on these reflex cases per 2018 guideline recommendations. The FISH data were analyzed to compare US Food and Drug Administration and ASCO/CAP 2007, 2013, and 2018 interpretations. Results.— Of 3548 invasive breast cancers with complete data available, the percentage agreement for FISH according to different guidelines was highest for ASCO/CAP 2018 versus US Food and Drug Administration (96.5%), followed by ASCO/CAP 2018 versus 2007 (93.8%), and lowest with ASCO/CAP 2018 versus 2013 (83.7%). Per the 2018 guideline, reflex IHC testing was performed on 633 breast cancers (17.8%); the majority of reflex testing results were negative (541 of 633; 85.5%). The overall distribution of HER2 FISH results (per the 2018 guideline) was 88.5% negative and 11.5% positive. Conclusions.— By eliminating the equivocal FISH category, the 2018 ASCO/CAP guideline significantly reduced the HER2 FISH–positive rate in tumors with equivocal (2+) IHC results.

Abstract Background: Berberine (BBR) is a plant-based nutraceutical that has been used for millennia to treat diarrheal infections and in contemporary medicine to improve patient lipid profiles. Reduction in lipids, particularly cholesterol, is achieved partly through up-regulation of bile acid synthesis and excretion into the gastrointestinal tract (GI). The efficacy of BBR is also thought to be dependent on structural and functional alterations of the gut microbiome. However, knowledge of the effects of BBR on gut microbiome communities is currently lacking. Distinguishing indirect effects of BBR on bacteria through altered bile acid profiles is particularly important in understanding how dietary nutraceuticals alter the microbiome. Results: Germfree mice were colonized with a defined minimal gut bacterial consortium capable of functional bile acid metabolism (Bacteroides vulgatus, Bacteroides uniformis, Parabacteroides distasonis, Bilophila wadsworthia, Clostridium hylemonae, Clostridium hiranonis, Blautia producta; B4PC2). Multi-omics (bile acid metabolomics, 16S rDNA sequencing, cecal metatranscriptomics) were performed in order to provide a simple in vivo model from which to identify network-based correlations between bile acids and bacterial transcripts in the presence and absence of dietary BBR. Significant alterations in network topology and connectivity in function were observed, despite similarity in gut microbial alpha diversity (P = 0.30) and beta-diversity (P = 0.123) between control and BBR treatment. BBR increased cecal bile acid concentrations, (P < 0.05), most notably deoxycholic acid (DCA) (P <0.001). Overall, analysis of transcriptomes and correlation networks indicates both bacterial species-specific responses to BBR, as well as functional commonalities among species, such as up-regulation of Na+/H+ antiporter, cell wall synthesis/repair, carbohydrate metabolism and amino acid metabolism. Bile acid concentrations in the GI tract increased significantly during BBR treatment and developed extensive correlation networks with expressed genes in the B4PC2 community.Conclusions: This work has important implications for interpreting the effects of BBR on structure and function of the complex gut microbiome, which may lead to targeted pharmaceutical interventions aimed to achieve the positive physiological effects previously observed with BBR supplementation.

Abstract Social determinants of health, including poverty, contribute significantly to health outcomes in the United States; however, their impact on pediatric hematopoietic cell transplantation (HCT) outcomes is poorly understood. We aimed to identify the association between neighborhood poverty and HCT outcomes for pediatric allogeneic HCT recipients in the Center for International Blood and Marrow Transplant Research database. We assembled 2 pediatric cohorts undergoing first allogeneic HCT from 2006 to 2015 at age ≤18 years, including 2053 children with malignant disease and 1696 children with nonmalignant disease. Neighborhood poverty exposure was defined a priori per the US Census definition as living in a high-poverty ZIP code (≥20% of persons below 100% federal poverty level) and used as the primary predictor in all analyses. Our primary outcome was overall survival (OS), defined as the time from HCT until death resulting from any cause. Secondary outcomes included relapse and transplantation-related mortality (TRM) in malignant disease, acute and chronic graft-versus-host disease, and infection in the first 100 days post-HCT. Among children undergoing transplantation for nonmalignant disease, neighborhood poverty was not associated with any HCT outcome. Among children undergoing transplantation for malignant disease, neighborhood poverty conferred an increased risk of TRM but was not associated with inferior OS or any other transplantation outcome. Among children with malignant disease, a key secondary finding was that children with Medicaid insurance experienced inferior OS and increased TRM compared with those with private insurance. These data suggest opportunities for future investigation of the effects of household-level poverty exposure on HCT outcomes in pediatric malignant disease to inform care delivery interventions.

Antiphospholipid syndrome (APS), an acquired autoimmune thrombophilia, is characterised by thrombosis and/or pregnancy morbidity in association with persistent antiphospholipid antibodies. The 16th International Congress on Antiphospholipid Antibodies Task Force on APS Treatment Trends reviewed the current status with regard to existing and novel treatment trends for APS, which is the focus of this Task Force report. The report addresses current treatments and developments since the last report, on the use of direct oral anticoagulants in patients with APS, antiplatelet agents, adjunctive therapies (hydroxychloroquine, statins and vitamin D), targeted treatment including rituximab, belimumab, and anti-TNF agents, complement inhibition and drugs based on peptides of beta-2-glycoprotein I. In addition, the report summarises potential new players, including coenzyme Q10, adenosine receptor agonists and adenosine potentiation. In each case, the report provides recommendations for clinicians, based on the current state of the art, and suggests a clinical research agenda. The initiation and development of appropriate clinical studies requires a focus on devising suitable outcome measures, including a disease activity index, an optimal damage index, and a specific quality of life index.

Abstract Endocrine therapy is underutilized to reduce breast cancer incidence among women at increased risk. Polygenic risk scores (PRSs) assessing 77 breast cancer genetic susceptibility loci personalizes risk estimates. We examined effect of personalized PRS breast cancer risk prediction on intention to take and endocrine therapy uptake among women at increased risk. Eligible participants had a 10-year breast cancer risk ≥5% by Tyrer–Cuzick model [International Breast Cancer Intervention Study (IBIS)] or ≥3.0 % 5-year Gail Model risk with no breast cancer history or hereditary breast cancer syndrome. Breast cancer risk was estimated, endocrine therapy options were discussed, and endocrine therapy intent was assessed at baseline. After genotyping, PRS-updated breast cancer risk estimates, endocrine therapy options, and intent to take endocrine therapy were reassessed; endocrine therapy uptake was assessed during follow-up. From March 2016 to October 2017, 151 patients were enrolled [median (range) age, 56.1 (36.0–76.4 years)]. Median 10-year and lifetime IBIS risks were 7.9% and 25.3%. Inclusion of PRS increased lifetime IBIS breast cancer risk estimates for 81 patients (53.6%) and reduced risk for 70 (46.4%). Of participants with increased breast cancer risk by PRS, 39 (41.9%) had greater intent to take endocrine therapy; of those with decreased breast cancer risk by PRS, 28 (46.7%) had less intent to take endocrine therapy (P &lt; 0.001). On multivariable regression, increased breast cancer risk by PRS was associated with greater intent to take endocrine therapy (P &lt; 0.001). Endocrine therapy uptake was greater among participants with increased breast cancer risk by PRS (53.4%) than with decreased risk (20.9%; P &lt; 0.001). PRS testing influenced intent to take and endocrine therapy uptake. Assessing PRS effect on endocrine therapy adherence is needed. Prevention Relevance: Counseling women at increased breast cancer risk using polygenic risk score (PRS) risk estimates can significantly impact preventive endocrine therapy uptake. Further development of PRS testing to personalize breast cancer risk assessments and endocrine therapy counselling may serve to potentially reduce the incidence of breast cancer in the future.

Summary: Social interactions are largely dependent on the interpretation of information conveyed through facial expressions. Although facial reanimation seeks restoration of the facial expression of emotion, outcome measures have not addressed this directly. This study evaluates the use of a machine learning technology to directly measure facial expression before and after facial reanimation surgery. Fifteen study subjects with facial palsy were evaluated both before and after undergoing cross-facial nerve grafting and free gracilis muscle transfer. Eight healthy volunteers were assessed for control comparison. Video footage of subjects with their face in repose and with a posed, closed-lip smile was obtained. The video data were then analyzed using the Noldus FaceReader software application to measure the relative proportions of seven cardinal facial expressions detected within each clip. The facial expression recognition application detected a far greater happy signal in postoperative (42 percent) versus preoperative (13 percent) smile videos (p < 0.0001), compared to 53 percent in videos of control faces smiling. This increase in postoperative happy signal was achieved in exchange for a reduction in the sad signal (15 percent to 9 percent; p = 0.092) and the neutral signal (57 percent to 37 percent; p = 0.0012). For video clips of patients in repose, no significant difference in happy emotion was detected between preoperative (3.1 percent) and postoperative (1.4 percent) states (p = 0.5). This study provides the first proof of concept for the use of a machine learning software application to objectively quantify facial expression before and after surgical reanimation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, IV.

BackgroundThe association of community factors and outcomes after hematopoietic cell transplantation (HCT) has not been comprehensively described. Using the County Health Rankings and Roadmaps (CHRR) and the Center for International Blood and Marrow Transplant Research (CIBMTR), this study evaluated the impact of community health status on allogeneic HCT outcomes.MethodsThis study included 18,544 adult allogeneic HCT recipients reported to the CIBMTR by 170 US centers in 2014‐2016. Sociodemographic, environmental, and community indicators were derived from the CHRR, an aggregate community risk score was created, and scores were assigned to each patient (patient community risk score [PCS]) and transplant center (center community risk score [CCS]). Higher scores indicated less healthy communities. The impact of PCS and CCS on patient outcomes after allogeneic HCT was studied.ResultsThe median age was 55 years (range, 18‐83 years). The median PCS was –0.21 (range, –1.37 to 2.10; standard deviation [SD], 0.42), and the median CCS was –0.13 (range, –1.04 to 0.96; SD, 0.40). In multivariable analyses, a higher PCS was associated with inferior survival (hazard ratio [HR] per 1 SD increase, 1.04; 99% CI, 1.00‐1.08; P = .0089). Among hematologic malignancies, a tendency toward inferior survival was observed with a higher PCS (HR, 1.04; 99% CI, 1.00‐1.08; P = .0102); a higher PCS was associated with higher nonrelapse mortality (NRM; HR, 1.08; 99% CI, 1.02‐1.15; P = .0004). CCS was not significantly associated with survival, relapse, or NRM.ConclusionsPatients residing in counties with a worse community health status have inferior survival as a result of an increased risk of NRM after allogeneic HCT. There was no association between the community health status of the transplant center location and allogeneic HCT outcomes.