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Medical management of heart failure (HF) has evolved and has achieved significant survival benefits, resulting in highly complex medication regimens. Complex medication regimens create challenges for older adults, including nonadherence and increased adverse drug events, especially associated with cognitive impairment, physical limitations, or lack of social support. However, the association between medication complexity and patients' health outcomes among older adults with HF is unclear. The purpose of this review is to address how the complexity of HF medications has been assessed in the literature and what clinical outcomes are associated with medication regimen complexity in HF. Further, we aimed to explore how older adults were represented in those studies. The Medication Regimen Complexity Index was the most commonly used tool for assessment of medication regimen complexity. Rehospitalization was most frequently assessed as the clinical outcome, and other studies used medication adherence, quality of life, healthcare utilization, healthcare cost, or side effect. However, the studies showed inconsistent results in the association between the medication regimen complexity and clinical outcomes. We also identified an extremely small number of studies that focused on older adults. Notably, current medication regimen complexity tools did not consider a complicated clinical condition of an older adult with multimorbidity, therapeutic competition, drug interactions, or altered tolerance to the usual dose strength of the medications. Furthermore, the outcomes that studies assessed were rarely comprehensive or patient centered. More studies are required to fill the knowledge gap identifying more comprehensive and accurate medication regimen complexity tools and more patient-centered outcome assessment.

To explore ways to improve O-RADS MRI scoring for fat-containing adnexal masses, by investigating methods for quantifying solid tissue volume and fat distribution and evaluating their associations with malignancy.This retrospective, single-center study included patients with fat-containing adnexal masses on MRI during 2008-2021. Two radiologists independently reviewed overall size (Size188 women (median age 35 years) with 163 benign and 25 malignant lesions were included. SizeOverall size, size of (any or non-Rokitansky-nodule) solid tissue, and fat distribution differed between benign and malignant fat-containing adnexal masses. Incorporating these would constitute simple and practical approaches to refining O-RADS MRI scoring.

Background/aim Previous reports have associated the KMT2A-ELL fusion gene, generated by t(11;19)(q23;p13.1), with acute myeloid leukemia (AML). We herein report a KMT2A-ELL and a novel ZNF56-KMT2A fusion genes in a pediatric T-lineage acute lymphoblastic leukemia (T-ALL). Materials and methods Genetic investigations were performed on bone marrow of a 13-year-old boy diagnosed with T-ALL. Results A KMT2A-ELL and a novel ZNF56-KMT2A fusion genes were generated on der(11)t(11;19)(q23;p13.1) and der(19)t(11;19)(q23;p13.1), respectively. Exon 20 of KMT2A fused to exon 2 of ELL in KMT2A-ELL chimeric transcript whereas exon 1 of ZNF56 fused to exon 21 of KMT2A in ZNF56-KMT2A transcript. A literature search revealed four more T-ALL patients carrying a KMT2A-ELL fusion. All of them were males aged 11, 11, 17, and 20 years. Conclusion KMT2A-ELL fusion is a rare recurrent genetic event in T-ALL with uncertain prognostic implications. The frequency and impact of ZNF56-KMT2A in T-ALL are unknown.

Purpose of the study: This study was aimed at identifying epigenome signature associated with risk of pediatric leukemia and uncovering molecular precursors of leukemia at birth in the blood of children before they develop the disease. Pediatric cancer is the leading cause of disease-related mortality in children and adolescents, with increasing incidence worldwide and lifelong sequelae in survivors. The most common form is leukemia, the causes of which are largely unknown. Growing evidence points to an origin in utero, when global redistribution of the epigenome modifications occurs driving tissue differentiation. Here, we sought to identify genome-wide differentially methylated genes at birth in newborns who later developed pediatric precursor B-cell ALL (pre-B ALL), compared with those who did not. Experimental procedures: Epigenome-wide DNA methylation was profiled in neonatal blood, with follow-up to pediatric pre-B ALL, using double-blinded analyses between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was done using an independent technology and population (totaling 317 cases and 483 control) and complemented with pan-tissue methylation-stability (n=5,023 tissues; 30 types) and methylation-expression (n=2,294 tissues; 26 types) analyses. At diagnosis, methylation analysis was performed in leukemia tissues from pre-B ALL patients (n=644) with at least ten-year follow-up. Results: We found a limited number of loci (among which an imprinted tumor suppressor gene) as being significantly hypermethylated at birth in nested cases relative to controls in all tested populations, including European and Hispanic ancestries. Some DMRs were found to be stable over follow-up years after birth and across surrogate blood and target bone marrow tissues. Differential methylation was found to be associated with a change in gene expression and with worse pre-B ALL patient survival, supporting a functional and translational role for differential methylation. Conclusions: Our results provide proof-of-concept to detect at birth epigenetic alterations predisposing to childhood leukemia, reproducible in three continents and two ethnicities. DNA methylation alterations evident before diagnosis could be precursors of pediatric pre-B ALL development and actionable targets for risk assessment and prognosis. Citation Format: Akram Ghantous, Semira Gonseth Nusslé, Farah Nassar, Natalia Spitz, Alexei Novoloaca, Olga Krali, Ritu Roy, Shaobo Li, Maxime Caron, Lilys Lam, Peter Daniel Fransquet, John Casement, John Strathdee, Mark S. Pearce, Helen M. Hansen, Adam J. De Smith, Daniel Sinnett, Siri Eldevik Håberg, Jill McKay, Jessica Nordlund, Per Magnus, Terence Dwyer, Richard Saffery, Joseph Leo Wiemels, Monica Cheng Munthe-Kaas, Zdenko Herceg. Epigenome-wide DNA methylation alterations precede diagnosis since birth and affect prognosis of pediatric B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB362.

Somatostatin receptor (SSTR)-targeted positron emission tomography/computed tomography (PET/CT) imaging has risen to the forefront for neuroendocrine tumor (NET) detection and management, yet the variability of significant uptake variability (SUV) as a semiquantitative measure of disease detection and tumor response to treatment has not been fully explored.We assess the reproducibility and interscan variability of SUV metrics of normal tissue and NET in serialBoth primary and metastatic hepatic lesions demonstrated SUV (SUVThe highly variable nature of regional SUV

Traditional quantitative perfusion imaging methods require complex data acquisition and analysis strategies; typically require ancillary arterial blood sampling for measurement of input functions; are limited to single organ or tissue regions in an imaging session; and because of their complexity, are not well suited for routine clinical implementation in a standardized fashion that can be readily repeated across diverse clinical sites. The whole-body perfusion method described in this chapter has the advantages of on-demand radiotracer production; simple tissue pharmacokinetics enabling standardized estimation of perfusion; short-lived radionuclides, facilitating repeat or combination imaging procedures; and scalability to support widespread clinical implementation. This method leverages the unique physiological characteristics of radiolabeled copper(II) bis(thiosemicarbazone) complexes and the detection sensitivity of positron emission tomography (PET) to produce quantitatively accurate whole-body perfusion images. This chapter describes the synthesis of ethylglyoxal bis(thosemicarbazonato)copper(II) labeled with copper-62 ([62Cu]Cu-ETS), its unique physiological characteristics, a simple tracer kinetic model for estimation of perfusion using image-derived input functions, and validation of the method against a reference standard perfusion tracer. A detailed description of the methods is provided to facilitate implementation of the perfusion imaging method in PET imaging facilities.

Traditional quantitative perfusion imaging methods require complex data acquisition and analysis strategies; typically require ancillary arterial blood sampling for measurement of input functions; are limited to single organ or tissue regions in an imaging session; and because of their complexity, are not well suited for routine clinical implementation in a standardized fashion that can be readily repeated across diverse clinical sites. The whole-body perfusion method described in this chapter has the advantages of on-demand radiotracer production; simple tissue pharmacokinetics enabling standardized estimation of perfusion; short-lived radionuclides, facilitating repeat or combination imaging procedures; and scalability to support widespread clinical implementation. This method leverages the unique physiological characteristics of radiolabeled copper(II) bis(thiosemicarbazone) complexes and the detection sensitivity of positron emission tomography (PET) to produce quantitatively accurate whole-body perfusion images. This chapter describes the synthesis of ethylglyoxal bis(thosemicarbazonato)copper(II) labeled with copper-62 ([

Cancer control depends on early detection, a discipline formalized in the 1950s by widespread use of the Papanicolaou test for detecting pre-invasive squamous epithelial neoplasia of the uterine cervix (1-3). Studies growing out of that public health initiative have revealed a long latency between the earliest cellular abnormalities and invasive cancer. Pre-invasive or intraepithelial neoplasia arises in predisposed benign tissue, often influenced by metaplasia or inflammation (4,5). These precursor lesions can be reliably diagnosed by the microscopic appearance, but the biological behavior of these lesions is difficult to predict by histology alone. In situ carcinoma of the cervix or breast has only a 50% probability of eventually becoming invasive cancer (1-3).

Purpose:Transforming growth factor-β1 (TGF-β1), a known immune suppressor, plays an important role in tumor progression and overall survival (OS) in many types of cancers. We hypothesized that genetic variations of single nucleotide polymorphisms (SNPs) in the TGF-β1 pathway can predict survival in patients with non-small cell lung cancer (NSCLC) after radiation therapy.Materials and Methods:Fourteen functional SNPs in the TGF-β1 pathway were measured in 166 patients with NSCLC enrolled in a multi-center clinical trial. Clinical factors, including age, gender, ethnicity, smoking status, stage group, histology, Karnofsky Performance Status, equivalent dose at 2 Gy fractions (EQD2), and the use of chemotherapy, were first tested under the univariate Cox's proportional hazards model. All significant clinical predictors were combined as a group of predictors named “Clinical.” The significant SNPs under the Cox proportional hazards model were combined as a group of predictors named “SNP.” The predictive powers of models using Clinical and Clinical + SNP were compared with the cross-validation concordance index (C-index) of random forest models.Results:Age, gender, stage group, smoking, histology, and EQD2 were identified as significant clinical predictors: Clinical. Among 14 SNPs, BMP2:rs235756 (HR = 0.63; 95% CI:0.42–0.93;p= 0.022), SMAD9:rs7333607 (HR = 2.79; 95% CI 1.22–6.41;p= 0.015), SMAD3:rs12102171 (HR = 0.68; 95% CI: 0.46–1.00;p= 0.050), and SMAD4: rs12456284 (HR = 0.63; 95% CI: 0.43–0.92;p= 0.016) were identified as powerful predictors of SNP. After adding SNP, the C-index of the model increased from 84.1 to 87.6% at 24 months and from 79.4 to 84.4% at 36 months.Conclusion:Genetic variations in the TGF-β1 pathway have the potential to improve the prediction accuracy for OS in patients with NSCLC.

Background/aim Fusion of histone-lysine N-methyltransferase 2A gene (KMT2A) with the Rho guanine nucleotide exchange factor 12 gene (ARHGEF12), both located in 11q23, was reported in some leukemic patients. We report a KMT2A-ARHGEF12 fusion occurring during treatment of a pediatric acute myeloid leukemia (AML) with topoisomerase II inhibitors leading to a secondary acute lymphoblastic leukemia (ALL). Materials and methods Multiple genetic analyses were performed on bone marrow cells of a girl initially diagnosed with AML. Results At the time of diagnosis with AML, the t(9;11)(p21;q23)/KMT2A-MLLT3 genetic abnormality was found. After chemotherapy resulting in AML clinical remission, a 2 Mb deletion in 11q23 was found generating a KMT2A-ARHGEF12 fusion gene. When the patient later developed B lineage ALL, a t(14;19)(q32;q13), loss of one chromosome 9, and KMT2A-ARHGEF12 were detected. Conclusion The patient sequentially developed AML and ALL with three leukemia-specific genomic abnormalities in her bone marrow cells, two of which were KMT2A-rearrangements.

Background - The rapidly expanding era of “omics” research is highly dependent on the availability of quality-proven biological material, especially for rare conditions such as pediatric malignancies. Professional biobanks provide such material, focusing on standardized collection and handling procedures, distinctive quality measurements, traceability of storage conditions, and accessibility. For pediatric malignancies, traditional tumor biobanking is challenging due to the rareness and limited amount of tissue and blood samples. The higher molecular heterogeneity, lower mutation rates, and unique genomic landscapes, however, renders biobanking of this tissue even more crucial. Aim - The aim of this study was to test and establish methods for a prospective and centralized biobank for infants, children, and adolescents up to 18 years of age diagnosed with cancer in Norway. Methods - Obtain judicial and ethical approvals and administration through a consortium, steering committee, and advisory board. Develop pipelines including SOPs for all aspects in the biobank process, including collection, processing and storing of samples and data, as well of quality controlling, safeguarding, distributing, and transport. Results - The childhood cancer biobanking started at Oslo University Hospital in March 2017 and was from 2019 run as a national Norwegian Childhood Cancer Biobank. Informed consent and biological samples are collected regionally and stored centrally. Approximately 12 000 samples from 510 patients and have been included by January 1, 2021, representing a 96% consent and participation rate among our newly diagnosed patients. Conclusion - A well-functioning nationwide collection and centralized biobank with standardized procedures and national storage for pediatric malignancies has been established with a high acceptance among families.

Background/Aim: Previous reports have associated the KMT2A-ELL fusion gene, generated by t(11;19)(q23;p13.1), with acute myeloid leukemia (AML). We herein report a KMT2A-ELL and a novel ZNF56-KMT2A fusion genes in a pediatric T-lineage acute lymphoblastic leukemia (T-ALL). Materials and Methods: Genetic investigations were performed on bone marrow of a 13-year-old boy diagnosed with T-ALL. Results: A KMT2A-ELL and a novel ZNF56-KMT2A fusion genes were generated on der(11)t(11;19)(q23;p13.1) and der(19)t(11;19)(q23;p13.1), respectively. Exon 20 of KMT2A fused to exon 2 of ELL in KMT2A-ELL chimeric transcript whereas exon 1 of ZNF56 fused to exon 21 of KMT2A in ZNF56-KMT2A transcript. A literature search revealed four more T-ALL patients carrying a KMT2A-ELL fusion. All of them were males aged 11, 11, 17, and 20 years. Conclusion: KMT2A-ELL fusion is a rare recurrent genetic event in T-ALL with uncertain prognostic implications. The frequency and impact of ZNF56-KMT2A in T-ALL are unknown.

Background/Aim: Fusion of histone-lysine N-methyltransferase 2A gene (KMT2A) with the Rho guanine nucleotide exchange factor 12 gene (ARHGEF12), both located in 11q23, was reported in some leukemic patients. We report a KMT2A-ARHGEF12 fusion occurring during treatment of a pediatric acute myeloid leukemia (AML) with topoisomerase II inhibitors leading to a secondary acute lymphoblastic leukemia (ALL). Materials and Methods: Multiple genetic analyses were performed on bone marrow cells of a girl initially diagnosed with AML. Results: At the time of diagnosis with AML, the t(9;11)(p21;q23)/KMT2A-MLLT3 genetic abnormality was found. After chemotherapy resulting in AML clinical remission, a 2 Mb deletion in 11q23 was found generating a KMT2A-ARHGEF12 fusion gene. When the patient later developed B lineage ALL, a t(14;19)(q32;q13), loss of one chromosome 9, and KMT2A-ARHGEF12 were detected. Conclusion: The patient sequentially developed AML and ALL with three leukemia-specific genomic abnormalities in her bone marrow cells, two of which were KMT2A-rearrangements.

This study tested the hypotheses that 1) changes in mid-treatment fluorodeoxyglucose (FDG)-positron emission tomography (PET) parameters are predictive of overall survival (OS) and 2) mid-treatment FDG-PET-adapted treatment has the potential to improve survival in patients with non-small cell lung cancer (NSCLC).Patients with stage I-III NSCLC requiring daily fractionated radiation were eligible. FDG-PET-CT scans were obtained prior to and mid-treatment with radiotherapy at 40-50 Gy. The normalized maximum standardized uptake value (NSUVmax), normalized mean SUV (NSUVmean), PET-metabolic tumor volume (MTV), total lesion glycolysis (TLG), and computed tomography-based gross tumor volume (CT-GTV) were consistently measured for all patients. The primary study endpoint was OS.The study is comprised of 102 patients who received 3-dimensional conformal radiotherapy, among whom 30 patients who received mid-treatment PET-adapted dose escalation radiotherapy. All PET-CT parameters decreased significantly (P 0.001) mid-treatment, with greater reductions in FDG-volumetric parameters compared to FDG-activity factors. Mid-treatment changes in MTV (P = 0.053) and TLG (P = 0.021) were associated with OS, while changes in NSUVmax, NSUVmean, and CT-GTV were not (all Ps0.1). Patients receiving conventional radiation (60-70 Gy) with MTV reductions greater than the mean had a median survival of 14 months, compared to those with MTV reductions less than the mean who had a median survival of 22 months. By contrast, patients receiving mid-treatment PET-adapted radiation with MTV reductions greater than the mean had a median survival of 33 months, compared to those with MTV reductions less than the mean who had a median survival of 19 months. Overall, PET-adapted treatment resulted in a 19% better 5-year survival than conventional radiation.Changes in mid-treatment PET-volumetric parameters were significantly associated with survival in NSCLC. A greater reduction in the mid-treatment MTV was associated with worse survival in patients treated with standard radiation, but with better survival in patients who received mid-treatment PET-adapted treatment.

Background: Radiation therapy plays an increasingly important role in the treatment of patients with non-small-cell lung cancer (NSCLC). The purpose of the present study is to assess the survival outcomes of radiotherapy treatment compared to other treatment modalities and to determine the potential role of advanced technologies in radiotherapy on improving survival. Methods: We used cancer incidence and survival data from the Surveillance, Epidemiology, and End Results database linked to U.S. Census data to compare survival outcomes of 288,670 patients with stage I-IV NSCLC treated between 1999 and 2008. The primary endpoint was overall survival. Results: Among the 288,670 patients diagnosed with stage I-IV NSCLC, 92,374 (32%) patients received radiotherapy-almost double the number receiving surgery (51,961, 18%). Compared to other treatment groups and across all stages of NSCLC, patients treated with radiotherapy showed greater median and overall survival than patients without radiation treatment (p < 0.0001). Radiotherapy had effectively improved overall survival regardless of age, gender, and histological categorization. Radiotherapy treatment received during the recent time period 2004 - 2008 is correlated with enhanced survival compared to the earlier time period 1999 - 2003. Conclusion: Radiation therapy was correlated with increased overall survival for all patients with primary NSCLC across stages. Combined surgery and radiotherapy treatment also correlates with improved survival, signaling the value of bimodal or multimodal treatments. Population-based increases in overall survival were seen in the recent time period, suggesting the potential role of advanced radiotherapeutic technologies in enhancing survival outcomes for lung cancer patients.

To assess a novel radiotracer aluminum [18F]fluoride-1,4,7-triazacyclononane-triacetic acid-pegylated dimeric RGD ([18F]ALF-NOTA-PRGD2, denoted as [18F]Alfatide) for positron emission tomography (PET)/X-ray computed tomography (CT) and explore the relationships between clinicopathological characteristics and maximum standard uptake values in primary (SUVP) and metastatic lymph nodes (SUVLN) of patients with esophageal squamous cell carcinoma (ESCC), as verified by pathologic examination and compared with those obtained with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]DG) PET. We prospectively enrolled patients with newly diagnosed ESCC who agreed to undergo [18F]Alfatide PET/CT or [18F]FDG PET/CT scans before surgery at Shandong Cancer Hospital from May 2011 to July 2017. SUVs and the pathological tumor-node-metastasis (pTNM) stages of primary tumors and metastatic lymph nodes (LNs) were measured and confirmed pathologically. Immunohistochemical (IHC) staining for integrin αvβ3 was performed on tumor samples (both primary tumors and metastatic LNs) collected from nine patients. Of 61 patients who underwent PET/CT scans, 46 then underwent curative surgery and were included in our analysis (n = 21 for [18F]Alfatide PET/CT and n = 25 for [18F]FDG PET/CT). No significant differences in the SUVP on [18F]Alfatide PET/CT or [18F]FDG PET/CT were observed among the cohorts according to gender, pathological stage, T stage, status of LNs, and differentiation (all P > 0.05). The SUVLN differed significantly between the pathological stages and status of LNs both on [18F]Alfatide PET/CT (P = 0.03, 0.003) and [18F]FDG PET/CT (P = 0.001. 0.05). The quantitated expression levels of αvβ3 in primary tumors and metastatic LNs were 1.67 ± 1.12 and 3.42 ± 2.93, respectively (P = 0.031). Our results suggest that SUVLN is influenced by pathological stage, LN status, and differentiation. SUVLN may therefore serve as a new parameter for risk stratification of with ESCC patients. Moreover, [18F]Alfatide PET can provide complementary molecular information about ESCC metastasis.