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Purpose. To describe a temporal approach, digitally assisted phacovitrectomy in a patient with severe kyphosis due to axial spondyloarthritis. Case Report. A 70-year-old male patient with proliferative diabetic retinopathy with vitreous hemorrhage and cataract and ankylosing spondylitis with severe kyphosis. A temporal approach, digitally assisted 25 G phacovitrectomy was performed with a Constellation platform and the NGENUITY visualization system. The Trendelenburg position was utilized. Conclusion. A temporal approach, digitally assisted phacovitrectomy may be used in select cases of severe kyphosis with positive outcomes.

Objectives: Human papillomavirus (HPV) is a set of viruses that affects both men and women and is transmitted through vaginal, anal, or oral sex. Higher HPV literacy, such as knowledge about the disease and how it can be prevented, increases the likelihood of HPV vaccine uptake, thereby preventing the spread of HIV. In this study, we investigated the level of HPV literacy and the associated factors with HPV literacy among adults in Minnesota. Methods: A cross-sectional survey was completed with 733 adults aged 18 years and older. Application of Andersen’s Behavioral Model of Health Services Use, along with the conduction of multiple regression analysis, helped examined the factors associated with HPV literacy. Results: The mean score of HPV literacy of participants was 6.05 (SD = 1.50) out of a total possible 8 points. This study indicated age and race/ethnicity disparities regarding HPV literacy. Education, health insurance coverage, and self-reported health status significantly predicted HPV literacy. Conclusion: Future efforts are needed to improve HPV literacy among those who have lower education levels and lack insurance coverage. Additionally, lower scores on specific HPV literacy items suggest that health education should target more specific knowledge aiming to improve general HPV literacy.

Higher prevalence of cancer-related risk factors, for example, tobacco use, obesity, poor diet, and physical inactivity, is observed in the U.S. Deep South and likely contributes to its increased cancer burden. While this region is largely rural, it is unknown whether cancer-related beliefs and lifestyle practices differ by rural–urban status or are more influenced by other factors. We contacted 5,633 Alabamians to complete a cross-sectional survey to discern cancer-related beliefs and lifestyle practices, and compared data from respondents residing in rural- versus urban-designated counties. Findings were summarized using descriptive statistics; rural–urban subgroups were compared using two-tailed, χ2 and t tests. Multivariable logistic regression models were used to explore associations by rural–urban status and other sociodemographic factors. Surveys were completed by 671 rural- and 183 urban-county respondents (15.2% response rate). Overall, the prevalence for overweight and obesity (77.8%) and sugar-sweetened beverage intake (273–364 calories/day) was higher than national levels. Most respondents (58%) endorsed raising the state tobacco tax. Respondents from rural- versus urban-designated counties were significantly more likely to be racial/ethnic minority, have lower education, employment, income, food security, and internet access, and endorse fatalistic cancer-related beliefs ( Prevention Relevance: Cancer incidence and mortality are higher in the U.S. Deep South, likely due to increased tobacco-use, obesity, poor diet, and physical inactivity. This study explores whether cancer-related beliefs and lifestyle practices differ by rural-urban status or other sociodemographic factors in a random sample of 855 residents across Alabama.

Objective: Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States and associated with over 90% of cervical cancer cases. The present study aimed to examine levels of HPV and HPV vaccine awareness and associated factors, particularly English proficiency, across various racial/ethnic groups. Methods: Two cross-sectional datasets, 2017 and 2018 Health Information National Trends Survey (HINTs), were analyzed for the current study. Binary logistic regression analyses were conducted. Findings: Non-Hispanic Whites had the highest levels while non-Hispanic Asians had the lowest levels of awareness regarding HPV and the HPV vaccine. English proficiency was significantly associated with increased HPV awareness among all groups except non-Hispanic Asian, and was significantly associated with greater HPV vaccine awareness in all groups. Discussion: In order to promote health equity across race/ethnicity, language barriers among minorities should be addressed when implementing health education on HPV and the HPV vaccine.

Introduction: Mullerian malformations are a group of malformations that result from an alteration of embryonic development. Most cases are asymptomatic, however, in pregnant patients it has been associated with recurrent abortion or premature delivery. Case presentation: 12 + 2 weeks pregnant woman consulted for abdominal pain, vomiting and fever. During the study, a transvaginal ultrasound was performed, where two endometric cavities and a pregnancy in the right horn were observed. The evolution of the patient was torpid, reaching hypovolemic shock, resolved by an emergency laparotomy where the rupture of the right horn was found. Discussion: The bicornuate uterus is the consequence of a partial fusion of the paramesonephric ducts during the fetal development, resulting in two functional uterine horns. Patients with bicornuate uterus may be asymptomatic, a uterine rupture is a rare but potentially severe complication of the bicornuate uterus and is usually presented during first and second trimester. Conclusions: Pregnancy with Mullerian anomalies often has preterm delivery, IUGR and malpresentation, and even more severe complication as uterine ruptura, so, requires proper counselling and close monitoring during antenatal period.

The image quality limitations of echo-planar diffusion-weighted imaging (DWI) are an obstacle to its widespread adoption in the breast. Steady-state DWI is an alternative DWI method with more robust image quality but its contrast for imaging breast cancer is not well-understood. The aim of this study was to develop and evaluate diffusion-weighted double-echo steady-state imaging with a three-dimensional cones trajectory (DW-DESS-Cones) as an alternative to conventional DWI for non-contrast-enhanced MRI in the breast. This prospective study included 28 women undergoing clinically indicated breast MRI and six asymptomatic volunteers. In vivo studies were performed at 3 T and included DW-DESS-Cones, DW-DESS-Cartesian, DWI, and CE-MRI acquisitions. Phantom experiments (diffusion phantom, High Precision Devices) and simulations were performed to establish framework for contrast of DW-DESS-Cones in comparison to DWI in the breast. Motion artifacts of DW-DESS-Cones were measured with artifact-to-noise ratio in volunteers and patients. Lesion-to-fibroglandular tissue signal ratios were measured, lesions were categorized as hyperintense or hypointense, and an image quality observer study was performed in DW-DESS-Cones and DWI in patients. Effect of DW-DESS-Cones method on motion artifacts was tested by mixed-effects generalized linear model. Effect of DW-DESS-Cones on signal in phantom was tested by quadratic regression. Correlation was calculated between DW-DESS-Cones and DWI lesion-to-fibroglandular tissue signal ratios. Inter-observer agreement was assessed with Gwet’s AC. Simulations predicted hyperintensity of lesions with DW-DESS-Cones but at a 3% to 67% lower degree than with DWI. Motion artifacts were reduced with DW-DESS-Cones versus DW-DESS-Cartesian (p < 0.05). Lesion-to-fibroglandular tissue signal ratios were not correlated between DW-DESS-Cones and DWI (r = 0.25, p = 0.38). Concordant hyperintensity/hypointensity was observed between DW-DESS-Cones and DWI in 11/14 lesions. DW-DESS-Cones improved sharpness, distortion, and overall image quality versus DWI. DW-DESS-Cones may be able to eliminate motion artifacts in the breast allowing for investigation of higher degrees of steady-state diffusion weighting. Malignant breast lesions in DW-DESS-Cones demonstrated hyperintensity with respect to surrounding tissue without an injection of contrast. LEVEL OF EVIDENCE: 2. TECHNICAL EFFICACY STAGE: 1.

Human papillomavirus (HPV) is recognized as a leading cause of multiple types of cancer. The current study examined HPV knowledge level and its associated factors, especially its relationship with HPV vaccine awareness, across race/ethnicity, including non-Hispanic White, non-Hispanic African American, and Hispanic.Cross-sectional data were merged from Cycles 1 (2017) and Cycle 2 (2018) of the National Cancer Institute (NCI) Health Information National Trends Survey 5 (HINTS5, totalOverall HPV knowledge level among participants was low (Mean = 1.68; SD = 1.44; range 0-4). Among three racial/ethnic groups, non-Hispanic African American had the lowest level of HPV knowledge (Mean = 1.51). Less than 30% answered correctly to each of the three items assessing knowledge of HPV-associated (HPVa) cancers other than cervical (e.g. if HPV can cause penile, anal, and/or oral cancer). The HPV vaccine awareness was significantly associated with HPV knowledge across all three racial/ethnic groups.The lowest level of HPV knowledge among non-Hispanic African American suggests that HPV education is urgently needed for this population. Specific interventions should emphasize information regarding HPVa cancers other than cervical cancer. Additionally, promoting awareness of the HPV vaccine will help to improve HPV knowledge among general population. Lastly, various factors associated with HPV knowledge across different racial/ethnic groups need to be addressed when implementing HPV education programs.

Background Posterior tibial tendon dysfunction (PTTD) is a common and debilitating tendinopathy that can lead to a profound decrease in gait function. While the clinical diagnosis and treatment of this disorder are well described, the pathomechanics have not been adequately characterized. The purpose of this systematic review and meta-analysis is to compare foot/ankle kinematics and kinetics in patients with PTTD with healthy controls during gait. Methods Relevant articles were selected thought Medline (Pubmed), Scopus, CINAHL, and Web of Science. Studies focused on foot/ankle kinematics and kinetics in patients with PTTD were involved. Articles were included if they: 1) compared patients with PTTD to healthy controls, 2) utilized kinematics or kinetics as the primary outcome measure, 3) evaluated gait tasks, and 4) were written in English. Results Eleven articles were included in this systematic review, and 8 studies were synthesized and analyzed. Our meta-analyses indicated increased dorsiflexion and abduction of the forefoot, as well as increased plantarflexion and eversion of hindfoot for patients with PTTD during stance of walking. Conclusion Our results from the meta-analysis showed more conclusive changes in the forefoot (increased dorsiflexion and abduction) and hindfoot (increased plantarflexion and eversion) kinematics during stance of walking, which may be associated with a pathological process of PTTD. This review provides an improved understanding of gait function in patients with PTTD and preliminary knowledge for future research.

To evaluate imaging characteristics, outcome of surgical excision or imaging follow-up on high-risk lesions diagnosed at MRI-guided vacuum-assisted breast biopsy (MRI-VABB). We retrospectively reviewed 598 lesions undergoing 9-gauge MRI-VABB from January 2015 to April 2018 to identify high risk breast lesions. We collected patient demographics, breast MRI BI-RADS descriptors, histopathological diagnosis at MRI-VABB and surgical excision, frequency of upgrade to malignancy and imaging follow-up of high-risk lesions. The x2 test and Fisher exact tests were performed for univariate analysis. 114 patients with 124/598 findings (20.7%) had high-risk lesions at MRI-VABB, including atypical ductal hyperplasia (ADH) (21/124, 16.9%), lobular neoplasia (40/124, 32.3%), radial scar/complex sclerosing lesion (RS/CSL) (13/124, 10.5%), papillary lesions (49/124, 39.5%), and flat epithelial atypia (FEA) (1/124, 0.8%). 84/124 (67.7%) high-risk lesions were excised. 19/84 (22.6%) were upgraded to malignancy (7 invasive cancer, 12 DCIS). The upgrade rate for ADH and lobular neoplasia was 7/18 (38.9%) and 9/31 (29.0%), respectively. The upgrade rate for RS/CSL was 1/10 (10%). Of the 25 papillary lesions excised, 2 (8%) demonstrated pathologic atypia and were upgraded to DCIS. The other 23 papillary lesions had no upgrade or atypia. Excised high-risk lesions showing upgrade varied from 0.4 to 6 cm in length (mean 1.6 cm). There was a non-significant trend (p = 0.054) between larger lesion and upgrade to malignancy; however, there were no other specific imaging features to predict malignancy upgrade. There were no specific MRI imaging characteristics of high-risk lesions to predict malignancy upgrade. Therefore, surgical excision is recommended for high-risk lesions, especially ADH or lobular neoplasia.

BACKGROUND: The cardiac sodium channel (SCN5A) mutation, R222Q, neutralizes a positive charge in the domain I voltage sensor. Mutation carriers display very frequent ectopy and dilated cardiomyopathy (DCM). OBJECTIVES: To describe the effect of SCN5A R222Q on murine myocyte and Purkinje fiber electrophysiology, and identify underlying mechanisms. METHODS: We generated mice carrying humanized wild-type (H) and mutant (RQ) SCN5A channels. We characterized whole heart and isolated ventricular and Purkinje myocyte properties. RESULTS: RQ/RQ mice were not viable. I(Na) from RQ/H ventricular myocytes displayed increased “window current” and hyperpolarizing shifts in both inactivation and activation compared to H/H, as previously reported in heterologous expression systems. Surprisingly, action potentials were markedly abbreviated in RQ/H myocytes (APD90: 12.6±1.3 ms versus 29.1±1.0 ms in H/H, p

Oxalobacter formigenes, a unique anaerobic bacterium that relies solely on oxalate for growth, is a key oxalate-degrading bacterium in the mammalian intestinal tract. Degradation of oxalate in the gut by O. formigenes plays a critical role in preventing renal toxicity in animals that feed on oxalate-rich plants. The role of O. formigenes in reducing the risk of calcium oxalate kidney stone disease and oxalate nephropathy in humans is less clear, in part due to difficulties in culturing this organism and the lack of studies which have utilized diets in which the oxalate content is controlled. Herein, we review the literature on the 40th anniversary of the discovery of O. formigenes, with a focus on its biology, its role in gut oxalate metabolism and calcium oxalate kidney stone disease, and potential areas of future research. Results from ongoing clinical trials utilizing O. formigenes in healthy volunteers and in patients with primary hyperoxaluria type 1 (PH1), a rare but severe form of calcium oxalate kidney stone disease, are also discussed. Information has been consolidated on O. formigenes strains and best practices to culture this bacterium, which should serve as a good resource for researchers.

Background: Nonunion following hindfoot arthrodesis may be caused by failure to maintain compression at the arthrodesis site. The ability of lag screws, commonly used in arthrodesis, to maintain compression in hindfoot bones has not been well characterized. The aim of this work was to quantify the stress relaxation response of hindfoot bone with initial and repeated compression with a lag screw. Methods: Ten sets of 25-mm-diameter bone cylinders were cut from the talus and calcaneus in fresh-thawed cadaveric feet. A load cell was compressed between cylinders with an 8.0-mm partially threaded cannulated lag screw simulating arthrodesis. For 7 sets, screws were tightened by 3 quarter-turns, rested for 3 minutes, retightened 1 quarter-turn, and rested for 30 minutes. Three sets served as controls in which screws were not retightened. Results: Maximum compression after initial screw tightening and retightening averaged 275 and 337 N ( P = .07), respectively. Compression 3 minutes after initial screw tightening and retightening averaged 199 and 278 N ( P = .027), respectively. The compression recorded 3 minutes after screw retightening was an average of 40% higher than that recorded 3 minutes after initial tightening. The average compression 30 minutes after screw retightening was 255 N, a compression loss of 25% from the average maximum compression after retightening. Eighty percent of this compression loss happened in an average of 5.5 minutes. Conclusion: Hindfoot bones exhibit compression loss over time during simulated arthrodesis. Compression maintenance in bone is improved with screw retightening. Further work is needed to understand the mechanism of action and determine optimum time for recompression. Clinical Relevance: Retightening lag screws before wound closure may improve compression at the arthrodesis site and thereby decrease the chance of nonunion. Level of Evidence: N/A, laboratory experiment.

[Image: see text] Myotonic dystrophy type 1 originates from d(CTG·CAG) repeats that undergo aberrant expansion during normal processing because the d(CTG) repeat forms stable hairpin structures. Bidirectional transcription of d(CTG·CAG) yields two RNA transcripts that undergo repeat-associated non-ATG (RAN) translation to form homopolymeric proteins. Thus, both the r(CUG) transcript and the r(CAG) transcript are known to be toxic. We report a pairwise fragment-based, target-guided approach to screen for proximity-induced click dimers formed on the nucleic acid template. This screen uses an azide/alkyne clickable fragment library of nucleic acid-binding ligands incubated in parallel, pairwise reactions as an alternative to our previously reported one-pot screening method. MALDI-TOF mass spectroscopy was used to detect template assisted click products. Hit compounds inhibited the in vitro transcription of d(CTG·CAG)(90) bidirectionally with IC(50) values in the low micromolar range. This approach may be broadly applicable to other trinucleotide repeat diseases and in targeting other disease-associated nucleic acid sequences.

In addition to being the most common sexually transmitted infection, the human papillomavirus (HPV) is associated with six types of cancer in men and women. The HPV vaccine provides long-lasting, effective protection from high-risk HPV infection, thus serving as a means of cancer prevention. An effective healthcare provider recommendation is well-established as the most significant influence on HPV vaccine uptake, and, as emerging providers, it is critical that medical students receive comprehensive training in this area. However, the type and extent of such training for current medical students in the USA is unclear. An online survey assessing HPV and HPV vaccine knowledge, attitudes, and vaccine status was distributed to all medical students at an Alabama university. Scales were developed to assess composite HPV and HPV knowledge scores and HPV vaccination intentions. Of those age-eligible, 32.1% reported completion of the HPV vaccine series while 15.2% reported partial completion. Knowledge of both HPV and HPV vaccination significantly increased with program year (p

Despite availability of a safe, effective vaccination, uptake and completion rates of human papillomavirus (HPV) vaccination remain low in the United States. This is particularly true in the southeast, which also sees some of the highest rates of HPV-associated (HPVa) cancers. We aimed to identify areas in Alabama in need of intervention with respect to HPVa cancers and HPV vaccination, and factors potentially associated with these rates by performing county-level secondary data analysis using state and national data sources. Alabama ranks 15th nationally in HPVa cancer rates, with 66.7% and 80.8% of counties having higher HPVa cancer rates than the national incidences of males and females, respectively. Regarding HPV vaccination, 95.5% and 98.5% of Alabama's counties have uptake rates less than the national averages for males and females, respectively. The seven counties with the highest HPV vaccination uptake ranged in rates from 60.2 to 73.6%. Counties with the highest HPV vaccination rates for adolescents were majority African American with low adult educational attainment rates and high rates of poverty and publicly-insured children/adolescents. These counties were also located in Alabama's Black Belt region, traditionally known for low socioeconomics, reduced access to social services, and negative health outcomes. Some counties with the highest rates of HPVa cancers also had among the highest rates of HPV vaccination, indicating a potential association between perceived susceptibility and desire to get HPV vaccine in these communities, warranting further investigation. Future work is needed to translate these findings into actionable intervention practices to increase HPV vaccination.

Introduction Although FDA approved for over 10 years, uptake of the human papillomavirus (HPV) vaccination has been slow, particularly among states in the Deep South with high cervical cancer incidence and mortality. The purpose of this study was to explore variables associated with cervical cancer among survivors who were age-eligible for the HPV vaccine and to assess HPV vaccination history, barriers, perceptions, and other associated behaviors within this cohort. Methods A mixed methods strategy was used for the study, first identifying eligible cervical cancer survivors from our institution and abstracting demographic and clinicopathologic medical record data. Twenty-three participants from this cohort then completed semi-structured qualitative telephone interviews regarding HPV vaccination participation, knowledge, and attitudes. Interviews were audio-recorded, transcribed, and analyzed using thematic content analysis. Results Of the 464 cervical cancer patients treated at our institution from 2011 to 2016, 137 (30%) were under age 40 at diagnosis. Seventy-seven women with invasive disease were identified (median age = 33 years), and 56% had been seen by a gynecologist within 5 years of diagnosis. Forty-six of these women met eligibility criteria for inclusion in the qualitative interview, of which 23 successfully completed (response rate = 50%). Of those interviewed, the majority (84%) reported current access to regular medical care. While 90.9% did not receive any doses of HPV vaccination, 78.3% stated they likely would have been vaccinated if it had it been recommended. Four major themes were identified within the interviews: HPV knowledge, vaccine acceptability, healthcare engagement, and provider communication. Conclusions Qualitative interviews revealed significant missed opportunities for prevention since most participants stated they would have been vaccinated if given the option. Substantial gaps in knowledge and mixed understanding HPV’s association with cervical cancer were observed, demonstrating potential missed opportunities for education and communication between providers of multiple specialties and their patients.

Refractory ceramic fibers (RCFs) are amorphous fibers that belong to a class of materials termed synthetic vitreous fibers (SVFs), also called man-made mineral fibers (MMMFs), which includes alkaline earth silicate wool, glass wool, rock (stone) wool, slag wool, and special-purpose glass fibers. RCFs are more durable and biopersistent than several other SVFs, although very much less biopersistent than either amosite or crocidolite asbestos. Chronic inhalation studies indicated that rats and hamsters exposed to RCF fibers developed fibrosis and tumors. Epidemiological studies at the University of Cincinnati funded by the Industry indicated that exposed workers; (1) exhibited symptoms (e.g., dyspnea) similar to those reported in other dust-exposed populations, (2) developed statistically, but not clinically, significant deficits in certain measures of pulmonary function in a cross sectional study, but no excessive decline in a longitudinal study, and (3) a dose related increase in pleural plaques, but no interstitial fibrosis. The 2003 mortality study indicated no incremental lung cancer and no cases of mesothelioma. RCF producers developed a comprehensive industry wide product stewardship program (PSP) beginning in the late 1980s. In conjunction with the PSP, there has been a progressive decrease in the TWA concentration of fibers by manufacturers and end-users. The research program has successfully produced more soluble fibers and undertaken efforts to develop larger diameter fibers. The results of the ongoing epidemiology studies confirm that occupational exposure to RCF is associated with the development of pleural plaques and minor decrements in lung function, but no interstitial fibrosis or incremental lung cancer.

Chemotherapy has limited success in the treatment of malignant melanoma due to fast development of drug resistance and the low bioavailability of chemotherapeutic drugs. Resveratrol (RES) is a natural polyphenol with recognized preventive and therapeutic anti-cancer properties. However, poor RES solubility hampers its bioactivity, thus creating a demand for suitable drug delivery systems to improve it. This work aimed to assess the potential of RES-loaded mesoporous silica nanoparticles (MSNs) for human melanoma treatment. RES was efficiently loaded (efficiency &gt, 93%) onto spheroidal (size~60 nm) MSNs. The encapsulation promoted the amorphization of RES and enhanced the release in vitro compared to non-encapsulated RES. The RES release was pH-dependent and markedly faster at pH 5.2 (acid environment in some tumorous tissues) than at pH 7.4 in both encapsulated and bulk forms. The RES release from loaded MSNs was gradual with time, without a burst effect, and well-described by the Weibull model. In vitro cytotoxicity studies on human A375 and MNT-1 melanoma cellular cultures showed a decrease in the cell viability with increasing concentration of RES-loaded MSNs, indicating the potent action of the released RES in both cell lines. The amelanotic cell line A375 was more sensitive to RES concentration than the melanotic MNT-1 cells.

Category: Diabetes; Ankle; Diabetes; Hindfoot Introduction/Purpose: Charcot neuroarthropathy of the hindfoot (Brodsky type 2 and 3) can involve significant talar collapse / bone loss leading to hindfoot instability, the goal of treatment to create a stable plantigrade shoeable ulcer and infection free foot. This can often be achieved with tibiotalocalcaneal (TTC) arthrodesis but a plantigrade foot can be challenging in setting of significant talar bone loss. Structural allograft has been used in association with TTC fusions in a number of settings but not explored in the treatment of charcot hindfoot. The goal of this study was to examine the outcomes of structural allografting combined with TTC arthrodesis for the treatment of charcot hindfoot. Methods: Retrospective review of all patients treated at our institution with a Brodsky type 2 or 3 was performed over a five year period from 2014 - 2019. We identified twenty-two patients, 12 males and 10 females with a mean age of 57 years. All underwent surgery by the senior author, a fellowship trained foot and ankle orthopedic surgeon. Patients with infection were treated with antibiotics and a Taylor spatial frame prior to definitive stabilization. Non-infected patients were either placed in a total contact cast (TCC) if they were in active charcot or underwent primary charcot reconstruction. If after initial treatment patients had a plantigrade foot, they were placed in stiff soled rocker bottom shoe with custom accommodative insoles. Patients who did not have a plantigrade foot underwent TTC arthrodesis to achieve this. Femoral head allograft was used if excessive talar bone loss or collapse of the hindfoot was noted. Results: At final follow up 13 patients (59%) of the cohort achieved grade 1, an infection and ulcer free plantigrade foot that was able to fit in a shoe. 7 (32%) of patients achieved grade 2, a plantigrade foot in brace, and 2 (9%) achieved level 3 a plantigrade foot. No patients in this cohort underwent amputation. Average duration of treatment until final status was 18 months (minimum 2, maximum 37), number of interventions 3.9 (minimum 1, maximum 10). Of the twelve patients who required allograft, they averaged 4.25 interventions and average time of 17.6 months until final status. Of those who did not require allograft, they averaged 3.4 interventions with follow up of 11.9 months. Conclusion: Our data suggests that patients with Brodsky type 2 and 3 charcot arthropathy of the ankle and hindfoot even with infection can be successfully treated with staged treatment. This includes external fixation and infection management, followed by tibiotalocalcaneal intramedullary nail fixation with or without femoral head allograft to allow for a plantigrade foot and weight bearing in a stiff soled rocker bottom shoe. Further study is needed to determine long term outcomes and relapse rates.

Background Spherical nucleic acids (SNAs) are nanostructures consisting of radially oriented, densely packed oligonucleotides arranged in a spherical 3D architecture. SNAs have different properties than linear oligonucleotides, including increased cellular uptake, which may enhance efficacy. Cavrotolimod (AST-008) is an SNA toll-like receptor 9 (TLR9) agonist designed to robustly activate innate and adaptive immune responses. Cavrotolimod is in development for the treatment of advanced solid tumors in combination with PD-1 blockade. Prior studies demonstrated that cavrotolimod, alone and in combination with PD-1 blockade, increased circulating levels of Th1-type cytokines and activated peripheral T cells and NK cells. Methods AST-008-102 is an ongoing Phase 1b/2 study (NCT03684785). The Phase 1b dose escalation stage examined intratumoral (IT) cavrotolimod at doses of 2, 4, 8, 16, and 32 mg in combination with pembrolizumab in patients with advanced solid tumors. Cavrotolimod was dosed once weekly for 8 weeks and once every 3 weeks thereafter. The Phase 2 dose expansion stage is examining cavrotolimod 32 mg IT in combination with IV pembrolizumab for the treatment of advanced Merkel cell carcinoma (MCC) and in combination with IV cemiplimab for the treatment of advanced cutaneous squamous cell carcinoma (CSCC). Both cohorts are enrolling patients with documented progression of disease on PD-(L)1 blockade. This analysis provides interim results of the Phase 1b stage. Results In the Phase 1b stage, 20 patients were enrolled across all planned dose levels. No dose-limiting toxicities, grade (G)4 toxicities, or treatment-related serious adverse events (AEs) were observed. The most common AEs were injection site reactions (ISRs) and flu-like symptoms. All treatment-related AEs were Conclusions IT administration of cavrotolimod appears to be safe and well tolerated in combination with pembrolizumab. Durable responses have occurred in patients previously experiencing progressive disease on PD-1 blockade. Trial Registration NCT03684785 Ethics Approval The study was approved by Institutional Review Boards of Dana-Farber Cancer Institute (IRB #18-584), John Wayne Cancer Institute (WIRB #20183064), University of Miami (IRB #20180957), University of Iowa (IRB #201810763), University of Cincinnati (WIRB #20183064), University of Washington (WIRB #20183064), MSKCC (IRB #20-174), UC San Francisco (WIRB #20183064), U Colorado (WIRB #20183064), Northwestern (IRB #STU00211083), U Arizona (WIRB #20183064), UC Irvine (WIRB #20183064), U Pitt (WIRB #20183064), and Washington University (WIRB #20183064).

Osteosarcoma (OS) patients exhibit poor overall survival, partly due to copy number variations (CNVs) resulting in dysregulated gene expression and therapeutic resistance. To identify actionable prognostic signatures of poor overall survival, we employed a systems biology approach using public databases to integrate CNVs, gene expression, and survival outcomes in pediatric, adolescent, and young adult OS patients. Chromosome 8 was a hotspot for poor prognostic signatures. The MYC-RAD21 copy number gain (8q24) correlated with increased gene expression and poor overall survival in 90% of the patients (n = 85). MYC and RAD21 play a role in replication-stress, which is a therapeutically actionable network. We prioritized replication-stress regulators, bromodomain and extra-terminal proteins (BETs), and CHK1, in order to test the hypothesis that the inhibition of BET + CHK1 in MYC-RAD21+ pediatric OS models would be efficacious and safe. We demonstrate that MYC-RAD21+ pediatric OS cell lines were sensitive to the inhibition of BET (BETi) and CHK1 (CHK1i) at clinically achievable concentrations. While the potentiation of CHK1i-mediated effects by BETi was BET-BRD4-dependent, MYC expression was BET-BRD4-independent. In MYC-RAD21+ pediatric OS xenografts, BETi + CHK1i significantly decreased tumor growth, increased survival, and was well tolerated. Therefore, targeting replication stress is a promising strategy to pursue as a therapeutic option for this devastating disease.

Objective: Cancer mortality in the U.S. Deep South exceeds national levels. A cross-sectional survey was undertaken across Alabama to discern cancer beliefs and screening practices, and compare data from racial/ethnic minority versus majority and rural versus urban respondents. Methods: Using population-based methods, we approached 5,633 Alabamians (ages 50-80) to complete a 58-item survey (administered in-person, via telephone, or the web). Descriptive statistics were used to summarize findings; two-tailed, chi-square and t-tests (α90% indicated stable housing, and healthcare coverage and access. Rural and minority versus urban and majority respondents were significantly more likely to have lower education, employment, and income, respectively. Most respondents equated cancer as a “death sentence” and were unable to identify the age at which cancer screening should begin. Few rural-urban subgroup differences were noted, though significant differences were observed between minority versus majority subgroups for mammography (36.7% versus 49.6%, p

Cisplatin has demonstrated extraordinary anticancer activity against a variety of solid tumors. However, its clinical efficacy is contrasted by its toxicity profile. Having in mind the need to reduce the toxicity, promote a sustained release and enhance the body-circulation time of cisplatin, herein novel nanocarriers consisting of core–shell silica-coated iron oxide nanoparticles functionalized with dicarboxylic acid groups were prepared and characterized. Cisplatin was conjugated with the functionalized nanoparticles by surface tethering. Controlled release of cisplatin was observed without burst effect and in a sustained profile for up to 3 days. In vitro studies showed cytotoxic and antiproliferative effects of the cisplatin nanoconjugates against a human pancreatic cancer cell line. Importantly, when compared with free cisplatin, nanoconjugates exhibited lower cytotoxic effects regarding nonmalignant human duct pancreatic cells.

Muscle’s function within an organism depends on the feedback between molecular to meter-scale processes. While the motions of muscle’s contractile machinery are well described in isolated preparations, only a handful of experiments have documented the kinematics of the lattice occurring when multi-scale interactions are fully intact. We used time-resolved x-ray diffraction to record the kinematics of the myofilament lattice within a normal operating context: the tethered flight ofManduca sexta. Since the primary flight muscles ofManduca sextaare synchronous, we used these results to reveal the timing ofin vivocross-bridge recruitment, which occurred 24 (s.d. 26) ms following activation. In addition, the thick filaments stretched an average of 0.75 (s.d. 0.32)% and thin filaments stretched 1.11 (s.d. 0.65)%. In contrast to otherin vivopreparations, lattice spacing changed an average of 2.72 (s.d. 1.47)%. Lattice dilation of this magnitude significantly impacts shortening velocity and force generation, and filament stretching tunes force generation. While kinematics were consistent within individual trials, there was extensive variation between trials. Using a mechanism-free machine learning model we searched for patterns within and across trials. While lattice kinematics were predictable within trials, the model could not create predictions across trials. This indicates that the variability we see across trials may be explained by latent variables occurring in this naturally functioning system. The diverse kinematic combinations we documented mirror muscle’s adaptability and may facilitate its robust function in unpredictable conditions.

Successful identification of an enlarged parathyroid gland (or at least a dominant, normal-size gland)—the only gland of interest 80% of the time—directs the initial approach for minimally invasive surgery. Identification of additional enlarged parathyroid glands (double adenomas or hyperplasia) prior to surgery allows the surgeon to plan a four-gland exploration but is a tougher radiologic task. Identification of a possible ectopic mediastinal gland (sometimes a supernumerary gland) is essential knowledge for the surgeon no matter what the planned surgery. Contrast CT scan supplemented by ultrasound can provide an excellent set of initial screening studies though there are difficulties in separating the enlarged parathyroid glands from abnormal thyroid tissue. Sestamibi scan is helpful in post surgical cases.

Enhancing parathyroid tissue must be separated from similar enhancing lobulations or excrescences of normal thyroid tissue and thyroid nodules. Most false positives on contrast CT are due to thyroid nodules or lobulations of thyroid tissue. The high density of iodine content on precontrast images identifies normal thyroid tissue and iodine rich nodules. Iodine depleted thyroid nodules may be echogenic on ultrasound, distinguishing them from echopoor parathyroid tissue. Autoimmune chronic thyroiditis tissue has the same appearance as parathyroid tissue on both CT and ultrasound and results in false positive and false negative studies. Subcapsular parathryoids are easily obscured by streak artefacts and grainy images. Large multinodular goiters obscure enlarged parathyroid glands by compression and large number of confounding nodules. Active hyperemic lymph nodes may mimick enlarged parathyroid glands, or obscure their presence if numerous. Vessels may obscure ectopic enlarged parathyroid glands.

Pre-contrast phase is essential to help distinguish thyroid tissue from parathyroid tissue by equating high density to iodine content. This is particularly important for distinguishing subcapsular parathyroid glands, but it is also critical in identifying ectopic rests of thyroid tissue. Arterial phase is performed during contrast infusion that starts 20–45 seconds from the start of a rapid 3 or 4 cc/second infusion of contrast followed by a saline flush. A parathyroid adenoma or enlarged parathyroid gland is bright on arterial phase and is picked out as a bright spot on scrolling through the images. The focus of attention is medial to the carotid arteries, since parathyroid glands almost always lie medial to or towards medial aspect of the normal carotid arteries. Venous phase is usually started 60–90 seconds following the start of the infusion or 30 seconds after the arterial phase, in different protocols. Some protocols use both 60 and 90 second runs (3 post contrast phases) which may be helpful when rate of opacification is not optimal. The parathyroid gland or adenoma washes out in the venous phase, distinguishing it from enhancing nodes, which usually have no washout or increase in enhancement.

International audience; Objective: Adult onset Still's disease (AOSD) is an inflammatory disorder characterized by high spiking fever, evanescent rash, polyarthritis, and many other systemic manifestations. Recurrent or persistent disease can lead to AA amyloidosis (AAA). Our objectives were to present 3 French cases and perform a systematic review of the literature, in order to determine the prevalence, characteristics, predisposing factors, and therapeutic response of AOSD-related AAA.Methods: A systematic literature review was performed by searching MEDLINE from 1971 to 2018. Two independent investigators selected reports of AAA complicating AOSD. New French cases were identified with the help of the Reference Center for rare Auto-Inflammatory Diseases and Amyloidosis (CEREMAIA). Patients with juvenile idiopathic arthritis were excluded.Results: The prevalence of AAA in AOSD was 0.88% (95%CI [0.49-1.28]) based on 45 articles. In addition to 3 new cases from the CEREMAIA, 16 patients were assessed for clinical presentation, risk factors, and therapeutic response of AOSD-related AAA. Mean age at AOSD onset was 29.6 ± 12.6 years, with a mean delay before AAA diagnosis of 16.75±5.8 years. Renal involvement was the most common manifestation of AAA. The majority of patients presented active AOSD at AAA diagnosis. Various treatments of AOSD-related AAA were attempted including corticosteroids and biotherapies.Conclusion: AAA is a rare and severe complication that may occur during the course of uncontrolled active AOSD. It could be prevented by early diagnosis and better control of AOSD, with more frequent use of biotherapies.

Minimally invasive parathyroidectomy guided by noninvasive localization studies has become the standard surgical approach to primary hyperparathyroidism. About 80% of the time, primary hyperparathyroidism is due to a solitary parathyroid adenoma, so accurate identification on screening studies will usually result in the desired limited surgery, verified by a drop of intraoperative parathormone level. The limited surgery may be converted to a four-gland exploration if the intraoperative parathormone does not drop. Four-gland exploration will be planned if multigland disease is diagnosed (or highly suspect) or if all studies are negative. If a mediastinal adenoma is diagnosed and no enlarged parathyroid gland is identified in the neck, mediastinal surgery is performed before a neck exploration. Ultrasound, sestamibi scan, contrast CT scan, and MRI are the noninvasive modalities available to find the starting point in evaluating patients with clinically diagnosed primary hyperparathyroidism.

Rare parathyroid lesions: (1) Cystic parathyroid lesions are uncommon. The cyst may be functional (with the presence of clinical primary hyperparathyroidism) or nonfunctional. Most functional parathyroid cysts are cystic degeneration or hemorrhage into a parathyroid adenoma derived from superior or inferior glands. Nonfunctional cysts, which are quite rare, are derived from inferior parathyroid glands and may be found in the mediastinum. (2). Parathyroid carcinoma is very rare but may be diagnosed if there is clear invasion of adjacent structures. Carcinoma should be considered if the adenoma is quite large, has calcification and has irregular, poorly defined margins. (3) Parathyroid lipoadenoma is a rare lesion consisting of nests of parathyroid parenchyma (chief cells and some oncocytic cells) in mature adipose tissue. These have predominantly fat character on CT and ultrasound and require a positive sestamibi scan for identification. (4) Parathyromatosis may result from seeding of cells during surgery or overgrowth from embryologic parathyroid rests. In postsurgical setting sestamibi scan is essential to distinguish small nodules of parathyroid tissue from scar. (5) Water-clear cell hyperplasia and adenomas is a very rare entity of proliferated vacuolated water-clear cells, which have abundant cytoplasmic glycogen. The glycogen content may give rise to unusual CT and ultrasound features.

Long-term follow-up is needed to evaluate the impact of short-term cancer research programs on the career trajectories of medical and graduate students. Participation in these programs may be crucial in fostering the next generation of cancer research scientists. This report presents the career outcomes and research productivity of 77 medical and public health students with 25 years of tracking data following their participation in a summer cancer research training program at the University of Alabama at Birmingham (UAB) in 1990-1998. Of 64 summer trainees with contact information, complete survey responses were received from 55 (86.0%) individuals. Over half reported clinical care of cancer patients and 18.2% stated that they were engaged in cancer research. Literature searches confirmed that 23.4% (18/77) of trainees have published cancer research papers. Future studies should explore the optimal timing of short-term post-baccalaureate academic cancer training experiences to identify participant characteristics and institutional factors that influence career choices and determine research productivity.

This literature review on refractory ceramic fibers (RCF) summarizes relevant information on manufacturing, processing, applications, occupational exposure, toxicology and epidemiology studies. Rodent toxicology studies conducted in the 1980s showed that RCF caused fibrosis, lung cancer and mesothelioma. Interpretation of these studies was difficult for various reasons (e.g. overload in chronic inhalation bioassays), but spurred the development of a comprehensive product stewardship program under EPA and later OSHA oversight. Epidemiology studies (both morbidity and mortality) were undertaken to learn more about possible health effects resulting from occupational exposure. No chronic animal bioassay studies on RCF have been conducted since the 1980s. The results of the ongoing epidemiology studies confirm that occupational exposure to RCF is associated with the development of pleural plaques and minor decrements in lung function, but no interstitial fibrosis or incremental lung cancer. Evidence supporting a finding that urinary tumors are associated with RCF exposure remains, but is weaker. One reported, but unconfirmed, mesothelioma was found in an individual with prior occupational asbestos exposure. An elevated SMR for leukemia was found, but was absent in the highly exposed group and has not been observed in studies of other mineral fibers. The industry will continue the product stewardship program including the mortality study.

Despite well-established links between exposure to ultraviolet radiation (UVR) and skin cancer, UVR-based tanning behaviors persist among college students. Understanding tanning motivations, perceptions, barriers, and demographic characteristics of this population is critical to modifying these behaviors, but is limited by variability in study design, sample size, and outcomes measured in the current literature. To help clarify the tanning behaviors of this population and provide a concise reference for future studies, this review examines existing reports to determine the comparability of tanning behaviors across multiple U.S. college populations. A systematic review of the literature was performed in July 2016 to identify studies investigating tanning behaviors among U.S. college students. Twenty-three studies met inclusion criteria. High rates of indoor tanning (IT) and outdoor tanning (OT) were found among college students. Key motivators included appearance, emotion, health perceptions, and the influence of parents, peers, and the media. Misconceptions regarding skin protection, low rates of sun protective behaviors, and tanning dependence were barriers against safe UVR exposure. Understudied demographic factors may account for variance in observed tanning behaviors, emphasizing the need for standardization efforts to consistently identify trends associated with geographical region, age, year in college, and sex. The findings presented in this review reaffirm that college students are at high risk for tanning-associated skin cancer, emphasizing the critical need for effective, targeted interventions. Improved interventions will reduce the burden of skin cancer within this group, ultimately contributing to longer, healthier lives.

BACKGROUND Diminished use and worse outcomes after immediate breast reconstruction (IBR) have been documented for Medicaid beneficiaries. However, to the authors' knowledge, the contribution of patient clustering at hospitals with a high percentage of Medicaid patients to these inequalities in IBR delivery is unknown. METHODS A cross-sectional analysis of patients undergoing IBR after mastectomy using the 2007 to 2011 Nationwide Inpatient Sample database was performed. Hospital Medicaid status was calculated as the percentage of all patients with Medicaid as a primary payer. Tertile groupings were generated to enable statistical analysis. Hierarchical regression models were used to investigate the link between Medicaid status and IBR use, outcomes, and costs. A subgroup of patients undergoing IBR for noninvasive cancer or those with increased genetic risk were used to study IBR use. RESULTS A total of 30,086 IBR cases in 1199 hospitals were analyzed. Hierarchical regression analysis demonstrated an association between high Medicaid burden hospitals and significantly decreased odds of IBR among patients with in situ disease and/or an elevated risk of cancer (odds ratio, 0.64; 95% confidence interval [95% CI], 0.507-0.806). Increasing age, obesity, being nonwhite, having more comorbid conditions, and having government insurance were found to be associated with diminished odds of IBR (P

Infection during pregnancy is common and the developing fetal brain is vulnerable to vertical transmission due to immaturity of the fetal immune system. Infection is a major cause of multiple organ abnormalities, including the neuraxis, due to the neurotropism of the infectious agents. This review sets out to give an overview of fetal infection, review the general principles of the nature and timing of the infectious insult with respect to outcomes, review the neuroimaging of infection by ultrasound and magnetic resonance imaging (MRI), and review the various pathogens involved, including the two most common, cytomegalovirus (CMV) and Toxoplasma, and also other common viral and nonviral infections.

African Americans in the United States are more likely than their white counterparts to experience greater incidence and mortality due to colorectal cancer (CRC). Present for decades, these disparities have prompted researchers to investigate underlying causes and potential explanations. While some biological variations have been observed between races, evidence shows that approximately 50% of these disparities can be attributed to differences and disparities in CRC screening, resulting in reduced polyp removal for CRC prevention and/or early detection of CRC among African Americans. Other major contributors to CRC disparities are differences in treatment and access to care. Significant efforts are needed to increase CRC screening among African Americans through targeted interventions to reduce barriers such as increasing education, promoting physician recommendations, and providing affordable and quality care. Intervention is also needed to educate the medical community about these issues and to change health policy to provide a multilevel approach with the best chance of success in reducing racial disparities in CRC.

Level of Evidence: Level V, expert opinion.

The widespread use of screening mammography has resulted in a remarkable rise in the diagnosis of Ductal Carcinoma In Situ (DCIS). A resultant challenge is the early screening of these patients to identify those with concurrent invasive breast cancer (IBC), as one in five DCIS at biopsy, are upgraded to IBC following surgery. Both x-ray mammography and multi-parametric Magnetic Resonance Imaging (MRI) lack the ability to distinguish DCIS from IBC reliably. Our robust methodology for 3D alignment of histopathology images and MRI provides a unique opportunity to spatially map digitized histopathology slides on pre-surgical MRI which is particularly important in the tumors where DCIS and IBC co-occur as well as for the study of tumor heterogeneity. In this proof-of-concept study, we developed and evaluated a methodological framework for the 3D spatial alignment of MRI and histopathology slices, using x-ray radiographs as intermediate modality. Our methodology involves (1) the co-registration of 2D x-ray radiographs showing macrosections and corresponding 2D histology slices, (2) the 3D reconstruction of the ex vivo specimen based on the x-ray images, and aligned histology slices, and (3) the registration of the 3D reconstructed ex vivo specimen with the 3D MRI. The spatially co-registered MRI and histopathology images may enable the identification of MRI features that distinguish aggressive from indolent disease on in vivo MRI.

To assess whether simultaneous hyperpolarized C-13 magnetic resonance spectroscopy (MRS)/positron emission tomography (PET)/multiparametric magnetic resonance (mpMR) imaging is feasible in an orthotopic canine prostate cancer (PCa) model using a clinical PET/MR system and whether the combined imaging datasets can be fused with transrectal ultrasound (TRUS) in real time for multimodal image fusion-guided targeted biopsy of PCa. Institutional Animal Care and Use Committee approval was obtained for this study. Canine prostate adenocarcinoma (Ace-1) cells were orthotopically injected into the prostate of four dogs. Once tumor engraftment was confirmed by TRUS, simultaneous hyperpolarized C-13 MRS of [1-13C]pyruvate, PET (2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG), [68Ga]NODAGA-SCH1), and mpMR (T2W, DWI) imaging was performed using a clinical PET/MR system. Multimodality imaging data sets were then fused with TRUS and image-guided targeted biopsy was performed. Imaging results were then correlated with histological findings. Successful tumor engraftment was histologically confirmed in three of the four dogs (dogs 2, 3, and 4) and simultaneous C-13 MRS/PET/mpMR was feasible in all three. In dog 2, C-13 MRS showed increased lactate signal in the tumor (lactate/totalC = 0.47) whereas mpMR did not show any signal changes. In dog 3, [18F]FDG-PET (SUVmean = 1.90) and C-13 MRS (lactate/totalC = 0.59) showed elevated metabolic activity in the tumor. In dog 4, [18F]FDG (SUVmean = 2.43), [68Ga]NODAGA-SCH1 (SUVmean = 0.75), and C-13 MRS (Lac/totalC = 0.53) showed elevated uptake in tumor compared to control tissue and multimodal image fusion-guided biopsy of the tumor was successfully performed. Simultaneous C-13 MRS/PET/mpMR imaging and multimodal image fusion-guided biopsy is feasible in a canine PCa model.

Breast cancer is the second most common cancer in women in the United States after skin cancer. Mammography remains the mainstay of cancer screening, but breast MRI has a role in screening of women at high risk of breast cancer (e.g., BRCA mutation). In women who are identified with breast cancer at

BACKGROUND Women treated with mantle irradiation for Hodgkin lymphoma (HL) are at an increased risk of developing breast cancer (BC). Current guidelines recommend screening breast magnetic resonance imaging (MRI) as an adjunct to mammography (M) in these patients. There are limited data, however, as to the impact of breast MRI on cancer detection rates. The aim of the current study is to evaluate the use of breast MRI in survivors of HL treated and followed at a single institution. MATERIALS AND METHODS We retrospectively reviewed 980 female patients treated with mantle irradiation for HL between 1961 and 2008. Records were reviewed to determine age at radiotherapy treatment, radiotherapy dose, breast imaging (including M and breast MRI), biopsy results if applicable, and incidence of BC. RESULTS A total of 118 patients had breast imaging performed at our institution. Median age at HL diagnosis was 28 years (range, 10 to 69 y). Median radiotherapy dose was 36 Gy (range, 20 to 45 Gy). Seventy-nine patients (67%) underwent M screening only, 1 (1%) breast MRI only, and 38 (32%) both M and breast MRI. Of these 38, 19 (50%) underwent 54 screening MRI studies (range per patient=1 to 8), 13 (34%) underwent preoperative MRI for workup of BC, and 6 (16%) initiated screening MRI of the contralateral breast only after diagnosed with BC. Fifty-nine biopsies were performed: 47 were prompted by suspicious M findings only, 10 by palpable findings on physical examination (PE), and 2 by suspicious breast MRI findings. Of the 47 biopsies prompted by M, 24 revealed malignant disease, whereas 23 proved to be benign. All 10 biopsies performed by palpation were malignant. Both biopsies prompted by MRI findings were benign. With M, there were 34 true-positive findings in 32 patients, 23 false-positive findings, and 1 false-negative finding. With screening MRI, there were 2 false-positive findings, 1 false-negative finding, and no true-positive findings. CONCLUSIONS The role of screening breast MRI in women previously irradiated for HL is evolving. Further education of patients and physicians is important to increase awareness of more sensitive BC screening modalities in this high-risk population. Future studies are necessary to determine the appropriate integration of screening breast MRI into the ongoing follow-up of these women.

141 Background: This study sought to understand treatment preferences and their association with financial toxicity in breast cancer patients served by Patient Advocate Foundation (PAF). Methods: This cross-sectional study used survey data from a nationwide sample of women with breast cancer who received assistance from PAF. Choice-based conjoint analysis elicited patient preferences and trade-offs. Latent class analysis segmented respondents into distinct preference groups. The Comprehensive Score for Financial Toxicity (COST) tool captured financial toxicity (range 0-44, lower scores indicate worse financial toxicity). Cramer’s V determined magnitude of relationships in bivariate associations. COST score differences by preference archetype was estimated by least square means and naïve 95% confidence intervals (CI) from adjusted generalized linear models. Results: Of 220 respondents (65% response rate), median age was 58 years (interquartile range [IQR] 49-66) and 60% had household incomes < $40,000. Most respondents were diagnosed with early stage cancer (91%), with 41% diagnosed within the past 2 years; 38% had recurred. Almost two-thirds (61%) were on active treatment. Treatment choice was most affected by preferences related to affordability and impact on activities of daily living (ADLs). Two distinct treatment preference archetypes emerged. The “Cost-Prioritizing Group” (75% of respondents) was most concerned about affordability, impact on ADLs, and burdening care partners. The “Functional Independence-Prioritizing Group” (25% of respondents) was most concerned about ability to work, physical side effects, and interference with important life events. Cost- vs. functional independence-prioritizing respondents were more often diagnosed with an early stage cancer (88% vs. 78%; V = .22), white (78% vs. 56%; V = .21), or privately insured (45% vs. 36%; V = .12). Functional independence- vs. cost-prioritizing respondents more often had household incomes < $40,000 (76% vs. 54%; V = .20), identified as Hispanic/Latino (20% vs. 9%; V = .15), or had Medicaid (15% vs. 7%; V = .12). COST scores were similar between archetypes in adjusted models (Cost-Prioritizing COST = 12, 95% CI 9-14; Functional Independence-Prioritizing COST = 11, 95% CI 9-13). Conclusions: Patients with breast cancer prioritized affordability or maintaining functional independence when making treatment decisions. Because of this variability, preference evaluation during treatment decision-making could optimize patients’ treatment experiences.

Patients with aggressive osteosarcoma (OS) have poor prognosis due in part to copy number variations (CNVs) that contribute to dysregulation of gene expression (GE) and therapeutic resistance. The objective of the present study was to utilize the TARGET database to integrate CNV and corresponding GE with poor prognosis in pediatric OS (n=85) followed by functional validation of prioritized targets. Cox regression analysis indicated that CNVs in 2642 genes correlated with relapse risk in pediatric OS. Furthermore, the top 10 genes with CNVs significantly associated with increased risk for relapse were present on chromosome 8. The MYC and RAD21 copy number gain (MYC-RAD21 CNV+) located on chromosome 8q correlated with increased GE and poor survival in >90% of the relapsed patients. Based on network analysis, the MYC-RAD21 CNV+ was prioritized for development of targeted therapy. MYC, an oncogenic driver of OS growth, can be indirectly inhibited by bromodomain and extra-terminal domain inhibitors (BETi). RAD21 expression has been associated with increased sensitivity to cell cycle checkpoint kinase 1 inhibitors (CHK1i) in melanoma. Additionally, mechanistic links exist between MYC and CHK1, especially during replication stress. Our hypothesis was that the MYC-RAD21 CNV+ serves as a biomarker of poor prognosis and therapeutic response to BETi+CHK1i therapy. Cell growth response to BETi and CHK1i was evaluated in MYC-RAD21 CNV+ pediatric OS cell lines and a patient-derived xenograft (PDX)-derived xenoline (TT2-77). OS lines (G292, MG63, U2OS, and TT2-77) were highly sensitive to single agent BETi/OTX-015, CHK1i/ SRA737 or CHK1i/LY2606368 at clinically relevant concentrations. Combination index and Bliss independence analysis indicated that BETi+CHK1i did not result in synergistic or additive inhibition of growth at clinically relevant concentrations. However, in OS lines Saos2 and Saos2-LM7 BETi+CHK1i resulted in additive to synergistic inhibition of growth at multiple dose-ratios and at clinically relevant concentrations. In the TT2-77 PDX, whole genome sequencing indicated that the original OS biopsy and the TT2-77 PDX generated from a resection sample harbor the MYC-RAD21 CNV+ (4 copies/amplicon). PDX tumor fragments were implanted into the flank of immunodeficient NOD/SCID/IL2Rγ mice. Once tumor volumes reached 100-150 mm3, mice were randomized and treated with four 5-day cycles of BETi/OTX-015 and/or CHK1i/SRA737. BETi+CHK1i significantly decreased TT2-77 growth, increased probability of survival, and was well tolerated. BETi+CHK1i is a promising therapeutic approach for treatment of relapsed pediatric MYC-RAD21 CNV+ OS. It is possible that MYC, BETs, RAD21 and CHK1 protein levels could dictate sensitivity to combination BETi+CHK1i independent of MYC-RAD2 CNV+ status. Studies are in progress to identify responder versus non-responder signatures in OS. Citation Format: Khadijeh Bijangi-Vishehsaraei, Pankita Pandya, Cheng Lijun, Tang Shan, Anthony Sinn, Melissa Trowbridge, Kathy Coy, Courtney Hemenway, Barbara Bailey, Harlan Shannon, Jixin Ding, Erika Dobrota, M. Reza Saadatzadeh, Adily Elmi, Jeremiah Shultz, Mary Murray, Mark Marshall, Michael Ferguson, Todd Bertrand, L. Daniel Wurtz, Sandeep Batra, Lang Li, Jamie Renbarger, Karen Pollok. Systems biology approach provides rationale for dual-targeted inhibition of BET and CHK1 in aggressive pediatric osteosarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 450.

Background: AST-008 is a novel spherical nucleic acid configuration of a toll-like receptor 9 (TLR9) agonist oligonucleotide, designed to trigger anti-tumor immune responses. Here we focus on immune activation upon AST-008 injection in the phase 1b/2 study in patients with advanced solid tumors (NCT03684785). Materials and Methods: AST-008 was injected intratumorally (IT) into one or more tumors QW for 8 doses, then Q3W thereafter, at doses from 2 to 32 mg. Starting at week 3, pembrolizumab was administered per label until toxicity or progression. Peripheral blood immune cell profiling and cytokine/chemokine analyses were performed before and 24 hours after both the first AST-008 dose (week 1) and the first combination dose (week 3). Serial tumor biopsies of lesions were collected from both AST-008-injected lesions and non-injected (“witness”) lesions at baseline, after IT AST-008 monotherapy, and after combination therapy. Results: Seventeen patients have been enrolled in the dose escalation cohort: median age 66 [range: 30-86], 82% male, median ECOG 1 [0-1]. Dose dependent lymphocyte activation was observed after IT AST-008. AST-008 dosing alone (16 mg cohort, n = 3) increased activated fractions of CD4+ (33%) and CD8+ T cells (64%), monocytes (97%) and NK cells (94%), compared to baseline (15%, 22%, 4%, and 37%, respectively). At AST-008 doses of 8 and 16 mg, the cell activation response within a dose level was generally similar in the presence or absence of pembrolizumab. In addition, the cytokines/chemokines IL-12p40, IL-1RA, IP-10, and MCP-1 were induced in a dose-proportional manner after IT AST-008 mono- or combination therapy. IT AST-008 resulted in average fold increase of 5, 12, and 16 for doses of 2, 4, and 8 mg dose cohorts, respectively, in IP-10 concentration from baseline (n = 11). Generally, combination therapy with pembrolizumab and AST-008 at doses of 2 and 4 mg produced a cytokine/chemokine response that was smaller than AST-008 alone (n = 5), but 8 mg dose responses were similar after monotherapy or combination therapy (n = 3). Preliminary analysis of serial biopsies by Nanostring revealed increased T cells and cytotoxic cells in the injected lesion after AST-008 dosing (n = 4) and in the non-injected witness lesion after combination therapy (n = 6). Combination therapy produced increases in B cells, T cells, cytotoxic cells and macrophages the AST-008 injected lesions (n = 6). Further PD data are being collected. The emerging safety profile consists mostly of grade (G) 1 and 2 injection site reactions and flu-like symptoms, reflecting local and systemic immune activation. One G3 lymphocytopenia has been observed, with no clinical consequences. No AST-008-related serious AEs or DLTs have been reported. Conclusions: IT AST-008 is well tolerated at the doses administered and is associated with dose-proportional systemic immune activation. Gene expression analysis suggests increased lymphocytes in the injected tumor after IT AST-008 and in both injected and witness tumors after combination therapy. Citation Format: Mohammed M. Milhem, Cesar A. Perez, Glenn J. Hanna, Trisha M. Wise-Draper, Shailender Bhatia, Alice S. Bexon, Weston L. Daniel, Steven J. O'Day. Phase 1b/2 study of an intratumoral TLR9 agonist spherical nucleic acid (AST-008) and pembrolizumab: Evidence of immune activation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-140.

TPS3164 Background: AST-008 is a potent spherical nucleic acid configuration of a toll-like receptor (TLR) 9 agonist oligonucleotide being developed for the treatment of MCC and CSCC in patients (pts) progressing on immune checkpoint inhibitor (CPI) monotherapy. Previously presented data suggests AST-008 elicits a Th1-type cytokine response and immune cell activation. This parallel-arm phase II design will permit assessment of efficacy in two advanced skin cancers with high unmet medical need. Methods: The study has an open label, multicenter phase Ib/II dose escalation/expansion design. The phase 1b dose escalation used a 3+3 design with increasing doses of intratumoral (IT) AST-008 plus standard flat dose pembrolizumab. The phase II dose expansion is using the recommended regimen (RP2D) of IT AST-008 plus flat dose pembrolizumab or cemiplimab to treat two cohorts of pts with advanced/metastatic MCC or CSCC, respectively. The key objective of the phase II expansion is to provide an estimate of preliminary efficacy of IT AST-008 with pembrolizumab or cemiplimab in pts whose disease progressed on a single-agent CPI therapy. Endpoints also include safety, pharmacokinetic and pharmacodynamic assessments. Pts must have at least two evaluable lesions by RECIST v1.1. One or more lesions may be injected with AST-008, but one lesion (the “witness” lesion) must remain un-injected throughout the study to differentially assess effects of AST-008 on the injected and witness lesions. The RP2D of AST-008 was derived from the dose escalation phase together with pembrolizumab. That RP2D is being used not only in the MCC cohort where AST-008 is combined with pembrolizumab, but also in the CSCC cohort where AST-008 is combined with cemiplimab. To ensure safety of the AST-008/cemiplimab combination, the first 6 pts in the CSCC cohort will be monitored for dose limiting toxicities through the first 5 weeks of dosing, and then the data review committee will assess safety before approving additional patient enrollment to that cohort. Each expansion cohort will enroll up to 29 pts with a Simon two-stage optimal design. In the first stage, 10 pts will be accrued. If there are 0 responses in these 10 pts, enrollment in that arm will be stopped. Otherwise, 19 additional pts will be accrued for a total of 29. The null hypothesis will be rejected if 4 or more responses are observed in 29 pts. This design yields a type I error rate of 0.05 and power of 80% when the true response rate is 20%. The planned phase II enrollment is 58 pts across about 15 US-based sites. Clinical trial information: NCT03684785 .

Purpose To compare positive predictive values (PPVs) of clumped versus non-clumped (homogenous and heterogenous) internal enhancement on MRI detected linear non-mass enhancement (NME) on MRI-guided vacuum assisted breast biopsy (MRI-VABB). Materials and Methods With IRB approval, radiology reports were retrospectively reviewed of 598 lesions undergoing 9-gauge MRI-VABB from January 2015 to April 2018 for lesions showing linear NME, recording clumped and non-clumped internal enhancement. We reviewed the electronic medical records for MRI-guided VABB pathology, any follow up surgery and imaging and/or clinical follow-up >1 year (mean 1.7 years). The X2 test was performed for univariate analysis. Results There were 120/598 (20%) linear NME MRI-VABB lesions with clumped (52/120, 43%) vs non-clumped (68/120, 57%) internal enhancement, average size 1.8 cm (range 0.3-7.6 cm). On MRI-VABB, cancer was identified in 22/120 (18%) lesions, ductal carcinoma in situ (DCIS) was found in 18/22 (82%) and invasive cancer (3 IDC, 1 ILC) in 4 (18%). 31/120 (26%) were high-risk lesions with 3/31 (10%) high-risk lesions upgraded to DCIS at surgery, which comprising a total of 25/120 (21%) malignancies. Malignancy was found in 12/52 (23%) clumped lesions and in 13/68 (19%) of non-clumped lesions that showed heterogenous (5/13, 38%) or homogenous (8/13, 62%) internal enhancement. The PPV of linear NME with clumped internal enhancement (23.1%; 95% CI, 11.6-34.6) was not significantly different from the PPV of non-clumped linear NME (19.1%; 95% CI, 9.8-28.4) (p=0.597). The PPV of linear NME lesions Citation Format: Shu-Tian Chen, James Covelli, Satoko Okamoto, Bruce Daniel, Wendy DeMartini, Debra Ikeda. Clumped vs non-clumped internal enhancement patterns in linear non-mass enhancement on breast MRI [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-02-05.

The activation of T helper 17 signaling plays a critical role in psoriasis pathogenesis, and systemically-administered IL-17 inhibitors are highly effective therapy for moderate-to-severe disease. We generated topically-delivered gene-regulating nanoconstructs, comprised of spherically-arrayed antisense DNA (liposomal spherical nucleic acids [L-SNAs]), which are able to penetrate human skin to knock down cutaneous gene targets. Topically-applied L-SNAs targeting the gene encoding the mouse IL-17A receptor (Il17ra) reversed the development of psoriasis clinically, histologically, and transcriptionally in imiquimod-treated psoriasis-like mouse skin. Il17ra L-SNAs reduced the modified PASI by 74% versus controls and decreased epidermal thickness by 56%. Il17ra L-SNA reduced Il17ra protein expression by 75% and significantly decreased the mRNA expression of psoriasis markers, including Defb4, Il17c, S100a7, Pi3, Krt16, and Tnfa versus scrambled spherical nucleic acid (Scr SNA) controls. A human IL17RA L-SNA penetrates 3-dimensional cultures and normal human explants to knock down IL17RA mRNA by 63% and 66%, respectively. After topical application to psoriatic 3-dimensional rafts, anti-human IL17RA L-SNAs reduced the expression of IL17RA (by 72%) and the IL-17-induced genes IL17C (by 85%), DEFB4 (by 83%), TNFA (by 77%), and PI3 (by 65%) versus scrambled L-SNA and vehicle controls (all P

Plantar fasciitis is the most common cause of chronic heel pain in adults, affecting both young active patients and older sedentary individuals. It results from repetitive stress to the plantar fascia at its origin on the medial tubercle of the calcaneus and is often associated with gastrocnemius tightness. The diagnosis can be made clinically with a focused history and physical examination; imaging is reserved for atypical presentations and those that do not respond to initial treatment. The most common presenting symptom is aching plantar heel pain, which is worst with first step in the morning or after periods of rest. Diagnosis is confirmed with point tenderness at the origin of the plantar fascia on the medial tubercle of the calcaneus. Initial treatment consists of activity modification, anti-inflammatory medication, gastrocnemius and plantar fascia stretching, and an in-shoe orthosis that lifts and cushions the heel. These nonoperative treatments lead to complete resolution of pain in 90% of patients but can take 3-6 months. Patients who remain symptomatic despite a 6-month trial of nonoperative therapy may be considered for minimally invasive treatment or surgery. Platelet-rich plasma injections and therapeutic ultrasound are among a number of minimally invasive treatments that stimulate the body’s healing response. Corticosteroid injections temporarily relieve pain, but may increase the risk of plantar fascia rupture and fat pad atrophy. Botulinum toxin injections relax the calf muscles, which decreases the stress in the plantar fascia. Operative treatments include gastrocnemius recession and medial head of gastrocnemius release, which decrease the stress on the plantar fascia and partial planter fasciotomy, which stimulates a healing response. Level of Evidence: Level V, expert opinion.