We dedicate this manuscript in memory of a dear friend and colleague Bella Kaufman.
The fifth International Consensus Symposium for Breast Cancer in Young Women (BCY5) took place virtually in October ...2020, organized by the European School of Oncology (ESO) and the European Society of Medical Oncology (ESMO). Consensus recommendations for the management of breast cancer in young women were updated from BCY4 with incorporation of new evidence to inform the guidelines. Areas of research priorities as well as specificities in different geographic and minority populations were identified. This manuscript summarizes the ESO–ESMO international consensus recommendations, which are also endorsed by the European Society of Breast Specialists (EUSOMA).
•Breast cancer in young women encompasses unique treatment and survivorship considerations.•Fertility, ovarian function suppression and premature menopause are major issues that need to be addressed.•The presence of a germline pathogenic variant impacts risk reduction measures, local management and systemic therapy.•Research on how new systemic therapies impact fertility and ovarian function is urgently needed.
Background A key question in the allergy field is to understand how tissue-specific disease is manifested. Eosinophilic esophagitis (EoE) is an emerging tissue-specific allergic disease with an ...unclear pathogenesis. Objective Herein we tested the hypothesis that a defect in tissue-specific esophageal genes is an integral part of EoE pathogenesis. Methods We interrogated the pattern of expression of esophagus-specific signature genes derived from the Human Protein Atlas in the EoE transcriptome and in EPC2 esophageal epithelial cells. Western blotting and immunofluorescence were used for evaluating expression of esophageal proteins in biopsy specimens from control subjects and patients with active EoE. Whole-exome sequencing was performed to identify mutations in esophagus-specific genes. Results We found that approximately 39% of the esophagus-specific transcripts were altered in patients with EoE, with approximately 90% being downregulated. The majority of transcriptional changes observed in esophagus-specific genes were reproduced in vitro in esophageal epithelial cells differentiated in the presence of IL-13. Functional enrichment analysis revealed keratinization and differentiation as the most affected biological processes and identified IL-1 cytokines and serine peptidase inhibitors as the most dysregulated esophagus-specific protein families in patients with EoE. Accordingly, biopsy specimens from patients with EoE evidenced a profound loss of tissue differentiation, decreased expression of keratin 4 (KRT4) and cornulin (CRNN) , and increased expression of KRT5 and KRT14 . Whole-exome sequencing of 33 unrelated patients with EoE revealed 39 rare mutations in 18 esophagus-specific differentially expressed genes. Conclusions A tissue-centered analysis has revealed a profound loss of esophageal tissue differentiation (identity) as an integral and specific part of the pathophysiology of EoE and implicated protease- and IL-1–related activities as putative central pathways in disease pathogenesis.
Hyperfractionated cyclophosphamide and dexamethasone (HyperCd) alone, or with carfilzomib(K) and/or daratumumab(D), represents a potential treatment option when rapid disease control is needed for ...patients with aggressive presentations of relapsed/refractory multiple myeloma (RRMM).
This is a single-center, retrospective analysis of adult patients with RRMM who received HyperCd with or without K and/or D between May 1, 2016 and August 1, 2019 at the University of Texas MD Anderson Cancer Center. We here report treatment response and safety outcomes.
Data from 97 patients, 12 with plasma cell leukemia (PCL), were reviewed in this analysis. Patients had had a median of 5 prior lines of therapy and received a median of 1 consecutive cycle of hyperCd-based therapy. The overall response rate (ORR) of all patients was 71.8% (HyperCd 75%, HyperCdK 64.3%, D-HyperCd 73.3%, and D-HyperCdK 76.9%). Median progression-free survival and overall survival among all patients was 4.3 months (HyperCd 3.1 months, HyperCdK 4.5 months, D-HyperCd 3.3 months, and D-HyperCdK 6 months) and 9.0 months (HyperCd 7.4 months, HyperCdK 9.0 months, D-HyperCd 7.5 months, and D-HyperCdK 15.2 months), respectively. Grade 3/4 hematologic toxicities were common, thrombocytopenia being the most frequent at 76%. Notably, 29-41% of patients per treatment group had existing grade 3/4 cytopenias at initiation of hyperCd-based therapy.
HyperCd-based regimens provided rapid disease control among MM patients, even when heavily pre-treated and with few remaining treatment options. Grade 3/4 hematologic toxicities were frequent, but manageable with aggressive supportive care.
To comprehensively assess the pharmacogenomic evidence of routinely used drugs for clinical utility.
Between January 2, 2011, and May 31, 2013, we assessed 71 drugs by identifying all drug/genetic ...variant combinations with published clinical pharmacogenomic evidence. Literature supporting each drug/variant pair was assessed for study design and methods, outcomes, statistical significance, and clinical relevance. Proposed clinical summaries were formally scored using a modified AGREE (Appraisal of Guidelines for Research and Evaluation) II instrument, including recommendation for or against guideline implementation.
Positive pharmacogenomic findings were identified for 51 of 71 cardiovascular drugs (71.8%), representing 884 unique drug/variant pairs from 597 publications. After analysis for quality and clinical relevance, 92 drug/variant pairs were proposed for translation into clinical summaries, encompassing 23 drugs (32.4% of drugs reviewed). All were recommended for clinical implementation using AGREE II, with mean ± SD overall quality scores of 5.18±0.91 (of 7.0; range, 3.67-7.0). Drug guidelines had highest mean ± SD scores in AGREE II domain 1 (Scope) (91.9±6.1 of 100) and moderate but still robust mean ± SD scores in domain 3 (Rigor) (73.1±11.1), domain 4 (Clarity) (67.8±12.5), and domain 5 (Applicability) (65.8±10.0). Clopidogrel (CYP2C19), metoprolol (CYP2D6), simvastatin (rs4149056), dabigatran (rs2244613), hydralazine (rs1799983, rs1799998), and warfarin (CYP2C9/VKORC1) were distinguished by the highest scores. Seven of the 9 most commonly prescribed drugs warranted translation guidelines summarizing clinical pharmacogenomic information.
Considerable clinically actionable pharmacogenomic information for cardiovascular drugs exists, supporting the idea that consideration of such information when prescribing is warranted.
Objective: To evaluate the weight loss efficacy, safety and tolerability of taranabant, a CB1R inverse agonist, in obese and overweight patients. Design: Multicenter, double-blind, randomized, ...placebo-controlled study.Subjects: Patients 18 years old, BMI 27–43 kg m−2, were randomized to placebo (n=209) or taranabant 0.5 mg (n=207), 1 mg (n=208) or 2 mg given orally once daily (n=417) for 52 weeks. Measurements: Key efficacy measurements included body weight (BW), waist circumference (WC), lipid endpoints and glycemic endpoints. Results: Based on a last observation carried forward analysis of the all-patients-treated population, mean change in BW for taranabant 0.5, 1, and 2 mg and placebo was −5.4, −5.3, −6.7 and −1.7 kg, respectively (P<0.001 for all doses vs placebo). The proportions of patients who lost at least 5 and 10% of their baseline BW at week 52 were significantly higher for all taranabant doses vs placebo (P<0.001 for all doses). Reductions in WC, percentage of body fat, and triglycerides were significant for taranabant 2 mg and in triglycerides for taranabant 1 mg vs placebo. There was no effect of taranabant vs placebo on other lipid or glucose-related endpoints. Incidences of adverse experiences classified in the gastrointestinal (diarrhea and nausea), nervous system (dizziness/dizziness postural), psychiatric-related (irritability and anger/aggression) and vascular (flushing/hot flush) organ systems were higher and statistically significant in the taranabant 2-mg group compared with the placebo group. Irritability was higher and statistically significant in all taranabant groups compared with the placebo group. Conclusion: All three doses of taranabant-induced clinically meaningful and statistically significant weight loss. Incidences of adverse experiences in organ systems known to express CB1R were higher in taranabant groups.
To evaluate the efficacy, safety and tolerability of taranabant in obese and overweight patients.
Double-blind, randomized, placebo-controlled study.
Patients were >or=18 years old, with body mass ...index of 27-43 kg m(-2), and 51% with metabolic syndrome (MS) randomized to placebo (N=417) or taranabant 2 mg (N=414), 4 mg (N=415) or 6 mg (N=1256) for 104 weeks.
Key efficacy measurements included body weight, waist circumference (WC), lipid and glycemic end points.
On the basis of risk/benefit assessments, the 6-mg dose was discontinued during year 1 (patients on 6 mg were down-dosed to 2 mg or placebo) and the 4-mg dose was discontinued during year 2 (patients on 4 mg were down-dosed to 2 mg). Changes from baseline in body weight at week 52 (all-patients-treated population, last observation carried forward analysis) were -2.6, -6.6 and -8.1 kg, respectively, for placebo and taranabant 2 and 4 mg (both doses P<0.001 vs placebo). For patients who completed year 1, changes from baseline in body weight at week 104 were -1.4, -6.4 and -7.6 kg for placebo and taranabant 2 and 4 mg, respectively (both doses P<0.001 vs placebo). The proportions of patients at weeks 52 and 104 who lost at least 5 and 10% of their baseline body weight were significantly higher and the proportions of patients who met criteria for MS were significantly lower for taranabant 2 and 4 mg vs placebo. The incidence of adverse experiences classified in the gastrointestinal, nervous, psychiatric, cutaneous and vascular organ systems were generally observed to be dose related with taranabant vs placebo.
Taranabant at the 2- and 4-mg dose was effective in achieving clinically significant weight loss over 2 years and was associated with dose-related increases in adverse experiences. On the basis of these and other data, an assessment was made that the overall safety and efficacy profile of taranabant did not support its further development for the treatment of obesity.
Purpose:
This study demonstrates a means of implementing an adaptive statistical iterative reconstruction (ASiR™) technique for dose reduction in computed tomography (CT) while maintaining similar ...noise levels in the reconstructed image. The effects of image quality and noise texture were assessed at all implementation levels of ASiR™. Empirically derived dose reduction limits were established for ASiR™ for imaging of the trunk for a pediatric oncology population ranging from 1 yr old through adolescence/adulthood.
Methods:
Image quality was assessed using metrics established by the American College of Radiology (ACR) CT accreditation program. Each image quality metric was tested using the ACR CT phantom with 0%–100% ASiR™ blended with filtered back projection (FBP) reconstructed images. Additionally, the noise power spectrum (NPS) was calculated for three common reconstruction filters of the trunk. The empirically derived limitations on ASiR™ implementation for dose reduction were assessed using (1, 5, 10) yr old and adolescent/adult anthropomorphic phantoms. To assess dose reduction limits, the phantoms were scanned in increments of increased noise index (decrementing mA using automatic tube current modulation) balanced with ASiR™ reconstruction to maintain noise equivalence of the 0% ASiR™ image.
Results:
The ASiR™ algorithm did not produce any unfavorable effects on image quality as assessed by ACR criteria. Conversely, low-contrast resolution was found to improve due to the reduction of noise in the reconstructed images. NPS calculations demonstrated that images with lower frequency noise had lower noise variance and coarser graininess at progressively higher percentages of ASiR™ reconstruction; and in spite of the similar magnitudes of noise, the image reconstructed with 50% or more ASiR™ presented a more smoothed appearance than the pre-ASiR™ 100% FBP image. Finally, relative to non-ASiR™ images with 100% of standard dose across the pediatric phantom age spectrum, similar noise levels were obtained in the images at a dose reduction of 48% with 40% ASIR™ and a dose reduction of 82% with 100% ASIR™.
Conclusions:
The authors’ work was conducted to identify the dose reduction limits of ASiR™ for a pediatric oncology population using automatic tube current modulation. Improvements in noise levels from ASiR™ reconstruction were adapted to provide lower radiation exposure (i.e., lower mA) instead of improved image quality. We have demonstrated for the image quality standards required at our institution, a maximum dose reduction of 82% can be achieved using 100% ASiR™; however, to negate changes in the appearance of reconstructed images using ASiR™ with a medium to low frequency noise preserving reconstruction filter (i.e., standard), 40% ASiR™ was implemented in our clinic for 42%–48% dose reduction at all pediatric ages without a visually perceptible change in image quality or image noise.
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, ...the major mammalian 3'-5' exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi-Goutières syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in ∼8370 patients with SLE and ∼7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)>10%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P=0.0008, OR=1.73, 95% CI=1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P=2.99E-13, OR=5.2, 95% CI=3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis.
Objectives This study was designed to evaluate the clinical and prognostic aspects of long QT syndrome (LQTS)-related cardiac events that occur in the first year of life (infancy). Background The ...clinical implications for patients with long QT syndrome who experience cardiac events in infancy have not been studied previously. Methods The study population of 3,323 patients with QT interval corrected for heart rate (QTc) ≥450 ms enrolled in the International LQTS Registry involved 20 patients with sudden cardiac death (SCD), 16 patients with aborted cardiac arrest (ACA), 34 patients with syncope, and 3,253 patients who were asymptomatic during the first year of life. Results The risk factors for a cardiac event among 212 patients who had an electrocardiogram recorded in the first year of life included QTc ≥500 ms, heart rate ≤100 beats/min, and female sex. An ACA before age 1 year was associated with a hazard ratio of 23.4 (p < 0.01) for ACA or SCD during ages 1 to 10 years. During the 10-year follow-up after infancy, beta-blocker therapy was associated with a significant reduction in ACA/SCD only in those with a syncopal episode within 2 years before ACA/SCD but not for those who survived ACA in infancy. Conclusions Patients with LQTS who experience ACA during the first year of life are at very high risk for subsequent ACA or death during their next 10 years of life, and beta-blockers might not be effective in preventing fatal or near-fatal cardiac events in this small but high-risk subset.
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