Impact of T-cell immunity on chemotherapy response in childhood acute lymphoblastic leukemia.

Although acute lymphoblastic leukemia (ALL) is highly responsive to chemotherapy, it is unknown how or which host immune factors influence the long-term remission of this cancer. To this end, we systematically evaluated the effects of T-cell immunity on Ph+ ALL therapy outcomes. Using a murine Arf-/-BCR-ABL1 B-cell ALL model, we showed that loss of T cells in the host drastically increased leukemia relapse after dasatinib or cytotoxic chemotherapy. Although ABL1 mutations emerged early during dasatinib treatment in both immunocompetent and immunocompromised hosts, T-cell immunity was essential for suppressing the outgrowth of drug-resistant leukemia. Bulk and single-cell transcriptome profiling of T cells during therapy pointed to the activation of type 1 immunity-related cytokine signaling being linked to long-term leukemia remission in mice. Consistent with these observations, interferon γ and interleukin 12 directly modulated dasatinib antileukemia efficacy in vivo. Finally, we evaluated peripheral blood immune cell composition in 102 children with ALL during chemotherapy and observed a significant association of T-cell abundance with treatment outcomes. Together, these results suggest that T-cell immunity plays pivotal roles in maintaining long-term remission of ALL, highlighting that the interplay between host immunity and drug resistance can be harnessed to improve ALL chemotherapy outcomes.

Comparing the resource implications of old and new colorectal adenoma surveillance guidelines in Australia.

BACKGROUND: The latest update to the Australian adenoma surveillance guideline in 2018 introduced a novel risk stratification system with updated surveillance recommendations. The resource implications of adopting this new system are unclear. AIMS: To quanitfy the resource demands of adopting new over old adenoma surveillance guidelines. METHODS: We studied data from 2443 patients undergoing colonoscopies, in which a clinically significant lesion was identified in their latest, or previous procedure(s) across five Australian hospitals. We excluded procedures with inflammatory bowel disease, new or prior history of colorectal cancer or resection, inadequate bowel preparation and incomplete procedures. Old and new Australian surveillance intervals were calculated according to the number, size and histological characteristics of lesions identified. We used these data to compare the rate of procedures according to each guideline. RESULTS: Based on the procedures for 766 patients, the new surveillance guidelines significantly increased the number of procedures allocated an interval of 1 year (relative risk (RR): 1.57, P = 0.009) and 10 years (RR: 3.83, P < 0.00001) and reduced those allocated to half a year (RR: 0.08, P = 0.00219), 3 years (RR: 0.51, P < 0.00001) and 5 years (RR: 0.59, P < 0.00001). Overall, this reduced the relative number of surveillance procedures by 21% over 10 years (25.92 vs 32.78 procedures/100 patient-years), which increased to 22% after excluding patients 75 or older at the time of surveillance (19.9 vs 25.65 procedures/100 patient-years). CONCLUSION: The adoption of the latest Australian adenoma surveillance guidelines can reduce demand for surveillance colonoscopy by more than a fifth (21-22%) over 10 years.

Nanoparticles as Drug Delivery Systems for the Targeted Treatment of Atherosclerosis.

Atherosclerosis continues to be a leading cause of morbidity and mortality globally. The precise evaluation of the extent of an atherosclerotic plaque is essential for forecasting its likelihood of causing health concerns and tracking treatment outcomes. When compared to conventional methods used, nanoparticles offer clear benefits and excellent development opportunities for the detection and characterisation of susceptible atherosclerotic plaques. In this review, we analyse the recent advancements of nanoparticles as theranostics in the management of atherosclerosis, with an emphasis on applications in drug delivery. Furthermore, the main issues that must be resolved in order to advance clinical utility and future developments of NP research are discussed. It is anticipated that medical NPs will develop into complex and advanced next-generation nanobotics that can carry out a variety of functions in the bloodstream.

Prognostic Factors Associated With Extubation Failure in Acutely Brain-Injured Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: Extubation failure in brain-injured patients is associated with increased morbidity. Our objective was to systematically review prognostic factors associated with extubation failure in acutely brain-injured adult patients receiving invasive ventilation in an ICU. DATA SOURCES: MEDLINE, Embase, and Cochrane Central were searched from inception to January 31, 2022. STUDY SELECTION: Two reviewers independently screened citations and selected English-language cohort studies and randomized trials examining the association of prognostic factors with extubation failure. Studies were considered if they included greater than or equal to 80% adult patients with acute brain injury admitted to the ICU and mechanically ventilated for greater than or equal to 24 hours. DATA EXTRACTION: Two reviewers extracted data on population, prognostic factors, extubation outcomes, and risk of bias (using the quality in prognostic factors tool). DATA SYNTHESIS: In the primary analysis, adjusted odds ratios (aOR) for each prognostic factor were pooled using random-effects models. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. The search identified 7,626 citations, of which 21 studies met selection criteria. Moderate-certainty evidence suggested increased risk of extubation failure with older age (aOR, 3.0 for upper vs lower tertile; 95% CI, 1.78-5.07) and longer duration of mechanical ventilation (aOR, 3.47 for upper vs lower tertile; 95% CI, 1.68-7.19). Presence of cough (aOR, 0.40; 95% CI, 0.28-0.57) and intact swallow (aOR, 0.34; 95% CI, 0.21-0.54) probably decreased risk of extubation failure (moderate certainty). Associations of other factors with extubation failure were informed by low or very low certainty evidence. CONCLUSIONS: Patient age, duration of mechanical ventilation, and airway reflexes were associated with extubation failure in brain-injured patients with moderate certainty. Future studies are needed to determine the optimal application of these variables in clinical practice.

Are we underutilising computer tomography colonography in Australia?

Computed tomography colonography (CTC) is a safe and accurate tool for colorectal cancer (CRC) screening in both symptomatic and asymptomatic patients. CTC requires dedicated radiological expertise and demonstrates a high sensitivity and specificity in polyp detection, which is similar to optical colonoscopy (OC). Newer preparation techniques for CTC, such as faecal tagging without catharsis might further improve both the tolerability and accuracy of the test. While exposure to ionising radiation, lack of capacity for therapeutic intervention and potentially diminished sensitivity for flat serrated polyps are limitations of CTC, the technique has a role in select populations. CTC should be considered in frail or elderly patients at high anaesthetic risk for OC, patients with stricturing colonic lesions as well as incomplete colonoscopy, or in patients at risk of delayed access to timely OC. With an ever-growing demand for endoscopic services, increased utilisation of CTC could reduce waiting times for colonoscopy, thereby broadening access to timely and effective CRC screening. Further research is required to improve further the detection of flat lesions, including sessile serrated polyps.

Impact of food challenge on local oesophageal immunophenotype in eosinophilic oesophagitis.

BACKGROUND: Eosinophilic oesophagitis (EoE) is caused by the ingestion of food antigens. Dietary avoidance can result in clinical and histological remission, while food reintroduction can cause recurrence. It is uncertain if food antigen processing and immune activation occurs locally, in the oesophagus. Therefore, we performed a comparative study of the density of cell surface proteins (known to be involved with antigen presentation) on oesophageal tissue prior to, and following food antigen induced disease recurrence. A secondary aim was to consider novel biomarkers. METHOD: Adult patients with a diagnosis of EoE, who had achieved histological remission with an elimination diet (<15 eosinophils per high power field at oesophageal biopsy), and who underwent food challenge with proven recurrence were included. Immunohistochemistry/immunofluorescence for CD1a, CD3, CD28, CD40, CD69, CD80, CD138, CXCR3 and HLA-DR was performed. Staining intensity of each biomarker (pixels/mm2 ) was quantified by semi-automated analysis (Studio-FL software). RESULTS: Fourteen cases of EoE (pre and post food challenge), 6 GORD and 5 healthy controls were included. HLA-DR, CD3, CD28, CD40 and CD 138 significantly increased with food reintroduction (P = <0.05). CD1a, CD 69, CD 80 and CXCR3 did not measurably change. CONCLUSION: The presence of cell surface proteins typically associated with antigen presentation (following food antigen induced recurrence) suggests immune activation occurs in the oesophagus, and the relative lack of langerhans cells (CD1a) may indicate this cell type is unimportant. The cell surface protein CD 138 increases with disease recurrence, is not elevated in GORD or healthy controls, and has promise as a biomarker.

Epidemiology of childhood malignant mediastinal masses and clinical factors associated with intensive care unit admission: A Singapore experience.

AIM: Majority of mediastinal masses in children are malignant. These masses are complex to manage as they have a risk of compression to surrounding structures. Many of these children have to be managed in the intensive care unit (ICU). Hence we sought to evaluate the local epidemiology of malignant mediastinal masses in children and their clinical presentation, and identified factors associated with ICU admission so that at-risk patients may be identified early. METHODS: This study is a retrospective review of institutional case records of 56 children below 18 years of age from 2000 to 2015 with a malignant mediastinal mass. We collected data on their presenting symptoms, clinical signs, radiological investigations, treatment and correlated these factors with admission to our ICU. RESULTS: Lymphoma was most common diagnosis, comprising 37 children (66.0%). There were 6 patients with neuroblastoma (10.7%), 3 patients with germ-cell tumour (5.4%) and 10 patients with T-cell acute lymphoblastic leukaemia (17.9%). Overall, 21 patients (37.5%) had to be admitted to the ICU. Almost all patients (98.2%) were symptomatic on presentation, of which lymphadenopathy was the most common (69.6%). Factors that are significantly associated with ICU admission are stridor, pericardial effusion and need for pleural drainage. CONCLUSIONS: Malignant mediastinal masses in children in our institution range from leukaemias and lymphomas to germ cell tumours and neuroblastomas, of which almost all are symptomatic. These children have a risk of cardiorespiratory collapse and many of them require intensive care. We identified factors that are associated with ICU admission, with the aim of early intervention of at-risk cases.

Emergency medical dispatch services across Pan-Asian countries: a web-based survey.

BACKGROUND: Dispatch services (DS's) form an integral part of emergency medical service (EMS) systems. The role of a dispatcher has also evolved into a crucial link in patient care delivery, particularly in dispatcher assisted cardio-pulmonary resuscitation (DACPR) during out-of-hospital cardiac arrest (OHCA). Yet, there has been a paucity of research into the emerging area of dispatch science in Asia. This paper compares the characteristics of DS's, and state of implementation of DACPR within the Pan-Asian Resuscitation Outcomes (PAROS) network. METHODS: A cross-sectional descriptive survey addressing population characteristics, DS structures and levels of service, state of DACPR implementation (including protocols and quality improvement programs) among PAROS DS's. RESULTS: 9 DS's responded, representing a total of 23 dispatch centres from 9 countries that serve over 80 million people. Most PAROS DS's operate a tiered dispatch response, have implemented medical oversight, and tend to be staffed by dispatchers with a predominantly medical background. Almost all PAROS DS's have begun tracking key EMS indicators. 77.8% (n = 7) of PAROS DS's have introduced DACPR. Of the DS's that have rolled out DACPR, 71.4% (n = 5) provided instructions in over one language. All DS's that implemented DACPR and provided feedback to dispatchers offered feedback on missed OHCA recognition. The majority of DS's (83.3%; n = 5) that offered DACPR and provided feedback to dispatchers also implemented corrective feedback, while 66.7% (n = 4) offered positive feedback. Compression-only CPR was the standard instruction for PAROS DS's. OHCA recognition sensitivity varied widely in PAROS DS's, ranging from 32.6% (95% CI: 29.9-35.5%) to 79.2% (95% CI: 72.9-84.4%). Median time to first compression ranged from 120 s to 220 s. CONCLUSIONS: We found notable variations in characteristics and state of DACPR implementation between PAROS DS's. These findings will lay the groundwork for future DS and DACPR studies in the PAROS network.

The Role of Natural Killer Cells as a Platform for Immunotherapy in Pediatric Cancers.

PURPOSE OF REVIEW: We aim to review the most recent findings in the use of NK cells in childhood cancers. RECENT FINDINGS: Natural killer cells are cytotoxic to tumor cells. In pediatric leukemias, adoptive transfer of NK cells can bridge children not in remission to transplant. Interleukins (IL2, IL15) can enhance NK cell function. NK cell-CAR therapy has advantages of shorter life span that lessens chronic toxicities, lower risk of graft versus host disease when using allogeneic cells, ability of NK cells to recognize tumor cells that have downregulated MHC to escape T cells, and possibly less likelihood of cytokine storm. Cytotoxicity to solid tumors (rhabdomyosarcoma, Ewing's sarcoma, neuroblastoma) is seen with graft versus tumor effect in transplant and in combination with antibodies. Challenges lie in the microenvironment which is suppressive for NK cells. NK cell immunotherapy in childhood cancers is promising and recent works aim to overcome challenges.

An Unrecognized Rash Progressing to Lyme Carditis: Important Features and Recommendations Regarding Lyme Disease.

We present a case report of 46-year-old man with no medical history, who complained of extreme fatigue, near-syncope, and palpitations. He initially presented in complete heart block. A transvenous pacemaker was placed in the emergency department, and he was started empirically on Ceftriaxone for Lyme disease. He was admitted and over the course of the next few days, his rhythm regressed to Mobitz type I first-degree atrioventricular block and then to normal sinus rhythm. This case report highlights some important features regarding Lyme carditis, a rare presentation of early disseminated Lyme disease (seen in a few weeks to months after the initial tick bite). In 25%-30% of patients, the characteristic targetoid rash may not be seen, a likely culprit of the disease not being detected early and progressing to disseminated disease. The most common cardiac complaint of Lyme disease is palpitations, occurring in 6.6% of patients, which may not accurately reflect progression into disseminated Lyme disease because it is a nonspecific finding. Conduction abnormality, occurring in 1.8% of patients, is a more specific finding of Borrelia invading cardiac tissue. Finally, this case report highlights a recommendation that patients with confirmed Lyme disease or those presenting with cardiac abnormalities or symptoms who have an atypical profile for a cardiac event should be screened with a 12-lead electrocardiogram, Lyme serology, and be considered for antibiotic therapy with the possibility of temporary pacing.

Approach to preventive care in the elderly.

OBJECTIVE: To guide family physicians in creating preventive screening and treatment plans for their elderly patients. SOURCES OF INFORMATION: The MEDLINE database was searched for Canadian guidelines on primary health care and the elderly; guidelines or meta-analyses or practice guidelines or systematic reviews related to mass screening in those aged 80 and older and the frail elderly, limited to between 2006 and July 2016; and articles on preventive health services for the elderly related to family practice or family physicians, limited to English-language publications between 2012 and July 2016. MAIN MESSAGE: Estimating life expectancy is not an easy or precise science, but frailty is an emerging concept that can help with this. The Canadian Task Force on Preventive Health Care offers cancer screening guidelines, but they are less clear for patients older than 74 years and management plans need to be individualized. Estimating remaining years of life helps guide your recommendations for preventive screening and treatment plans. Risks often increase along with an increase in frailty and comorbidity. Conversely, benefits often diminish as life expectancy decreases. Preventive management plans should take into account the patient's perspective and be mutually agreed upon. A mnemonic device for key primary care preventive areas-CCFP, short for cancer, cardiovascular disease, falls and osteoporosis, and preventive immunizations-might be useful. CONCLUSION: Family physicians might find addressing the following areas helpful when considering a preventive health intervention: age, life expectancy (including concept of frailty), comorbidities and functional status, risks and benefits of screening or treatment, and values and preferences of the patient.

[Aborder les soins préventifs chez les aînés].

OBJECTIF: Guider les médecins de famille dans l'élaboration de plans de dépistage et de traitements préventifs à l'intention de leurs patients âgés. SOURCES DE L'INFORMATION: Une recension a été effectuée dans la base de données MEDLINE pour trouver des lignes directrices canadiennes sur les soins de santé primaires et les personnes âgées; des lignes directrices, des méta-analyses, des guides de pratique clinique ou des révisions systématiques portant sur le dépistage de masse chez les 80 ans et plus et les aînés fragiles, se limitant à ceux publiés entre 2006 et juillet 2016; et des articles sur les services de santé préventifs à l'intention des aînés et présentant un intérêt pour la pratique familiale ou les médecins de famille, limités à ceux publiés en anglais entre 2012 et juillet 2016. MESSAGE PRINCIPAL: L'estimation de l'espérance de vie n'est pas une science facile ou précise, mais la fragilité est un concept émergent susceptible d'être utile à cet égard. Le Groupe d'étude canadien sur les soins de santé préventifs propose des lignes directrices sur le dépistage du cancer, mais elles sont moins précises en ce qui concerne les patients de plus de 74 ans et il faut donc individualiser les plans de prise en charge. L'estimation des années de vie qui restent aide à orienter vos recommandations concernant les plans de dépistage et de traitements préventifs. Les risques augmentent souvent proportionnellement avec la fragilité et la comorbidité. D'autre part, les bienfaits diminuent souvent à mesure que l'espérance de vie raccourcit. Les plans de prise en charge préventive devraient tenir compte des points de vue du patient et être convenus d'un commun accord. Un moyen mnémonique pour se rappeler des principaux domaines de prévention en soins primaires - CCMF, abréviation pour cancer, cardiovasculaire, mauvais équilibre, chute et ostéoporose, fiche de vaccinations préventives - pourrait se révéler utile. CONCLUSION: Les médecins de famille pourraient trouver utile de tenir compte des éléments suivants lorsqu'ils envisagent une intervention en soins préventifs : l'âge, l'espérance de vie (incluant le concept de la fragilité), la comorbidité et l'état fonctionnel, les risques et les bienfaits du dépistage ou du traitement, de même que les valeurs et les préférences du patient.

Additive effects of TPMT and NUDT15 on thiopurine toxicity in children with acute lymphoblastic leukemia across multiethnic populations.

BACKGROUND: Thiopurines such as mercaptopurine (MP) are widely used to treat acute lymphoblastic leukemia (ALL). Thiopurine-S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) inactivate thiopurines, and no-function variants are associated with drug-induced myelosuppression. Dose adjustment of MP is strongly recommended in patients with intermediate or complete loss of activity of TPMT and NUDT15. However, the extent of dosage reduction recommended for patients with intermediate activity in both enzymes is currently not clear. METHODS: MP dosages during maintenance were collected from 1768 patients with ALL in Singapore, Guatemala, India, and North America. Patients were genotyped for TPMT and NUDT15, and actionable variants defined by the Clinical Pharmacogenetics Implementation Consortium were used to classify patients as TPMT and NUDT15 normal metabolizers (TPMT/NUDT15 NM), TPMT or NUDT15 intermediate metabolizers (TPMT IM or NUDT15 IM), or TPMT and NUDT15 compound intermediate metabolizers (TPMT/NUDT15 IM/IM). In parallel, we evaluated MP toxicity, metabolism, and dose adjustment using a Tpmt/Nudt15 combined heterozygous mouse model (Tpmt+/-/Nudt15+/-). RESULTS: Twenty-two patients (1.2%) were TPMT/NUDT15 IM/IM in the cohort, with the majority self-reported as Hispanics (68.2%, 15/22). TPMT/NUDT15 IM/IM patients tolerated a median daily MP dose of 25.7 mg/m2 (interquartile range = 19.0-31.1 mg/m2), significantly lower than TPMT IM and NUDT15 IM dosage (P < .001). Similarly, Tpmt+/-/Nudt15+/- mice displayed excessive hematopoietic toxicity and accumulated more metabolite (DNA-TG) than wild-type or single heterozygous mice, which was effectively mitigated by a genotype-guided dose titration of MP. CONCLUSION: We recommend more substantial dose reductions to individualize MP therapy and mitigate toxicity in TPMT/NUDT15 IM/IM patients.

Dual-acting stapled peptides target both HIV-1 entry and assembly.

BACKGROUND: Previously, we reported the conversion of the 12-mer linear and cell-impermeable peptide CAI to a cell-penetrating peptide NYAD-1 by using an i,i + 4 hydrocarbon stapling technique and confirmed its binding to the C-terminal domain (CTD) of the HIV-1 capsid (CA) protein with an improved affinity (K(d) ~ 1 µM) compared to CAI (K(d) ~ 15 µM). NYAD-1 disrupts the formation of both immature- and mature-like virus particles in in vitro and cell-based assembly assays. In addition, it displays potent anti-HIV-1 activity in cell culture against a range of laboratory-adapted and primary HIV-1 isolates. RESULTS: In this report, we expanded the study to i,i + 7 hydrocarbon-stapled peptides to delineate their mechanism of action and antiviral activity. We identified three potent inhibitors, NYAD-36, -66 and -67, which showed strong binding to CA in NMR and isothermal titration calorimetry (ITC) studies and disrupted the formation of mature-like particles. They showed typical α-helical structures and penetrated cells; however, the cell penetration was not as efficient as observed with the i,i + 4 peptides. Unlike NYAD-1, the i,i + 7 peptides did not have any effect on virus release; however, they impaired Gag precursor processing. HIV-1 particles produced in the presence of these peptides displayed impaired infectivity. Consistent with an effect on virus entry, selection for viral resistance led to the emergence of two mutations in the gp120 subunit of the viral envelope (Env) glycoprotein, V120Q and A327P, located in the conserved region 1 (C1) and the base of the V3 loop, respectively. CONCLUSION: The i,i + 7 stapled peptides derived from CAI unexpectedly target both CA and the V3 loop of gp120. This dual-targeted activity is dependent on their ability to penetrate cells as well as their net charge. This mechanistic revelation will be useful in further modifying these peptides as potent anti-HIV-1 agents.

Ascites, hydrocolpos, hydrometrocolpos with normal amniotic fluid in a fetus with partial urorectal septum malformation sequence.

Urorectal septum malformation sequence (URSMS) describes a range of anatomic anomalies in the urogenital and lower gastrointestinal organs caused by incomplete urorectal membrane septation and persistence of the cloacal membrane. Partial URSMS is a milder version characterized by a single perineal opening. We report a case of partial URSMS that associated an intact Mullerian system, single perineal opening, blind colon, imperforate anus and vagina, urethrovaginal connection, and ambiguous genitalia. Hydrocolpos, hydrometrocolpos, and ascites were seen in utero and confirmed on postnatal surgery. This case describes the changes in sonographic findings that evolved throughout the gestation.

Thromboembolic Disorder in COVID-19 Infection.

Coronavirus (COVID-19) is a global pandemic with over 600 million cases identified. In addition to extensive pulmonary complications of COVID-19, one feature unique to many patients with severe COVID-19 infections is coagulopathy with a rising prevalence of multi-systemic thromboembolic manifestations. Global data suggests a relationship between coagulopathy and mortality. In this review, we highlight multiple COVID-19 thromboembolic complications with emphasis on pathophysiology, clinical management, and radiological manifestations.

Associations of T-Cell Receptor Repertoire Diversity with L-Asparaginase Allergy in Childhood Acute Lymphoblastic Leukemia.

Asparaginase is a critical component of therapy for childhood acute lymphoblastic leukemia (ALL), but it is commonly associated with allergy, which results in morbidity and poorer outcomes. The underlying basis of this allergy is undoubtedly immune-mediated, but the exact components of T-cell immunity have yet to be characterized. We performed longitudinal TCR sequencing of 180 bone marrow samples from 67 children with B-ALL treated as part of the Ma-Spore-ALL-2010 trial, and we evaluated the associations of TCR profile with asparaginase hypersensitivity, with functional validation of asparaginase activity in a separate cohort of 113 children. We found that a more diverse and dynamically changing TCR repertoire was associated with increased risk of clinical hypersensitivity and decreased L-asp activity. Allergic patients had a higher proportion of infrequent clonotypes, as well as a significantly lower degree of shared clonotypes amongst the cohort. Allergic patients also had significantly higher longitudinal variability of clonotypes across timepoints, where a higher dissimilarity between diagnosis and week 5 represented an 8.1-fold increased risk of an allergic event. After an allergy had occurred, there was shaping and convergence of the TCR repertoire towards a common antigen. Understanding the immunological basis of T-cell responses in allergy lays the groundwork for developing predictive biomarkers or strategies to mediate this common toxicity in childhood ALL.

Prognostic and Pharmacotypic Heterogeneity of Hyperdiploidy in Childhood ALL.

PURPOSE: High hyperdiploidy, the largest and favorable subtype of childhood ALL, exhibits significant biological and prognostic heterogeneity. However, factors contributing to the varied treatment response and the optimal definition of hyperdiploidy remain uncertain. METHODS: We analyzed outcomes of patients treated on two consecutive frontline ALL protocols, using six different definitions of hyperdiploidy: chromosome number 51-67 (Chr51-67); DNA index (DI; DI1.16-1.6); United Kingdom ALL study group low-risk hyperdiploid, either trisomy of chromosomes 17 and 18 or +17 or +18 in the absence of +5 and +20; single trisomy of chromosome 18; double trisomy of chromosomes 4 and 10; and triple trisomy (TT) of chromosomes 4, 10, and 17. Additionally, we characterized ALL ex vivo pharmacotypes across eight main cytotoxic drugs. RESULTS: Among 1,096 patients analyzed, 915 had B-ALL and 634 had pharmacotyping performed. In univariate analysis, TT emerged as the most favorable criterion for event-free survival (EFS; 10-year EFS, 97.3% v 86.8%; P = .0003) and cumulative incidence of relapse (CIR; 10-year CIR, 1.4% v 8.8%; P = .002) compared with the remaining B-ALL. In multivariable analysis, accounting for patient numbers using the akaike information criterion (AIC), DI1.16-1.6 was the most favorable criterion, exhibiting the best AIC for both EFS (hazard ratio [HR], 0.45; 95% CI, 0.23 to 0.88) and CIR (HR, 0.45; 95% CI, 0.21 to 0.99). Hyperdiploidy and subgroups with favorable prognoses exhibited notable sensitivities to asparaginase and mercaptopurine. Specifically, asparaginase sensitivity was associated with trisomy of chromosomes 16 and 17, whereas mercaptopurine sensitivity was linked to gains of chromosomes 14 and 17. CONCLUSION: Among different definitions of hyperdiploid ALL, DI is optimal based on independent prognostic impact and also the large proportion of low-risk patients identified. Hyperdiploid ALL exhibited particular sensitivities to asparaginase and mercaptopurine, with chromosome-specific associations.

Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response.

Contemporary chemotherapy for childhood acute lymphoblastic leukemia (ALL) is risk-adapted based on clinical features, leukemia genomics and minimal residual disease (MRD); however, the pharmacological basis of these prognostic variables remains unclear. Analyzing samples from 805 children with newly diagnosed ALL from three consecutive clinical trials, we determined the ex vivo sensitivity of primary leukemia cells to 18 therapeutic agents across 23 molecular subtypes defined by leukemia genomics. There was wide variability in drug response, with favorable ALL subtypes exhibiting the greatest sensitivity to L-asparaginase and glucocorticoids. Leukemia sensitivity to these two agents was highly associated with MRD although with distinct patterns and only in B cell ALL. We identified six patient clusters based on ALL pharmacotypes, which were associated with event-free survival, even after adjusting for MRD. Pharmacotyping identified a T cell ALL subset with a poor prognosis that was sensitive to targeted agents, pointing to alternative therapeutic strategies. Our study comprehensively described the pharmacological heterogeneity of ALL, highlighting opportunities for further individualizing therapy for this most common childhood cancer.

Anthracycline-Free Protocol for Favorable-Risk Childhood ALL: A Noninferiority Comparison Between Malaysia-Singapore ALL 2003 and ALL 2010 Studies.

PURPOSE: To investigate whether, for children with favorable-risk B-cell precursor ALL (BCP-ALL), an anthracycline-free protocol is noninferior to a modified Berlin-Frankfurt-Muenster ALL-IC2002 protocol, which includes 120 mg/m2 of anthracyclines. PATIENTS AND METHODS: Three hundred sixty-nine children with favorable-risk BCP-ALL (age 1-9 years, no extramedullary disease, and no high-risk genetics) who cleared minimal residual disease (≤0.01%) at the end of remission induction were enrolled into Ma-Spore (MS) ALL trials. One hundred sixty-seven standard-risk (SR) patients (34% of Malaysia-Singapore ALL 2003 study [MS2003]) were treated with the MS2003-SR protocol and received 120 mg/m2 of anthracyclines during delayed intensification while 202 patients (42% of MS2010) received an anthracycline-free successor protocol. The primary outcome was a noninferiority margin of 1.15 in 6-year event-free survival (EFS) between the MS2003-SR and MS2010-SR cohorts. RESULTS: The 6-year EFS of MS2003-SR and MS2010-SR (anthracycline-free) cohorts was 95.2% ± 1.7% and 96.5% ± 1.5%, respectively (P = .46). The corresponding 6-year overall survival was 97.6% and 99.0% ± 0.7% (P = .81), respectively. The cumulative incidence of relapse was 3.6% and 2.6%, respectively (P = .42). After adjustment for race, sex, age, presenting WBC, day 8 prednisolone response, and favorable genetic subgroups, the hazard ratio for MS2010-SR EFS was 0.98 (95% CI, 0.84 to 1.14; P = .79), confirming noninferiority. Compared with MS2003-SR, MS2010-SR had significantly lower episodes of bacteremia (30% v 45.6%; P = .04) and intensive care unit admissions (1.5% v 9.5%; P = .004). CONCLUSION: In comparison with MS2003-SR, the anthracycline-free MS2010-SR protocol is not inferior and was less toxic as treatment for favorable-risk childhood BCP-ALL.