Background
Psychological effects of mastectomy for women with breast cancer have driven treatments that optimize cosmesis while strictly adhering to oncologic principles. Although skin-sparing ...mastectomy is oncologically safe, questions remain regarding the use of nipple–areola complex (NAC)-sparing mastectomy (NSM). We prospectively evaluated NSM for patients undergoing mastectomy for early-stage breast cancer or risk reduction.
Methods
We enrolled 33 early-stage breast cancer and high-risk patient; 54 NSMs were performed. NAC viability and surgical complications were evaluated. Intraoperative and postoperative pathologic assessments of the NAC base tissue were performed. NAC sensory, cosmetic and quality of life (QOL) outcomes were also assessed.
Results
Twenty-one bilateral and 12 unilateral NSMs were performed in 33 patients, 37 (68.5%) for prophylaxis and 17 (31.5%) for malignancy. Mean age was 45.4 years. Complications occurred in 16 NACs (29.6%) and 6 skin flaps (11.1%). Operative intervention for necrosis resulted in 4 NAC removals (7.4%). Two (11.8%) of the 17 breasts with cancer had ductal carcinoma-in-situ at the NAC margin, necessitating removal at mastectomy. All evaluable patients had nipple erection at 6 and 12 months postoperatively. Cosmetic outcome, evaluated by two plastic surgeons, was acceptable in 73.0% of breasts and 55.8% of NACs, but lateral displacement occurred in most cases. QOL assessment indicated patient satisfaction.
Conclusions
NSM is technically feasible in select patients, with a low risk for NAC removal resulting from necrosis or intraoperative detection of cancer, and preserves sensation and QOL. Thorough pathologic assessment of the NAC base is critical to ensure disease eradication.
Menstrual cycle-related conditions, such as dysmenorrhea and heavy bleeding, are common amongst those under 25 years. Despite having significant impact on work, education, and social activities, most ...do not seek medical advice, preferring to self-manage their symptoms. We aimed to determine if access to a web-based resource was a feasible and acceptable method for improving menstrual health literacy and encouraging health seeking behavior.
People were eligible to participate if they were currently living in Australia, aged 14-25 years, and had menstruated for at least 12 months. Access to the resource, comprising evidence-based information on the menstrual cycle, the Period ImPact and Pain Assessment (PIPPA) tool, and guidance on self-management options, was provided for three menstrual cycles.
Seventy-five participants with a mean age of 20.4 years were enrolled with 56 (75%) providing pre and post measures. Recruitment rate and retention rates met pre-specified criteria for feasibility. Eighty five percent of the participants reported the web-based resource was easy to use, and 90% reported they found the information provided 'very helpful'. Just under half (48%) reported the resource changed what they thought was a 'normal' period. Forty-three percent visited their doctor regarding their menstrual symptoms during the study period, with 84% indicating that they made the appointment due to the resource; over half (56%) who visited their doctor received a referral to a gynecologist.
Access to a web-based resource on menstrual health literacy was found to be acceptable and feasible to young people and may encourage health-seeking behavior.
Epigenetic alterations in the cancer methylome are common in breast cancer and provide novel options for tumour stratification. Here, we perform whole-genome methylation capture sequencing on small ...amounts of DNA isolated from formalin-fixed, paraffin-embedded tissue from triple-negative breast cancer (TNBC) and matched normal samples. We identify differentially methylated regions (DMRs) enriched with promoters associated with transcription factor binding sites and DNA hypersensitive sites. Importantly, we stratify TNBCs into three distinct methylation clusters associated with better or worse prognosis and identify 17 DMRs that show a strong association with overall survival, including DMRs located in the Wilms tumour 1 (WT1) gene, bi-directional-promoter and antisense WT1-AS. Our data reveal that coordinated hypermethylation can occur in oestrogen receptor-negative disease, and that characterizing the epigenetic framework provides a potential signature to stratify TNBCs. Together, our findings demonstrate the feasibility of profiling the cancer methylome with limited archival tissue to identify regulatory regions associated with cancer.
Truncating variants in the Titin gene (TTNtvs) are common in individuals with idiopathic dilated cardiomyopathy (DCM). However, a comprehensive genomics-first evaluation of the impact of TTNtvs in ...different clinical contexts, and the evaluation of modifiers such as genetic ancestry, has not been performed.
We reviewed whole exome sequence data for >71 000 individuals (61 040 from the Geisinger MyCode Community Health Initiative (2007 to present) and 10 273 from the PennMedicine BioBank (2013 to present) to identify anyone with TTNtvs. We further selected individuals with TTNtvs in exons highly expressed in the heart (proportion spliced in PSI >0.9). Using linked electronic health records, we evaluated associations of TTNtvs with diagnoses and quantitative echocardiographic measures, including subanalyses for individuals with and without DCM diagnoses. We also reviewed data from the Jackson Heart Study to validate specific analyses for individuals of African ancestry.
Identified with a TTNtv in a highly expressed exon (hiPSI) were 1.2% individuals in PennMedicine BioBank and 0.6% at Geisinger. The presence of a hiPSI TTNtv was associated with increased odds of DCM in individuals of European ancestry (odds ratio 95% CI: 18.7 9.1-39.4 {PennMedicine BioBank} and 10.8 7.0-16.0 {Geisinger}). hiPSI TTNtvs were not associated with DCM in individuals of African ancestry, despite a high DCM prevalence (odds ratio, 1.8 0.2-13.7; P=0.57). Among 244 individuals of European ancestry with DCM in PennMedicine BioBank, hiPSI TTNtv carriers had lower left ventricular ejection fraction (β=-12%, P=3×10
), and increased left ventricular diameter (β=0.65 cm, P=9×10
). In the Geisinger cohort, hiPSI TTNtv carriers without a cardiomyopathy diagnosis had more atrial fibrillation (odds ratio, 2.4 1.6-3.6) and heart failure (odds ratio, 3.8 2.4-6.0), and lower left ventricular ejection fraction (β=-3.4%, P=1×10
).
Individuals of European ancestry with hiPSI TTNtv have an abnormal cardiac phenotype characterized by lower left ventricular ejection fraction, irrespective of the clinical manifestation of cardiomyopathy. Associations with arrhythmias, including atrial fibrillation, were observed even when controlling for cardiomyopathy diagnosis. In contrast, no association between hiPSI TTNtvs and DCM was discerned among individuals of African ancestry. Given these findings, clinical identification of hiPSI TTNtv carriers may alter clinical management strategies.
Placental insufficiency (PI) lowers fetal oxygen and glucose concentrations, which disrupts glucose-insulin homeostasis and promotes fetal growth restriction (FGR). To date, prenatal treatments for ...FGR have not attempted to correct the oxygen and glucose supply simultaneously. Therefore, we investigated whether a five-day correction of oxygen and glucose concentrations in PI-FGR fetuses would normalize insulin secretion and glucose metabolism. Experiments were performed in near-term FGR fetal sheep with maternal hyperthermia-induced PI. Fetal arterial oxygen tension was increased to normal levels by increasing the maternal inspired oxygen fraction and glucose was infused into FGR fetuses (FGR-OG). FGR-OG fetuses were compared to maternal air insufflated, saline-infused fetuses (FGR-AS) and control fetuses. Prior to treatment, FGR fetuses were hypoxemic and hypoglycemic and had reduced glucose-stimulated insulin secretion (GSIS). During treatment, oxygen, glucose, and insulin concentrations increased, and norepinephrine concentrations decreased in FGR-OG fetuses, whereas FGR-AS fetuses were unaffected. On treatment day 4, glucose fluxes were measured with euglycemic and hyperinsulinemic-euglycemic clamps. During both clamps, rates of glucose utilization and production were greater in FGR-AS than FGR-OG fetuses, while glucose fluxes in FGR-OG fetuses were not different than control rates. After five-days of treatment, GSIS increased in FGR-OG fetuses to control levels and their ex vivo islet GSIS was greater than FGR-AS islets. Despite normalization in fetal characteristics, GSIS, and glucose fluxes, FGR-OG and FGR-AS fetuses weighed less than controls. These findings show that sustained, simultaneous correction of oxygen and glucose normalized GSIS and whole-body glucose fluxes in PI-FGR fetuses after the onset of FGR.
Targeted nanoparticle delivery is a promising strategy for increasing efficacy and limiting side effects of therapeutics. When designing a targeted liposomal formulation, the in vivo biodistribution ...of the particles must be characterized to determine the value of the targeting approach. Peroxisome proliferator-activated receptor (PPAR) agonists effectively treat metabolic syndrome by decreasing dyslipidemia and insulin resistance but side effects have limited their use, making them a class of compounds that could benefit from targeted liposomal delivery. The adipose targeting sequence peptide (ATS) could fit this role, as it has been shown to bind to adipose tissue endothelium and induce weight loss when delivered conjugated to a pro-apoptotic peptide. To date, however, a full assessment of ATS in vivo biodistribution has not been reported, leaving important unanswered questions regarding the exact mechanisms whereby ATS targeting enhances therapeutic efficacy. We designed this study to evaluate the biodistribution of ATS-conjugated liposomes loaded with the PPARα/γ dual agonist tesaglitazar in leptin-deficient ob/ob mice. The ATS-liposome biodistribution in adipose tissue and other organs was examined at the cellular and tissue level using microscopy, flow cytometry, and fluorescent molecular tomography. Changes in metabolic parameters and gene expression were measured by target and off-target tissue responses to the treatment. Unexpectedly, ATS targeting did not increase liposomal uptake in adipose relative to other tissues, but did increase uptake in the kidneys. Targeting also did not significantly alter metabolic parameters. Analysis of the liposome cellular distribution in the stromal vascular fraction with flow cytometry revealed high uptake by multiple cell types. Our findings highlight the need for thorough study of in vivo biodistribution when evaluating a targeted therapy.
Despite sleep disturbance being a common complaint in individuals with autism, specific sleep phenotypes and their relationship to adaptive functioning have yet to be identified. This study used ...cluster analysis to find distinct sleep patterns and relate them to independent measures of adaptive functioning in individuals with autism. Approximately 50,000 nights of care-giver sleep/wake logs were collected on school-days for 106 individuals with low functioning autism (87 boys, 14.77 ± 3.11 years) for 0.5-6 years (2.2 ± 1.5 years) from two residential schools. Using hierarchical cluster analysis, performed on summary statistics of each individual across their recording duration, two clusters of individuals with clearly distinguishable sleep phenotypes were found. The groups were summarized as 'unstable' sleepers (cluster 1, n = 41) and 'stable' sleepers (cluster 2, n = 65), with the former exhibiting reduced sleep duration, earlier sleep offset, and less stability in sleep timing. The sleep clusters displayed significant differences in properties that were not used for clustering, such as intellectual functioning, communication, and socialization, demonstrating that sleep phenotypes are associated with symptom severity in individuals with autism. This study provides foundational evidence for profiling and targeting sleep as a standard part of therapeutic intervention in individuals with autism.
Objective: This study examined youth stressor reactivity in the form of links between daily stressors and adolescents' negative affect, physical health symptoms, and cortisol patterns. We also tested ...whether youth gender and parental warmth moderated these linkages. Method: Participants were the children of employees in the information technology division of a large company (N = 132, mean age = 13.39 years, 55% female). Youth completed daily diary telephone interviews on 8 consecutive evenings and provided saliva samples at 4 time points over 4 days to assess daily stressors and youth physiological and affective functioning. Parental warmth was assessed during in-home interviews. Multilevel modeling was used to account for interdependencies in the data. Results: Youth who experienced more daily stressors, on average, reported more negative affect and physical health symptoms, on average. Furthermore, on days youth reported more stressors than usual (compared to their own across-day average), they also exhibited more physical health symptoms, reduced evening cortisol decline (e.g., flatter slopes), higher bedtime cortisol, and more negative affect. Girls had stronger within-person linkages between daily stressors and daily negative affect than boys. Parental warmth moderated these within-person linkages: Youth who experienced more parental warmth had lower negative affect and steeper cortisol decline than usual on less stressful days. However, youth who experienced less parental warmth had higher negative affect and their cortisol levels declined less, even on days with lower-than-usual stress. Conclusions: Daily stressors are associated with youth's affective and physiological functioning, but parental warmth can support youth's stress recovery.
Fetal sheep with placental insufficiency-induced intrauterine growth restriction (IUGR) have lower hindlimb oxygen consumption rates (OCRs), indicating depressed mitochondrial oxidative ...phosphorylation capacity in their skeletal muscle. We hypothesized that OCRs are lower in skeletal muscle mitochondria from IUGR fetuses, due to reduced electron transport chain (ETC) activity and lower abundances of tricarboxylic acid (TCA) cycle enzymes. IUGR sheep fetuses (
= 12) were created with mid-gestation maternal hyperthermia and compared with control fetuses (
= 12). At 132 ± 1 days of gestation, biceps femoris muscles were collected, and the mitochondria were isolated. Mitochondria from IUGR muscle have 47% lower State 3 (Complex I-dependent) OCRs than controls, whereas State 4 (proton leak) OCRs were not different between groups. Furthermore, Complex I, but not Complex II or IV, enzymatic activity was lower in IUGR fetuses compared with controls. Proteomic analysis (
= 6/group) identified 160 differentially expressed proteins between groups, with 107 upregulated and 53 downregulated mitochondria proteins in IUGR fetuses compared with controls. Although no differences were identified in ETC subunit protein abundances, abundances of key TCA cycle enzymes isocitrate dehydrogenase (NAD
) 3 noncatalytic subunit β (IDH3B), succinate-CoA ligase ADP-forming subunit-β (SUCLA2), and oxoglutarate dehydrogenase (OGDH) were lower in IUGR mitochondria. IUGR mitochondria had a greater abundance of a hypoxia-inducible protein, NADH dehydrogenase 1α subcomplex 4-like 2, which is known to incorporate into Complex I and lower Complex I-mediated NADH oxidation. Our findings show that mitochondria from IUGR skeletal muscle adapt to hypoxemia and hypoglycemia by lowering Complex I activity and TCA cycle enzyme concentrations, which together, act to lower OCR and NADH production/oxidation in IUGR skeletal muscle.
Genomic screening can improve clinical outcomes, but presentation of individuals with risk for polyposis identified via genomic screening is unknown. To inform assessment of clinical utility of ...genomic screening for polyposis risk, clinical presentation of individuals in an unselected health care system cohort with an APC pathogenic or likely pathogenic (P/LP) variant causative of familial adenomatous polyposis are described.
Electronic health records of individuals with an APC P/LP variant identified via the MyCode program (MyCode APC+) were reviewed to assess adenoma burden and compare it among individuals with a clinical diagnosis of familial adenomatous polyposis and matched variant-negative controls.
The prevalence of APC P/LP variants in this health care cohort is estimated to be 1 in 2800. Twenty-four MyCode APC+ individuals were identified during the study period. Median age at result disclosure was 53 years. Rate of clinical polyposis was 8%. Two of six participants with a classic region variant and none of those with an attenuated region variant had polyposis. MyCode APC+ participants did not differ from controls in cumulative adenoma count.
APC P/LP variant prevalence estimate in the MyCode cohort is higher than prior published prevalence rates. Individuals with APC P/LP variants identified via genomic screening had a low adenoma burden.
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