bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and implementation of an LIS-based validation system for autoverification toward zero defects in the automated reporting of laboratory test results
Authors: Jin Di , Wang Qing , Peng Dezhi , Wang Jiajia , Li Bijuan , Cheng Yating , Mo Nanxun , Deng Xiaoyan , Tao Ran
Published: June 2021

Background

Validation of the autoverification function is one of the critical steps to confirm its effectiveness before use. It is crucial to verify whether the programmed algorithm follows the expected logic and produces the expected results. This process has always relied on the assessment of human–machine consistency and is mostly a manually recorded and time-consuming activity with inherent subjectivity and arbitrariness that cannot guarantee a comprehensive, timely and continuous effectiveness evaluation of the autoverification function. To overcome these inherent limitations, we independently developed and implemented a laboratory information system (LIS)-based validation system for autoverification.

Methods

We developed a correctness verification and integrity validation method (hereinafter referred to as the "new method") in the form of a human–machine dialog. The system records personnel review steps and determines whether the human–machine review results are consistent. Laboratory personnel then analyze the reasons for any inconsistency according to system prompts, add to or modify rules, reverify, and finally improve the accuracy of autoverification.

Results

The validation system was successfully established and implemented. For a dataset consisting of 833 rules for 30 assays, 782 rules (93.87%) were successfully verified in the correctness verification phase, and 51 rules were deleted due to execution errors. In the integrity validation phase, 24 projects were easily verified, while the other 6 projects still required the additional rules or changes to the rule settings. Taking the Hepatitis B virus test as an example, from the setting of 65 rules to the automated releasing of 3000 reports, the validation time was reduced from 452 (manual verification) to 275 h (new method), a reduction in validation time of 177 h. Furthermore, 94.6% (168/182) of laboratory users believed the new method greatly reduced the workload, effectively controlled the report risk and felt satisfied. Since 2019, over 3.5 million reports have been automatically reviewed and issued without a single clinical complaint.

Conclusion

To the best of our knowledge, this is the first report to realize autoverification validation as a human–machine interaction. The new method effectively controls the risks of autoverification, shortens time consumption, and improves the efficiency of laboratory verification.
Molecular identification of Pentatrichomonas hominis in animals in central and western Thailand
Authors: Mahittikorn Aongart , Udonsom Ruenruetai , Koompapong Khuanchai , Chiabchalard Rachatawan , Sutthikornchai Chantira , Sreepian Preeyaporn Monatrakul , Mori Hirotake , Popruk Supaluk
Published: June 2021

Background

Pentatrichomonas hominis inhabits the digestive tracts of several vertebrates, such as humans, monkeys, pigs, dogs, cats and rats. This protozoan was originally considered a commensal of the digestive tract but has subsequently been identified as a potential zoonotic parasite and a causative agent of diarrhoea. Molecular techniques are considered more sensitive and specific to detect P. hominis. This study aimed to determine the presence and genetic diversity of P. hominis in animals in Thailand. A total of 403 faecal samples were collected from 119 cats, 55 dogs, 73 goats, 35 monkeys, 55 cattle and 66 pigs, and the presence of P. hominis was determined using the nested polymerase chain reaction method. Sequence analysis of small-subunit ribosomal RNA genes was used to determine the genotype of the organism.

Results

Twenty-six samples (26/403, 6.45%) were positive for P. hominis. The highest prevalence was found in cats (21/119; 17.65%), followed by cattle (3/55; 5.45%) and dogs (2/55; 3.64%). Seven out of 26 nucleotides demonstrated 100% sequence identity with existing sequences; additionally, 16 novel sequence patterns were identified. All nucleotide sequences of P. hominis-positive samples were shown in the same branch with the previously described P. hominis sequences found in humans, dogs and goat.

Conclusion

This is the first study on P. hominis infections in animals in Thailand. Our findings revealed that the prevalence of P. hominis was significantly higher in cats than in cattle and dogs. Cats were the main reservoir host; however, P. hominis can infect several kinds of animals. Therefore, the proper waste management of animals is necessary to reduce and prevent infection in the community.
The effect of dietary supplementation with silkworm pupae meal on gastrointestinal function, nitrogen retention and blood biochemical parameters in rabbits
Authors: Gugołek Andrzej , Kowalska Dorota , Strychalski Janusz , Ognik Katarzyna , Juśkiewicz Jerzy
Published: June 2021

Background

The aim of this study was to determine the effect of dietary inclusion of silkworm pupae meal (SPM) on nutrient digestibility, nitrogen utilization, gastrointestinal physiology and blood biochemical parameters in rabbits. Thirty Termond White rabbits were divided into three groups: SBM – fed a diet containing 10% soybean meal (SBM), SPM5 – fed a diet containing 5% SBM and 5% SPM, and SPM10 – fed a diet containing 10% SPM.

Results

Nutrient digestibility and nitrogen retention decreased with increasing SPM inclusion levels in rabbit diets. The dietary inclusion of SPM caused a significant increase in the stomach pH. Group SPM10 rabbits were characterized by the highest cecal tissue and digesta weights. The lowest cecal pH was noted in group SPM5. The relative weights of colonic tissue and digesta tended to increase with increasing levels of SPM. The total and intracellular activity of bacterial α-galactosidase decreased significantly in both SPM groups. The replacement of SBM with SPM led to a decrease in the activity of bacterial β-glucuronidase in the cecal digesta. The intracellular activity of bacterial α-arabinofuranosidase increased, and its release rate decreased in the cecum of rabbits in SPM groups. The extracellular activity of bacterial β-xylosidase in the cecal digesta tended to decrease in group SPM10. The highest extracellular and intracellular activity of bacterial β-cellobiosidase in the cecal digesta was noted in the SPM5 treatment. The lowest and the highest activity of bacterial N-acetyl-β-D-glucosaminidase (NAGase) was observed in groups SBM and SPM10. The SPM10 treatment contributed to a decrease in the cecal concentrations of butyric, iso-valeric and valeric acids. The lowest total concentration of putrefactive short-chain fatty acids (PSCFAs) was observed in group SPM10. The cecal concentration of propionic acid tended to increase in group SPM5, whereas the cecal concentration of iso-butyric acid tended to decrease in group SPM10. The colonic concentration of iso-valeric acid was lowest in group SPM5. SPM treatments resulted in a significant increase in plasma albumin concentration. Plasma urea concentration was significantly higher in group SPM10 than in SBM and SPM5.

Conclusions

The results of this study suggest that rabbit diets can be supplemented with SPM at up to 5%.
Identification of prognostic lipid droplet-associated genes in pancreatic cancer patients via bioinformatics analysis
Authors: Bai Rubing , Rebelo Artur , Kleeff Jörg , Sunami Yoshiaki
Published: June 2021

Background

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States both in females and in males, and is projected to become the second deadliest cancer by 2030. The overall 5-year survival rate remains at around 10%. Cancer metabolism and specifically lipid metabolism plays an important role in pancreatic cancer progression and metastasis. Lipid droplets can not only store and transfer lipids, but also act as molecular messengers, and signaling factors. As lipid droplets are implicated in reprogramming tumor cell metabolism and in invasion and migration of pancreatic cancer cells, we aimed to identify lipid droplet-associated genes as prognostic markers in pancreatic cancer.

Methods

We performed a literature search on review articles related to lipid droplet-associated proteins. To select relevant lipid droplet-associated factors, bioinformatics analysis on the GEPIA platform (data are publicly available) was carried out for selected genes to identify differential expression in pancreatic cancer versus healthy pancreatic tissues. Differentially expressed genes were further analyzed regarding overall survival of pancreatic cancer patients.

Results

65 factors were identified as lipid droplet-associated factors. Bioinformatics analysis of 179 pancreatic cancer samples and 171 normal pancreatic tissue samples on the GEPIA platform identified 39 deferentially expressed genes in pancreatic cancer with 36 up-regulated genes (ACSL3, ACSL4, AGPAT2, BSCL2, CAV1, CAV2, CAVIN1, CES1, CIDEC, DGAT1, DGAT2, FAF2, G0S2, HILPDA, HSD17B11, ICE2, LDAH, LIPE, LPCAT1, LPCAT2, LPIN1, MGLL, NAPA, NCEH1, PCYT1A, PLIN2, PLIN3, RAB5A, RAB7A, RAB8A, RAB18, SNAP23, SQLE, VAPA, VCP, VMP1) and 3 down-regulated genes (FITM1, PLIN4, PLIN5). Among 39 differentially expressed factors, seven up-regulated genes (CAV2, CIDEC, HILPDA, HSD17B11, NCEH1, RAB5A, and SQLE) and two down-regulation genes (BSCL2 and FITM1) were significantly associated with overall survival of pancreatic cancer patients. Multivariate Cox regression analysis identified CAV2 as the only independent prognostic factor.

Conclusions

Through bioinformatics analysis, we identified nine prognostic relevant differentially expressed genes highlighting the role of lipid droplet-associated factors in pancreatic cancer.
The occurrence of coronary artery lesions in Kawasaki disease based on C-reactive protein levels: a retrospective cohort study
Authors: An Hyo Soon , Kim Gi Beom , Song Mi Kyoung , Lee Sang Yun , Kwon Hye Won , Lee Joo Won , Bae Eun Jung
Published: June 2021

Background

This study aimed to assess the occurrence of coronary artery lesions (CAL) in patients with Kawasaki disease (KD) according to serum C-reactive protein (CRP) levels.

Methods

This retrospective analysis was based on the nationwide survey of KD conducted in the Republic of Korea between 2015 and 2017. We enrolled 9131 patients and defined low (< 3 mg/dL) and high (≥3 mg/dL) CRP groups. Demographic data, clinical characteristics, z-scores, and scores based on the Japanese criteria for CAL were compared between the two groups. Logistic regression analysis was used to identify CAL risk factors.

Results

The low CRP group accounted for 23% of patients. The mean age at diagnosis was higher in high CRP group compared to the low CRP group (34.4 ± 24.9 vs 31.7 ± 24.8 months, p < 0.001). Fever duration before treatment was not significantly different between the two groups (5.1 ± 1.7 days vs. 5.2 ± 2.1 days; p = 0.206). A non-response to intravenous immunoglobulin treatment was found in 1377 patients (20.1%) and 225 patients (11.7%) in the high and low CRP groups, respectively (p < 0.001). CAL were found in 12.9 and 18.3% of the high and low CRP patients, respectively (p < 0.001), based on z-scores; and in 9.9 and 12.5%, respectively (p = 0.001), based on the Japanese criteria in the acute phase. The giant coronary artery aneurysm occurrence ratio was similar between groups (p = 1.0).

Conclusions

CAL occurred in patients with both high and low CRP. Therefore, patients with KD should be carefully monitored regardless of their CRP levels.
Notes on current Mbyá-Guarani medicinal plant exchanges in southern Brazil
Authors: de Andrade Julian Henrique Carlotto , Rodrigues José , Benites André , Benites Cornélio , Acosta Arlindo , Benites Marcelina , Benites Cocelina , Gomes Ilda , da Silva Jaime Valdir , Antunes Eunice , Antunes Elisete , Martins José , Timóteo Daniel Martins , Franco Santiago , Morinico José Cirilo Pires , da Silva Fernanda Ribeiro , Hanazaki Natalia
Published: June 2021

Background

Experts in the Atlantic Forest, the Guarani people have the habit of transporting and exchanging plants due to their mobility throughout the territory. Historically, this habit contributed to the species composition and diversification among different phytophysiognomies that comprise the Atlantic Forest. Medicine and spirituality are traits that stand out within the Guarani culture, which is based on a holistic understanding of physical and spiritual well-being for the person’s health. To achieve this balance, they use a range of native and adapted plant species. Our goal is to understand some of the Guarani contributions to the cultural landscape in the Atlantic Forest.

Methods

We conducted semi-structured interviews with key persons asking about the importance of forest environments for Guarani health and about visits to other Guarani villages and plants exchanged. Data analysis was qualitative, and through a bipartite network of exchanged plants to show current plant exchanges between villages.

Results

We visited seven Guarani Indigenous Territories in south Brazil, and with the participation of 12 respondents, we registered 27 species that were exchanged through different phytophysiognomies in the Atlantic Forest. These results show an intense movement of plants currently occurring between villages and the importance of these movements for both individual health and the integrity of the environments in which the Guarani villages are inserted.

Conclusions

We observed a search for the maintenance of traditional species in the Guarani medical system, and we highlight the fundamental role of Guarani management in the conservation of the southern Atlantic Forest in indigenous territories.
CT and MRI radiomics of bone and soft-tissue sarcomas: a systematic review of reproducibility and validation strategies
Authors: Gitto Salvatore , Cuocolo Renato , Albano Domenico , Morelli Francesco , Pescatori Lorenzo Carlo , Messina Carmelo , Imbriaco Massimo , Sconfienza Luca Maria
Published: June 2021

Background

Feature reproducibility and model validation are two main challenges of radiomics. This study aims to systematically review radiomic feature reproducibility and predictive model validation strategies in studies dealing with CT and MRI radiomics of bone and soft-tissue sarcomas. The ultimate goal is to promote achieving a consensus on these aspects in radiomic workflows and facilitate clinical transferability.

Results

Out of 278 identified papers, forty-nine papers published between 2008 and 2020 were included. They dealt with radiomics of bone (n = 12) or soft-tissue (n = 37) tumors. Eighteen (37%) studies included a feature reproducibility analysis. Inter-/intra-reader segmentation variability was the theme of reproducibility analysis in 16 (33%) investigations, outnumbering the analyses focused on image acquisition or post-processing (n = 2, 4%). The intraclass correlation coefficient was the most commonly used statistical method to assess reproducibility, which ranged from 0.6 and 0.9. At least one machine learning validation technique was used for model development in 25 (51%) papers, and K-fold cross-validation was the most commonly employed. A clinical validation of the model was reported in 19 (39%) papers. It was performed using a separate dataset from the primary institution (i.e., internal validation) in 14 (29%) studies and an independent dataset related to different scanners or from another institution (i.e., independent validation) in 5 (10%) studies.

Conclusions

The issues of radiomic feature reproducibility and model validation varied largely among the studies dealing with musculoskeletal sarcomas and should be addressed in future investigations to bring the field of radiomics from a preclinical research area to the clinical stage.
Human amnion-derived mesenchymal stem cells improved the reproductive function of age-related diminished ovarian reserve in mice through Ampk/FoxO3a signaling pathway
Authors: Liu Hanwen , Jiang Chunyan , La Boya , Cao Meng , Ning Song , Zhou Jing , Yan Zhengjie , Li Chuyu , Cui Yugui , Ma Xiang , Wang Meilian , Chen Li , Yu Youjia , Chen Feng , Zhang Yuexin , Wu Huimin , Liu Jiayin , Qin Lianju
Published: June 2021

Background

Age-related diminished ovarian reserve (AR-DOR) reduced the quality of oocytes, resulting in decreased female fertility. Aging is tightly related to abnormal distribution and function of mitochondria, while mitophagy is a major process to maintain normal quality and quantity of mitochondria in cells, especially in oocytes which containing a large number of mitochondria to meet the demand of energy production during oocyte maturation and subsequent embryonic development. Ampk/FoxO3a signaling is crucial in the regulation of mitophagy. It is reported mesenchymal stem cells (MSCs) can improve ovarian function. Here we aim to explore if human amnion-derived mesenchymal stem cells (hAMSCs) are effective in improving ovarian function in AR-DOR mice and whether Ampk/FoxO3a signaling is involved.

Methods

The AR-DOR model mice were established by 32-week-old mice with 3–8 litters, significantly low serum sex hormone levels and follicle counts. The old mice were divided into 5 treatment groups: normal saline (NS, control), 1% human serum albumin (HSA, resolver), low dose (LD, 5.0 × 106cells/kg), middle dose (MD, 7.5 × 106cells/kg), and high dose (HD, 10.0 × 106cells/kg). The prepared hAMSCs were injected through tail vein. Serum sex hormone level, follicle counts, fertilization rate, gestation rate, little size, apoptosis of granulosa and stromal cells, expression level of Sod2, Ampk, and ratio of phosphorylated FoxO3a to total FoxO3a in ovaries were examined.

Results

Our results show that after hAMSC transplantation, the ovarian function in AR-DOR mice was significantly improved, meanwhile the apoptosis of granulosa and stromal cells in the ovaries was significantly repressed, the expression level of Ampk and the ratio of phosphorylated FoxO3a to total FoxO3a both were significantly increased, meanwhile increased Sod2 expression was also observed.

Conclusion

Our results demonstrate hAMSC transplantation via tail-injection can improve ovarian function of AR-DOR mice through Ampk/FoxO3a signaling pathway.
Epidural catheter migration during cesarean
Authors: AlJa’bari Aboud
Published: June 2021

Background

Early detection and vigilance of high spinal anesthesia post epidural catheter migration in cesarean section leads to safe conduct of anesthesia. Our case describes the migration of a previously functioning epidural catheter in the subarachnoid space.

This migration can be explained by patient posture changes and movements.

Case presentation

A 32 year – old G2P0 medically free female parturient (height 160cm, weight 65 kg), admitted to the labor ward with a 4 cm cervical dilatation, an epidural catheter was inserted in the L3-4 space, and an aspiration test was negative for CSF/blood through epidural catheter.

Epidural catheter was fixed on her back using sterile dressings. Epidural mixture of 0.1% bupivacaine and fentanyl 2 mcg/ml started. Due to fetal distress, cesarean section was urgently planned. She was given a bolus dose through the epidural catheter,10 minutes after skin incision, the patient suddenly started to complain of difficulty of breathing and drowsiness. Moreover, her oxygen saturation suddenly started to drop so rapid sequence induction with cricoid pressure applied and was performed till she was intubated. Her pupils were reactive and dilated. She had stable vital signs. She was reversed with neostigmine and atropine after the use of nerve stimulator.

Aspiration from the epidural catheter was performed. A clear 10mls fluid was aspirated. The fluid was sent to the lab for analysis and found to be CSF. Upon extubation, the patient was conscious and obeying commands. She completely recovered the motor power of her upper and lower limbs while she was admitted to ICU for observation and she was discharged the next day without any residual anesthesia.

Conclusion

Aspiration test and epinephrine test dose is always recommend to be performed prior to local epidural anesthetic for cesarean section even if the function of the epidural catheter was previously established. Careful observation of neurologic signs is also important.
Potent phytochemicals against COVID-19 infection from phyto-materials used as antivirals in complementary medicines: a review
Authors: Sharanya C. S. , Sabu A. , Haridas M.
Published: June 2021

Background

Following the outbreak of the COVID-19 pandemic, there was a surge of research activity to find methods/drugs to treat it. There has been drug-repurposing research focusing on traditional medicines. Concomitantly, many researchers tried to find in silico evidence for traditional medicines. There is a great increase in article publication to commensurate the new-found research interests. This situation inspired the authors to have a comprehensive understanding of the multitude of publications related to the COVID-19 pandemic with a wish to get promising drug leads.

Main body

This review article has been conceived and made as a hybrid of the review of the selected papers advertised recently and produced in the interest of the COVID-19 situation, and in silico work done by the authors. The outcome of the present review underscores a recommendation for thorough MDS analyses of the promising drug leads. The inclusion of in silico work as an addition to the review was motivated by a recently published article of Toelzer and colleagues. The in silico investigation of free fatty acids is novel to the field and it buttresses the further MDS analysis of drug leads for managing the COVID-19 pandemic.

Conclusion

The review performed threw light on the need for MDS analyses to be considered together with the application of other in silico methods of prediction of pharmacologic properties directing towards the sites of drug-receptor regulation. Also, the present analysis would help formulate new recipes for complementary medicines.
Seismic cracking mechanism and control for pre-stressed concrete box girders of continuous rigid-frame bridges: Miaoziping bridge in Wenchuan earthquake as an example
Authors: Tong Lei , Wang Rongxia , Wang Dongsheng
Published: June 2021

The box girder of the Miaoziping Bridge, a three-span prestressed concrete continuous rigid-frame bridge, suffered a serious crack in its box section’s web near the 1/6 to 1/2 length of the side span and the middle-span length of 1/4 to 3/4, as a result of the 2008 Wenchuan earthquake, which also caused large lateral residual displacements at both ends of the side span. In this study, eight strong-motion records near the bridge site and two other records (El Centro and Taft) are selected as inputs for time-history analysis of the bridge. The cantilever construction process and initial stress of the box girder are considered in a bridge model for seismic numerical simulation. Further, the simulation results are compared with the actual earthquake damage. The cracking mechanism, influencing factors and control of the girder crack damage are discussed. The high-stress zones of the box girder agree with the seismic damage observed, even various seismic inputs are considered. The findings reveal that the maximum (principal) tensile stress of the girder exceeds the tensile strength of the concrete under the seismic excitations, and cracks occur. Under various input directions of ground motions, the proportion of the main girder stresses induced by the earthquake shows differences. After the failure of the shear keys in the transverse direction of the bridge, the stresses of the girder decrease in the mid-span. However, the beams at both ends of the side spans revealed large lateral displacements. Considering that the uplift of the beam ends, stress and axial torque of the girder’s side span are greatly reduced. Setting bi-directional friction pendulum bearings on the transition pier is an effective damping measure to control web cracking of the mid-span and lateral drifts of the beam ends.
My journey into mental healthcare as an international medical graduate (IMG)
Authors: Toparlak Süreyya Melike
Published: June 2021

Over half of doctors who joined the General Medical Council's (GMC) medical register in the UK in 2020 were from Black, Asian and minority ethnic (BAME) background, and I am one of them. Having experienced clinical settings across three different countries, I think my journey deserves to be shared with others as a unique experience. My story will help medical students and early career doctors have a general idea of different clinical settings and hopefully will encourage them to chase their dreams. I hope to inspire people.
Targeted gene expression classifier identifies pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients at high risk for end induction minimal residual disease positivity.
Authors: Meyer Lauren K. , Roy Ritu , Huang Benjamin J. , Delgado-Martin Cristina , Vincent Tiffaney L. , Wood Brent L. , Liu Yu , Zhang Jinghui , Mullighan Charles Grenfell , Horton Terzah M. , Loh Mignon L. , Devidas Meenakshi , Raetz Elizabeth A. , Hayashi Robert J. , Winter Stuart S. , Dunsmore Kimberly P. , Hunger Stephen , Teachey David T. , Olshen Adam B. , Hermiston Michelle L.
Published: June 2021

10002

Background: The heterogeneity of T-ALL has hindered biomarker identification and limited biology-based risk stratification. Historically, minimal residual disease (MRD) has been the strongest predictor of poor outcomes. However, stratification by MRD does not allow for risk-adapted therapy early in treatment, which may induce deeper remissions and decrease risk of relapse. We hypothesized that gene expression profiling at diagnosis may have prognostic value in identifying high risk patients. Methods: We analyzed RNA-seq data from 189 diagnostic samples from the Children’s Oncology Group (COG) AALL0434 trial. Using leave-one-out cross-validation, we identified a set of genes that optimally differentiated MRD+ and MRD- samples. We then derived a risk score (RS) that indicates a probability of being MRD+ for a given gene expression pattern. Finally, we validated this model in an independent cohort of COG AALL1231 samples. Results: The AALL0434 early T-cell precursor (ETP) samples (n = 19), which have high rates of MRD+, had the highest RS, with an average of 81.3 (SD 18.7), versus 24.9 (SD 22.7) for non-ETPs (n = 146). Intriguingly, non-ETPs with RS > 50 had a gene expression pattern that mirrored ETPs and was distinct from the remaining non-ETPs. In this RS > 50 non-ETP cohort, 80% were MRD+, versus 20% of the < 50 cohort (p < 0.0001). When applied to 31 diagnostic non-ETP samples from COG AALL1231, 57% of the RS > 50 cohort were MRD+, versus 17% of the RS < 50 cohort (p = 0.05). Importantly, AALL0434 used prednisone during induction, while AALL1231 used dexamethasone, indicating that the predictive value is independent of the induction steroid. Finally, we converted our model to the customizable Nanostring nCounter platform by analyzing 96 AALL0434 samples on the Nanostring assay. The Nanostring data closely recapitulated the RNA-seq data, with a tight correlation between the resulting RS (concordance correlation coefficient = 0.91). Conclusions: We have developed a gene expression classifier that differentiates a subset of non-ETP T-ALLs with an ETP-like gene expression pattern and a high risk of MRD+, and have adapted the classifier to a clinically tractable targeted platform. Identification of this high-risk subset at diagnosis has the potential to facilitate risk-adapted trials to evaluate the utility of novel or more intensive therapies aimed at improving clinical outcomes.
Efficacy of naxitamab in patients with refractory/relapse (R/R) high-risk neuroblastoma (HR-NB) by bone/bone marrow (BM) evaluation, potential sites of residual disease.
Authors: Kushner Brian H. , Morgenstern Daniel A. , Nysom Karsten , Bear Melissa K. , Tornøe Karen , Losic Nedjad , Mora Jaume
Published: June 2021

10022

Background: NB is the most common extracranial solid tumor in children and half of patients present with high-risk disease. Bone and BM are frequent sites of metastatic disease and can serve as a reservoir for residual disease driving relapse. Naxitamab, a GD2-binding monoclonal antibody, was recently approved in the United States in combination with GM-CSF for the treatment of pediatric patients ≥1 year of age and adult patients with R/R HR-NB in the bone/BM who have demonstrated a partial response (PR), minor response (MR), or stable disease (SD) to prior therapy. Here we describe outcomes from the registrational Trial 201 (NCT03363373) detailed by bone/BM involvement. Methods: HR-NB patients with primary refractory disease or incomplete response to salvage treatment following relapse or progressive disease (PD) (in both cases including SD, MR and PR) with disease limited to bone and/or BM were eligible. Naxitamab was administered over ≥30 min in the outpatient setting on Days 1, 3 and 5 at 3 mg/kg/infusion (9 mg/kg/cycle) in combination with GM-CSF at 250 µg/m2/day on Days -4 to 0 and at 500 µg/m2/day on days 1 to 5. Treatment cycles were repeated every 4 weeks. Response was assessed after Cycle 2 and then every 2-3 months by revised International Neuroblastoma Response Criteria (INRC) using BM biopsies/aspirates and 123I-MIBG scintigraphy or FDG-PET. Effectiveness was concluded if the lower limit of the Clopper-Pearson exact 95% confidence interval (CI) of overall response rate (ORR) was >20%. We report efficacy data on 22 patients and safety data on the first 25 patients enrolled. Results: 13 (59%) patients had NB in bone, 2 (9%) had NB in BM, and 7 (32%) had NB in both bone and BM. Summary of overall response and response by compartment. Conclusions: Naxitamab provided clinically meaningful activity in both bone and BM with ORR of 68% and had a manageable AE profile. Clinical trial information: NCT03363373. [Table: see text]
Updated outcomes for patients with completely resected pulmonary recurrent osteosarcoma: A report from the Children’s Oncology Group.
Authors: Chou Alexander J. , Krailo Mark D. , Han Ruxu , Buxton Allen , Reed Damon R. , Gorlick Richard Greg , DuBois Steven G. , Isakoff Michael , Janeway Katherine A. , Hingorani Pooja
Published: June 2021

10023

Background: Amongst patients with recurrent osteosarcoma (OS), those with resectable pulmonary-only relapse appear to have the best outcomes. Prior analysis of patients with completely resected recurrent OS enrolled on a Children’s Oncology Group (COG) Phase 2 trial AOST0221, which studied the efficacy of inhaled GMCSF, showed a 12- month disease control rate (DCR12) of only 20% (95% CI, 10 – 34%). DCR12 based on this analysis was used as the historical benchmark for efficacy analysis in two recently completed trials, AOST1321 (completely resected cohort only) and AOST1421. We analyzed the stability of the DCR12 benchmark using data from these contemporary studies. Methods: Patients were eligible for AOST1321 if they had undergone resection of all sites of recurrent or refractory OS within 30 days of enrollment and for AOST1421 if they had lung only recurrent OS completely resected within 4 weeks of enrollment. AOST1321 evaluated denosumab while AOST1421 evaluated dinutuximab. Patients with refractory disease, extrapulmonary recurrence or without histological confirmation of relapse were excluded from this analysis. DCR12 was defined as having at least stable disease 12 months after the start of protocol therapy. We report the DCR12 observed on AOST1321, AOST1421 and AOST0221. Results: One hundred and twenty-eight evaluable patients with completely resected recurrent OS were enrolled on AOST0221 (N=49), AOST1321 (N=38) and AOST1421 (N=41). One hundred and one patients were included in this analysis (AOST0221: 37, AOST 1321: 25, AOST1421:39). DCR12 was 14 % (95% CI, 5% – 26%) for AOST0221, 24% (95%CI 10-42%) for AOST1321, and 31% (95% CI, 17% - 45%) for AOST1421. Risk for disease progression did not differ across the 3 included studies. DCR12 for all three studies combined was 23% (95% CI, 15% – 31%). Conclusions: Prognosis for recurrent OS remains dismal, even for those with resectable pulmonary-only disease. Although not statistically significant, dinutuximab may have activity in a select group of relapsed OS patients; combination studies using dinutuximab are planned. The previously described benchmark of disease control at 12 months remained relatively consistent in recent studies for those patients who have resectable pulmonary-only relapse. Therefore, DCR12 remains a useful outcome measure in fully resected OS with lung only metastases. Analyses are ongoing to better define the appropriate threshold to define investigational agent activity in this specific patient population.
Efficacy of clinical breast examination in chest-irradiated female survivors of childhood Hodgkin lymphoma (HL).
Authors: Wong Florence Lennie , Lee Janie M. , Leisenring Wendy M. , Neglia Joseph Philip , Howell Rebecca M. , Smith Susan A. , Oeffinger Kevin C. , Moskowitz Chaya S. , Henderson Tara O. , Mertens Ann , Nathan Paul C. , Yasui Yutaka , Landier Wendy , Armstrong Gregory T. , Robison Leslie L. , Bhatia Smita
Published: June 2021

10028

Background: Female survivors of childhood HL treated with ≥10 Gy of chest radiation are at high risk for breast cancer (BC). The Children’s Oncology Group (COG) guidelines recommend CBE annually starting at puberty and then semiannually from age 25, plus lifetime annual mammography (MAM) and breast Magnetic Resonance Imaging (MRI) starting 8y after chest radiation or age 25, whichever is later. While imaging-based screening recommendations are largely consistent with US guidelines for women at high BC risk, only the COG guidelines recommend CBE. The benefits of lifetime CBE starting from puberty for life in chest-irradiated HL survivors is unknown. Methods: Life-years (LYs) and lifetime BC mortality risk were estimated from a simulated cohort of 5-million HL survivors using the data from 5y female survivors of HL in the Childhood Cancer Survivor Study (CCSS) treated with ≥10 Gy of chest radiation. The simulated cohort underwent annual MAM+MRI from age 25 for life, with and without annual CBE from age 11 (presumed age of puberty) to age 24 and with and without semiannual CBE from age 25 for life with 100% adherence. BC included in-situ and invasive BC. Treatment-related BC incidence and non-BC mortality risks were estimated from the CCSS data. Risks at age <25 were extrapolated from the CCSS estimates while risks beyond age 50 were extrapolated additionally using the US population rates. CBE sensitivity (17.8%, in-situ and invasive BC) and specificity (98%) and MAM+MRI sensitivity (84.2-86.0%, in-situ; 96.7-97.1%, invasive) and specificity (75.3%) were obtained from the medical literature. Results: The CCSS cohort included 1057 female HL survivors. BC (all invasive) developed in three patients at age <25 (ages: 23, 24, 24). In the simulated cohort receiving no screening, lifetime BC risk was 40.8% and BC mortality was 17.5%. HL survivors around age 50 were at a 7.4-fold higher risk of developing BC and a 5.2-fold higher risk of non-BC mortality when compared with the general population. Compared to no annual CBE for ages 11-24y, undergoing annual CBE did not increase gains in LYs or reduce lifetime BC mortality relative to no screening (Table). Among those who survived to age ≥25, undergoing semiannual CBE from age 25 for life compared to no semiannual CBE also resulted in little gain in LYs or reduction in lifetime BC mortality relative to no screening. Conclusions: Lifetime CBE starting at puberty in conjunction with MAM+MRI appears to add little survival benefits compared with no CBE, suggesting that COG guidelines may be revised without adverse effect on long-term outcomes for chest-irradiated female survivors of childhood HL.[Table: see text]
Preclinical evaluation of the ETS inhibitor TK216 against relapsed and refractory childhood leukemia.
Authors: Sharma Ritul , Thakur Satbir , Jain Mohit , Zhang Chunfen , Langevin Anne-Marie , Narendran Aru
Published: June 2021

10033

Background: Although survival rates have improved in the recent past, relapse and refractory disease remain a significant cause of death in children with leukemia. This calls for an urgent need for the development of novel therapies that could effectively treat leukemias in children. The E26 transformation specific (ETS) family of transcription factors regulate various normal cellular functions but are abnormally expressed in various cancers, including leukemia. TK216 is an ETS inhibitor, that has shown pre-clinical activity and clinical efficacy in solid tumors. In this study, we explore the feasibility of using TK216 as a therapeutic agent for the treatment of high risk refractory pediatric leukemia. Methods: A panel of pediatric leukemia derived cell lines and primary blast cells representing a spectrum of molecular abnormalities seen in pediatric leukemia were treated in vitro with TK216 to determine cytotoxicity. Normal lymphocytes were used as controls and cell viability was determined 72 hours post-treatment by Alamar blue assay. The induction of tumor cell apoptosis and target modulation were detected by Western blotting. Alterations in the cell cycle were assessed by FACS analysis with PI staining. Drug combination studies were carried out with established anti-leukemic agents to identify synergy for greater therapeutic efficiency. Results: TK216 decreased cell viability in leukemia cells compared to normal lymphocyte controls in a dose-dependent manner with variations in sensitivity noted with inherent molecular abnormalities. The IC50 values observed ranged from 0.22 µM for the most sensitive cell line, MV4-11 to 0.95 µM for least sensitive cell line, SUP-B15. Apoptosis induction upon TK216 treatment was confirmed by PARP cleavage and caspase 3 activation. Cell cycle analysis demonstrated increased sub-G1 population of cells after TK216 treatment. A strong correlation between sub-G1 population and sensitivity of the cell line towards TK216 (47% in MV4-11 vs 3.72% in SUP-B15) was observed. Screening of a panel of 200 FDA approved anti-cancer agents in drug combination studies identified potential agents for drug synergy. Significant drug synergy was noted with TK216 in combination with the epigenetic modifier 5-azacytidine and the Bcl-2 inhibitor, Venetoclax. [Combination Index for Venetoclax and TK216, mean = 0.65 for MV4-11 and 0.33 for SUP-B15]. Conclusions: Data from our study demonstrate that the ETS inhibitor TK216 induces apoptosis and cell cycle arrest in pediatric leukemia cells at physiologically relevant concentrations. Our combination studies identified distinct anti-cancer agents that could be used for developing effective drug combination regimens with TK216. Overall, our findings provide essential preclinical data for the consideration of TK216 in early phase clinical trials for the treatment of selected high-risk and refractory childhood leukemia.
Late health outcomes in survivors of Wilms tumor: A report from the St. Jude Lifetime (SJLIFE) cohort study.
Authors: Foster Kayla L. , Green Daniel M. , Mirzaei Salehabadi Sedigheh , Xing Mengqi , Ness Kirsten K. , Krull Kevin R. , Brinkman Tara M. , Ehrhardt Matthew J. , Chemaitilly Wassim , Dixon Stephanie B , Bhakta Nickhill , Brennan Rachel Christine , Krasin Matthew J. , Davidoff Andrew M. , Robison Leslie L. , Hudson Melissa M. , Mulrooney Daniel A.
Published: June 2021

10038

Background: We aimed to characterize late health, neurocognitive, and physical performance outcomes among survivors of Wilms tumor. Methods: Wilms tumor survivors (n = 280), ≥ 5 years from diagnosis, participating in SJLIFE were clinically assessed along with a community control sample (n = 625). Health outcomes were graded per a modified Common Terminology Criteria for Adverse Events (grade 1 [mild] to grade 4 [life threatening]). Standardized neurocognitive testing was graded using age-adjusted z-scores. Aerobic function (six-minute walk), mobility (timed up and go) and flexibility (sit and reach) were assessed. Associations between treatment exposures and prevalent conditions were examined by multivariable logistic regression, adjusted for current age, sex and race. Results: Survivors (59% female, 73% white), median age 3 years (range 0-15) at diagnosis and 31 years (9-58) at evaluation, were comprehensively evaluated on the St. Jude campus. Two-thirds (67%) were treated with doxorubicin (median dose 175 mg/m2 range 52-490), 167 (60%) received abdominal radiation (median dose 12 Gy range 8.8-61.2) and 25% received chest radiation (12 Gy range 9-44). By age 40 years, survivors averaged 12.7 (95% confidence interval [CI] 11.7-13.8) grade 1-4 and 7.5 (CI 6.7-8.2) grade 2-4 conditions, compared to 4.2 (CI 3.9-4.6) and 2.3 (CI 2.1-2.5), respectively, among controls. The most prevalent medical conditions (grade ≥ 2) are reported in the table. Abnormal glucose metabolism was associated with abdominal radiation (relative risk [RR] 5.1 CI 1.4-19.0); restrictive pulmonary defects with chest radiation (RR 24.0 CI 3.2-180); and cardiomyopathy (RR 15.6 CI 1.9-128), pulmonary diffusion (RR 4.5 CI 1.3-15.1), and chronic kidney disease (RR 4.5 CI 1.3-16.1) with doxorubicin exposure. Survivors had a three-fold higher risk (standardized incidence ratio 3.5, CI 2.2-6.6) for subsequent neoplasms. Impairments (grade ≥ 2) in executive function (20% vs. 12%), attention (17% vs. 9%), memory (21% vs. 10%), and processing speed (20% vs. 8%) were more frequent in survivors than controls (p < 0.05). Impairments in aerobic function (13.6%), mobility (13.6%), and flexibility (11.1%) were higher than expected (p < 0.01). Significant associations were not identified between treatment exposures and neurocognitive or physical performance outcomes. Conclusions: Systematic clinical assessment identified a significant burden of chronic health conditions and previously unrecognized neurocognitive and physical performance limitations in survivors of Wilms tumor.[Table: see text]
Nonhematologic neoplasia in biallelic BRCA2 mutated Fanconi anemia.
Authors: Chinnabhandar Vasant , DeFor Todd E , Tryon Rebecca , Wagner John E , MacMillan Margaret L
Published: June 2021

10041

Background: Fanconi anemia (FA) is a cancer predisposition disorder. Affected individuals do not tolerate conventional doses of chemotherapy or radiation well. Biallelic BRCA2 mutations cause a rare (̃3%) form of FA. Most patients with this subtype have a family history of breast cancer and die in early childhood. Optimal management remains uncertain. Herein, we report the world’s largest single center cohort of biallelic BRCA2 patients, with a focus on non-hematologic malignancies. Methods: The University of Minnesota’s prospectively maintained FA database was analyzed for data on biallelic BRCA2 mutated FA patients. IRB-approved consent was obtained for all subjects. Results: Twenty patients with biallelic BRCA2 were identified. Median age of FA diagnosis was 1.5 years (range: 0-16.2 years). All patients had a significant history of cancer in the family with breast cancer being particularly frequent (65%). Eight (40%) patients developed non-hematologic neoplasia before 18 years of age. These included 10 malignant tumors and 4 benign neoplastic lesions; 3 patients had more than one solid tumor (see Table). Surgical resection was attempted in all malignant tumors, dose reduced adjuvant chemotherapy was utilized in 5 cases and radiation in one case. Thirteen (65%) patients developed hematologic malignancies (AML=6, ALL=3, MDS=4), all without preceding marrow failure. Fourteen patients underwent allogeneic HCT. Eleven patients have died, 3 from solid tumors and 5 from leukemias. Nine patients are currently alive, of whom 3 are post-HCT. Only 4 (age range: 6.5-16.3 years) patients in the cohort remain free of any oncologic diagnoses. Conclusions: Patients with FA due to biallelic BRCA2 mutations have a unique phenotype with an extraordinarily high risk of early-onset de-novo acute leukemia and solid tumors, often both diagnosed in the same patient. They require extensive, lifelong cancer surveillance from an early age to optimize outcomes. Therapy for malignant diagnoses should aim to minimise exposure to genotoxic / crosslinking agents and radiation. BRCA2 mutation testing in family members and appropriate genetic counselling is essential. Additionally, a family history of BRCA2 mutated cancers should prompt FA testing in offspring with any relevant FA-related clinical findings. Nonhematologic neoplasia and therapy.[Table: see text]
Health-related unemployment trends among survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Bhatt Neel S. , Goodman Pamela , Leisenring Wendy M. , Armstrong Gregory T. , Chow Eric Jessen , Hudson Melissa M. , Krull Kevin R. , Nathan Paul C. , Oeffinger Kevin C. , Robison Leslie L. , Kirchhoff Anne C. , Mulrooney Daniel A.
Published: June 2021

10048

Background: The impact of treatment era and chronic health conditions on health-related unemployment among childhood cancer survivors has not been studied. Methods: Childhood cancer survivors (age ≥25 years) enrolled in the CCSS (3,420 diagnosed in the 1970s, 3,564 in the 1980s, and 2,853 in the 1990s) were matched 1:5 on sex, race/ethnicity, census bureau division, age, and year of survey to the Behavioral Risk Factor Surveillance System (BRFSS), a nationally representative population. Among survivors, health-related unemployment was defined as self-reported unemployment due to illness/disability and for BRFSS participants as self-reported inability to work. To standardize follow-up, health-related unemployment was assessed either in 2002-05 or 2014-16 for both cohorts. Sex stratified standardized prevalence ratio (SPR) and relative SPR (rSPR) with 95% confidence intervals (CI) for health-related unemployment were estimated using multivariable generalized linear models, with BRFSS background rates to assess the impact of treatment era and moderate to severe health conditions (per the Common Terminology Criteria for Adverse Events). Results: Prevalence of health-related unemployment in survivors (median age 9 years [range 0-20] at diagnosis and 33 years [25-54] at follow-up) was significantly higher compared to BRFSS participants (females: 11.3% vs 3.7%; SPR 3.0, 95% CI 2.7-3.3; males: 10.5% vs 3.0%; SPR 3.5, 95% CI 3.1-3.9). Health-related unemployment risks declined among survivors in more recent decades (ptrend< 0.001) for females: 1970s SPR 3.8, 95% CI 3.2-4.5, 1980s SPR 2.9, 95% CI 2.5-3.5, 1990s SPR 2.5, 95% CI 2.1-3.0; and males: 1970s SPR 3.6, 95% CI 2.9-4.4, 1980s SPR 3.8, 95% CI 3.1-4.7, 1990s SPR 3.0, 95% CI 2.5-3.7. Among survivors, multivariable models identified associations between presence of specific health conditions and elevated health-related unemployment (Table) adjusting for all statistically significant health conditions, race/ethnicity, treatment era, age at survey, and diagnosis. Among females, rSPR for endocrine conditions differed between 1970s and 1990s (interaction p = 0.04); fewer significant health conditions remained in the final model for males. Conclusions: While prevalence for health-related unemployment has declined over time, childhood cancer survivors remain at higher risk compared to the general population. These elevated risks are associated with chronic health conditions and affect female survivors more than male survivors.[Table: see text]