CAR-T cell therapy: Efficacy in management of cancers, adverse effects, dose-limiting toxicities and long-term follow up.

Chimeric Antigen Receptor T-cell (CAR-T) therapy has emerged as a groundbreaking and highly promising approach for the management of cancer. This paper reviews the efficacy of CAR-T therapy in the treatment of various hematological malignancies, also, with a mention of its effect on solid tumors, for which they have not received FDA approval yet. Different common and uncommon side effects are also discussed in this paper, with attention to the effect of each drug separately. By reviewing the recommendations of the FDA for CAR-T therapy research, we have extensively discussed dose-limiting toxicities. This further highlights the need for precise dosing strategies, striking a balance between therapeutic benefits and potential risks. Additionally, we reviewed the long-term follow-up of patients receiving CAR-T therapy to gain valuable insights into response durability and late-onset effects.

Comparative effects of epidural analgesia and intramuscular morphine on maternal and neonatal outcomes: a retrospective cohort study.

BACKGROUND: The global practice of pain management during labor involves the use of epidural analgesia or intramuscular morphine. However, the impact of these methods on maternal and neonatal short-term outcomes remains uncertain. OBJECTIVE: This study aimed to evaluate the effect of labor exposure to epidural analgesia and intramuscular morphine on neonatal intensive care unit admission rates and other associated maternal and neonatal outcomes such as sepsis, respiratory distress, instrumental delivery, birth trauma, low Apgar score, and chorioamnionitis. STUDY DESIGN: A study at the Women's Wellness and Research Center in Qatar analyzed 7721 low-risk normal vaginal deliveries from January 2017 to April 2018. Results were analyzed using descriptive and backward stepwise multinomial regression analysis, categorizing outcomes on the basis of pain management during active labor. RESULTS: Of the 7607 participants in the final sample, 2606 received epidural analgesia, 1338 received intramuscular morphine, 286 received both, and 3304 received neither. Multinomial regression analysis revealed no difference in neonatal intensive care unit admission in the epidural analgesia group or in the intramuscular morphine group compared with the group that received neither intervention. However, the analysis showed a significant association between the combined use of epidural analgesia and intramuscular morphine and neonatal intensive care unit admission due to respiratory depression (adjusted odds ratio, 8.63; 95% confidence interval, 1.07-69.46; P=.04). Moreover, there was a significant association between prolonged duration of the second stage of labor and receiving epidural analgesia alone (adjusted odds ratio, 1.02; 95% confidence interval, 1.01-1.02; P<.001) or the combination of epidural analgesia and intramuscular morphine (adjusted odds ratio, 1.02; 95% confidence interval, 1.01-1.03; P<.001). In addition, the combined use of epidural analgesia and intramuscular morphine was associated with gestational age (adjusted odds ratio, 1.86; 95% confidence interval, 1.19-2.90; P=.01) and infant sex (adjusted odds ratio, 3.72; 95% confidence interval, 1.54-9.01; P=.003). Intramuscular morphine alone was only linked to low Apgar score at 1 minute (adjusted odds ratio, 6.29; 95% confidence interval, 1.33-29.83; P=.02). CONCLUSION: In low-risk mothers, combining epidural analgesia and intramuscular morphine during labor increases NICU admission risk due to respiratory depression. However, the individual use of either method shows distinct clinical profile. Further research is warranted to enhance understanding and optimize pain management protocols.

Balanced crystalloids versus isotonic saline in pediatric sepsis: a comprehensive systematic review and meta-analysis.

Purpose: We conducted a comprehensive meta-analysis to compare the effects of balanced crystalloids (BC) and isotonic saline (IS) in pediatric sepsis. Methods: A systematic search was performed for studies comparing BC and IS in pediatric sepsis. Outcomes included mortality, acute kidney injury (AKI), need for renal replacement therapy (RRT), hospital length of stay (LOS), and pediatric intensive care unit (PICU) LOS. A random-effect models was used to calculated pooled odds ratios (OR) and mean differences (MD) with 95% confidence intervals (CIs). Results: The analysis included six studies with 8753 children. BC demonstrated significant reductions in overall mortality (OR 0.84, 95% CI 0.71 to 0.98, P = 0.03, I2 = 0%) and AKI (OR 0.74, 95% CI 0.57 to 0.96, P = 0.03, I2 = 37%) compared to IS. RRT need was similar between the BC and IS groups (OR 0.79, 95% CI 0.60 to 1.02, P = 0.07, I2 = 0%). Hospital and PICU LOS did not differ significantly. However, subgroup analysis of randomized controlled trials revealed significantly shorter hospital LOS in the BC group (mean difference -0.66 days, 95% CI -1.10 to -0.23, P = 0.003, I2 = 0%). Conclusion: Our meta-analysis demonstrates that using BC in pediatric sepsis is associated with reduced mortality, AKI, and hyperchloremia rates compared to IS, while maintaining similar hospital and PICU LOS. Large-scale randomized controlled trials are needed to validate these findings.

The Contemporary Role of Hematopoietic Stem Cell Transplantation in the Management of Chronic Myeloid Leukemia: Is It the Same in All Settings?

Hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) patients has transitioned from the standard of care to a treatment option limited to those with unsatisfactory tyrosine kinase inhibitor (TKI) responses and advanced disease stages. In recent years, the threshold for undergoing HSCT has increased. Most CML patients now have life expectancies comparable to the general population, and therefore, the goal of therapy is shifting toward achieving treatment-free remission (TFR). While TKI discontinuation trials in CML show potential for achieving TFR, relapse risk is high, affirming allogeneic HSCT as the sole curative treatment. HSCT should be incorporated into treatment algorithms from the time of diagnosis and, in some patients, evaluated as soon as possible. In this review, we will look at some of the recent advances in HSCT, as well as its indication in the era of aiming for TFR in the presence of TKIs in CML.

Male Fertility and Fatherhood in Chronic Myeloid Leukemia: Current Understanding and Future Perspectives.

Chronic myeloid leukemia (CML), while traditionally a disease of the elderly, has recently risen in incidence among younger patients. Hence, fertility concerns have emerged considering the disease process and treatments, especially with the current scarce and conflicting recommendations. This review explores the impact of CML treatments including the first-line tyrosine kinase inhibitors (TKIs) and other treatments on male fertility in chronic myeloid leukemia (CML) patients. The aim of this review was to compile the available evidence on male fertility to ultimately tailor treatment plans for male CML patients for whom fertility and future chances for conception pose a concern. The data available on the conventional and newer TKIs to address fertility concerns were reviewed, particularly the potential long- and short-term effects. Also, the possible side effects on subsequent generations were a crucial focus point of this review to reach a more comprehensive CML management approach. We found and compared the evidence on TKIs approved to treat CML. We also reported the effects of hydroxyurea, interferon, and transplantation, which are considered second-line treatments. Our findings suggest that these drugs might have an undiscovered effect on fertility. More research with larger sample sizes and longer follow-up periods is essential to solidify our understanding of these effects.

Phenotypic switching of vascular smooth muscle cells in atherosclerosis, hypertension, and aortic dissection.

Vascular smooth muscle cells (VSMCs) play a critical role in regulating vasotone, and their phenotypic plasticity is a key contributor to the pathogenesis of various vascular diseases. Two main VSMC phenotypes have been well described: contractile and synthetic. Contractile VSMCs are typically found in the tunica media of the vessel wall, and are responsible for regulating vascular tone and diameter. Synthetic VSMCs, on the other hand, are typically found in the tunica intima and adventitia, and are involved in vascular repair and remodeling. Switching between contractile and synthetic phenotypes occurs in response to various insults and stimuli, such as injury or inflammation, and this allows VSMCs to adapt to changing environmental cues and regulate vascular tone, growth, and repair. Furthermore, VSMCs can also switch to osteoblast-like and chondrocyte-like cell phenotypes, which may contribute to vascular calcification and other pathological processes like the formation of atherosclerotic plaques. This provides discusses the mechanisms that regulate VSMC phenotypic switching and its role in the development of vascular diseases. A better understanding of these processes is essential for the development of effective diagnostic and therapeutic strategies.

An Overview of the Immune Modulatory Properties of Long Non-Coding RNAs and Their Potential Use as Therapeutic Targets in Cancer.

Long non-coding RNAs (lncRNAs) play pivotal roles in regulating immune responses, immune cell differentiation, activation, and inflammatory processes. In cancer, they are gaining prominence as potential therapeutic targets due to their ability to regulate immune checkpoint molecules and immune-related factors, suggesting avenues for bolstering anti-tumor immune responses. Here, we explore the mechanistic insights into lncRNA-mediated immune modulation, highlighting their impact on immunity. Additionally, we discuss their potential to enhance cancer immunotherapy, augmenting the effectiveness of immune checkpoint inhibitors and adoptive T cell therapies. LncRNAs as therapeutic targets hold the promise of revolutionizing cancer treatments, inspiring further research in this field with substantial clinical implications.

Symptom burden, fatigue, sleep quality and perceived social support in hemodialysis patients with musculoskeletal discomfort: a single center experience from Egypt.

BACKGROUND AND AIMS: Musculoskeletal disorders (MSDs) are commonly encountered in hemodialysis (HD) patients. However, the causes linked to these disorders are still partially defined. The aim of this study was to determine the frequency of MSDs and their relationship to a variety of clinico-social characteristics such as sleep quality, mood disorders, fatigue, and social support, in addition to the patients' clinical and therapeutic profile. METHOD: The study included 94 patients on maintenance HD. Clinical and Sociodemographic data was gathered. To investigate the prevalence and trends of MSDs, the Nordic Musculoskeletal Questionnaire (NMQ-E) was employed. Patients completed the modified Edmonton Symptom Assessment System, Pittsburgh Sleep Quality Index (PSQI), multidimensional Fatigue Inventory (MFI-20), and Perceived Social Support from Family Scales. Univariate and multivariate regression analysis were used to assess the determinants of MSDs. RESULTS: The patients' mean age was 49.73 and 59.6% were males. Seventy-two percent of patients were afflicted by MSDs. Knee pain (48.9%), low back pain (43.6%), shoulder pain (41.6%), hip/thigh pain (35.1%), and neck pains (35.1%) were the most reported MSD domains. Pain (p = 0.001), fatigue (p = 0.01), depression (p = 0.015), and anxiety (p = 0.003) scores were substantially higher in patients with MSDs. Furthermore, patients with MSDs engaged in less physical activity (p = 0.02) and perceived less social support (p = 0.029). Patients with MSDs had lower subjective sleep quality, daytime dysfunction domains, and global PSQI scores (p = 0.02, 0.031, 0.036, respectively). Female gender (p = 0.013), fatigue (p = 0.012), depression (p = 0.014), anxiety (p = 0.004), lower activity (p = 0.029), and PSQI score (0.027), use of erythropoiesis-stimulating agents (ESAs), antihypertensive drugs, calcium and Iron supplementation were all significantly associated with MSDs. At the multivariable regression model, administration of ESAs (p = 0.017) and pain score (p = 0.040) were the only independent variables associated with the outcome. CONCLUSION: MSDs are quite common among HD patients. Female gender, pain, fatigue, depression, anxiety, reduced activity, poor sleep quality, and use of ESAs are all significantly associated with MSDs in HD patients. Patients with MSD perceived less social support compared to the other group. Patients treated with antihypertensive drugs, calcium and iron supplements were more likely to suffer MSDs.

Progression of diabetic nephropathy and vitamin D serum levels: A pooled analysis of 7722 patients.

BACKGROUND AND AIM: Low serum Vitamin D levels have been associated with diabetic nephropathy (DN). Our study aimed to analyse the serum levels of vitamin D in patients suffering from DN and the subsequent changes in serum vitamin D levels as the disease progresses. METHODS: PubMed, Embase, SCOPUS and Web of Science were searched using keywords such as '25 hydroxyvitamin D' and 'diabetic nephropathy'. We included observational studies that reported the association between the serum 25 hydroxy vitamin D levels and diabetic nephropathy without restriction to age, gender, and location. R Version 4.1.2 was used to perform the meta-analysis. The continuous outcomes were represented as mean difference (MD) and standard deviation (SD) and dichotomous outcomes as risk ratios (RR) with their 95% confidence interval (CI). RESULTS: Twenty-three studies were included in our analysis with 7722 patients. Our analysis revealed that vitamin D was significantly lower in diabetic patients with nephropathy than those without nephropathy (MD: -4.32, 95% CI: 7.91-0.74, p-value = .0228). On comparing diabetic patients suffering from normoalbuminuria, microalbuminuria, or macroalbuminuria, we found a significant difference in serum vitamin D levels across different groups. Normoalbuminuria versus microalbuminuria showed a MD of -1.69 (95% CI: -2.28 to -1.10, p-value = .0002), while microalbuminuria versus macroalbuminuria showed a MD of (3.75, 95% CI: 1.43-6.06, p-value = .0058), proving that serum vitamin D levels keep declining as the disease progresses. Notwithstanding, we detected an insignificant association between Grade 4 and Grade 5 DN (MD: 2.29, 95% CI: -2.69-7.28, p-value = .1862). CONCLUSION: Serum Vitamin D levels are lower among DN patients and keep declining as the disease progresses, suggesting its potential benefit as a prognostic marker. However, on reaching the macroalbuminuria stage (Grades 4 and 5), vitamin D is no longer a discriminating factor.

Recurrent asymptomatic large pleural effusion due to endometriosis. A case report.

Pleural endometriosis is a rare manifestation of endometriosis that usually presents with catamenial symptoms, with or without complications. Here, we present a case of incidentally discovered pleural involvement of endometriosis in an asymptomatic young female. Pleurocentesis revealed bloody exudative pleural effusion with lymphocytic predominance. Thoracoscopy revealed inflamed parietal pleura, and the biopsy confirmed endometriotic involvement.

Comparative efficacy and safety of PD-1/PD-L1 inhibitors in triple negative breast cancer: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Triple-Negative Breast Cancer (TNBC) is a lethal subtype of breast cancer with limited treatment options. The purpose of this Network Meta-Analysis (NMA) is to compare the efficacy and safety of inhibitors of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in treating TNBC. METHODS: Our search strategy was used in six databases: PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature database, Embase, Scopus, and Web of Science up to November 2nd, 2022, as well as a thorough search in the most used trial registries. We included phase II and III randomized controlled trials that looked at the efficacy of PD-1/PD-L1 inhibitors in the treatment of TNBC and reported either Overall Survival (OS), Progression-Free Survival (PFS), or pathological Complete Response (pCR). The risk of bias was assessed utilizing Cochrane's risk of bias 2 tool, and the statistical analysis was performed using a frequentist contrast-based method for NMA by employing standard pairwise meta-analysis applying random effects model. RESULTS: 12 trials (5324 patients) were included in our NMA including seven phase III trials. Pembrolizumab in a neoadjuvant setting achieved a pooled OS of 0.82 (95% Confidence Interval (CI) 0.65 to 1.03), a PFS of 0.82 (95% CI 0.71 to 0.94) and a pCR 2.79 (95% CI 1.07 to 7.24) compared to Atezolizumab's OS of 0.92 (95% CI 0.74 to 1.15), PFS of 0.82 (95% CI 0.69 to 0.97), and pCR of 1.94 (95% CI 0.86 to 4.37). Atezolizumab had less grade ≥ 3 adverse events (OR 1.48, 95% CI 0.90 to 2.42) than Pembrolizumab (OR 1.90, 95% CI 1.08 to 3.33) in the neoadjuvant setting. CONCLUSIONS: PD-1/PD-L1 inhibitors exhibited varying efficacy in terms of OS, PFS, and pCR. They were associated with an increase in immune-related adverse effects. When used early in the course of TNBC, PD-1/PD-L1 inhibitors exert their maximum benefit. Durvalumab as a maintenance treatment instead of chemotherapy has shown promising outcomes. Future studies should focus on PD-L1 expression status and TNBC subtypes, since these factors may contribute to the design of individualized TNBC therapy regimens. Systematic review registration PROSPERO Identifier: CRD42022380712.

The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.

Intrachromosomal amplification of chromosome 21 defines a subtype of high-risk childhood acute lymphoblastic leukemia (iAMP21-ALL) characterized by copy number changes and complex rearrangements of chromosome 21. The genomic basis of iAMP21-ALL and the pathogenic role of the region of amplification of chromosome 21 to leukemogenesis remains incompletely understood. In this study, using integrated whole genome and transcriptome sequencing of 124 patients with iAMP21-ALL, including rare cases arising in the context of constitutional chromosomal aberrations, we identified subgroups of iAMP21-ALL based on the patterns of copy number alteration and structural variation. This large data set enabled formal delineation of a 7.8 Mb common region of amplification harboring 71 genes, 43 of which were differentially expressed compared with non-iAMP21-ALL ones, including multiple genes implicated in the pathogenesis of acute leukemia (CHAF1B, DYRK1A, ERG, HMGN1, and RUNX1). Using multimodal single-cell genomic profiling, including single-cell whole genome sequencing of 2 cases, we documented clonal heterogeneity and genomic evolution, demonstrating that the acquisition of the iAMP21 chromosome is an early event that may undergo progressive amplification during disease ontogeny. We show that UV-mutational signatures and high mutation load are characteristic secondary genetic features. Although the genomic alterations of chromosome 21 are variable, these integrated genomic analyses and demonstration of an extended common minimal region of amplification broaden the definition of iAMP21-ALL for more precise diagnosis using cytogenetic or genomic methods to inform clinical management.

Anxiety and depression in maintenance hemodialysis patients: prevalence and their effects on health-related quality of life.

PURPOSE: The aims of the study are to explore the prevalence and risk factors of anxiety and depression in hemodialysis (HD) patients and to study their relationship with quality of life (QOL). METHODS: This cross-sectional study involved 298 HD patients. Sociodemographic, clinical, and laboratory data of the patients were obtained from their records. Anxiety and depression were assessed by utilizing Hospital Anxiety and Depression Scale (HADS). In addition, QOL of the patients were evaluated by fulfilling the Kidney Disease Quality of Life-36. RESULTS: This study included 298 HD patients (male 59.1%) with a median age of 49 years. Abnormal and borderline cases of anxiety were recognized in 49.6%, 26.2% of the patients, respectively, while depression cases and borderline cases were identified in 55 and 28.2% of the patients, respectively. Percentages of females (41 and 48% vs 26.4%, respectively), and patients who were not working (92.3 and 93.9% vs 72.2%, respectively) increased significantly in borderline and abnormal anxiety groups. Patients who did not work, led an inactive lifestyle, and smoked had considerably greater percentages in the borderline and abnormal HADS-depression categories than normal patients. Abnormal cases of depression and anxiety had significantly longer duration of HD than other two groups. Abnormal and borderline cases of anxiety and depression had worse QOL components than the normal patients. CONCLUSION: Anxiety and depression are prevalent among HD patients in Egypt, and several sociodemographic and clinical risk factors are associated. In addition, these mental disorders are associated with poor QOL.

Statistical Methods Inspired by Challenges in Pediatric Cancer Multi-omics.

Pediatric cancer multi-omics is a uniquely rewarding and challenging domain of biomedical research. Public generosity bestows an abundance of resources for the study of extremely rare diseases; this unique dynamic creates a research environment in which problems with high-dimension and low sample size are commonplace. Here, we present a few statistical methods that we have developed for our research setting and believe will prove valuable in other biomedical research settings as well. The genomic random interval (GRIN) method evaluates the loci and frequency of genomic abnormalities in the DNA of tumors to identify genes that may drive the development of malignancies. The association of lesions with expression (ALEX) method evaluates the impact of genomic abnormalities on the RNA transcription of nearby genes to inform the formulation of biological hypotheses on molecular mechanisms. The projection onto the most interesting statistical evidence (PROMISE) method identifies omic features that consistently associate with better prognosis or consistently associate with worse prognosis across multiple measures of clinical outcome. We have shown that these methods are statistically robust and powerful in the statistical bioinformatic literature and successfully used these methods to make fundamental biological discoveries that have formed the scientific rationale for ongoing clinical trials. We describe these methods and illustrate their application on a publicly available T-cell acute lymphoblastic leukemia (T-ALL) data set. A companion github site ( https://github.com/stjude/TALL-example ) provides the R code and data necessary to recapitulate the example data analyses of this chapter.

Stephanion to cranial base penetrating stab wound with outstanding recovery: A case report.

Background: Mortality due to head trauma is common in developed countries in all age groups. Nonmissile penetrating skull base injuries (PSBIs) due to foreign bodies are quite rare, accounting for about 0.4%. PSBI carries that a poor prognosis brainstem involvement usually is often fatal. We are reporting the first case of PSBI with a foreign body insertion site through the stephanion with a remarkable outcome. Case Description: The 38-year-old male patient was referred with a penetrating stab wound to the head through the stephanion caused by a knife after a conflict in the street. He had no focal neurological deficit or cerebrospinal fluid leak, and Glasgow coma scale (GCS) was 15/15 on admission. A preoperative computed tomography scan showed the path of the stab beginning at the stephanion, which is the point where the coronal suture crosses the superior temporal line, heading toward the cranial base. Postoperatively, GCS was 15/15 without any deficit apart from the left wrist drop, possibly due to a left arm stab. Conclusion: Careful investigations and diagnoses must be made to ensure convenient knowledge of the case due to the variety of injury mechanisms, foreign body characteristics, and individual patients' characteristics. Reported cases of PSBIs in adults have not reported a stephanion skull base injury. Although brain stem involvement is usually fatal, our patient had a remarkable outcome.

Polygenic Pharmacogenomic Markers as Predictors of Toxicity Phenotypes in the Treatment of Acute Lymphoblastic Leukemia: A Single-Center Study.

PURPOSE: Acute lymphoblastic leukemia (ALL) is the most prevalent cause of childhood cancer and requires a long course of therapy consisting of three primary phases with interval intensification blocks. Although these phases are necessary to achieve remission, the primary chemotherapeutic agents have potentially serious toxicities, which may lead to delays or discontinuations of therapy. The purpose of this study was to perform a comprehensive pharmacogenomic evaluation of common antileukemic agents and develop a polygenic toxicity risk score predictive of the most common toxicities observed during ALL treatment. METHODS: This cross-sectional study included 75 patients with pediatric ALL treated between 2012 and 2020 at the University of Florida. Toxicity data were collected within 100 days of initiation of therapy using CTCAE v4.0 for toxicity grading. For pharmacogenomic evaluation, single-nucleotide polymorphisms (SNPs) and genes were selected from previous reports or PharmGKB database. 116 unique SNPs were evaluated for incidence of various toxicities. A multivariable multi-SNP modeling for up to 3-SNP combination was performed to develop a polygenic toxicity risk score of prognostic value. RESULTS: We identified several SNPs predictive of toxicity phenotypes in univariate analysis. Further multivariable SNP-SNP combination analysis suggest that susceptibility to chemotherapy-induced toxicities is likely multigenic in nature. For 3-SNPscore models, patients with high scores experienced increased risk of GI (P = 2.07E-05, 3 SNPs: TYMS-rs151264360/FPGS-rs1544105/GSTM1-GSTM5-rs3754446), neurologic (P = .0005, 3 SNPs: DCTD-rs6829021/SLC28A3-rs17343066/CTPS1-rs12067645), endocrine (P = 4.77E-08, 3 SNPs: AKR1C3-rs1937840/TYMS-rs2853539/CTH-rs648743), and heme toxicities (P = .053, 3 SNPs: CYP3A5-rs776746/ABCB1-rs4148737/CTPS1-rs12067645). CONCLUSION: Our results imply that instead of a single-SNP approach, SNP-SNP combinations in multiple genes in drug pathways increases the robustness of prediction of toxicity. These results further provide promising SNP models that can help establish clinically relevant biomarkers allowing for greater individualization of cancer therapy to maximize efficacy and minimize toxicity for each patient.

SAMHD1 single nucleotide polymorphisms impact outcome in children with newly diagnosed acute myeloid leukemia.

Cytarabine arabinoside (Ara-C) has been the cornerstone of acute myeloid leukemia (AML) chemotherapy for decades. After cellular uptake, it is phosphorylated into its active triphosphate form (Ara-CTP), which primarily exerts its cytotoxic effects by inhibiting DNA synthesis in proliferating cells. Interpatient variation in the enzymes involved in the Ara-C metabolic pathway has been shown to affect intracellular abundance of Ara-CTP and, thus, its therapeutic benefit. Recently, SAMHD1 (SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1) has emerged to play a role in Ara-CTP inactivation, development of drug resistance, and, consequently, clinical response in AML. Despite this, the impact of genetic variations in SAMHD1 on outcome in AML has not been investigated in depth. In this study, we evaluated 25 single nucleotide polymorphisms (SNPs) within the SAMHD1 gene for association with clinical outcome in 400 pediatric patients with newly diagnosed AML from 2 clinical trials, AML02 and AML08. Three SNPs, rs1291128, rs1291141, and rs7265241 located in the 3' region of SAMHD1 were significantly associated with at least 1 clinical outcome: minimal residual disease after induction I, event-free survival (EFS), or overall survival (OS) in the 2 cohorts. In an independent cohort of patients from the COG-AAML1031 trial (n = 854), rs7265241 A>G remained significantly associated with EFS and OS. In multivariable analysis, all the SNPs remained independent predictors of clinical outcome. These results highlight the relevance of the SAMHD1 pharmacogenomics in context of response to Ara-C in AML and warrants the need for further validation in expanded patient cohorts.

Genome-wide CRISPR/Cas9 screen identifies etoposide response modulators associated with clinical outcomes in pediatric AML.

Etoposide is used to treat a wide range of malignant cancers, including acute myeloid leukemia (AML) in children. Despite the use of intensive chemotherapeutic regimens containing etoposide, a significant proportion of pediatric patients with AML become resistant to treatment and relapse, leading to poor survival. This poses a pressing clinical challenge to identify mechanisms underlying drug resistance to enable effective pharmacologic targeting. We performed a genome-wide CRISPR/Cas9 synthetic-lethal screening to identify functional modulators of etoposide response in leukemic cell line and integrated results from CRISPR-screen with gene expression and clinical outcomes in pediatric patients with AML treated with etoposide-containing regimen. Our results confirmed the involvement of well-characterized genes, including TOP2A and ABCC1, as well as identified novel genes such as RAD54L2, PRKDC, and ZNF451 that have potential to be novel drug targets. This study demonstrates the ability for leveraging CRISPR/Cas9 screening in conjunction with clinically relevant endpoints to make meaningful discoveries for the identification of prognostic biomarkers and novel therapeutic targets to overcome treatment resistance.

The genomic landscape of pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Here, using whole-genome, exome and transcriptome sequencing of 2,754 childhood patients with ALL, we find that, despite a generally low mutation burden, ALL cases harbor a median of four putative somatic driver alterations per sample, with 376 putative driver genes identified varying in prevalence across ALL subtypes. Most samples harbor at least one rare gene alteration, including 70 putative cancer driver genes associated with ubiquitination, SUMOylation, noncoding transcripts and other functions. In hyperdiploid B-ALL, chromosomal gains are acquired early and synchronously before ultraviolet-induced mutation. By contrast, ultraviolet-induced mutations precede chromosomal gains in B-ALL cases with intrachromosomal amplification of chromosome 21. We also demonstrate the prognostic significance of genetic alterations within subtypes. Intriguingly, DUX4- and KMT2A-rearranged subtypes separate into CEBPA/FLT3- or NFATC4-expressing subgroups with potential clinical implications. Together, these results deepen understanding of the ALL genomic landscape and associated outcomes.

A ten-gene DNA-damage response pathway gene expression signature predicts gemtuzumab ozogamicin response in pediatric AML patients treated on COGAAML0531 and AAML03P1 trials.

Gemtuzumab ozogamicin (GO) is an anti-CD33 monoclonal antibody linked to calicheamicin, a DNA damaging agent, and is a well-established therapeutic for treating acute myeloid leukemia (AML). In this study, we used LASSO regression modeling to develop a 10-gene DNA damage response gene expression score (CalDDR-GEx10) predictive of clinical outcome in pediatric AML patients treated with treatment regimen containing GO from the AAML03P1 and AAML0531 trials (ADE + GO arm, N = 301). When treated with ADE + GO, patients with a high CalDDR-GEx10 score had lower complete remission rates (62.8% vs. 85.5%, P = 1.7 7 * 10-5) and worse event-free survival (28.7% vs. 56.5% P = 4.08 * 10-8) compared to those with a low CalDDR-GEx10 score. However, the CalDDR-GEx10 score was not associated with clinical outcome in patients treated with standard chemotherapy alone (ADE, N = 242), implying the specificity of the CalDDR-GEx10 score to calicheamicin-induced DNA damage response. In multivariable models adjusted for risk group, FLT3-status, white blood cell count, and age, the CalDDR-GEx10 score remained a significant predictor of outcome in patients treated with ADE + GO. Our findings present a potential tool that can specifically assess response to calicheamicin-induced DNA damage preemptively via assessing diagnostic leukemic cell gene expression and guide clinical decisions related to treatment using GO.