bluuebunny/crossref_metadata_2025 huggingface dataset:
Job demands, job resources, and health outcomes among nursing professionals in private and public healthcare sectors in Sweden – a prospective study
Authors: Thapa Dip Raj , Stengård Johanna , Ekström-Bergström Anette , Areskoug Josefsson Kristina , Krettek Alexandra , Nyberg Anna
Published: June 2022

Background

Nursing professionals exhibit high prevalence of stress-related health problems. Job demands and job resources are parallel drivers of health and well-being among employees. Better job resources associate with better job satisfaction, job motivation and engagement even when job demands are high. To date, there is limited research which explores the association between job demands, job resources and health outcomes among nursing professionals in the Swedish context. The aim of this study was therefore to investigate Swedish nursing professionals’ job demands and job resources in relation to health outcomes, with comparisons between the private and public healthcare sectors. The specific research questions were as follows: (1) Are there differences between private and public healthcare regarding job demands, job resources, and health outcomes? and (2) Are there prospective associations between job demands and job resources in relation to health outcomes?

Methods

Data were drawn from the Swedish Longitudinal Occupational Survey of Health (SLOSH) 2016 and 2018, including 520 nurses and 544 assistant nurses working in the private and public healthcare sectors from 2016 (baseline). Data were analyzed using binary logistic regression.

Results

Nursing professionals reported higher threats, lower bullying, lower control, lower social support, and lower cohesion in the public healthcare units compared to the private healthcare units. The prospective analyses showed that job resources in terms of social support and rewards were associated with higher self-rated health and lower burnout. Cohesion was associated with higher self-rated health. Job demands in terms of psychological demands and job efforts were associated with lower self-rated health, higher burnout, and higher sickness absence, while emotional demands were associated with higher burnout.

Conclusions

Nursing professionals’ job resources are deficient in public healthcare units. Job resources are associated with positive health outcomes, whereas job demands are associated with negative health outcomes, among nursing professionals. Strengthening job resources among nursing professionals in the private and public healthcare sectors can promote and sustain their work-related health.
Bioengineering in salivary gland regeneration
Authors: Hajiabbas Maryam , D’Agostino Claudia , Simińska-Stanny Julia , Tran Simon D. , Shavandi Amin , Delporte Christine
Published: June 2022

Salivary gland (SG) dysfunction impairs the life quality of many patients, such as patients with radiation therapy for head and neck cancer and patients with Sjögren’s syndrome. Multiple SG engineering strategies have been considered for SG regeneration, repair, or whole organ replacement. An in-depth understanding of the development and differentiation of epithelial stem and progenitor cells niche during SG branching morphogenesis and signaling pathways involved in cell–cell communication constitute a prerequisite to the development of suitable bioengineering solutions. This review summarizes the essential bioengineering features to be considered to fabricate an engineered functional SG model using various cell types, biomaterials, active agents, and matrix fabrication methods. Furthermore, recent innovative and promising approaches to engineering SG models are described. Finally, this review discusses the different challenges and future perspectives in SG bioengineering.
Circulating levels of AGEs and soluble RAGE isoforms are associated with all-cause mortality and development of cardiovascular complications in type 2 diabetes: a retrospective cohort study
Authors: Sabbatinelli Jacopo , Castiglione Stefania , Macrì Federica , Giuliani Angelica , Ramini Deborah , Vinci Maria Cristina , Tortato Elena , Bonfigli Anna Rita , Olivieri Fabiola , Raucci Angela
Published: June 2022

Background

Advanced glycation end-products (AGEs) and their interaction with the receptor for advanced glycation end-products (RAGE) play a pivotal role in the development and progression of type 2 diabetes. In this retrospective cohort study, we explored the association of circulating levels of soluble RAGE (sRAGE) isoforms, i.e., endogenous secretory esRAGE and cleaved cRAGE, AGEs and their respective ratios with 15-year all-cause mortality in type 2 diabetes.

Methods

Baseline AGEs and sRAGE isoforms concentration were measured by ELISA in 362 patients with type 2 diabetes and in 125 age- and gender-matched healthy control subjects (CTR). Independent predictors of mortality were determined using Cox proportional-hazards models and used to build and validate a nomogram for all-cause mortality prediction in type 2 diabetes.

Results

AGEs, total sRAGE, cRAGE and the AGEs/sRAGE and AGEs/esRAGE ratios were significantly increased in patients with type 2 diabetes compared to CTR (p < 0.001). In CTR subjects, but not in type 2 diabetes patients, a significant negative correlation between cRAGE and age was confirmed (p = 0.003), whereas the AGEs/sRAGE (p = 0.032) and AGEs/cRAGE (p = 0.006) ratios were positively associated with age. At an average follow-up of 15 years (4,982 person-years), 130 deaths were observed. The increase in the AGEs/cRAGE ratio was accompanied by a higher risk of all-cause mortality in patients with type 2 diabetes (HR per each SD increment = 1.30, 95% CI 1.15–1.47; p < 0.001). Moreover, sRAGE was associated with the development of major adverse cardiovascular events (MACE) in type 2 diabetes patients without previous MACE (OR for each SD increase: 1.48, 95% CI 1.11–1.89). A nomogram based on age, sex, HbA1c, systolic blood pressure, and the AGEs/cRAGE ratio was built to predict 5-, 10- and 15-year survival in type 2 diabetes. Patients were categorized into quartiles of the monogram scores and Kaplan-Meier survival curves confirmed the prognostic accuracy of the model (log-rank p = 6.5 × 10− 13).

Conclusions

The ratio between AGEs and the cRAGE isoform is predictive of 15-year survival in patients with type 2 diabetes. Our data support the assessment of circulating AGEs and soluble RAGE isoforms in patients with type 2 diabetes as predictors of MACE and all-cause mortality.
CircVAPA promotes small cell lung cancer progression by modulating the miR-377-3p and miR-494-3p/IGF1R/AKT axis
Authors: Hua Jinghan , Wang Xiaolin , Ma Liying , Li Jingxin , Cao Guozhen , Zhang Shaobo , Lin Wenchu
Published: June 2022

Background

Multiple lines of evidence have demonstrated that circular RNAs (circRNAs) play oncogenic or tumor-suppressive roles in various human cancers. Nevertheless, the biological functions of circRNAs in small cell lung cancer (SCLC) are still elusive.

Methods

CircVAPA (annotated as hsa_circ_0006990) was identified by mining the circRNA profiling dataset of six paired SCLC tissues and the RNA-seq data of serum samples from 36 SCLC patients and 118 healthy controls. The circVAPA expression level was evaluated using quantitative real-time PCR in SCLC cells and tissues. Cell viability, colony formation, cell cycle and apoptosis analysis assays and in vivo tumorigenesis were used to reveal the biological roles of circVAPA. The underlying mechanism of circVAPA was investigated by Western blot, RNA pulldown, RNA immunoprecipitation, dual-luciferase reporter assay and rescue experiments.

Results

We revealed that circVAPA, derived from exons 2-4 of the vesicle-associated membrane protein-associated protein A (VAPA) gene, exhibited higher expression levels in SCLC cell lines, clinical tissues, and serum from SCLC patients than the controls, and facilitated SCLC progression in vitro and in vivo. Mechanistically, circVAPA activated the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway by modulating the miR-377-3p and miR-494-3p/insulin-like growth factor 1 receptor (IGF1R) axis to accelerate SCLC progression. Furthermore, circVAPA depletion markedly enhanced the inhibitory effects of BMS-536924, an IGF1R kinase inhibitor in cellular and xenograft mouse models.

Conclusions

CircVAPA promotes SCLC progression via the miR-377-3p and miR-494-3p/IGF1R/AKT axis. We hope to develop clinical protocols of combinations of circVAPA inhibition and BMS-536924 addition for treating SCLC with circVAPA upregulation.
Identifying the critical states and dynamic network biomarkers of cancers based on network entropy
Authors: Liu Juntan , Ding Dandan , Zhong Jiayuan , Liu Rui
Published: June 2022

Background

There are sudden deterioration phenomena during the progression of many complex diseases, including most cancers; that is, the biological system may go through a critical transition from one stable state (the normal state) to another (the disease state). It is of great importance to predict this critical transition or the so-called pre-disease state so that patients can receive appropriate and timely medical care. In practice, however, this critical transition is usually difficult to identify due to the high nonlinearity and complexity of biological systems.

Methods

In this study, we employed a model-free computational method, local network entropy (LNE), to identify the critical transition/pre-disease states of complex diseases. From a network perspective, this method effectively explores the key associations among biomolecules and captures their dynamic abnormalities.

Results

Based on LNE, the pre-disease states of ten cancers were successfully detected. Two types of new prognostic biomarkers, optimistic LNE (O-LNE) and pessimistic LNE (P-LNE) biomarkers, were identified, enabling identification of the pre-disease state and evaluation of prognosis. In addition, LNE helps to find “dark genes” with nondifferential gene expression but differential LNE values.

Conclusions

The proposed method effectively identified the critical transition states of complex diseases at the single-sample level. Our study not only identified the critical transition states of ten cancers but also provides two types of new prognostic biomarkers, O-LNE and P-LNE biomarkers, for further practical application. The method in this study therefore has great potential in personalized disease diagnosis.
Health system resilience during COVID-19 understanding SRH service adaptation in North Kivu
Authors: Ho Lara S. , Bertone Maria Paola , Mansour Wesam , Masaka Cyprien , Kakesa Jessica
Published: June 2022

Background

There is often collateral damage to health systems during epidemics, affecting women and girls the most, with reduced access to non-outbreak related services, particularly in humanitarian settings. This rapid case study examines sexual and reproductive health (SRH) services in the Democratic Republic of the Congo when the COVID-19 hit, towards the end of an Ebola Virus Disease (EVD) outbreak, and in a context of protracted insecurity.

Methods

This study draws on quantitative analysis of routine data from four health zones, a document review of policies and protocols, and 13 key-informant interviews with staff from the Ministry of Public Health, United Nations agencies, international and national non-governmental organizations, and civil society organizations.

Results

Utilization of SRH services decreased initially but recovered by August 2020. Significant fluctuations remained across areas, due to the end of free care once Ebola funding ceased, insecurity, number of COVID-19 cases, and funding levels. The response to COVID-19 was top-down, focused on infection and prevention control measures, with a lack of funding, technical expertise and overall momentum that characterized the EVD response. Communities and civil society did not play an active role for the planning of the COVID-19 response. While health zone and facility staff showed resilience, developing adaptations to maintain SRH provision, these adaptations were short-lived and inconsistent without external support and funding.

Conclusion

The EVD outbreak was an opportunity for health system strengthening that was not sustained during COVID-19. This had consequences for access to SRH services, with limited-resources available and deprioritization of SRH.
Two metrics on rooted unordered trees with labels
Authors: Wang Yue
Published: June 2022

Background

The early development of a zygote can be mathematically described by a developmental tree. To compare developmental trees of different species, we need to define distances on trees. If children cells after a division are not distinguishable, developmental trees are represented by the space $${\mathcal {T}}$$
T
of rooted trees with possibly repeated labels, where all vertices are unordered. If children cells after a division are partially distinguishable, developmental trees are represented by the space $${\mathcal {P}}$$
P
of rooted trees with possibly repeated labels, where vertices can be ordered or unordered.

Results

On $${\mathcal {T}}$$
T
, the space of rooted unordered trees with possibly repeated labels, we define two metrics: the best-match metric and the left-regular metric, which show some advantages over existing methods. On $${\mathcal {P}}$$
P
, the space of rooted labeled trees with ordered or unordered vertices, there is no metric, and we define a semimetric, which is a variant of the best-match metric. To compute the best-match distance between two trees, the expected time complexity and worst-case time complexity are both $${\mathcal {O}}(n^2)$$

O
(

n
2

)

, where n is the tree size. To compute the left-regular distance between two trees, the expected time complexity is $${\mathcal {O}}(n)$$

O
(
n
)

, and the worst-case time complexity is $${\mathcal {O}}(n\log n)$$

O
(
n
log
n
)

.

Conclusions

For rooted labeled trees with (fully/partially) unordered vertices, we define metrics (semimetric) that have fast algorithms to compute and have advantages over existing methods. Such trees also appear outside of developmental biology, and such metrics can be applied to other types of trees which have more extensive applications, especially in molecular biology.
Ruxolitinib-corticosteroid as first-line therapy for newly diagnosed high-risk acute graft versus host disease: study protocol for a multicenter, randomized, phase II controlled trial
Authors: Dou Liping , Peng Bo , Li Xin , Wang Lu , Jia Mingyu , Xu Lingmin , Li Fei , Liu Daihong
Published: June 2022

Background

The response rate of the first-line therapy with corticosteroid for acute graft versus host disease (aGVHD) is about 50%, and steroid-refractory disease is associated with high mortality. The improved response rate to the first-line therapy of newly diagnosed aGVHD patients would result in therapeutic benefits. Ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, has been approved for the treatment of steroid-refractory acute GVHD. The addition of ruxolitinib to the first-line therapy may improve the efficacy of corticosteroids.

Methods

This investigator-initiated, open-label, multicenter, prospective randomized, and controlled two-arm phase II study compares the efficacy and safety of ruxolitinib combined with 1 mg/kg methylprednisolone versus 2 mg/kg methylprednisolone alone in newly diagnosed aGVHD patients. Patients with intermediate or high-risk aGVHD, as defined by the Minnesota aGVHD high-risk score and biomarker algorithm, are eligible for this study. A total of 198 patients will be randomized at a 1:1 ratio and assigned a GVHD risk (intermediate versus high risk) and disease status before transplantation (complete remission versus no complete remission). The primary endpoint is the overall response rate on day 28, which is defined as an improvement of at least one stage in the severity of aGVHD in one organ without deterioration in any other organ or disappearance of any GVHD signs from all organs without requiring new systemic immunosuppressive treatment. The secondary objectives consist of response time, response duration, overall survival, disease-free survival, non-relapse mortality, failure-free survival, and changes in serum levels of proinflammatory cytokines and GVHD-related biomarkers.

Discussion

This open-label, multicenter, two-arm randomized trial will evaluate whether the addition of ruxolitinib combined with corticosteroid is superior to corticosteroid alone in newly diagnosed high-risk aGVHD.

Trial registration

ClinicalTrials.gov NCT04061876 (version number: 2019.5.18). Registered on July 16, 2019
Continuous or interrupted suture technique for hepaticojejunostomy during pancreatoduodenectomy (HEKTIK trial): study protocol of a randomized controlled multicenter trial
Authors: Brunner Maximilian , Golcher Henriette , Krautz Christian , Kersting Stephan , Weber Georg F. , Grützmann Robert
Published: June 2022

Background

Hepaticojejunostomy is commonly performed in hepato-bilio-pancreatic surgery, particularly during pancreaticoduodenectomy. The purpose of this study is to evaluate the safety and efficiency of two commonly applied suture techniques (the interrupted versus the continuous suture technique) in patients undergoing a hepaticojejunostomy during pancreatoduodenectomy.

Methods

The HEKTIK trial is a multicenter, randomized controlled, patient-blinded surgical explorative trial with two parallel study groups. An adaptive sample size design was chosen: First, 100 patients scheduled for surgery including a hepaticojejunostomy will be randomized 1:1 either to the interrupted suture technique or the continuous suture technique after informed consent. Based on this data, needed sample size will be adjusted.

The primary endpoint will be the occurrence of anastomotic leakage of hepaticojejunostomy, defined as bilirubin concentration in the drain fluid at least 3 times the serum bilirubin concentration on or after postoperative day 3 or as the need for radiologic or operative intervention resulting from biliary collections or bile peritonitis (according to the definition of ISGLS). Further perioperative parameters like other morbidities as well as duration and costs of the hepaticojejunostomy will be analyzed as secondary outcomes.

Discussion

Until now there are no randomized controlled comparative data of these two suture techniques for hepaticojejunostomy. The HEKTIK trial will investigate the yet unanswered question of whether the interrupted suture or the continuous suture technique has advantages performing a hepaticojejunostomy during pancreatoduodenectomy.

Trial registration

German Clinical Trials Register DRKS00024395. Registered on 01 February 2021.
Establishment of a gnotobiotic pig model of Clostridioides difficile infection and disease
Authors: Nyblade Charlotte , Parreno Viviana , Zhou Peng , Hensley Casey , Oakes Vanessa , Mahsoub Hassan M. , Kiley Kelsey , Frazier Maggie , Frazier Annie , Zhang Yongrong , Feng Hanping , Yuan Lijuan
Published: June 2022

Clostridioides difficile (C. difficile) is a gram-positive, spore-forming, anaerobic bacterium known to be the most common cause of hospital-acquired and antibiotic-associated diarrhea. C. difficile infection rates are on the rise worldwide and treatment options are limited, indicating a clear need for novel therapeutics. Gnotobiotic piglets are an excellent model to reproduce the acute pseudomembranous colitis (PMC) caused by C. difficile due to their physiological similarities to humans and high susceptibility to infection. Here, we established a gnotobiotic pig model of C. difficile infection and disease using a hypervirulent strain. C. difficile-infected pigs displayed classic signs of C. difficile infection, including severe diarrhea and weight loss. Inoculated pigs had severe gross and microscopic intestinal lesions. C. difficile infection caused an increase in pro-inflammatory cytokines in samples of serum, large intestinal contents, and pleural effusion. C. difficile spores and toxins were detected in the feces of inoculated animals as tested by anaerobic culture and cytotoxicity assays. Successful establishment of this model is key for future work as therapeutics can be evaluated in an environment that accurately mimics what happens in humans. The model is especially suitable for evaluating potential prophylactics and therapeutics, including vaccines and passive immune strategies.
Delayed hydrocephalus after excision of a colloid cyst: a case report
Authors: Gray Logan , Quig Nathan , Kang Myungsa
Published: June 2022

Background

In this case report we describe an unusual case of a patient who underwent resection of a colloid cyst and then presented 6 weeks postoperatively with obstructive hydrocephalus. There appear to be no prior reports of such a delayed complication after colloid cyst resection.

Case presentation

A 50-year-old Caucasian woman underwent resection of a colloid cyst with an uncomplicated perioperative course. Postoperative imaging demonstrated complete resection of the cyst. She was discharged home on postoperative day 4 but presented 6 weeks later with symptoms of obstructive hydrocephalus resulting in poor neurologic outcome and ultimately death.

Conclusion

Patients presenting with symptoms of hydrocephalus after resection of a colloid cyst should be followed closely, and timely placement of an external ventricular drain may be critical.
Time to update the Japanese standard population for comparing mortality rates
Authors: Dhungel Bibha , Wada Koji , Tanaka Hirokazu , Gilmour Stuart
Published: June 2022

For the last three decades, Japan has been using the population of 1985 for age standardisation to compare mortality rates over time. With the population of Japan declining and ageing rapidly every year, there is a need to update the standard population to make the comparison representative of the current scenario. This is particularly relevant owing to declining mortality rates among the super-ageing Japanese elderly population and more data availability for older age groups. The choice of one population as standard over another is arbitrary because it does not make much difference to the trends in rates. The proportion of elderly in Japan is increasing rapidly and is expected to be one-third of the total population by 2030, in contrast to the proportion of 10% in the 1980s. Using a standard population with a lower proportion of elderly may weight the rates disproportionately for this age group. It is typically suitable to change the standard population every 25 to 30 years. It is advisable to choose the population of 2015 as the new standard population as suggested by the working group of the Ministry of Health, Labour and Welfare of Japan for revising the standard population. However, it should be noted that the newly calculated age-standardised mortality rates will no longer be comparable to those calculated using the older standard populations. Updating the standard population will produce age-standardised rates for recent years closer to the crude rates and would thus reduce the extent of misinterpreting decreased mortality risks using age-standardised rates that do not closely resemble the crude rates.
How I do it: Modified Lichtenberger-Brown tracheoesophageal puncture procedure
Authors: Sapundzhiev Nikolay R. , Asenov Asen G. , Spasova Blagovesta , Genova Petya S. , Davidov Georgi I. , Ivanova Darina
Published: June 2022

Background

Tracheoesophageal puncture (TEP) with use of a prosthesis is nowadays a standard for voice restoration after laryngectomy. Different TEP approaches exist.

Methods

We retrospectively reviewed our series of patients who underwent TEP by a novel technique, based partially on the Lichtenberger endo-extralaryngeal needle carrier. The instrument is covered with a protective Nelaton catheter and introduced via the mouth to the neopharynx/esophagus. No rigid endoscope is used for visualization of the TEP site. The tip is palpated through the stoma at the posterior tracheal wall and incision is done to the catheter tip. The prosthesis is introduced through the mouth and the neopharynx in a retrograde fashion.

Results

In 14 laryngectomees with postoperative radiation voice prosthesis was successfully placed with this technique. A total of 18 procedures were performed. One misplacement occurred. No other early or late complications were observed or any other TEP or prosthesis related problems.

Conclusions

The rationale of our technique is to simplify the procedure, avoid risk-bearing approaches and instruments such as rigid endoscopes, simplify the armamentarium and reduce tissue trauma. The initial clinical experience in 18 TEPs confirmed it usefulness in both standard and anatomically challenging situations.

The current study obtained the ethical approval from the Faculty of Medicine at Medical University “Prof. Dr. Paraskev Stoyanov”—Varna, Bulgaria (Protocol 087/24.10.2019 (retrospectively registered).

Graphical Abstract
Survival of patients with neuroblastoma before versus after reduction of therapy due to the change in age cut-off from 12 to 18 months in Children’s Oncology Group (COG) risk stratification.
Authors: London Wendy B. , Bender Hannah , Irwin Meredith , Hogarty Michael D. , Castleberry Robert P. , Maris John M. , Kao Pei-Chi , Naranjo Arlene , Cohn Susan Lerner
Published: June 2022

10013

Background: In 2006, COG reclassified subgroups of toddlers diagnosed with neuroblastoma from high-(HR) to intermediate-risk (IR), when the age cut-off for increased risk was raised from 365 days (12 mo) to 547 days (18 mo) (London, J Clin Onc 2005). The aim of this retrospective study was to determine if excellent outcome was maintained after a reduction of therapy. Methods: Children < 3 yrs old at diagnosis, enrolled on a COG biology study from 1990-2018, were eligible (n = 9,189). Therapy was reduced for two “cohorts of interest” based on the age cut-off change: 365-546 days old with INSS stage 4, MYCN not amplified, favorable INPC, hyperdiploid tumors (12-18mo/Stage4/FavBiology); and, 365-546 days old with INSS stage 3 tumors with non-amplified MYCN and unfavorable INPC (12-18mo/Stage3/NotAmp/UnfavINPC). Log rank tests compared event-free (EFS) and overall survival (OS) curves. Results: In the cohorts of interest, patient (pt) characteristics were similar for ≤2006 vs > 2006. For 12-18mo/Stage4/FavBiology, 5-year EFS and OS (± std error) before (≤2006; n = 40) versus after (> 2006; n = 55) the reduction in therapy were similar: 89±5.1% versus 87±4.6% (p = 0.7), and 89±5.1% versus 94±3.2% (p = 0.4), respectively (Table). For 12-18mo/Stage3/NotAmp/UnfavINPC, the 5-year EFS and OS were both 100%, before (n = 6) and after (n = 4) 2006. For the combined cohorts for ≤2006 versus > 2006, EFS and OS were 91±4.4% versus 88±4.3% (p = 0.6), and 91±4.5% versus 95±2.9% (p = 0.5), respectively. Within HR pts diagnosed ≤2006, EFS/OS were 91±4.4%/91±4.5% for (12-18mo/Stage4/FavBiology plus 12-18mo/Stage3/NotAmp/UnfavINPC) vs 38±1.3%/43±1.3% for all other HR pts < 3 yrs old (p < 0.0001; Table). Within IR pts diagnosed > 2006, EFS/OS were 88±4.3%/95±2.9% for (12-18mo/Stage4/FavBiology plus 12-18mo/Stage3/NotAmp/UnfavINPC) vs 88±0.9%/95±0.6% for all other IR pts < 3 yrs old (p = 0.9). Conclusions: Our 19 year study demonstrates that excellent outcome is maintained among toddlers with Stage4/FavBiology and Stage3/Not Amp/Unfav INPC neuroblastoma with a significant reduction of therapy from high- to intermediate-risk treatment. Importantly, pts were likely spared acute toxicity and late effects known to be associated with HR therapy. Efforts to identify additional pt cohorts who may not require HR therapy to achieve long-term survival are critical to improve the long-term health of children with neuroblastoma. [Table: see text]
Modifiable risk factors for late mortality among five-year survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
Authors: Dixon Stephanie B , Liu Qi , Ehrhardt Matthew J. , Chow Eric Jessen , Oeffinger Kevin C. , Mertens Ann C. , Nathan Paul C. , Howell Rebecca M. , Leisenring Wendy M. , Krull Kevin R. , Ness Kirsten K. , Hudson Melissa M. , Robison Leslie L. , Yasui Yutaka , Armstrong Gregory T.
Published: June 2022

10014

Background: The impact ofmodifiable lifestyle and cardiovascular risk factors (CVRFs) on risk for late mortality in adult survivors of childhood cancer is not well established. Methods: All-cause and health-related late (>5 years from cancer diagnosis) mortality (HRM; excludes death from primary cancer and external causes) were evaluated in five-year survivors diagnosed <21 years of age using the National Death Index through 2017. Modifiable lifestyle (smoking status, alcohol use, physical activity, body mass index [BMI]; combined to create a score [0-4] and categorized as unhealthy [0-2], moderate [2.5 or 3], healthy [3.5 or 4]) and CVRFs (hypertension [HTN], diabetes [DM], dyslipidemia) were assessed as time-varying covariates. Standardized mortality ratios (SMRs) and absolute excess risk of death per 1000 person-years (AER) with 95% confidence intervals (CIs) were estimated. Multivariable models estimated the relative risk (RR) of death adjusted for demographic and socioeconomic variables. Results: Among 20,051 adult survivors (median age 40.0 years, range 18.7 – 67.7), 19% reported ≥1 CVRF (13% HTN, 9% dyslipidemia, 5% DM) and few reported a healthy lifestyle (29% healthy, 40% moderate, 31% unhealthy). There were 1476 deaths due to health-related causes. While all survivors experienced an increased risk of HRM compared to the US population, risk was lower among those with a healthy vs. unhealthy lifestyle (SMR 3.5, 95% CI 3.1-3.9 vs. 6.2, 5.7-6.7) and very high among underweight survivors (11.1, 9.3-13.3) and those with both HTN and DM (13.0, 9.2-18.0). Stratified by lifestyle score, the excess risk of HRM was lowest in those with a healthy lifestyle across survival time (Table). Similar trends were seen when stratified by 0, 1 and 2 CVRFs. In multivariable models, compared to survivors with no CVRFs and healthy lifestyle, no CVRFs and unhealthy lifestyle was associated with a 50% increased risk of HRM (RR 1.5, 95% CI 1.2-1.8) and unhealthy lifestyle plus HTN a 2-fold increased risk of HRM (2.2, 1.6-2.8). Regardless of lifestyle group, ≥2 CVRF increased risk for HRM at least 2-fold (p-values <0.001). Conclusions: A reduction in excess deaths is observed among adult survivors of childhood cancer with a healthy lifestyle and no CVRFs as they age. Interventions that target improved lifestyle choices and prevention or aggressive treatment of modifiable CVRFs may reduce risk for late mortality. [Table: see text]
Outcomes of Hispanic and non-Hispanic white pediatric and young adult patients with B-cell acute lymphoblastic leukemia after commercial tisagenlecleucel.
Authors: Vandris Panayiotis , Chao Karen , Baggott Christina , Phillips Christine L. , Qayed Muna , Rossoff Jenna , Si Lim Stephanie J. , Winestone Lena E. , Stefanski Heather E. , Talano Julie-An M. , Margossian Steven , Verneris Michael R. , Myers Gary Douglas , Karras Nicole A. , Brown Patrick A. , Satwani Prakash , Mackall Crystal , Curran Kevin J. , Laetsch Theodore Willis , Schultz Liora M.
Published: June 2022

10016

Background: Population-level data show significantly inferior outcomes for Hispanic children, adolescents, and young adults (CAYA) diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) relative to non-Hispanic whites (NHW). Here, we compare outcomes between Hispanic and NHW CAYA patients with relapsed and/or refractory (RR) B-ALL receiving tisagenlecleucel, a CD19-specific chimeric antigen receptor (CAR) T cell therapy. Methods: We used data from the Pediatric Real World CAR Consortium retrospective cohort of 200 patients who underwent cell shipment for standard-of-care tisagenlecleucel between August 2017 and March 2020 (N=15 US institutions). Race/ethnicity was identified by medical record review. Patients reported as belonging to more than one racial/ethnic group were classified as multiracial and excluded from analysis. Baseline factors, outcomes, and safety post-infusion were characterized for Hispanic vs. NHW infused patients. Outcomes included complete response (CR) rate, overall survival (OS), duration of response (DOR), and duration of B-cell aplasia (DBA). A multivariate Cox model for OS was constructed, including all baseline factors. Results: Among 185 infused patients, 90 (48.6%) were NHW and 70 (37.8%) were Hispanic. Among 15 non-infused patients, 3 (20.0%) were NHW and 5 (33.3%) were Hispanic. Hispanic patients were significantly older at diagnosis (mean: 10.7 vs. 8.3 years, p=0.02) and had significantly shorter time from diagnosis to infusion (mean: 34.4 vs. 46.4 months, p=0.04). Hispanic and NHW patients did not significantly differ across sex, leukemia type, number of prior lines of therapy, receipt of prior CD19-directed therapy, level of disease burden pre-infusion, and number of relapses pre-infusion. Hispanic and NHW patients did not significantly differ across 1-month CR, 6-month OS, 1-year OS, 18-month OS, 6-month DOR, 1-year DOR, 6-month DBA, and 1-year DBA (Table). On multivariate analysis including the above covariates, OS did not significantly differ for Hispanic patients (HR=1.04, p=0.92). Hispanic and NHW patients did not significantly differ across grade ≥ 3 cytokine release syndrome, grade ≥ 3 neurotoxicity, grade 4 neutropenia, tumor lysis syndrome, or number of infections post-infusion. Conclusions: Outcomes were similar between Hispanic and NHW CAYA RR B-ALL patients receiving tisagenlecleucel in the real-world setting. Increasing access to CAR therapy among Hispanic CAYA B-ALL patients could help mitigate population-level disparities in outcomes observed after receipt of conventional therapies. [Table: see text]
Menin inhibitors as targeted therapeutics in KMT2a rearranged infant leukemia and the identification of effective treatment combinations.
Authors: Sharma Ritul , Zhang Chunfen , Maese Luke Devon , Lacayo Norman James , Narendran Aru
Published: June 2022

10024

Background: KMT2a rearrangements are a hallmark of infant (less than 1 year of age) leukemia and are associated with poor prognosis. Menin is a ubiquitous protein that binds to the N-terminal of the KMT2a-fusion protein to mediate the oncogenic activity of KMT2a-rearranged leukemia cells. In this study, we evaluated the effect of multiple menin inhibitors and effective drug combinations for the treatment of KMT2A-rearranged infant leukemia. Methods: FISH analysis and immunoblotting confirmed the presence of KMT2a-fusion in the primary patient samples and cell lines studied. Lymphocytes from healthy donors were used as controls. Cells were treated with various concentration of multiple menin inhibitors for 72 hours and growth inhibition was measured using alamar blue assay. Infant leukemia cells were treated with a panel of FDA-approved agents (n = 221) to identify potential synergy, additive- and antagonistic-effects with specific menin inhibitors. Therapeutic drug interaction properties were established by calculating combination indices (CI) using the Chou-Talalay method. Mode of cell death and cellular target modulations were determined by western blot analysis. The effect of targeting menin in the context of the leukemogenic bone marrow microenvironment was determined through stromal cell co-cultures. Results: A comprehensive analysis of menin inhibitors on infant leukemia cell lines and primary patient cells exhibited significant and quantitatively diverse responses in cells with distinct molecular properties. Within the panel of menin inhibitors, infant B-ALL cells were found to be more sensitive to MI-463, MI-503 and MI-136 with a mean IC50 of 5.9µM, 6.1µM and 10.2µM, respectively. On the other hand, MI-3 exhibited an IC50 of 35.6µM. The cytotoxic effect of menin inhibitors on normal lymphocytes was minimal, suggesting a favourable therapeutic window (p < 0.0001). High-throughput screening with a library of > 200 FDA-approved drugs revealed significant sensitivity of distinct infant leukemia cells to proteasome, HDAC and CDK9 inhibitors. Among these, substantial drug synergy was observed between menin and proteasome inhibitors. For example, carfilzomib synergised with menin inhibitors over a broad range of concentrations with a CI value of 0.7. Conclusions: In this study, we present and discuss the initial proof-of-concept preclinical data for the effective anti-leukemic activity of menin inhibition against KMT2A-rearranged infant leukemia cells. Furthermore, the comprehensive drug screen and drug combination studies identified a spectrum of mechanistically-validated synergies, providing usable data for the formulation of multi-agent clinical studies for this currently unmet need in pediatric oncology.
A fully automated MRI-based deep-learning algorithm for classifying germinomas and nongerminomatous germ cell tumors.
Authors: Li Yanong
Published: June 2022

10035

Background: Intracranial germ cell tumors (iGCTs) are classified into two pathological subtypes (Germinomas [GEs] and nongerminomatous germ cell tumors [NGGCTs]), with distinct treatment strategies and prognosis. Accurate preoperative determination of iGCT subtypes is essential for clinical decision-making and prognosis assessment. We aim to develop and validate a deep-learning algorithm to automatically segment the iGCTs and classify their subtypes using preoperativeT2-weighted (T2W) images. Methods: Brain MR imaging and corresponding pathologic information were retrospectively obtained for 594 iGCTs, including 269 GEs and 325 NGGCTs from Beijing Tiantan Hospital (between January 1, 2008, and October 31, 2020). The retrospective set was subdivided into the training (n = 416) and test (n = 178) sets to develop and test a 3D nnU-Net using T2W images (here we named iGCT-net) for iGCT segmentation and its subtypes (GEs and NGGCTs) classification, simultaneously. A prospective cohort (n = 73, 56 GEs and 17 NGGCTs) was designed as a simulation set to test the model in a simulated clinical application. Dice scores were computed to assess tumor segmentation. Accuracy, sensitivity, specificity, and area under the curve (AUC) were used to assess the GEs and NGGCTs classification. Sensitivity analysis on subgroups with tumor locating at suprasellar, pineal, and basal ganglia in test and simulation set, respectively. Results: For tumor segmentation, the iGCT-net achieved a dice score of 0. 73 and 0.80 in test and simulation sets, respectively. For GEs and NGGCTs classification in the test set, the iGCT-net achieved an accuracy of 90.96%, sensitivity of 86.84% and specificity of 82.26%, and AUC of 84.87%. The iGCT-net showed 83.65% accuracy in the simulation set, with sensitivity of 83.56% and specificity of 83.72%, and AUC was 81.17%. In sensitivity analysis, the accuracies of the iGCT-net presented for the suprasellar region, pineal region, and basal ganglia region were 86.84%, 92.92%, and 61.73% in the test set, and 92.31%, 88.89%, and 72.27% for suprasellar region, pineal region, and basal ganglia region in the simulation set. Conclusions: We developed and validated a fully automatic deep learning algorithm to segment iGCT and classify GEs and NGGCTs with a high accuracy using only T2W images based on a large dataset.
Clinical and biological features prognostic of survival after relapse of INRGSS-stage MS pattern neuroblastoma: A report from the International Neuroblastoma Risk Group (INRG) project.
Authors: Campbell Kevin M. , Kao Pei-Chi , Naranjo Arlene , Kamijo Takehiko , Ramanujachar Ramya , London Wendy B. , DuBois Steven G.
Published: June 2022

10044

Background: Neuroblastoma (NB) presenting with INRGSS MS metastatic pattern highlights the extreme heterogeneity within NB and subsequent difficulty in risk assignment. Depending on tumor biology, patients with stage MS disease may be classified as very-low risk or as high-risk. While outcomes at initial diagnosis have been well-described, outcomes after relapse are less well defined. Methods: From the INRG Data Commons, we investigated clinical and biological characteristics of patients diagnosed 1984-2021 with stage MS pattern NB (INSS stage 4s, INSS stage 4 or INRG stage MS) who subsequently experienced disease relapse or progression, excluding patients whose first event was death. Using Kaplan-Meier methods, post-relapse overall survival (OS)± standard error (SE) was calculated from the time of first relapse/progression until death or last contact, overall and by era of diagnosis: < 2000 vs ≥2001. Univariate Cox models were used to identify factors prognostic of post-relapse OS. Results: 209 patients met eligibility criteria,103 diagnosed < 2001 and 106 ≥2001. Of patients diagnosed ≥2001, 89% (n = 94) were < 365 days old at diagnosis; tumors were MYCN amplified in 21% (21/102) and diploid in 31% (20/64). Of this same cohort, time from initial diagnosis to relapse was < 6 months in 40% (n = 42), 6-12 months in 25% (n = 26), and > 12 months in 36% (n = 38) of patients. Of 60 patients with known site of relapse/progression diagnosed ≥2001, 73% (44) were metastatic (29) or primary plus metastatic (15). Among these, 16% (5/32) remained stage MS pattern while 84% (27/32) had metastatic sites beyond MS sites. Five-year post-relapse OS±SE was 53±3.5% overall (n = 209), and higher for those diagnosed ≥2001 (62±5.0%; n = 106) compared to those diagnosed < 2001 (44±4.9%; n = 103) (p = 0.0046). In patients diagnosed ≥2001, factors prognostic of superior post-relapse OS included: age < 365 days; not Hispanic; MYCN non-amplified; no 1p loss/aberration, hyperdiploidy; low/intermediate MKI; LDH < 1400 U/L, favorable INPC histology; and < 12 months from initial diagnosis to first relapse. Conclusions: Most patients with relapsed stage MS NB have metastatic relapse and these relapses more commonly occur at sites outside liver, skin, and bone marrow. Patients diagnosed ≥2001 with MS pattern NB have substantially better post-relapse OS compared to those diagnosed < 2001. In the cohort of patients with MS pattern NB diagnosed ≥2001, most of the well-accepted prognostic factors for OS at diagnosis are also prognostic of post-relapse OS.
Thyroid gland definitive ultrasound screening in childhood cancer survivors following radiotherapy.
Authors: Baran Julia A. , Halada Stephen , Bauer Andrew J. , Li Yimei , Isaza Amber , Patel Tasleema , Sisko Lindsay , Ginsberg Jill P. , Kazahaya Ken , Adzick N. Scott , Mostoufi-Moab Sogol
Published: June 2022

10049

Background: Childhood cancer survivors (CCS) are at risk for radiotherapy (RT) late effects, including second malignancies. Optimal screening for thyroid cancer (TC) in CCS post-RT remains controversial. We assessed the clinical benefit of thyroid ultrasound (US) surveillance in CCS exposed to RT. Methods: 316 CCS (175 males) were prospectively surveilled with thyroid US between 2002 and 2021 at the Children’s Hospital of Philadelphia. Patients were screened upon referral to the Survivorship Program. Thyroid US, clinicopathologic features, and endocrine-related outcomes were ascertained. Outcomes were compared using primary CCS diagnosis age cohorts of ≤ 3, > 3 to ≤ 10, and > 10 years. Risk factors for thyroid nodule(s) and TC were evaluated using Kruskal Wallis and ANOVA [OR (95% CI)]. Results: The most common CCS diagnoses were leukemia (32%), CNS tumor (26%), and neuroblastoma (18%). Patients received TBI (43%) and/or RT to craniospinal (43%), chest (13%), and neck regions (7%). About 48% (n = 152) of patients presented thyroid nodule(s) (Table). Forty-six patients underwent surgery, and 28 had TC, including 19 with ATA low-risk, 2 with ATA intermediate-risk, and 7 with ATA high-risk disease. Of the 9 patients with intermediate- or high-risk disease, 5 were ≤ 3 years, 3 were > 3 to ≤ 10 years, and 1 was > 10 years at the time of RT exposure. Eight patients with TC demonstrated pathogenic variant(s). RT exposure at ≤ 3 years old conferred 2-fold increased risk for nodule(s) compared to RT at > 10 years [OR = 2.14 (1.44-2.84) p = 0.03]. Female sex [OR = 1.73 (1.25-2.21) p = 0.02] and greater interval between RT and first US [OR = 1.10 (1.04-1.15) p = 0.001] were additional independent risk factors. Conclusions: Younger age at RT exposure is associated with increased risk of and shorter latency for developing TC. Thyroid US surveillance appears most beneficial in CCS exposed to RT ≤ 3 years old in an effort to diagnose TC at an earlier stage prior to metastasis. [Table: see text]
Treatment exposure-based risk-stratification for care of survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
Authors: Dinan Michaela Ann , Stratton Kayla , Leisenring Wendy M. , Yasui Yutaka , Chow Eric Jessen , Moskowitz Chaya S. , Yeh Jennifer M , Noyd David H , Armstrong Gregory T. , Oeffinger Kevin C.
Published: June 2022

10056

Background: Treatment exposure-based risk-stratification oflong-term cancer survivors is needed to allocate tailored health care in survivorship clinics. Investigators from the United Kingdom (UK) developed a treatment exposure-based algorithm that stratifies survivors into low, medium, and high risk groups. Because this algorithm has not been validated, we sought to use the large, diverse population of the Childhood Cancer Survivor Study (CCSS) to validate risk for poor outcomes. Methods: Five-year survivors of childhood cancer (diagnosed between 1970-1999 at < 21 years of age) were categorized into low, medium, and high risk groups based on treatment exposures and diagnoses (Table). Primary endpoints included cumulative health-related (i.e., non-recurrence, non-external) late mortality and cumulative incidence of grade 3-5 chronic conditions (CTCAEv4.03) conditional on reaching age 20 without the outcome. Siblings were a comparison group for chronic conditions. Cox proportional hazards models among survivors estimated hazard ratios (HRs) and 95% confidence intervals (CI) adjusted for sex and race. Results: A total of 21,504 survivors were analyzed with a median follow-up of 22 years. Application of the risk stratification algorithm resulted in 3,152 low risk, 6,443 medium risk, and 11,909 high risk survivors. Among those who survived to age 20 without any grade 3-5 conditions, the risk of developing one by age 35 was 12.2% (95% CI 1.0-14.7%), 14.2% (12.8-15.7%) and 25.4% (24.2-26.6%) for low, medium, and high-risk patients, respectively, and 6.9% (6.1-7.9%) for siblings. HRs of grade 3-5 conditions for medium (HR 1.8, 95% CI 1.6-2.1) and high (HR 3.9, 95% CI 3.5-4.4) risk relative to low risk survivors, respectively, were elevated. Cumulative health-related mortality was similarly associated with risk categories; conditional on being alive at age 20, survivors within low, medium, and high risk groups had cumulative incidences of 2.3% (95% CI 1.7-3.1%), 3.3% (2.8-3.9%) and 6.1% (5.6-6.6%), respectively, by age 35. Conclusions: Risk categorizations based on treatment exposures were effective at providing generalized risk stratification within the CCSS with respect to risk of grade 3-5 conditions and health related mortality, particularly for identifying high risk survivors. These risk groups may be useful to physicians in determining follow-up intervals and guiding management and long-term surveillance of these survivors. [Table: see text]