bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro evaluation of the influence of titanium nitride coating on the retention force between components of two-part abutments
Authors: Freifrau von Maltzahn Nadine , Holstermann Jan , Stiesch Meike , Kohorst Philipp
Published: June 2021

Background

Two-part abutments are typically made up of a base composed of titanium and a ceramic build-up. The long-term outcomes are affected by the mechanical durability. The purpose of the present investigation was to evaluate and compare the retention force of two-part abutment systems with titanium or titanium nitride bases—as fixed with zirconia components and with various surface treatments.

Methods

A total of 60 two-part abutments were investigated—with a titanium base (n = 30) or titanium nitride coated bases (n = 30) and bonded with zirconia ceramic build-ups. The bonding surfaces were treated with aluminium oxide blasting, with an average particle size of 110 µm. The titanium bases were then pretreated with Alloy Primer or Clearfil Ceramic Primer. The ceramic build-ups were only treated with Clearfil Ceramic Primer. For twenty test specimens, no chemical pretreatment was performed. Test specimens were classified into six groups in accordance with the pretreatment (A–F; n = 10). A resin-based luting agent was employed to attach the two parts. Specimens were then subjected to artificial thermal aging (104 cycles with 5 °C/55 °C). The retention force between the two parts was then investigated with a pull-off test. The findings were analyzed by ANOVA statistics. Fracture patterns were examined by electron microscopy.

Results

In the absence of primer, titanium nitride coated bases gave significantly greater retention forces than other samples (p < 0.05). Chemical preconditioning with silane coupling agents did not effect on the retention force of coated bases.

Conclusions

The results of the current study suggested that modifying metal surfaces by coating the base with titanium nitride not only has esthetic and biological advantages, but also enhances the mechanical properties of the adhesive bond of two-part abutments.
Effects, barriers and facilitators in predischarge home assessments to improve the transition of care from the inpatient care to home in adult patients: an integrative review
Authors: Kirchner-Heklau Uta , Krause Kai , Saal Susanne
Published: June 2021

Background

Predischarge home assessments (PDHA) aim to support safe discharge from hospital or rehabilitation. There is insufficient evidence on the effectiveness of PDHA. For adults with any diagnosis, we aimed to determine (1) the effects of PDHA on outcomes associated with the successful return to community living (e.g., Activities of Daily Living, falls) and (2) the associated barriers and facilitators in order to derive recommendations for clinical practice.

Methods

We searched Medline, EMBASE, CINAHL, five additional databases and other sources. We included individual and cluster randomized (RCT/cRCT) and controlled clinical trials comparing PDHA versus usual care/other intervention, as well as qualitative/mixed methods studies dealing with PDHA. Critical appraisal was performed according to the Cochrane risk-of-bias tool in quantitative studies and the Critical Appraisal Skills Programme (CASP) as well as the McMaster University Guidelines for Critical Review Form for qualitative studies and data extraction. Meta-analysis, thematic synthesis and integrative synthesis were performed.

Results

Eight RCTs (n = 1072) and ten qualitative studies (n = 336) met the inclusion criteria. RCTs reported a variety of outcomes (n = 17). We are uncertain if PDHA has any effect on patient outcomes in Activities of Daily Living, quality of life, mobility and fear of falling, falls and hospital readmissions (with moderate to very low quality of the evidence). The qualitative studies revealed facilitators and barriers which should be considered by therapists when conducting PDHA. These were related to the following topics: patient safety education, patient information, patients’ acceptance of modifications and aids, functional assessment, standardization of procedures as well as the consideration of relevant patient conditions and contextual factors in PDHA.

Conclusion

There is no evidence from the meta-analysis for the effectiveness of PDHA. Further robust studies are needed to adapt and evaluate PDHA interventions, taking the identified stakeholders’ views on PDHA into account and following the current recommendations for the development and evaluation of complex interventions.

Trial registration

The review was registered and methods were reported on PROSPERO on 18th July 2018 (CRD42018100636).
Boundaries potentiate polycomb response element-mediated silencing
Authors: Erokhin Maksim , Gorbenko Fedor , Lomaev Dmitry , Mazina Marina Yu , Mikhailova Anna , Garaev Azat K. , Parshikov Aleksander , Vorobyeva Nadezhda E. , Georgiev Pavel , Schedl Paul , Chetverina Darya
Published: June 2021

Background

Epigenetic memory plays a critical role in the establishment and maintenance of cell identities in multicellular organisms. Polycomb and trithorax group (PcG and TrxG) proteins are responsible for epigenetic memory, and in flies, they are recruited to specialized DNA regulatory elements termed polycomb response elements (PREs). Previous transgene studies have shown that PREs can silence reporter genes outside of their normal context, often by pairing sensitive (PSS) mechanism; however, their silencing activity is non-autonomous and depends upon the surrounding chromatin context. It is not known why PRE activity depends on the local environment or what outside factors can induce silencing.

Results

Using an attP system inDrosophila, we find that the so-called neutral chromatin environments vary substantially in their ability to support the silencing activity of the well-characterizedbxdPRE. In refractory chromosomal contexts, factors required for PcG-silencing are unable to gain access to the PRE. Silencing activity can be rescued by linking thebxdPRE to a boundary element (insulator). When placed next to the PRE, the boundaries induce an alteration in chromatin structure enabling factors critical for PcG silencing to gain access to thebxdPRE. When placed at a distance from thebxdPRE, boundaries induce PSS by bringing thebxdPREs on each homolog in close proximity.

Conclusion

This proof-of-concept study demonstrates that the repressing activity of PREs can be induced or enhanced by nearby boundary elements.

Graphical abstract
Sexual conflict drives micro- and macroevolution of sexual dimorphism in immunity
Authors: Bagchi Basabi , Corbel Quentin , Khan Imroze , Payne Ellen , Banerji Devshuvam , Liljestrand-Rönn Johanna , Martinossi-Allibert Ivain , Baur Julian , Sayadi Ahmed , Immonen Elina , Arnqvist Göran , Söderhäll Irene , Berger David
Published: June 2021

Background

Sexual dimorphism in immunity is believed to reflect sex differences in reproductive strategies and trade-offs between competing life history demands. Sexual selection can have major effects on mating rates and sex-specific costs of mating and may thereby influence sex differences in immunity as well as associated host–pathogen dynamics. Yet, experimental evidence linking the mating system to evolved sexual dimorphism in immunity are scarce and the direct effects of mating rate on immunity are not well established. Here, we use transcriptomic analyses, experimental evolution and phylogenetic comparative methods to study the association between the mating system and sexual dimorphism in immunity in seed beetles, where mating causes internal injuries in females.

Results

We demonstrate that female phenoloxidase (PO) activity, involved in wound healing and defence against parasitic infections, is elevated relative to males. This difference is accompanied by concomitant sex differences in the expression of genes in the prophenoloxidase activating cascade. We document substantial phenotypic plasticity in female PO activity in response to mating and show that experimental evolution under enforced monogamy (resulting in low remating rates and reduced sexual conflict relative to natural polygamy) rapidly decreases female (but not male) PO activity. Moreover, monogamous females had evolved increased tolerance to bacterial infection unrelated to mating, implying that female responses to costly mating may trade off with other aspects of immune defence, an hypothesis which broadly accords with the documented sex differences in gene expression. Finally, female (but not male) PO activity shows correlated evolution with the perceived harmfulness of male genitalia across 12 species of seed beetles, suggesting that sexual conflict has a significant influence on sexual dimorphisms in immunity in this group of insects.

Conclusions

Our study provides insights into the links between sexual conflict and sexual dimorphism in immunity and suggests that selection pressures moulded by mating interactions can lead to a sex-specific mosaic of immune responses with important implications for host–pathogen dynamics in sexually reproducing organisms.
Evaluation of the effect of vitamin D supplementation on spermatogram, seminal and serum levels of oxidative stress indices in asthenospermia infertile men: a study protocol for a triple-blind, randomized controlled trial
Authors: Maghsoumi-Norouzabad Leila , Zare Javid Ahmad , Mansoori Anahita , Dadfar Mohammadreza , Serajian Amirarsalan
Published: June 2021

Background

It is suggested that vitamin D may have a beneficial role in male reproduction. The male reproductive system is a target tissue for vitamin D. This study will aim to evaluate the effects of vitamin D supplementation on sperm parameters, seminal and serum levels of oxidative stress and serum endocrine factors in asthenospermia infertile men.

Methods/design

This randomized, triple-blind, placebo-controlled clinical trial will be conducted on 86 infertile men with idiopathic asthenozoospermia (the mobility of sperm < 40% and rapid progressive sperm motility < 32%), with serum levels of vitamin D less than 30 ng / ml in the “Infertility Clinic of Ahvaz Jahad daneshgahi”, Iran.

Main outcomes measure (s)

Demographic data, dietary intake, physical activity, sun exposure, anthropometric indices, serum and seminal levels of MDA (Malondialdehyde), 8-hydroxy-2- Dioxy Guanosine (8-OHDG), Total Antioxidant Capacity (TAC) and calcium, sperm DNA fragmentation index (DFI), serum 25-OHD, luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (T), estradiol (E2), sex hormone-binding globulin (SHBG), free androgen index (FAI = T/SHBG. 100), T/LH and T/E2 ratios, prolactin (PRO), parathyroid hormone (PTH), osteocalcin (OCN), phosphorus and sperm parameters.

Discussion

The deficiency of vitamin D as an antioxidant is common all over the world. Numerous observational studies have shown a positive association between vitamin D levels and semen quality. However, few clinical studies have been conducted in this area. So considering with the high prevalence of this antioxidant deficiency specifically in infertile men, it seems that the supplementation of vitamin D in infertile men with insufficient levels or deficiency may improve the status of oxidative stress and thereby may affect sperm parameters and endocrine factors involved in male fertility.

Trial registration

Iran Clinical Trials Registry, ID:IRCT20151128025274N4, registered on 28 March 2018.
Comprehensive analysis of LncRNAs expression profiles in an in vitro model of steatosis treated with Exendin-4
Authors: Errafii Khaoula , Al-Akl Neyla S. , Khalifa Olfa , Arredouani Abdelilah
Published: June 2021

Background and aims

The hallmark of non-alcoholic fatty liver disease (NAFLD) is the excessive hepatic lipid accumulation. Currently, no pharmacotherapy exists for NAFLD. However, the glucagon-like peptide-1 receptor agonists have recently emerged as potential therapeutics. Here, we sought to identify the long non-coding RNAs (LncRNAs) associated with the steatosis improvement induced by the GLP-1R agonist Exendin-4 (Ex-4) in vitro.

Methods

Steatosis was induced in HepG2 cells with oleic acid. The transcriptomic profiling was performed using total RNA extracted from untreated, steatotic, and Ex-4-treated steatotic cells. We validated a subset of differentially expressed LncRNAs with qRT-PCR and identified the most significantly enriched cellular functions associated with the relevant LncRNAs.

Results

We confirm that Ex-4 improves steatosis in HepG2 cells. We found 379 and 180 differentially expressed LncRNAs between untreated and steatotic cells and between steatotic and Ex-4-treated steatotic cells, respectively. Interestingly, 22 upregulated LncRNAs in steatotic cells became downregulated with Ex-4 exposure, while 50 downregulated LncRNAs in steatotic cells became upregulated in the presence of Ex-4. Although some LncRNAs, such as MALAT1, H19, and NEAT1, were previously associated with NAFLD, the association of others with steatosis and the positive effect of Ex-4 is being reported for the first time. Functional enrichment analysis identified many critical pathways, including fatty acid and pyruvate metabolism, and insulin, PPAR, Wnt, TGF-β, mTOR, VEGF, NOD-like, and Toll-like receptors signaling pathways.

Conclusion

Our results suggest that LncRNAs may play essential roles in the mechanisms underlying steatosis improvement in response to GLP-1R agonists and warrant further functional studies.
First report of X-linked hypohidrotic ectodermal dysplasia with a hemizygous c.1142G > C in the EDA gene: variant of uncertain significance or new pathogenic variant?
Authors: Tumminello Mario , Gangemi Antonella , Matina Federico , Guardino Melania , Giuffrè Bianca Lea , Corsello Giovanni
Published: June 2021

Background

Hypohidrotic Ectodermal Dysplasia (HED) is a genetic disorder which affects structures of ectodermal origin. X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of disease. XLHED is characterized by hypotrichosis, hypohydrosis and hypodontia. The cardinal features of classic HED become obvious during childhood.

Identification of a hemizygous EDA pathogenic variant in an affected male confirms the diagnosis.

Case presentation

We report on a male newborn with the main clinical characteristics of the X-linked HED including hypotrichosis, hypodontia and hypohidrosis. Gene panel sequencing identified a new hemizygous missense variant of uncertain significance (VUS) c.1142G > C (p.Gly381Ala) in the EDA gene, located on the X chromosome and inherited from the healthy mother.

Conclusion

Despite the potential functional impact of VUS remains uncharacterized, our goal is to evaluate the clinical potential consequences of missense VUS on EDA gene. Even if the proband’s phenotype is characteristic for classic HED, further reports of patients with same clinical phenotype and the same genomic variant are needed to consider this novel VUS as responsible for the development of HED.
The impact of National Containment Measures on a Pediatric Italian regional Hub for COVID-19, an observational study
Authors: Crea Francesca , Panfili Filippo Maria , Amodeo Maria Elisa , Fintini Danilo , Rossi Francesco Paolo , Trenta Italo , Menichella Alessandra , Ossella Chiara , Deidda Andrea , Lidano Roberta , Macchiarulo Giulia , Lambiase Caterina , Barbieri Maria Antonietta , Raponi Massimiliano
Published: June 2021

Background

Numerous studies described the epidemiological link and main clinical features of pediatric COVID-19, during the first pandemic period. Our study encompasses several different phases since the National Lockdown in Italy. The primary outcome is (I) to analyze the prevalence of positive NST (Nasopharyngeal Swab Test) among the largest Italian Pediatric cohort admitted to a single regional PED Hub for COVID-19 during an eight-month period. Secondary outcomes are: (II) the description of trend of admissions in our PED and (III) the categorization of the positive patients according to clinical manifestations and epidemiological link.

Methods

We described 316 patients with a positive NST for SARS-CoV2, on a total of 5001 nasopharyngeal swabs performed among 13,171 admissions at our PED, over a period starting from March 17th, 2020 to December 1st, 2020. Age, epidemiological link, clinical features and hospitalizations were analyzed according to different lockdown phases. Data were collected anonymously from electronic records and analyzed using SPSS 22.00 statistics software (Chicago, IL).

Results

Thirty-six percent of total admissions have been tested. During the post lockdown period, we performed the highest percentage of NST (Nasopharyngeal Swab Test) 49.7%, and among them 7.9% were positive. The prevalence of infection during a 10-month period was 2.3%. Mean age was 6.5 years old. Familial Link accounted for the 67.7% of infection, while Extrafamilial and Unknown link accounted for 17 and 14.9%, respectively. Familial link is predominant during all phases. Seventeen patients showed an intra-scholastic link, and the highest prevalence was observed in the 7–10 years age group, with a prevalence of 12.8% (5 patients). Fever was the most frequent symptom (66%), in particular among preschooler children aged 0–6 years (71.9%). Older children were more frequently symptomatic. Seven patients were admitted with MIS-C diagnosis.

Conclusions

Different levels of containment measures caused important changes in number of positive NST for SARS-CoV2. Familial link was predominant in our cohort, during all phases of Lockdown. The risk of being infected at home is four time greater than the risk of being infected from an extra familial individual. Further studies are needed to evaluate the clear impact of intra-scholastic link. The constant improvement in knowledge on onset symptoms and risk factor for SARS-CoV2 infection and its complications (e.g. MIS-C), can impact on number of hospitalizations, ICU admissions and early management.
State of the art on lung organoids in mammals
Authors: Archer Fabienne , Bobet-Erny Alexandra , Gomes Maryline
Published: June 2021

The number and severity of diseases affecting lung development and adult respiratory function have stimulated great interest in developing new in vitro models to study lung in different species. Recent breakthroughs in 3-dimensional (3D) organoid cultures have led to new physiological in vitro models that better mimic the lung than conventional 2D cultures. Lung organoids simulate multiple aspects of the real organ, making them promising and useful models for studying organ development, function and disease (infection, cancer, genetic disease). Due to their dynamics in culture, they can serve as a sustainable source of functional cells (biobanking) and be manipulated genetically. Given the differences between species regarding developmental kinetics, the maturation of the lung at birth, the distribution of the different cell populations along the respiratory tract and species barriers for infectious diseases, there is a need for species-specific lung models capable of mimicking mammal lungs as they are of great interest for animal health and production, following the One Health approach. This paper reviews the latest developments in the growing field of lung organoids.
Potential applications of aptamers in veterinary science
Authors: Niederlender Solène , Fontaine Jean-Jacques , Karadjian Grégory
Published: June 2021

Aptamers are small nucleic acids that fold in a three-dimensional conformation allowing them to bind specifically to a target. This target can be an organic molecule, free or carried in cells or tissues, or inorganic components, such as metal ions. Analogous to monoclonal antibodies, aptamers however have certain advantages over the latter: e.g., high specificity for their target, no to low immunogenicity and easy in vitro selection. Since their discovery more than 30 years ago, aptamers have led to various applications, although mainly restricted to basic research. This work reviews the applications of aptamers in veterinary science to date. First, we present aptamers, how they are selected and their properties, then we give examples of applications in food and environmental safety, as well as in diagnosis and medical treatment in the field of veterinary medicine. Because examples of applications in veterinary medicine are scarce, we explore the potential avenues for future applications based on discoveries made in human medicine. Aptamers may offer new possibilities for veterinarians to diagnose certain diseases—particularly infectious diseases—more rapidly or “at the patient’s bedside”. All the examples highlight the growing interest in aptamers and the premises of a potential market. Aptamers may benefit animals as well as their owners, breeders and even public health in a “One Health” approach.
Exercise and QUality diet After Leukemia (The EQUAL Study): An intervention trial in the Childhood Cancer Survivor Study (CCSS).
Authors: Tonorezos Emily S. , Clark Jeanne M. , Moskowitz Chaya S. , Ford Jennifer S. , Armstrong Gregory T. , Chou Joanne F. , Mubdi Nidha Z. , McDonald Aaron , Sklar Charles A. , Ramanathan Lakshmi , Robison Leslie L. , Oeffinger Kevin C.
Published: June 2021

10015

Background: Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for obesity and cardiovascular (CV) disease. Exposure to cranial radiotherapy (CRT) increases risks. We tested whether a weight loss intervention that was successful in the general population could result in weight loss or improvements CV risk factors for ALL survivors. Methods: Obese and overweight 5-year ALL survivors diagnosed < age 21 from CCSS were randomized to a 24-month remotely delivered diet/physical activity intervention or self-directed weight loss (control), stratified by CRT. The intervention emphasized a low calorie DASH diet and physical activity via an app, a website, and weekly coach calls. The primary endpoint was difference in weight loss after 24 months, using an intent-to-treat analysis. Secondary endpoints: differences in changes in blood pressure, cholesterol, and triglycerides. Analyses were performed using linear mixed effects; the study was designed to detect a difference of 2.75 kg. Results: Of 358 survivors (59% female, 91% White non-Hispanic, median age 37, IQR: 33-43), 181 were randomized to the intervention and 177 to control. Baseline mean (SD) weight was 98.6 kg (24.0) for intervention and 94.9 kg (20.3) for controls. 55 (30%) of intervention participants were adherent beyond one year. At 12 months, after controlling for CRT, sex, race/ethnicity, and age, the adjusted mean (SE) change in weight from baseline was -1.83kg (0.7) for intervention and -0.16kg (0.64) for control participants. At 24 months, the adjusted mean (SE) change in weight was -0.36kg (0.78) for intervention and +0.18kg (0.66) for control participants with the average difference of -0.54 kg (95%CI: -2.5,1.5, p=0.59) between the arms. A small proportion had at least 5% weight loss at 24 months (intervention 24%; control 17%). No significant differences in CV risk factors were observed. Conclusions: A 24-month phone and app/web-based diet and physical activity intervention that was successful for weight loss in the general population did not result in greater weight loss or improvement in CV risk factors among adult survivors of childhood ALL. Reduced adherence to the intervention beyond 12 months, or lack of ALL survivor-specific tailoring, may account for these findings. Clinical trial information: NCT02244411. [Table: see text]
Preclinical evaluation of an engineered oncolytic herpes simplex virus for pediatric osteosarcoma.
Authors: Hutchins Sara , Marayati Raoud , Bownes Laura V. , Quinn Colin H. , Stewart Jerry E. , Friedman Gregory K. , Coleman Jennifer M. , Gillespie G. Yancey , Markert James M. , Beierle Elizabeth A.
Published: June 2021

10040

Background: Osteosarcoma is the most common primary bone tumor in children. For those with relapsed or metastatic disease, the five-year survival rate is approximately 20%, and survivors often suffer from long-term disability from current therapies. The high morbidity and mortality for these patients highlight a great need for improved therapies. One such novel therapeutic approach is oncolytic herpes simplex virus (oHSV) immunovirotherapy. We previously demonstrated that M002, an engineered oHSV that contains deletions of the neurovirulence gene preventing infection of normal cells, effectively infects and kills neuroblastoma and rhabdomyosarcoma. Currently, similar oHSVs are being evaluated in early phase clinical trials for children and adults with relapsed or refractory brain tumors. To date, there has been limited investigation of oncolytic virotherapy in osteosarcoma. Thus, we sought to examine the ability of oHSV, M002, to infect and kill osteosarcoma cells in vitro. Methods: We evaluated two long-term passaged human osteosarcoma cell lines, U2-OS and MG-63. Flow cytometry was used to assess baseline expression of oHSV viral entry-mediated receptors (CD111, CD112, syndecan, HVEM). Single and multi-step viral recovery experiments measured virus infectivity and replication. Cells were infected with increasing multiplicity of infection (MOI) of M002, and cell viability was measured 72 hours post-infection via alamarBlue assay. Results: Both MG-63 and U2-OS cells expressed HSV entry molecules (Table) including high levels of the primary HSV entry molecule CD111. Single step virus recovery experiments in MG-63 cells infected at a MOI of 10 plaque-forming units (PFU)/cell demonstrated a 3 log-fold increase in virus titer from 12 to 24 hours post-infection. For multi-step experiments, MG-63 cells were infected with a MOI of 0.1 PFU/cell; viral replication significantly increased from 1.1x103 PFU at 6 hours post-infection to 3.8x1010 PFU at 72 hours post-infection. M002 successfully decreased osteosarcoma viability with a lethal dose in 50% of cells (LD50)of 2.82 and0.67 PFU/cell for MG-63 and U2-OS cells, respectively. Notably, at a virus MOI of 5 PFU/cell, viability was decreased by 64% ± 0.1% (p<0.001 vs control) in MG-63 cells and 96% ± 0.1% (p<0.001 vs control) in U2-OS cells. Conclusions: MG-63 and U2-OS osteosarcoma cells express high levels of HSV entry receptors. Virus recovery experiments demonstrated the ability of M002 to infect cells and replicate over time. The viability of osteosarcoma cells significantly decreased following infection with M002. These data suggest M002 may be a promising novel therapeutic option for patients with osteosarcoma and warrant further investigation for translation to the clinical setting.[Table: see text]
Late morbidity and mortality among survivors of neuroblastoma treated with contemporary therapy: A report from the Childhood Cancer Survivor Study.
Authors: Friedman Danielle Novetsky , Goodman Pamela J. , Leisenring Wendy M. , Diller Lisa , Cohn Susan Lerner , Tonorezos Emily S. , Howell Rebecca M. , Smith Susan A. , Wolden Suzanne L. , Neglia Joseph Philip , Ness Kirsten K. , Gibson Todd M. , Nathan Paul C. , Robison Leslie L. , Oeffinger Kevin C. , Armstrong Gregory T. , Sklar Charles A. , Henderson Tara O.
Published: June 2021

10044

Background: Survival rates for neuroblastoma vary widely based on risk group. Therapies have evolved over the past four decades to de-intensify treatment for individuals with low/intermediate risk disease and intensify therapy for those with high risk disease. Risk stratification is predicted to result in differential outcomes in late morbidity and mortality; the magnitude of these differences has not been well studied. Methods: We evaluated late mortality, subsequent malignant neoplasms (SMN) and chronic health conditions (CHC) graded according to CTCAE v4.03 among 491 5-year CCSS survivors of neuroblastoma diagnosed 1987-1999 at ≥1 year of age. Using age, stage at diagnosis, and treatment, survivors were classified into risk groups (low [n=182]; intermediate [n=70]; high [n=239]). Standardized mortality ratios (SMR) and standardized incidence ratios (SIR) of SMN were calculated using rates from NCHS and SEER, respectively. Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for CHC compared to 1,029 CCSS siblings. Results: Among survivors (48% male; median age 22 years, range 7-42; median follow-up 19 years, range 5-29), 80.4% with low risk disease were treated with surgery alone, while 77.8% with high risk disease received surgery, radiation, chemotherapy ± transplant. The 15-year cumulative incidence of all-cause mortality was 9.2% (CI: 7.1-11.4), with a recurrence-related mortality of 7.3% (CI: 5.3-9.3) and SMN-related mortality of 0.3% (CI: 0-0.7). All-cause mortality was significantly higher in all risk groups: (low, SMR=5.8 [CI: 2.6-13.0]; intermediate, SMR=5.7 [CI: 1.4-23.5]; high, SMR=38.6 [CI: 27.9-53.5]). The risk of SMN was elevated among high risk survivors (SIR=25.1, CI: 16.7-37.6), but did not differ from the US population for survivors of low or intermediate risk disease. Table describes the HR of CHCs (grades 1-5 and 3-5) in survivors, by risk group, as compared with siblings, as well as categories of CHCs for which survivors were at increased risk. Conclusions: Long-term survivors of neuroblastoma have a high risk of late morbidity and mortality; risk is particularly pronounced among survivors of high risk disease. Vigilant lifelong medical surveillance will be required for this relatively young population as they age.[Table: see text]
Development and validation of a prediction model for kidney failure in long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Wu Natalie Lucy , Chen Yan , Dieffenbach Bryan V. , Li Nan , Ehrhardt Matthew J. , Green Daniel M. , Hingorani Sangeeta , Howell Rebecca M. , Jefferies John L. , Mulrooney Daniel A. , Oeffinger Kevin C. , Robison Leslie L. , Weil Brent R. , Yuan Yan , Yasui Yutaka , Hudson Melissa M. , Leisenring Wendy M. , Armstrong Gregory T. , Chow Eric Jessen
Published: June 2021

10047

Background: Kidney failure (need for dialysis or kidney transplantation, or death due to kidney disease) is a rare but serious late effect for survivors of childhood cancer. We aimed to develop a model using demographic and treatment characteristics to predict individual risk of kidney failure among five-year survivors of childhood cancer. Methods: CCSS survivors without kidney failure at five years after cancer diagnosis (n = 25,483) were assessed for subsequent kidney failure by age 40. Outcomes were self-reported and corroborated by the Organ Procurement and Transplantation Network and the National Death Index. A sibling cohort (n = 5045) served as a comparator. Piecewise exponential models with backward selection estimated the relationships between potential predictors and kidney failure and were converted to integer risk scores. Additional results from the St. Jude Lifetime Cohort Study (SJLIFE, n = 2490) and the National Wilms Tumor Study (NWTS, n = 6760) validated the models. Results: Among CCSS survivors, 204 developed late kidney failure. We developed a model with sex, race/ethnicity, age at cancer diagnosis, nephrectomy, exposure to specific chemotherapy, any abdominal radiation, presence of genitourinary anomalies, and early-onset hypertension (Table). Risk scores achieved an area under the curve (AUC) and concordance (C) statistic of 0.65 and 0.68 for kidney failure by age 40. Validation cohort AUC and C statistics were 0.83/0.86 for SJLIFE (8 cases) and 0.61/0.63 for NWTS (91 cases). An alternative model with specific chemotherapy doses and kidney-specific radiation dosimetry had similar AUC and C statistic (0.67/0.70). Integer risk scores were collapsed to form statistically distinct low (score <3; 87 cases of 17,326), moderate (score 3-5; 63 cases of 4667), and high (score 6+; 18 cases of 401) risk groups. These groups corresponded to cumulative incidences in CCSS of kidney failure by age 40 of 0.6% (95% CI 0.4-0.7%), 2.3% (95% CI 1.6-3.2%), and 9.4% (95% CI 4.4-16.7%), compared with 0.2% (95% CI 0.1-0.5%) among siblings. Conclusions: Using readily available information, we were able to identify low, moderate, and high risk groups for developing kidney failure following treatment for childhood cancer. These prediction models may help guide screening and interventional strategies for higher risk survivors.[Table: see text]
Safety of trastuzumab emtansine (T-DM1) in patients (pts) with HER2-positive locally advanced or metastatic breast cancer (mBC): Final results from KAMILLA Cohorts 1 (global) and 2 (Asia).
Authors: Wuerstlein Rachel , Ellis Paul , Montemurro Filippo , Antón Torres Antonio , Delaloge Suzette , Zhang Qingyuan , Wang Xiaojia , Wang Shusen , Zhimin Shao , Li Huiping , Rachman Andhika , Vongsaisuwon Mawin , Liu Haiying , Fear Simon , Pena-Murillo Claudia , Barrios Carlos H.
Published: June 2021

1039

Background: KAMILLA is an open-label, single-arm, phase 3b safety study of T-DM1 in pts with HER2-positive advanced BC (NCT01702571). The treated (safety) population of KAMILLA comprises 2 cohorts: a larger global Cohort 1 (n=2002) and a smaller Asia Cohort 2 (n=181 [China, n=154; Thailand, n=15; Indonesia, n=12]). Here we report results from Cohort 2 in the context of those previously reported for Cohort 1. Methods: Pts had HER2-positive, locally advanced or mBC with progression after chemotherapy and anti-HER2 therapy or ≤6 months (mo) of completing adjuvant therapy. T-DM1 3.6 mg/kg was given intravenously every 3 weeks until disease progression, consent withdrawal, or unacceptable toxicity. Primary endpoints were grade ≥3 (G≥3) adverse events of primary interest (AEPIs), specifically hepatic events, allergic reactions, thrombocytopenia (TCP), and hemorrhage events; all other G≥3 treatment-related AEs (TRAEs); and all-grade pneumonitis. Results: As of 31 July 2019,KAMILLA enrolled 2185 pts (Cohort 1, n=2003; Cohort 2, n=182), of which 2002 and 181 in each cohort, respectively, received ≥1 study dose and were included in the safety population. Baseline characteristics were generally similar between cohorts. Median (range) T-DM1 exposure was 5.6 mo (0–46) for Cohort 1 and 5.0 mo (0–31) for Cohort 2. The overall G≥3 AEPI rate was higher in Cohort 2 vs Cohort 1 (Table), mostly driven by a higher G≥3 TCP rate in Cohort 2. In Cohort 2, G≥3 TCP (the most frequently reported G≥3 AEPI) did not appear to be associated with G≥3 hemorrhagic events — the majority of G≥3 TCP events (128/138) fully resolved, with a duration of ≤15 days for 98/138 of these events. G≥3 TRAE rates were 18.4% in Cohort 1 and 48.6% in Cohort 2, the latter mainly due to TCP and platelet count decreased; any-grade pneumonitis rates were 1.0% and 2.2%, respectively. No other safety signals were identified. Median progression-free survival and overall survival were similar for both cohorts (Table). Conclusions: These data confirm prior observations in an Asian subgroup of the phase 3 EMILIA trial of T-DM1 in pts with previously treated mBC. Although the G≥3 TCP rate was higher in the Asia cohort, the majority of these events resolved fully. OS and PFS were similar in both cohorts. These data reinforce the favorable T-DM1 benefit-risk profile in mBC. Clinical trial information: NCT01702571 .[Table: see text]
Clinicopathological characteristics of exceptional responders who achieve durable remissions beyond five years (DR5) in HER2+(H+) metastatic breast cancer (MBC).
Authors: Skrobo Darko , Walsh Naomi , Berenguer Jose , Walshe Janice Maria , Higgins Michaela Jane , Fennelly David William , Ballot Jo , Quinn Cecily , Gullo Giuseppe , Crown John
Published: June 2021

1046

Background: The introduction of anti-H2 targeted therapies has resulted in substantially improved outcomes for patients (pts) with H+MBC, yet despite survival prolongation, most patients so-treated will still ultimately die from MBC. Some patients do however, achieved prolonged remissions. In this report we outline the long-term outcomes of patients with H+MBC who were treated in our institution, with at least five-year follow-up from the diagnosis of MBC. Methods: As part of our larger single-institution “Thousand Patient HER-2 Database”, we conducted a retrospective review of all patients in whom a diagnosis of H+MBC was made prior to December 2015 (range 2000-2015 years). The DR5 category included only those who had never experienced relapse or progression following initial anti-H2 therapy for MBC, and who were alive at 5 years. Patients were designated as (1) DR5, defined as never relapse with an overall survival (OS) > 5 years; (2) nonDR, which included those who had no or shorter remission, but also included nine pts who did achieve a 5 year CR, but who subsequently relapsed. OS was calculated from the date of diagnosis of MBC. The frequency distribution was assessed by Fisher’s Exact Test or Chi-Square Test, as appropriate. OS and PFS were calculated according to Kaplan Meier method, and evaluated by Log-rank test. Univariate and multivariate Cox proportional hazards regression analysis was used to evaluate the effect of clinicopathological features on OS and PFS. Results: A total of 245 patients diagnosed with advanced H+MBC were identified. The median survival was 38 months, (range 0.3 – 248 months). Among these, 85 patients (35%) experienced an OS > 5 years, with 34 designated as DR5. The median OS for DR5 was 117 months, whereas nonDR (n = 211) had median OS of 33 months. The median age was similar between groups (DR5 53 yrs vs nonDR 56 yrs). A higher incidence of visceral disease was present in nonDR compared to DR5 (69% vs 44%). Of all patients diagnosed with de novo H+MBC, 23% achieved DR5. Presence of visceral disease, number of metastases and site of metastases were statistically significant negative predictors of achieving DR5 (P < 0.05). Presence of ER positive disease was not associated with OS. Conclusions: A meaningful subset of patients (14%) with advanced H+MBC achieve prolonged remission beyond five years with H2 targeted therapy. Nearly one quarter of those with de novo H+MBC achieve DR5. As de novo H+MBC now constitutes a higher proportion of all H+MBC than it did in the pre-trastuzumab era, an increasing proportion of H+MBC may now be achieving DR5. Prospective identification of variables to predict DR5 could assist in the stratification of patients for whom additional therapy is needed.
Breast cancer screening for carriers of ATM, CHEK2, and PALB2 pathogenic variants: A comparative modeling analysis.
Authors: Lowry Kathryn P. , Geuzinge H. Amarens , Stout Natasha K. , Alagoz Oguzhan , Hampton John M. , Kerlikowske Karla , Miglioretti Diana L. , Schecter Clyde , Sprague Brian L. , Trentham-Dietz Amy , Tosteson Anna N.A. , Van Ravesteyn Nicolien , Yaffe Martin , Yeh Jennifer , Couch Fergus , Kraft Peter , Polley Eric , Mandelblatt Jeanne S. , Kurian Allison W. , Robson Mark E. ,   Cancer Intervention and Surveillance Modeling Network (CISNET); Breast Cancer Surveillance Consortium (BCSC); Cancer Risk Estimates Related to Susceptibility (CARRIERS)
Published: June 2021

10500

Background: Inherited pathogenic variants in ATM, CHEK2, and PALB2 confer moderate to high risks of breast cancer. The optimal approach to screening in these women has not been established. Methods: We used two simulation models from the Cancer Intervention and Surveillance Modeling Network (CISNET) and data from the Cancer Risk Estimates Related to Susceptibility consortium (CARRIERS) to project lifetime breast cancer incidence and mortality in ATM, CHEK2, and PALB2 carriers. We simulated screening with annual mammography from ages 40-74 alone and with annual magnetic resonance imaging (MRI) starting at ages 40, 35, 30, and 25. Joint and separate mammography and MRI screening performance was based on published literature. Lifetime outcomes per 1,000 women were reported as means and ranges across both models. Results: Estimated risk of breast cancer by age 80 was 22% (21-23%) for ATM, 28% (26-30%) for CHEK2, and 40% (38-42%) for PALB2. Screening with MRI and mammography reduced breast cancer mortality by 52-60% across variants (Table). Compared to no screening, starting MRI at age 30 increased life years (LY)/1000 women by 501 (478-523) in ATM, 620 (587-652) in CHEK2, and 1,025 (998-1,051) in PALB2. Starting MRI at age 25 versus 30 gained 9-12 LY/1000 women with 517-518 additional false positive screens and 197-198 benign biopsies. Conclusions: For women with ATM, CHEK2, and PALB2 pathogenic variants, breast cancer screening with MRI and mammography halves breast cancer mortality. These mortality benefits are similar to those for MRI screening for BRCA1/2 mutation carriers and should inform practice guidelines.[Table: see text]
Nearly half of TP53 variants are misattributed to Li-Fraumeni syndrome: A clinical evaluation of individuals with TP53 variants detected by hereditary cancer panel assays on blood or saliva.
Authors: Schwartz Alison , Hyman Sophie , Stokes Samantha , Castillo Danielle , Weitzel Jeffrey N. , Rana Huma Q. , Garber Judy Ellen
Published: June 2021

10501

Background: Multigene panel testing (MGPT) has identified TP53 pathogenic or likely pathogenic (P/LP) variants in patients with diverse phenotypes from no cancer to classic Li-Fraumeni syndrome (LFS). There is increasing recognition of variants at low allelic fraction (VAF) for TP53 in particular, which can be suggestive of post-zygotic mosaicism or aberrant clonal expansion (ACE), comprising clonal hematopoiesis of indeterminate potential (CHIP) or occult hematologic neoplasia. Distinguishing among these categories is essential because of widely different cancer risk and management implications for patients and their relatives. We report an evaluation of TP53 positive probands to determine germline versus somatic status from a cancer genetics clinic. Methods: We reviewed probands with TP53 P/LP variants by MGPT on blood (N = 83) or saliva (N = 1) samples from 2012-2019. Available VAFs were collected from commercial testing laboratories. Probands positive for a known familial variant, who met LFS testing criteria without indication of low VAF, or who carried the Brazil founder p.R337H variant were considered germline. For those with uncertain germline status, data was obtained from ancillary testing of family members, cultured skin fibroblasts, and other somatic benign or tumor tissues. TP53 variants were further categorized based on all available data. Results: Of the 84 probands, 28 (33%) had germline TP53 P/LP variants determined by above initial criteria; 18 (21%) were confirmed germline through ancillary testing. Seven (8%) individuals were classified as having constitutional mosaicism. In eleven (13%) individuals, the TP53 variants were consistent with ACE, in 9 (11%) with CHIP and in 2 (2%) with a hematologic malignancy (1 CLL, 1 NHL). Five (6%) cases could not be categorized despite ancillary testing. Fifteen (18%) probands declined any further workup. Conclusions: A TP53 P/LP variant found on peripheral blood or saliva MGPT does not always originate in the germline. In a clinical cancer genetics cohort, only 54% of patients had TP53 P/LP germline variants; these patients plus those with constitutional mosaicism (8%) require intensified surveillance. Assessment of VAF, family member testing, and analysis of TP53 in cultured fibroblasts or other tissue samples may distinguish germline and constitutional mosaic variants from the ACE spectrum. Expanding use of MGPT will increase this clinical challenge, which may motivate the modification of lab reports to include VAF and possible non-germline explanations. The findings of this study support a framework of multiple strategies to discern true constitutional status of a TP53 P/LP variant.
Development of AI-powered imaging biomarker for breast cancer risk assessment on the basis of mammography alone.
Authors: Kim Ki Hwan , Nam Hyeonseob , Lim Eunji , Ock Chan-Young
Published: June 2021

10519

Background: There is increasing interest in early detection of breast cancer by utilizing MRI in high-risk populations. However, it is still challenging to define and enrich the high-risk population. In this study, we developed an artificial intelligence (AI)-powered Imaging Biomarker in Mammography (IBM) to discover unique mammographic patterns, beyond simple density evaluations, that are related to breast cancer. Methods: A total of 49,577 mammography exams were collected to develop the AI-powered IBM, in which 6,218 were cancers. First, we evaluated the hypothesis that the unaffected breast of cancer patients would have a different pattern than that of non-cancer patients, by training AI (IBM-A) with unaffected breast in cancer patients and breasts of non-cancer patients. We then utilized further images of the cancer patients to train AI (IBM-B). This time we used both affected and unaffected breasts of cancer patients and breasts of non-cancer patients, allowing IBM-B to additionally learn patterns related to breast cancer. The IBMs were evaluated using the internal data (n = 2,058) that included 719 cancers. To demonstrate the feasibility of early detection by using IBM-B, it was tested with external data (n = 4,158) from an independent institution. This included pre-index exams (n = 292) taken prior to index exams acquired at the time of cancer diagnosis. Results: With the internal data, IBM-A showed AUC of 0.842, suggesting that AI could learn the difference between the normal breast of cancer patients and non-cancer patients. With IBM-B, which used additional cancer images to train, AUC was improved to 0.852. Based on the internal validation, IBM-B was chosen for the external validation, in which pre-index examinations were used only. IBM-B showed AUC of 0.777 in discriminating the pre-index exams of cancer patients and those of non-cancer patients. The radiologists excluded the apparent missed cancers (n = 87) by reviewing the pre-index exams retrospectively. After, the recalculated AUC of IBM-B was 0.770, suggesting that IBM-B can distinguish between mammograms of patients who will develop breast cancer in the future and those who will not. The mean IBM-B scores in pre-index exams of cancer group (0.580) were significantly higher than those in the normal (0.258, P < 0.001) and benign (0.258, P < 0.001) groups. Conclusions: AI-powered IBM could detect the unique parenchymal pattern associated with high breast cancer risks, and we show the potential of the AI-powered IBM to be used as an independent biomarker to select high-risk populations based on mammography alone.[Table: see text]