Citations

Abstract Ultrasound-guided percutaneous ethanol ablation procedures for locoregional recurrences in papillary thyroid carcinoma (PTC) can be repeatedly performed over years. Skin metastases (SM) from PTC generally portend a lethal prognosis. Our patient case report demonstrates the innovative use in low-risk PTC (LRPTC) of treatment modalities designed to prevent neck re-explorations and capable of eliminating both locoregional recurrences and SM. In 2004, a 48-year-old man presented with neck nodal metastases due to PTC. He underwent a near-total thyroidectomy and nodal dissection, confirming an 8-mm PTC involving 2 ipsilateral node metastases. Postoperatively, he received 2 doses of radioactive iodine (RAI) for remnant uptake (cumulative dose 338 mCi); posttherapy scanning was unrevealing. In 2007, he underwent right neck dissection for further node metastases. In 2008, a guided biopsy confirmed a level IV node metastasis. He was referred to our institution for ethanol ablation. Two node metastases were ablated and subsequently disappeared. During 2010-2016, he developed an additional 6 node metastases, which were treated with ethanol ablation; all disappeared on high-resolution sonography. FDG-PET-CT scans in 2009 and 2016 were negative for distant spread. In 2016, a SM in his right neck was removed by dermatologic surgery. In 2017-2018, 2 further SM were excised with negative margins, one after Mohs surgery. He has now been disease-free for 20 months. In conclusion, despite 3 neck surgeries and 2 RAI therapies, our patient repeatedly developed both locoregional recurrences and SM. All 11 disease foci were eliminated with minimally invasive procedures which should more often be considered as effective treatment options in LRPTC.

Abstract Context Preeclampsia is a leading cardiovascular complication in pregnancy lacking effective diagnostic and treatment strategies. Objective To investigate the diagnostic and therapeutic target potential of the angiogenesis proteins, FK506-binding protein like (FKBPL) and CD44. Design and Intervention FKBPL and CD44 plasma concentration or placental expression were determined in women pre- or postdiagnosis of preeclampsia. Trophoblast and endothelial cell function was assessed following mesenchymal stem cell (MSC) treatment and in the context of FKBPL signaling. Settings and Participants Human samples prediagnosis (15 and 20 weeks of gestation; n ≥ 57), or postdiagnosis (n = 18 for plasma; n = 4 for placenta) of preeclampsia were used to determine FKBPL and CD44 levels, compared to healthy controls. Trophoblast or endothelial cells were exposed to low/high oxygen, and treated with MSC-conditioned media (MSC-CM) or a FKBPL overexpression plasmid. Main Outcome Measures Preeclampsia risk stratification and diagnostic potential of FKBPL and CD44 were investigated. MSC treatment effects and FKBPL-CD44 signaling in trophoblast and endothelial cells were assessed. Results The CD44/FKBPL ratio was reduced in placenta and plasma following clinical diagnosis of preeclampsia. At 20 weeks of gestation, a high plasma CD44/FKBPL ratio was independently associated with the 2.3-fold increased risk of preeclampsia (odds ratio = 2.3, 95% confidence interval [CI] 1.03-5.23, P = 0.04). In combination with high mean arterial blood pressure (>82.5 mmHg), the risk further increased to 3.9-fold (95% CI 1.30-11.84, P = 0.016). Both hypoxia and MSC-based therapy inhibited FKBPL-CD44 signaling, enhancing cell angiogenesis. Conclusions The FKBPL-CD44 pathway appears to have a central role in the pathogenesis of preeclampsia, showing promising utilities for early diagnostic and therapeutic purposes.

Characterizing the release profile for materials-directed local delivery of bioactive molecules and its effect on bone regeneration is an important step to improve our understanding of, and ability to optimize, the bone healing response. This study examined the local delivery of parathyroid hormone (PTH) using a thiol-ene hydrogel embedded in a porous poly(propylene fumarate) (PPF) scaffold for bone regeneration applications. The aim of this study was to characterize the degradation-controlled in vitro release kinetics of PTH from the thiol-ene hydrogels, in vivo hydrogel degradation in a subcutaneous implant model, and bone healing in a rat critical size bone defect. Tethering PTH to the hydrogel matrix eliminated the early timepoint burst release that was observed in previous in vitro work where PTH was free to diffuse out of the matrix. Only 8% of the tethered PTH was released from the hydrogel during the first 2 weeks, but by day 21, 80% of the PTH was released, and complete release was achieved by day 28. In vivo implantation revealed that complete degradation of the hydrogel alone occurred by day 21; however, when incorporated in a three-dimensional printed osteoconductive PPF scaffold, the hydrogel persisted for >56 days. Treatment of bone defects with the composite thiol-ene hydrogel–PPF scaffold, delivering either 3 or 10 μg of tethered PTH 1-84, was found to increase bridging of critical size bone defects, whereas treatment with 30 μg of tethered PTH resulted in less bone ingrowth into the defect area. Continued development of this biomaterial delivery system for PTH could lead to improved therapies for treatment of nonunion fractures and critical size bone defects.

AbstractMonitoring and blunting are coping styles that characterize how people respond when faced with personally threatening situations. High monitors tend to pay more attention to, scan for, and amplify threatening cues; high blunters tend to avoid information and seek distractions when faced with a threatening event. This study sought to investigate possible differential effects of monitoring and blunting coping styles on information preferences in a hypothetical cancer diagnosis scenario in the adult general public of Minnesota. In a survey administered at a large public venue (2016 Minnesota State Fair), participants were asked to imagine they carried a gene mutation and were diagnosed with colon cancer. They indicated their information preference [modified Cassileth Information Styles Questionnaire (MCISQ)], completed two coping style measures [Miller Behavioral Style Scale (MBSS) and Threatening Medical Situations Inventory (TMSI)], rated their perceived severity of colon cancer (low, moderate, high), and answered demographic questions. Eight hundred fifty‐five individuals provided usable data. Participants classified as monitors on the TMSI had significantly higher MCISQ scores (i.e., preferred more information) than those classified as blunters (p = .004). Those scoring high on monitoring and low on blunting on the MBSS preferred significantly more information than those scoring high on both monitoring and blunting (p = .04). Linear regression analysis revealed being a monitor (TMSI), scoring high on monitoring (MBSS), rating colon cancer as more severe, and having a higher education level were significant positive predictors of MCISQ scores. Results suggest individual differences in coping style, perceived severity, and education level affect desire for information. Genetic counselors should consider these patient characteristics (e.g., asking patients about their information preferences) and tailor their approaches accordingly.

Abstract Background: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening. Methods: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3–T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups. Results: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age. Conclusions: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS. Impact: Personalized genetic risk assessments could inform prostate cancer screening decisions.

Objectives: With over 2 million cases of acute respiratory failure in the United States per year, noninvasive ventilation has become a leading treatment modality, often supplanting invasive mechanical ventilation as the initial treatment of choice. Most acute respiratory failure patients use a full face (oronasal) mask with noninvasive ventilation, which is known to impair communication, but its popularity and benefit has led many providers to accept the communication impairment. Medical staff periodically remove masks to communicate with patients, but patients are often limited to short utterances and risk lung derecruitment upon removal of positive pressure. These problems can lead to noninvasive ventilation failure, which is often linked to worse outcomes than first initiating invasive mechanical ventilation and can lead to increased hospitalization costs. Data Sources: We searched MEDLINE and Google Scholar for “speech,” “communication,” “impairment,” “failure,” “complications,” “NIPPV,” “NIV,” and “noninvasive ventilation.” Study Selection: We included articles with patients in acute respiratory failure. We excluded articles for patients using noninvasive ventilation therapy for obstructive sleep apnea. Data Synthesis: Communication impairment has been associated with increasing noninvasive ventilation anxiety (odds ratio, 1.25). Of patients using noninvasive ventilation, 48% require early discontinuation, 22% refuse noninvasive ventilation, and 9% are ultimately intubated. Improvements to communication have been shown to reduce fear and anxiety in invasive mechanical ventilation patients. Analogous communication problems exist with effective solutions in other fields, such as fighter pilot masks, that can be easily implemented to enhance noninvasive ventilation patient care, increase adherence to noninvasive ventilation treatment, and improve patient outcomes. Conclusions: Communication impairment is an underappreciated cause of noninvasive ventilation complications and failure and requires further characterization. Analogous solutions—such as throat microphones and mask-based microphones—that can be easily implemented show potential as cost-effective methods to reduce noninvasive ventilation failure.

Abstract Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. Methods: We conducted a gene–environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case–control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10−6) was observed in the meta-analysis (PGxE = 1.2 ×10−6, PJoint = 4.2 ×10−7). Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. Impact: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

Purpose The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. Methods We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. Results The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. Conclusions We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

Background and Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 ( NBEAL ), 10q23.1 ( TSPAN14/FAM231A ), and 10q24.33 ( SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 ( NOS3 ) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.