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Accurate assessment of radiation-induced breast toxicity is crucial for the management of breast radiation therapy (RT). Standard assessment of breast toxicity based on clinicians' visual inspection and palpation has considerable inter- and intra-observer variability. To overcome this challenge, we present an ultrasound histogram method that objectively evaluates radiation-induced breast toxicity longitudinally. In a prospective study, patients enrolled (n = 67) received ultrasound scans at four time points: prior to RT, last day of RT, 3-4 wk post-RT and 9-12-wk post-RT. Ultrasound scans were acquired at five locations (tumor bed and 3, 6, 9 and 12 o'clock) on both breasts. Two hundred sixty-four ultrasound scans and 2640 B-mode images were analyzed. The histogram differences between irradiated and contralateral breasts were calculated to evaluate radiation-induced breast changes. On the basis of the B-mode images, the severity of breast toxicity was graded as absent, mild, moderate or severe. The performance of the histogram method was assessed with the receiver operating characteristic (ROC) curve. The areas under the ROC curve ranged from 0.78 to 0.9 (sensitivity: 0.88-0.96, specificity: 0.53-0.83) at the lower quadrant for differentiating absent/mild from moderate/severe toxicity at various time points. This study provides preliminary evidence that ultrasound histogram differences can serve as an imaging biomarker to longitudinally assess radiation-induced acute toxicity.

This cross-sectional study investigates intersections among race, ethnicity, and sex from 2000 to 2019 among senior faculty in radiation oncology.

Purpose Reduction mammoplasty (RM) during breast-conserving surgery is popular among women with large-volume breasts because it reduces redundant breast folds and may decrease skin-related morbidity from radiation therapy. However, RM may obscure the lumpectomy cavity (LC) and pose challenges to administering an LC boost, potentially affecting local control. We investigated the impact of RM on acute side effects and use of LC boosts. Methods and materials The records of 645 consecutive women treated with whole-breast irradiation at an urban university and 2 community practices between January 2012 and December 2014 were reviewed on an institutional review board–approved study. The primary endpoint was grade ≥3 radiation dermatitis; the secondary endpoint was use of LC boost. Student 2-sample t tests, Pearson χ2 tests, Fisher exact tests, and univariate and multivariable logistic regression analyses were performed. Results Forty-three (7%) RMs were performed in 650 treated breasts. No significant differences in grade 3 toxicities were identified among RM and non-RM patients. LC boost was delivered to 474 breasts. Fewer (16/43) RM patients received LC boosts compared with non-RM patients (458/607), P = .0001. RM patients were more likely to have neoadjuvant chemotherapy, stage III or multifocal disease, higher body mass index, larger planning treatment volumes, and conventional fractionation (P Conclusions RM was associated with decreased use of LC boost without significant differences in acute toxicities. Further investigation to delineate LCs in patients undergoing RM or identify alternative strategies for delivering LC dose is needed.

Purpose: Evolving cancer screening guidelines can confuse the public. Caregivers of patients undergoing radiation oncology may represent a promising outreach target for disseminating and clarifying screening information. We aimed to: (1) determine the incidence of cancer screening in this cohort, and (2) identify barriers to and deficiencies in screening. Methods: We distributed a 21-item survey on cancer screening history and related concerns to caregivers ≥ 18 years old at one urban and two suburban radiation oncology centers. Reported screening habits were compared with American Cancer Society/American Urological Association guidelines for breast, cervical, colon, and prostate cancer. Statistical analysis included Pearson χ2 tests. Results: A total of 209 caregivers (median age, 55.5 years; 146 women) were surveyed. Although 92% had primary care physicians (PCPs), only 58% reported being informed about recommended screening intervals. Participants ≤ 49 years old were less likely to report PCP discussion of cancer screening than older participants (41% and 66%, respectively; P = .006). Ninety-eight respondents (47%) had one or more screening concern(s). Among screening-eligible caregivers, 23 (18%) reported not undergoing regular colonoscopies. Fourteen women (13%) did not have Papanicolaou smears at recommended intervals, and 21 (18%) did not have annual mammograms. Six men (21%) did not undergo annual prostate screening. Decreased recommended screening with colonoscopy and mammography correlated with younger age. Conclusion: This survey of relatively unexplored caregivers identified cancer screening deficiencies and concerns that might be addressed by targeted interventions. With approximately 60% of patients with cancer receiving radiation therapy, advice in the radiation oncology setting could positively affect cancer screening behaviors in caregivers.

Understanding mechanisms controlling expression of the α-spectrin gene is important for understanding erythropoiesis, membrane biogenesis, and spectrin-linked hemolytic anemia. We showed previously that a minimal α-spectrin promoter directed low levels of expression only in early erythroid development, indicating elements outside the promoter are required for expression in adult erythrocytes. Addition of noncoding exon 1′ and intron 1′ conferred a 10-fold increase in activity in reporter gene assays. In this report, we used a transgenic mouse model to show that addition of exon 1′ and intron 1′ to the α-spectrin promoter conferred tissue-specific expression of a linked Aγ-globin gene in erythroid cells at all developmental stages. Expression was nearly position-independent, as 21 of 23 lines expressed the transgene, and γ-globin protein was present in 100% of erythrocytes, indicating uniform expression. Additional in vivo studies revealed that exon 1′ functions as an insulator with barrier-element activity. Chromatin immunoprecipitation assays demonstrated that this region was occupied by the upstream stimulatory factors 1/2 (USF1/USF2), similar to the well-characterized chicken HS4 insulator. These data identify the first barrier element described in an erythrocyte membrane protein gene and indicate that exon 1′ and intron 1′ are excellent candidate regions for mutations in patients with spectrin-linked hemolytic anemia.

The human ankyrin-1 gene (ANK1) contains 3 tissue-specific alternative promoters. We have shown previously that the erythroid-specific ankyrin 1 (ANK1E) core promoter contains a 5′ DNase I hypersensitive site (HS) with barrier insulator function that prevents gene silencing in vitro and in vivo. Mutations in the ANK1E barrier region lead to decreased ANK1 mRNA levels and hereditary spherocytosis. In this report, we demonstrate a second ANK1E regulatory element located in an adjacent pair of DNase I HS located 5.6 kb 3′ of the ANK1E promoter at the 3′ boundary of an erythroid-specific DNase I–sensitive chromatin domain. The 3′ regulatory element exhibits enhancer activity in vitro and in transgenic mice, and it has the histone modifications associated with an enhancer element. One of the ANK1E 3′HS contains an NF-E2 binding site that is required for enhancer function. We show that a chromatin loop brings the 3′ enhancer and NF-E2 into proximity with the 5′ barrier region including the ANK1E core promoter. These observations demonstrate a model for the tissue-specific activation of alternative promoters that may be applicable to the ∼ 30% of mammalian genes with alternative promoters that exhibit distinct expression patterns.

Aortic valve bypass (AVB [apicoaortic conduit]) relieves aortic stenosis (AS) by connecting the apex of the left ventricle to the descending thoracic aorta with a valved conduit. AVB is performed through a small left thoracotomy, without cardiopulmonary bypass, aortic cross-clamping, cardiac arrest, or debridement of the native aortic valve. Little is known about hemodynamics, including ventricular performance, relative conduit blood flow, and progression of native AS after AVB.Forty-seven very high risk patients underwent AVB for AS between 2003 and 2009. The mean age was 82 years. Predismissal and interval transthoracic quantitative two-dimensional and Doppler echocardiography was performed in a core laboratory.No patient had obstruction of the native aortic valve or the conduit during follow-up. The AVB effectively relieved left ventricular outflow tract obstruction (average peak gradient across the conduit was 5.6 +/- 3.8 mm Hg). Native aortic valve stenosis did not progress after AVB (0.63 +/- 0.16 cm(2) before surgery to 0.7 +/- 0.24 cm(2) at latest follow-up more than 6 months; p = 0.16). Total stroke volume increased after AVB from 60 mL +/- 22 mL to 107 mL +/- 27 mL (p0.0001). Left ventricular outflow was distributed in a predictable fashion between the conduit and the native aortic valve, with 63% +/- 10% of the flow directed to the conduit. Relative conduit flow remained stable (68% +/- 8%) at latest follow-up more than 6 months (p = 0.17).Aortic valve bypass effectively relieves the outflow tract obstruction of AS. Placement of an apical valved conduit halts the biologic progression of AS.

Mutations in erythrocyte ankyrin, ankyrin-1, are the most common cause of typical hereditary spherocytosis. Co-inheritance of cardiac, muscular, and neurologic diseases such as cardiomyopathy, psychomotor retardation, and spinocerebellar abnormalities with hereditary spherocytosis has been described. In the nb/nb mouse, an ankyrin-1 mutation manifests in erythroid cells with ankyrin deficiency and a spherocytosis phenotype, and in neural cells with an age-dependent psychomotor disorder due to loss of cerebellar Purkinje cells. These observations highlight the importance of understanding ankyrin-1 structure, function, and regulation in erythroid and nonerythroid cells. In erythroid cells, ankyrin expression is directed by a compact promoter controlled by a single GATA-1 site. Nonerythroid ankyrin-1 isoforms have been described with diversity arising from alternate splicing, alternate polyadenylation, and, in skeletal muscle, use of an alternate, tissue-specific promoter. Using 5′ RACE, we identified 2 additional alternate first exons of the ankyrin-1 cDNA. One encoded a first exon with an initiator methionine followed by 12 amino acids, designated exon 1A, that spliced in-frame to erythroid exon 2 sequences. The other, designated 1B, encoded a novel initiator methionine followed by 40 highly charged amino acids that also spliced in-frame to the erythroid exon 2. Both exons, found in human and mouse, link directly to the downstream exons encoding the ankyrin repeat and spectrin binding domains of ankyrin-1. Exon 1B mapped to a location 98.5 kb 5′ of erythroid exon 1 (1E) and exon 1A mapped 30.1 kb 3′ of exon 1E. Northern blot and quantitative RT-PCR analyses demonstrated that 1B was expressed in heart, skeletal muscle, and brain. Similar to what we previously reported for the promoter of the erythroid-specific exon 1, 1E, DNase I hypersensitive site (HS) mapping identified a pair of HS in genomic DNA, one immediately 5′ of exon 1B and one that mapped 6.6 kb downstream of this site (chr8:41,873,229 and 41,866,593, UCSC assembly, Mar 2006). Luciferase-reporter gene expression studies with plasmids containing either a 700bp or a 278bp fragment of the 1B flanking sequence directed high-level luciferase expression in RD cells (human rhabdomyosarcoma) but no luciferase expression in K562 (erythroid) or HeLa (fibroblastoid) cells. Consistent with its tissue-restricted pattern of expression, a polyclonal antipeptide antibody raised against novel sequence in exon 1B reacted with peptides of 220, 205, 45, and 40 kDa on immunoblots prepared from muscle and brain but not erythrocytes. In contrast to erythroid-specific exon 1E and tissue-restricted exon 1B, mRNAs containing exon 1A were detected in all 18 tissues examined. Like the 1E and 1B promoters, mapping identified an HS in the 5′ flanking genomic DNA/promoter region of exon 1A and another 6 kb downstream (chr8:41,873,229 and 41,866,593). An exon 1A anti-peptide antibody reacted with peptides of 205, 195, and 190 kDa on immunoblots prepared from numerous tissues, including erythrocytes ghosts. Regulation of ankyrin-1 expression by alternate promoters directing novel NH2-termini provides the basis for a complex pattern of tissue-specific ankyrin-1 isoform diversity. Characterization of the downstream alternate exon composition of the tissue-specific exon 1B and ubiquitous exon 1A-containing transcripts will allow a systematic evaluation of whether a specific spherocytosis-linked ankyrin-1 mutation could lead to a nonerythroid phenotype.