bluuebunny/crossref_metadata_2025 huggingface dataset:
Double burden of malnutrition and its associated factors among women in low and middle income countries: findings from 52 nationally representative data
Authors: Alem Adugnaw Zeleke , Yeshaw Yigizie , Liyew Alemneh Mekuriaw , Tessema Zemenu Tadesse , Worku Misganaw Gebrie , Tesema Getayeneh Antehunegn , Alamneh Tesfa Sewunet , Teshale Achamyeleh Birhanu , Chilot Dagmawi , Ayalew Hiwotie Getaneh
Published: August 2023

Background

Double burden of malnutrition (DBM) is an emerging global public health problem. The United Nations member states adopted eradicating all forms of malnutrition as an integral component of the global agenda. However, there is evidence of a high burden of undernutrition among women and rising rates of overweight and obesity, especially in low and middle income countries (LMICs). Therefore, this study aimed to investigate the prevalence and associated factors of underweight, overweight, and obesity among women of reproductive age in LMICs.

Methods

Data for the study were drawn from a recent 52 Demographic and Health Surveys (DHS) conducted in LMICS. We included a sample of 1,099,187 women of reproductive age. A multilevel multinomial logistic regression model was used to identify factors associated with DBM. Adjusted relative risk ratio (RRR) with a 95% Confidence Interval (CI) was reported to show an association.

Results

The prevalence of underweight, overweight, and obesity in LMICs among women of reproductive age was 15.2% (95% CI: 15.1–15.3), 19.0% (95% CI: 18.9- 19.1), and 9.1% (95% CI: 9.0–9.2), respectively. This study found that women aged 24–34 years, aged ≥ 35 years, with primary, secondary, and above educational level, from wealthy households, using modern contraceptives, exposed to media (radio and television), and with high parity (more than one birth) were more likely to have overweight and obesity and less likely to have underweight. Moreover, the risk of having obesity (RRR = 0.59; 95% CI = 0.58–0.60 and overweight (RRR = 0.78; 95% CI = 0.77–0.79) were lower among rural women, while the risk of being underweight was (RRR = 1.13; 95% CI = 1.11–1.15) higher among rural women compared to urban women.

Conclusion

The prevalence of underweight, overweight, and obesity was high among women of reproductive age in LMICs. Underweight, overweight, and obesity are influenced by sociodemographic, socioeconomic, and behavioral-related factors. This study shows that, in order to achieve Sustainable Development Goal 2, a multifaceted intervention approach should be considered to prevent both forms of malnutrition in women of reproductive age. This can be achieved by raising awareness and promoting healthy behaviors such as healthy eating and physical activity, especially among educated women, women from wealthy households, and women exposed to the media.
Health-promoting work schedules among nurses and nurse assistants in France: results from nationwide AMADEUS survey
Authors: Fond Guillaume , Lucas Guillaume , Boyer Laurent
Published: August 2023

Background

The study aimed to investigate the relationship between different work schedules and self-reported working conditions and health risk behaviours among nurses and nurse assistants (NNA) in France. It hypothesized that work schedules, particularly long shifts, could impact work-life balance, workload, stress levels, burnout, and smoking habits. NNA had the option to work either with a 7-hour schedule, 5 days per week, or with long work schedules consisting of ten to twelve-hour shifts, three days per week. These schedules could potentially influence various aspects of their professional lives.

Methods

The survey followed the guidelines of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and was administered to NNA working in public and private national healthcare facilities in France. The researchers used the Job Content Questionnaire to assess the work environment and the French version of the 22-item Maslach Burnout Inventory (MBI) scale to measure burnout.

Results

A total of 3,133 NNA participated in the study, including 2,369 nurses (75.6%) and 764 nurse assistants (24.4%). Among them, 1,811 individuals (57.8%) followed a 7-hour work schedule, while 1,322 individuals (42.2%) had a long work schedule. Multivariate analyses revealed that NNA working with long schedules reported higher psychological demands, more frequent burnout, a higher number of daily smoked cigarettes, and greater coffee consumption. These findings were independent of other factors such as sector of employment, type of healthcare facility, job status, work schedules, night shifts, department specialty, age, and family responsibilities.

Conclusions

While some NNA may choose long schedules to have more days off, those working with these schedules experience greater work-related burdens and engage in worse health risk behaviours as a coping mechanism. It emphasizes the importance of considering health-promoting work schedules to address the high psychological demands and burnout experienced by NNA with long schedules. Implementing changes in work schedules could potentially improve the overall well-being and job satisfaction of these healthcare professionals.
Association between the distal tibiofibular syndesmosis morphology classification and ankle osteoarthritis: a retrospective study
Authors: Huang Lei , Zhang XiaoHong , Yang Siyi , Qing Jiwen , Wu Wangyu , Shi Houyin , Wang Dingxuan , Zhang Lei
Published: August 2023

Background

Syndesmosis injury is proposed to contribute to ankle stability and osteoarthritis (OA). However, whether distal tibiofibular syndesmosis structure is closely related to ankle OA is unclear. We hypothesized that different DTS morphology classifications would affect the biomechanics properties in ankle OA. The study aimed to determine the association between the distal tibiofibular syndesmosis (DTS) morphological classification and ankle OA.

Methods

This is a retrospective study examining imaging data of 147 patients (87 males and 60 females) with ankle OA. Magnetic resonance imaging was used to access the DTS morphological classification, according to measuring various parameters. Joint space narrowing and osteophytes were measured using ankle weight-bearing radiography. The classification and parameters were analyzed to determine the relationship between the syndesmosis classification and the abnormality of ankle OA.

Results

Five morphological classifications of the DTS, including Chevron (19.6%), Widow’s peak (16.2%), Flat (22.3%), Trapezoid (32.0%), and Crescent (19.6%), were shown. There were statistical differences between DTS classification and tibial angle surface angle (TAS) (P = .009) and talar tilt angle (TTA) (P = .014). The TAS (degree) of the Crescent (86.47 ± 3.21) was less than Chevron (88.75 ± 2.72) (P = .006), Widow’s peak (89.26 ± 3.15) (P = .001), Flat (88.83 ± 3.62) (P = .003) and Trapezoid (88.11 ± 2.62) (P = .041), respectively. The TTA (degree) of Crescent (86.83 ± 5.30) was less than Chevron (89.28 ± 2.46) and Widow’s peak (89.82 ± 3.41). The men were greater than women for TAS (P = .008) and angle (P = .003), which are consistent with osteophyte (P = .019) and the modified Kellgren–Lawrence grades (P = .041) between gender.

Conclusions

DTS morphological classification might affect the biomechanics properties in TAS and TTA in ankle OA. In clinical practice, surgeons should pay attention to the effects of DTS on ankle OA.

Level of Evidence: Level III, retrospective study.
Prognostic implication of downregulated exosomal miRNAs in patients with sepsis: a cross-sectional study with bioinformatics analysis
Authors: Shin Beomsu , Lee Jin Young , Im Yunjoo , Yoo Hongseok , Park Junseon , Lee Joo Sang , Lee Ki-Young , Jeon Kyeongman
Published: August 2023

Background

Despite the understanding of sepsis-induced extracellular vesicles (EVs), such as exosomes, and their role in intercellular communication during sepsis, little is known about EV contents such as microRNA (miRNA), which modulate important cellular processes contributing to sepsis in body fluids. This study aimed to analyze the differential expression of exosomal miRNAs in plasma samples collected from sepsis patients and healthy controls, and to identify potential miRNA regulatory pathways contributing to sepsis pathogenesis.

Methods

Quantitative real-time PCR-based microarrays were used to profile plasma exosomal miRNA expression levels in 135 patients with sepsis and 11 healthy controls from an ongoing prospective registry of critically ill adult patients admitted to the intensive care unit. The identified exosomal miRNAs were tested in an external validation cohort (35 sepsis patients and 10 healthy controls). And then, functional enrichment analyses of gene ontology, KEGG pathway analysis, and protein–protein interaction network and cluster analyses were performed based on the potential target genes of the grouped miRNAs. Finally, to evaluate the performance of the identified exosomal miRNAs in predicting in-hospital and 90-day mortalities of sepsis patients, receiver operating characteristic curve (ROC) and Kaplan–Meier analyses were performed.

Results

Compared with healthy controls, plasma exosomes from sepsis patients showed significant changes in 25 miRNAs; eight miRNAs were upregulated and 17 downregulated. Additionally, the levels of hsa-let-7f-5p, miR-331-3p miR-301a-3p, and miR-335-5p were significantly lower in sepsis patients than in healthy controls (p < 0.0001). These four miRNAs were confirmed in an external validation cohort. In addition, the most common pathway for these four miRNAs were PI3K-Akt and mitogen-activated protein kinase (MAPK) signaling pathways based on the KEGG analysis. The area under the ROC of hsa-let-7f-5p, miR-331-3p, miR-301a-3p, and miR-335-5p level for in-hospital mortality was 0.913, 0.931, 0.929, and 0.957, respectively (p < 0.001), as confirmed in an external validation cohort. Also, the Kaplan–Meier analysis showed a significant difference in 90-day mortality between sepsis patients with high and low miR-335-5p, miR-301a-3p, hsa-let-7f-5p, and miR-331-3p levels (p < 0.001, log-rank test).

Conclusion

Among the differentially-expressed miRNAs detected in microarrays, the top four downregulated exosomal miRNAs (hsa-let-7f-5p, miR-331-3p miR-301a-3p, and miR-335-5p) were identified as independent prognostic factors for in-hospital and 90-day mortalities among sepsis patients. Bioinformatics analysis demonstrated that these four microRNAs might provide a significant contribution to sepsis pathogenesis through PI3K-Akt and MAPK signaling pathway.
Determinants of quality of life in adults with epilepsy: a multicenter, cross-sectional study from Germany
Authors: Siebenbrodt Kai , Willems Laurent M. , von Podewils Felix , Mross Peter Michael , Strüber Michael , Langenbruch Lisa , Bierhansl Laura , Gorny Iris , Schulz Juliane , Gaida Bernadette , Conradi Nadine , Süß Annika , Rosenow Felix , Strzelczyk Adam
Published: August 2023

Background

Assessment of quality of life (QoL) has become an important indicator for chronic neurological diseases. While these conditions often limit personal independence and autonomy, they are also associated with treatment-related problems and reduced life expectancy. Epilepsy has a tremendous impact on the QoL of patients and their families, which is often underestimated by practitioners. The aim of this work was to identify relevant factors affecting QoL in adults with epilepsy.

Methods

This cross-sectional, multicenter study was conducted at four specialized epilepsy centers in Germany. Patients diagnosed with epilepsy completed a standardized questionnaire focusing on QoL and aspects of healthcare in epilepsy. Univariate regression analyses and pairwise comparisons were performed to identify variables of decreased QoL represented by the overall Quality of Life in Epilepsy Inventory (QOLIE-31) score. The variables were then considered in a multivariate regression analysis after multicollinearity analysis.

Results

Complete datasets for the QOLIE-31 were available for 476 patients (279 [58.6%] female, 197 [41.4%] male, mean age 40.3 years [range 18–83 years]). Multivariate regression analysis revealed significant associations between low QoL and a high score on the Liverpool Adverse Events Profile (LAEP; beta=-0.28, p < 0.001), Hospital Anxiety and Depression Scale – depression subscale (HADS-D; beta=-0.27, p < 0.001), Neurological Disorders Depression Inventory in Epilepsy (NDDI-E; beta=-0.19, p < 0.001), revised Epilepsy Stigma Scale (beta=-0.09, p = 0.027), or Seizure Worry Scale (beta=-0.18, p < 0.001) and high seizure frequency (beta = 0.14, p < 0.001).

Conclusion

Epilepsy patients had reduced QoL, with a variety of associated factors. In addition to disease severity, as measured by seizure frequency, the patient’s tolerability of anti-seizure medications and the presence of depression, stigma, and worry about new seizures were strongly associated with poor QoL. Diagnosed comorbid depression was underrepresented in the cohort; therefore, therapeutic decisions should always consider individual psychobehavioral and disease-specific aspects. Signs of drug-related adverse events, depression, fear, or stigmatization should be actively sought to ensure that patients receive personalized and optimized treatment.

Trial Registration

German Clinical Trials Register (DRKS00022024; Universal Trial Number: U1111-1252-5331).
After the sun: a nanoscale comparison of the surface chemical composition of UV and soil weathered plastics
Authors: Foetisch Alexandra , Filella Montserrat , Watts Benjamin , Bragoni Maeva , Bigalke Moritz
Published: August 2023

Once emitted into the environment, macro- (MaP), micro- (MP) and nanoplastics (NP) are exposed to environmental weathering. Yet, the effects of biogeochemical weathering factors occurring in the soil environment are unknown. As the transport, fate, and toxicity of MP and NP depend directly on their surface properties, it is crucial to characterize their transformation in soils to better predict their impact and interactions in this environment. Here, we used scanning transmission x-ray micro spectroscopy to characterize depth profiles of the surface alteration of environmental plastic debris retrieved from soil samples. Controlled weathering experiments in soil and with UV radiation were also performed to investigate the individual effect of these weathering factors on polymer surface alteration. The results revealed a weathered surface on a depth varying between 1 µm and 100 nm in PS, PET and PP environmental plastic fragments naturally weathered in soil. Moreover, the initial step of surface fragmentation was observed on a PS fragment, providing an insight on the factors and processes leading to the release of MP and NP in soils. The comparison of environmental, soil incubated (for 1 year) and UV weathered samples showed that the treatments led to different surface chemical modifications. While the environmental samples showed evidence of alteration involving oxidation processes, the UV weathered samples did not reveal oxidation signs at the surface but only decrease in peak intensities (indicating decrease of the number of chemical C bonds). After a one-year incubation of samples in soil no clear aging effects were observed, indicating that the aging of polymers can be slow in soils.
Surgical repair of platypnea-orthodeoxia syndrome caused by patent foramen ovale, ascending aortic dilation, and pectus excavatum: a case report
Authors: Wada Yuki , Hirokami Jun , Nagasawa Atsushi , Marui Akira , Ohno Nobuhisa
Published: August 2023

Background

Platypnea-orthodeoxia syndrome (POS) is a relatively uncommon clinical syndrome characterized by dyspnea and deoxygenation accompanying postural changes, such as sitting or standing from a recumbent position.

Case presentation

We describe the case of a 76-year-old woman who was hospitalized with dyspnea in the sitting position, which was relieved in the right lateral decubitus position. The patient was diagnosed with POS caused by a patent foramen ovale (PFO), dilation and elongation of the ascending aorta, and pectus excavatum. We performed PFO closure and replacement of the ascending aorta via median sternotomy. The patient’s postoperative percutaneous oxygen saturation dramatically increased in the sitting position.

Conclusions

Elongated and dilated ascending aorta and pectus excavatum with PFO may be risk factors for POS. In older patients, surgical intervention is an important treatment option for POS caused by cardiac and aortic comorbidities.
Personalized medicine for brain metastases (BrMets) through patient-derived organoid (PDO) drug testing.
Authors: Morikawa Aki , Serhan Habib , Udager Aaron M. , Bao Liwei , Qin Zhaoping , Cheng Xu , Heth Jason , Soellner Matthew , Merajver Sofia , Merrill Nathan
Published: August 2023

11

Background: Therapeutic development for BrMets remains a critical need. Our previous work on functional precision medicine using patient-derived xenografts (PDXs) from BrMets suggested that drug sensitivity testing may help prioritize drug selection. However, the time needed to establish PDXs makes the PDX platform less desirable for translation into the clinic. Thus, we examined the feasibility of PDOs from BrMets to evaluate the drug sensitivities in a clinically meaningful time frame. Methods: BrMets were prospectively collected from clinically indicated neurosurgery. We collected DNA and RNA and cultured tumors as 3D organoids. Drugs were curated for each case based on clinical characteristics and molecular profiles when known a priori. The drugs included standard of care and investigational drugs. Rapid Nanostring PanCancer profiling was conducted to examine if contemporary source tumor profiling would inform additional drug selection. Results: 21 patients with breast cancer were consented to the biobanking program. 3 patients had no tissues collected. 17 PDOs were established from 20 cases: 3 without PDO were necrosis without viable tumors or primary brain tumors. 2 patients had multiple collections (recurrence and synchronous lesions). Clinical subtypes included HR+/- HER2+ (N=7), HR+HER2- (N=2), HR-HER2- (N=8). The median number of drugs tested was 19.5 (range:7-32). The median time for drug testing was 12.5 days (range: 9-32). Nanostring profiling was conducted at the time of drug testing in 12/17 PDOs, and pathway analysis indicated potential targeted drugs. The most common alteration was TP53 mutation with additional NGS. The potentially targetable alterations included mutation to PIK3CA, EGFR, FGFR, CDK2NA, and CDK4. The pair of initial and recurrent lesions was molecularly similar but demonstrated differential response to select chemotherapies following patient exposure to radiation. On the other hand, the pair of synchronous lesions showed discordance in PIK3CA status and discordant sensitivity to Pi3K inhibitors. Conclusions: Predictive drug testing with BrMet PDOs in a clinically meaningful time frame is feasible. The use of real-time PDO drug testing along with molecular profiling could be potentially leveraged to further personalize therapy and discover novel therapy options for patients with BrMets. We are currently conducting clinical correlations and working toward clinical validation of our proposed drug testing platform.
Personalized K-Track assay to detect actionable mutations and minimal residual disease in solid tumors.
Authors: Tu Lan N , Nguyen Hoang Van-Anh
Published: August 2023

110

Background: Minimal residual disease (MRD) refers to a small number of cancer cells that remain in the body after curative-intent treatment, causing relapse and metastasis. Current tumor biomarkers and imaging methods have limited sensitivity and specificity to monitor MRD for solid tumors. Circulating tumor DNA (ctDNA) in liquid biopsy has emerged as a promising biomarker to detect MRD but current ctDNA assays remain mostly inaccessible and unaffordable for developing countries. Methods: In this prospective multi-center study, 441 Vietnamese patients diagnosed with breast, colorectal, gastric, lung, liver and ovarian cancers, eligible for curative-intent surgery were recruited. Genomic DNA from tumor tissue and paired white blood cells were sequenced to profile all tumor-derived genomic alterations including actionable mutations in 95 cancer-associated genes. Our bioinformatic algorithm then ranked top alterations unique for individual patient, which were then used to monitor ctDNA presence in serial plasma samples collected before surgery and at scheduled visits after surgery by multiplex PCR and ultra-deep sequencing. Results: The assay had limit of detection for somatic mutations down to at least 0.05% variant allele frequency in liquid biopsy.The sensitivity to detect ctDNA in the pre-operative plasma was 91%, 95%, 70%, 77%, 69% and 47% for colorectal, liver, lung, ovarian, high-risk breast cancer and gastric cancer respectively; the specificity was >99%. After 18-month follow-up, our interim analysis revealed a promising 89% detection rate of post-operative ctDNA in all patients that had metastasis and recurrence (31/35), with the lead time of 2.5-13 months ahead of clinical diagnosis. Conclusions: The K-Track assay is streamlined and affordable with dual clinical utilities in residual cancer surveillance and actionable mutation profiling for targeted therapies. The assay could lay foundation to empower precision cancer medicine in Vietnam and developing countries.
Effect of ruxolitinib and magrolimab on calreticulin in myelofibrosis CD34+ cells in vitro: Proof of concept for combination therapy.
Authors: Rinaldi Ciro Roberto , Boasman Kristian , Simmonds Matthew
Published: August 2023

118

Background: In solid tumours, calreticulin (CALR) overexpression produces a pro-phagocytic signal and is counteracted by concomitant expression of anti- phagocytic CD47, reflecting an apoptosis vs survival mechanism. We have previously found that CD47, not CALR, is overexpressed on the membrane of patients with MPN. Anti-CD47 Magrolimab, is currently being evaluated in clinical trials in AML, MDS but have yet to be tested, either in monotherapy or in combination in MF. Methods: Mononuclear cells were collected by Ficoll separation from bone marrow of 6 MF patients and from 2 controls. CD34+ cells and monocytes were purified using Dynabeads kits from Thermofisher. Cells expression of CALR and CD47 was measured by flow cytometry, before and after incubation with ruxolitinib (Jak inhibitor) alone and in combination with magrolimab. Cells survival was calculated after combining CD34 with monocytes. Informed Consent was obtained for all samples collected. Results: CD47 membrane expression was 57% in untreated MF cells compared to 12% in the control samples and CALR membrane expression was 51.8% in untreated MF cell compared to 12.5% in the control samples. After incubation with ruxolitinib, MF CD34+ cell survival decreased to 98.2%. Following Incubation with magrolimab alone, MF CD34+ cells show no changes in survival (100% alive). The combination of ruxolitinib and magrolimab reduced slightly the MF CD34+ cell survival to 92%. A substantial membrane overexpression of CALR was observed in MF CD34+ cells when incubated with Ruxo and Magrolimab, 74.1%, vs Ruxo alone 52.6%, Magrolimab alone 53.4% and in untreated (51.8%). Interestingly, in the healthy controls, the exposure to combination therapy did not cause the same degree of CALR overexpression (20.7% vs 12.5%), indicating a much stronger pro-phagocytic effect following magrolimab/ruxolitinib combo in MF cancer cells. Conclusions: In vitro, treatment with ruxolitinib or ruxolitinib plus magrolimab, slightly reduce the overall cell survival rate in CD34+ MF samples, comparing with no significant changes in single agent magrolimab. However, the combination of Ruxolitinib and Magrolimab significantly increases CALR membrane expression comparing with Ruxo or Magrolimab alone, signalling a much stronger pro-phagocytic message in MF cells comparing with controls. The induced CALR over-expression, could stimulate a stronger immune response in vivo, where the presence of macrophages would allow removal of CALR rich cells and potentiate the cytoreductive activity towards MF clone. These data support the rational of combining Ruxolitinib with Magrolimab in the next clinical trial stage in myelofibrosis.
Preclinical development of ARD103, a CLL-1 CAR-T produced by a 3-day DashCAR technology, for acute myeloid leukemia.
Authors: Kuan Chien-Tsun , Huang Kao-Jean , Yang Jacob, Shun-Jen , Wu Tsung Han , Yeh Hom-Ming
Published: August 2023

119

Background: Acute myeloid leukemia (AML) is the most common acute leukemia in adults. More than half of the AML patients experienced primary refractory or relapse after current treatments, such as chemotherapy, hematopoietic stem cell transplantation, and targeted therapy. AML patients are in urgent need of novel therapeutic strategies. Leukemic stem cells (LSCs), which cause the treatment failure and leukemia relapsed. Human C-type lectin-like molecule-1 (CLL-1) is a surface antigen expressed on both AML malignant blast cells and LSCs, but not on normal hematopoietic stem cells, suggesting that CLL-1 is a compelling target with low off-tumor toxicity for novel AML treatment. Methods: ARD103 is a second-generation chimeric antigen receptor (CAR)-T cell, expressing a novel extracellular anti-CLL-1 scFv fused to a CD28 transmembrane domain, a CD28 co-stimulatory domain, and a CD3ζ activation domain. ARD103 was generated using lentiviral vector in an optimized 3-day DashCAR manufacturing process and demonstrated high percentage of CAR population (>80%), high percentages of memory T cells (Tscm and Tcm are >70%) and profound effector cytokine production (IFN-γ, granzyme A, perforin and granulysin). Results: ARD103, CLL-1 CAR-T exhibited specific killing on various CLL-1-expressing AML cell lines, such as U937, THP-1, and HL60, correlated to the levels of CLL-1 expression. In the AML U937-Luc xenograft mouse model, the CLL-1 CAR-T cells prolonged the survival time significantly (p < 0.0001), with superior CAR-T cell persistence, to the end point of the study at 48 days compared to the median survival time at 23 days in the untreated or control groups. Furthermore, the xenograft mice receiving as minimum as 3 x105 CAR-T cells per mouse were able to elicit effective recall responses after tumor rechallenge and survived for more than 60 days. The off-target binding interactions of ARD103 CAR-T cells using a human cell microarray showed a specific and strong interaction with CLL-1 but not with other human membrane/extracellular proteins. In the aspect of on-target off-tumor toxicity, the hematotoxicity assessment on ARD103 exerted modest (5%-23%) or no effect on colony formation inhibition of CD34+ cells derived from human normal bone marrow or peripheral blood, respectively. Furthermore, autologous ARD103 cells were successfully prepared from relapsed/refractoryAML patients and demonstrated to mediate specific cytotoxicity to primary AML blasts and LSCs derived from the same patients. Conclusions: Taken together, the ARD103 CLL-1 CAR-T candidate has demonstrated excellent anti-AML potency and efficacy with minimal safety concerns, and warrant to be further developed preclinically and clinically for the treatment of relapsed/refractory AML patients. Keywords: Acute myeloid leukemia; CLL-1; Chimeric antigen receptor-T cell; Immunotherapy.
Clinical applications of measurable residual disease monitoring by multi-parametric flow cytometry and next-generation sequencing in B-cell precursor acute lymphoblastic leukemia.
Authors: Lee Gun-Dong , Ahn Ari , Lee Jong-Mi , Kim Myungshin
Published: August 2023

121

Background: Minimal residual disease (MRD) is accepted as the strongest independent prognostic factor in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The most frequently used methods for MRD monitoring include multi-parametric flow cytometry (MFC) and next-generation sequencing (NGS)-based IGH/IGK gene rearrangement. Both methods have been described to reach a low sensitivity threshold and be broadly applicable to most patients with BCP-ALL, although the clinical MRD cut-off of the two methods has not been fully defined. In this study, we compared MFC-MRD and NGS-MRD and established their clinical cut-off in BCP-ALL. Methods: Bone marrow aspirates with less than 5% blasts were obtained from 117 treated BCP-ALL patients. MFC-MRD assessment was performed using DuraClone RE ALB tubes (Beckman Coulter, Marseille, France) modified by adding 5 additional antibodies. In total, up to 1×105 cells were acquired using DxFLEX flow cytometer (Beckman Coulter), and all acquired data were analyzed using the Kaluza software v2.1. NGS-MRD was performed using the LymphoTrack IGH and IGK assay panels (InVivoScribe, San Diego, CA). We amplified 240 ng of high-quality DNA with a single multiplex master mix containing primers, and the library DNA was denatured and loaded onto a Miseq reagent kit v2. The FASTQ files were analyzed using the LymphoTrack MRD software v2.0.2. MRD evaluated using both of MFC and NGS in each sample, and the virtual sensitivity of both methods was 10-5. For 84 patients available, we analyzed the relapse-free survival (RFS) and overall survival (OS) rate for each MRD status and established a clinical cutoff. Results: We found a high correlation between methods (r=0.640) and a concordance rate of 81.2% for detecting MRD at 0.01% level. An MRD value of 0.01% proved to be a significant threshold value for 1-year RFS and OS. There was a difference in prognosis in both RFS and OS, but statistical significance was found only in RFS (MFC-MRD: 93.4±3.2% for MRD <0.01% vs. 37.5±27.3% for MRD ≥0.01%, P=0.007; NGS-MRD: 93.7±3.6% for MRD <0.01% vs. 68.8±14.2% for MRD ≥0.01%, P=0.016). In a Kaplan-Meier estimate of RFS at a threshold of 0.01%, patients who were negative for MRD by MFC and positive by NGS (n=12) had an intermediate prognosis between patients who were negative by both MFC and NGS (n=55) and patients who were positive by both MFC and NGS (n=11) (98.14±3.2%, 83.34±10.8%, 40.94±29.5%, respectively, P=0.017). Conclusions: An MRD threshold of 0.01% for both MFC and NGS is reasonable for clinical identification of poor-risk patients. NGS-MRD detection improves risk stratification for BCP-ALL.
The evolution of an oncology site network partnership in a COVID era clinical trial environment.
Authors: Helou Sarah , Vidhyarkorn Tanya , Churchill Sarah , Russell Janice
Published: August 2023

125

Background: As a leader in cancer therapy research, Roche created the immunotherapy Centers of Research Excellence (imCORE) Network, a worldwide research network designed to connect members in an open environment of shared information, expertise, and decisions. This network is dedicated to advancing the comprehension of the underlying science and shared operational challenges in order to accelerate the most promising new treatment options for patients. Pre-pandemic the imCORE network was an established partnership model leader with several years of experience. Relationships between site and sponsor were established and consistent. Regularly cadenced face to face and virtual meetings provided proven pathways for open communication and collaboration opportunities. A pipeline of operational efficiencies, pain point interventions, best practices and strategies were brainstormed, co-created, and implemented across multiple workstreams. COVID arrived in March of 2020 and over the course of the next months to years the world changed. These changes were felt acutely, directly impacted clinical research, and specifically impacted imCORE sites, their patients, the network, and how it operates. Methods: This paper focuses on the Roche Sponsored clinical trial operational excellence aspects of the network. Data is collected from network sites related to pre and "post" COVID priorities and impacts. The data is then analyzed to produce best practice recommendations for oncology research sites and networks. Results: It highlights the direct impacts of COVID to a sponsored trial site network. This includes specific measures the network has taken to evolve to fit the needs of its sites and their patients and presents a pathway forward for site networks to consider in the new reality of COVID era clinical trials. Conclusions: COVID impacted and continues to impact clinical research sites and sponsored trial networks in significant and lasting ways. Site and network operations need to evolve to meet the needs of patients and staff in this new reality.
Associations of wearable tracker use with physical activity and health outcomes in patients with cancer: Findings from the HINTS-SEER (2021).
Authors: Pu Junlan , Cho Youmin
Published: August 2023

131

Background: Physical inactivity is a global issue for cancer survivors. Wearable trackers are promising to address physical inactivity by providing real-time feedback on physical activity (PA) and offer opportunities for self-monitoring and goal setting. Meta-analysis has reported the effects of interventions that incorporate wearable trackers on improved physical inactivity and related health outcomes (e.g., BMI, anxiety and depression, and self-rated health). However, wearable trackers were often used an an adjunct to PA interventions, and the effectiveness of wearable trackers alone is unknown. The aim of this study was to determine the association of wearable trackers with PA and health outcomes (BMI, anxiety and depression, and self-rated health) in patients with cancer, using a national dataset. Methods: Data from 957 cancer survivors from Health Information National Trends Survey – Surveillance, Epidemiology, and End Results Program (HINTS-SEER-2021) were analyzed. The outcome variables examined were: time spent in moderate to vigorous physical activity (MVPA), weekly frequency of strength training, BMI, anxiety/depression levels, and self-assessed health status. The primary independent variable was whether cancer survivors had used wearable devices within the past 12 months. Design-based linear regression for continuous outcome variables and ordinal logistic regression for ordinal outcome variables were conducted to determine the associations, after controlling for sociodemographic, cancer-related clinical (i.e., type, stage, time since diagnosis), and general health-related factors (i.e., BMI and smoking). All data analyses accounted for the complex survey design and sample weights. Results: Only 28% of cancer survivors reported wearable devices use. Bivariate analyses showed younger age, higher income, and employed status were significantly associated with wearable tracker use ( P<.001). Wearable devices use was significantly associated with higher time spent in MVPA (b=37.94, 95% OR:8.38, 67.5; P=.01), more frequent strength training per week (adjusted OR=1.50, 95% OR: 1.09, 2.06; P=.01), and better self-rated health status (adjusted OR=1.58, 95% OR:1.09, 2.29; P=.01), but not associated with BMI or anxiety/depression. Conclusions: This study suggests that the uptake of wearable devices is low and highlights the digital divide among patients with cancer. This study has confirmed the associations of wearable tracker use with PA and self-rated health, supporting using wearable trackers as a promising tool to facilitate PA promotion.
The response rates to surveys among breast cancer patients using different manners of distribution: A prospective study of integrated rehabilitation.
Authors: Kurir Borovcic Mateja , Mavric Zlatka , Mozetic Anamarija , Zagar Tina , Zadravec Zaletel Lorna , Kozjek Nada Rotovnik , Mlakar Mastnak Denis , Borstnar Simona , Besic Nikola
Published: August 2023

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Background: Communication with breast cancer patients is crucial within individualised integrated rehabilitation, where the patients are at the centre of the provided health care services. Anonymous surveys could be used as one of the tools to check the needs of patients, the effectiveness of various aspects of the interventions offered and to obtain valuable feedback from patients. Our aim was to determine which manner of conducting anonymous surveying among breast cancer patients would be most suitable for improving the health service of individualized integrated rehabilitation. Methods: The subjects of our prospective study were 600 females (29-65 (mean 52) years of age), who participated in the pilot study on the individualized integrated rehabilitation of breast cancer patients receiving treatment at Institute of Oncology Ljubljana in 2019-2022. Questionnaires of implemented surveys were anonymous with different manners of distribution and on three different topics. The first survey was conducted via standard post sending questionnaires on papers to the patients to inquire about their satisfaction with the provided services after the conclusion of their treatment. The second survey was conceded via email, sending online questionnaires to inquire about appropriateness of interventions and patients' opinions about spa treatment. The third survey was conducted half via email and half via text message on mobile phone (SMS) to inquire about the most suitable terms of the regular physical activity during oncological treatment. The survey response rate was calculated as the number of valid surveys received (numerator) divided by the number of surveys distributed (denominator). If all questions were not answered, the survey was invalid. Results: There was a significant difference in the response rate of the patients to the anonymous surveys, depending on the manner of distribution of the survey. The response rate of patients who got questionnaires by regular mail were 51%, 28% and 13% if received by e-mail and 27% if sent via SMS. The difference in the response rate in the survey on physical activity, received by email or by SMS, was statistically significant (p= 0,0026). Conclusions: The highest response rate of breast cancer patients was received by sending the questionnaires via regular post. Clinical trial information: V3-1906. [Table: see text]
Clinical impact of discrepancy in PD-L1 expression on tumor cells between 22C3 and SP142 assay on the efficacy of pembrolizumab in advanced NSCLC patients.
Authors: Miyakoshi Jun , Yoshida Tatsuya , Shirasawa Masayuki , Torasawa Masahiro , Matsumoto Yuji , Masuda Ken , Kashima Jumpei , Shinno Yuki , Okuma Yusuke , Goto Yasushi , Horinouchi Hidehito , Shiraishi Kouya , Kohno Takashi , Yatabe Yasushi , Yamamoto Noboru , Ohe Yuichiro
Published: August 2023

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Background: Pembrolizumab and atezolizumab monotherapy has been the standard of care in treatment-naïve advanced NSCLC with high PD-L1 expression. On the other hand, the evaluation of PD-L1 expression as companion diagnostics is different between two agents (Clone: 22C3 and SP142). PD-L1 Immunohistochemistry Comparability Study showed that the SP142 assay showed significantly less sensitivity to detect PD-L1 expression on TCs, leading to the discrepancy in cases with PD-L1 high expression on tumor cells (TCs). This study aimed to evaluate the clinical impact of the discrepancy in PD-L1 high expression on the efficacy of pembrolizumab monotherapy in advanced NSCLC patients. Methods: We retrospectively reviewed advanced NSCLC patients with PD-L1 high expression (22C3: TPS ≥ 50%) who received first-line pembrolizumab monotherapy, and had sufficient tumor tissues for evaluating PD-L1 expression on TCs (SP142). Additionally, RNA-sequence analysis was performed to evaluate the biological differences in the discrepancy cases with PD-L1 high expression on TCs. Results: A total of 45 patients (PD-L1 expression TPS [22C3]: ≥ 50%) were included. Of these patients, 5 / 9 / 18 / 13 patients had PD-L1 expression (SP142): TC 0 / 1 / 2 / 3, respectively. The objective response rate (ORR) and median PFS (mPFS) of pembrolizumab in all pts were 62% (95% confidence interval [CI], 47-76) and 7.52 months (mo, 95% CI, 4.73-10.97). The ORR and PFS in patients with TC ≤ 1 were significantly worse than those with TC ≥ 2 (TC ≤ 1 vs. TC ≥ 2: ORR 21% vs. 81%, p < 0.001, and mPFS 3.81 mo vs. 8.05 mo, p = 0.004, Table). In patients with PD-L1 TPS ≥ 90% (n = 34), the ORR and PFS in patients with TC ≤ 1 were also significantly worse than those with TC ≥ 2 (TC ≤ 1 vs TC ≥ 2: ORR 0% vs. 82%, p < 0.001, and mPFS 2.04 mo vs. 10.97 mo, p < 0.001, Table). Additionally, RNA-sequence analysis showed that tumors with TC ≤ 1 had significantly suppressed immune-related pathways (ALLOGRAFT REJECTION and IFNG RESPONSE) and significantly lower T-cell-inflamed gene expression profiles compared with those with TC ≥ 2. Conclusions: Discrepancy in PD-L1 expression on tumor cells between 22C3 and SP142 assay was a negative predictive factor for pembrolizumab monotherapy and showed suppressed tumor microenvironment.[Table: see text]
Characteristics of Met gene and its relationship with immune index TMB/MMR genes/DDR genes in Chinese NSCLC population.
Authors: Zhang Hongying , Liu Zikai , Feng Libao , Xu Yan , He Hongsheng , Luo Peng
Published: August 2023

147

Background: Patients with driver gene mutations in NSCLC can benefit significantly from corresponding targeted therapy, but respond poorly to immunotherapy (such as EGFR, ALK). As a driver gene of NSCLC, the relationship between the characteristics of Met and many immune indicators in the Chinese population is still unclear. This study aims to elucidate the characteristics of the Met gene and its relationship with immune indicators in the Chinese NSCLC population. Methods: 732 Formalin-Fixed Paraffin-Embedded (FFPE) lung adenocarcinoma samples were collected and detected by Next Generation Sequencing 603-gene panel from July 31, 2021 to March 14, 2023 were selected from the study. The biomarkers of immunotherapy (TMB-High [≥10/Mb], MSI-High, and PD-L1 22C3 [TPS], DDR-related genes (ATM, ATR, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, MRE11, PALB2, RAD50, RAD51C, RAD51D) and MMR-related genes (MLH1, MSH2, MSH6, PMS2) were also calculated. Results: Among the 732 subjects included in the previous detection, a total of 32 cases were detected to carry Met-related gene mutations. The detection rate of Met gene was 4.37%, which was consistent with the mutation probability of Met mutation of 4-6% in previous studies. The median age was 65 (13-97). 81% of patients belonged to mutations of unknown clinical significance (26/32); 15% of patients belonged to exon 14 skipping type (5/32); Met amplification accounted for the least, accounting for only 6% (2/32 ). The top 3 loci of mutation frequency were Met_L221W (4/32), MET_Q1067K (2/32), and MET_F206S (2/32). The gene partners of Met co-mutation were analyzed, and the top five genes were PPP2R1A, HIST1H3G, CDKN1B, SYK, and ERBB4. In the analysis of the immune indicators of the Met mutant population and the Met wild-type population, the Mann-Whitney U test found that among the TMB indicators, the mean value of the Met group was 8.09 with a standard deviation of 7.91, and the mean value of the un-Met group was 5.94 with a standard deviation of 4.98. Met was correlated with TMB with statistical difference (P value 0.02). Among the MSI indicators, the mean value of the Met group was 8.16, and the mean value of the un-Met group was 7.76. The correlation between Met and MSI status was not significant. We also paid attention to Met and DDR-related genes and MMR-related genes. Mann-Whitney U analysis showed that there was no significant correlation between MET group and wild-type MET group and DDR gene (p-value: 1.0), but there was a significant relationship between MET group and wild-type MET group and MMR gene (p-value: 0.026). Conclusions: In the Chinese NSCLC population, there is a correlation between Met expression and TMB, and the Met mutation will increase the TMB value. Met expression was significantly correlated with MMR-related gene mutations.
Genomic predictors for early recurrence of hepatocellular carcinoma (HCC) after curative resection.
Authors: Huang Lisha , Zhang Shuilong , Kai Zhentian , Xu Yan
Published: August 2023

157

Background: Early recurrence of HCC after curative resection is common. However, the association between genetic alterations and early HCC recurrence, especially in Chinese patients (pts), remains largely unknown. Methods: We retrospectively analyzed 214 formalin-fixed paraffin-embedded (FFPE) tumor specimens of HCC patients that were collected from June 2016 to October 2021. Clinical outcomes related to frequently mutated genes were evaluated in 176 pts with a median follow-up time of 21.9 months. Tumor tissue samples were detected by OncoDrug-Seq 603-gene panel assay through next-generation sequencing. Early recurrence was defined as the appearance of an intra- or extrahepatic tumor nodule within 1 year of curative resection. Results: In multivariate analysis, three tumor suppressor genes related to early recurrence, namely PRDM1, NOTCH3, and MGA. PRDM1 mutations and NOTCH3 mutations were the risk factor for early recurrence (＜1 y after surgical resection) (hazard ratio (HR), 4.22; 95% confidence interval (CI), 1.96-9.06; p＜0.001 ) (HR, 2.96; 95% CI, 1.43-6.13; p=0.003). These two mutated genes were also significantly associated with overall survival (HR, 3.39; 95%CI, 1.23-9.34; p=0.018) (HR, 5.22; 95%CI, 2.10-12.99; p＜0.001). We found a trend toward an increased risk of early recurrence in pts with MGA mutation. (HR, 2.06; 95%CI, 1.05-4.05; p=0.027). Conclusions: Mutations in these three tumor suppressor genes were shown to be shorter time intervals to relapse after curative resection. We also demonstrated that pts who have these markers require more frequent monitoring and follow-up visits.
Functional outcomes of bony sarcoma in adolescent and young adult patients: A systematic review.
Authors: Zheng Xuan Ong , Poon Eileen Yi Ling
Published: August 2023

161

Background: Sarcomas are heterogeneous rare cancers, and while it affects 1% of all adult cancers, they affect 10-20% of Adolescents and Young Adults(AYAs). Sarcomas can be divided into soft tissue sarcomas(STS) and bony sarcomas(BS). The 5-year survival rates range between 50-60% but have remained stagnant. While the management of BS involves systemic treatment and morbid surgeries, functional outcomes and quality-of-life(QoL) have been largely overlooked. These changes are usually persistent and irreversible, with significant impact on mobility, function and body image. There are many facets of functional outcomes, including physical, social and psychological. These outcomes directly affect patients’ independence, self-confidence and future job endeavors, yet hardly any specific research has gone into it. Methods: A systematic review yielded 833relevant papers, but only 27was included for final analysis. Inclusion criteria included literature published in English, focused on AYAs 16-39 years, BS and papers assessing functional outcomes after treatment. We also included studies that investigated survivorship in pediatric BS, as these patients will transit into young adults who are childhood cancer survivors. Results: Outcomes of AYA are poorer in all aspects – physical function, social reintegration and psychological health. The heterogeneity among AYA patients, and large differences require individualized care based on stages of their personal development. There is greater adjustment required in AYAs due to higher physical, social and financial demands as they mature and aim to become independent. Current tools to assess HRQoL in AYAs are not standardized or validated in this age group. More research is required to identify long term outcomes post-treatment and into survivorship. Conclusions: AYAs have often been referred to as the ‘lost tribe’, with many of their needs overlooked. They are stricken with a cancer diagnosis during their prime and it is essential to manage them holistically to preserve and maximize their functional outcomes.