Citations

Abstract Objective To provide a comprehensive assessment of various fractionation schemes in radiation therapy for breast cancer, with a focus on side effects, cosmesis, quality of life, risks of recurrence, and survival outcomes. Design Systematic review and meta-analysis. Data sources Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (from inception to 23 October 2023). Study selection Included studies were randomised controlled trials focusing on conventional fractionation (CF; daily fractions of 1.8-2 Gy, reaching a total dose of 50-50.4 Gy over 5-6 weeks), moderate hypofractionation (MHF; fraction sizes of 2.65-3.3 Gy for 13-16 fractions over 3-5 weeks), and/or ultra-hypofractionation (UHF; schedule of only 5 fractions). Data extraction Two independent investigators screened studies and extracted data. Risk of bias and quality of evidence were assessed using the Cochrane Collaboration’s tool and the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach, respectively. Data synthesis Pooled risk ratios (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random effects model. Heterogeneity was analysed using Cochran’s Q test and I 2 statistic. Network meta-analysis was used to integrate all available evidence. Main outcome measures The pre-specified primary outcome was grade ≥2 acute radiation dermatitis and late radiation therapy related side effects; secondary outcomes included cosmesis, quality of life, recurrence, and survival metrics. Results From 1754 studies, 59 articles representing 35 trials (20 237 patients) were assessed; 21.6% of outcomes showed low risk of bias, whereas 78.4% had some concerns or high risk, particularly in outcome measurement (47.4%). The RR for grade ≥2 acute radiation dermatitis for MHF compared with CF was 0.54 (95% CI 0.49 to 0.61; P<0.001) and 0.68 (0.49 to 0.93; P=0.02) following breast conserving therapy and mastectomy, respectively. Hyperpigmentation and grade ≥2 breast shrinkage were less frequent after MHF than after CF, with RRs of 0.77 (0.62 to 0.95; P=0.02) and 0.92 (0.85 to 0.99; P=0.03), respectively, in the combined breast conserving therapy and mastectomy population. However, in the breast conserving therapy only trials, these differences in hyperpigmentation (RR 0.79, 0.60 to 1.03; P=0.08) and breast shrinkage (0.94, 0.83 to 1.07; P=0.35) were not statistically significant. The RR for grade ≥2 acute radiation dermatitis for UHF compared with MHF was 0.85 (0.47 to 1.55; P=0.60) for breast conserving therapy and mastectomy patients combined. MHF was associated with improved cosmesis and quality of life compared with CF, whereas data on UHF were less conclusive. Survival and recurrence outcomes were similar between UHF, MHF, and CF. Conclusions MHF shows improved safety profile, cosmesis, and quality of life compared with CF while maintaining equivalent oncological outcomes. Fewer randomised controlled trials have compared UHF with other fractionation schedules, but its safety and oncological effectiveness seem to be similar with short term follow-up. Given the advantages of reduced treatment time, enhanced convenience for patients, and potential cost effectiveness, MHF and UHF should be considered as preferred options over CF in appropriate clinical settings, with further research needed to solidify these findings. Systematic review registration PROSPERO CRD42023460249.

PURPOSE Although cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 90%, ALL remains a leading cause of cancer death in children. Half of relapses arise in children initially classified with standard-risk (SR) disease. MATERIALS AND METHODS To identify genomic determinants of relapse in children with SR ALL, we performed genome and transcriptome sequencing of diagnostic and remission samples of children with SR (n = 1,381) or high-risk B-ALL with favorable cytogenetic features (n = 115) enrolled on Children's Oncology Group trials. We used a case-control study design analyzing 439 patients who relapsed and 1,057 who remained in complete remission for at least 5 years. RESULTS Genomic subtype was associated with relapse, which occurred in approximately 50% of cases of PAX5 -altered ALL (odds ratio [OR], 3.31 [95% CI, 2.17 to 5.03]; P = 3.18 × 10 –8 ). Within high-hyperdiploid ALL, gain of chromosome 10 with disomy of chromosome 7 was associated with favorable outcome (OR, 0.27 [95% CI, 0.17 to 0.42]; P = 8.02 × 10 –10 ; St Jude Children's Research Hospital validation cohort: OR, 0.22 [95% CI, 0.05 to 0.80]; P = .009), and disomy of chromosomes 10 and 17 with gain of chromosome 6 was associated with relapse (OR, 7.16 [95% CI, 2.63 to 21.51]; P = 2.19 × 10 –5 ; validation cohort: OR, 21.32 [95% CI, 3.62 to 119.30]; P = .0004). Genomic alterations were associated with relapse in a subtype-dependent manner, including alterations of INO80 in ETV6::RUNX1 ALL, IKZF1 , and CREBBP in high-hyperdiploid ALL and FHIT in BCR::ABL1 -like ALL. Genomic alterations were also associated with the presence of minimal residual disease, including NRAS and CREBBP in high-hyperdiploid ALL. CONCLUSION Genetic subtype, patterns of aneuploidy, and secondary genomic alterations determine risk of relapse in childhood ALL. Comprehensive genomic analysis is required for optimal risk stratification.

PURPOSE Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear. METHODS Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes. RESULTS Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2 -, DUX4 -, and KMT2A -rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases. CONCLUSION Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

Abstract Aims Operating on patients with severe degenerative mitral regurgitation (DMR) is based on ACC/AHA or ESC/EACTS guidelines. Doubts persist on best surgical indications and their potential association with postoperative survival loss. We sought to investigate whether guideline-based indications lead to late postoperative survival loss in DMR patients. Methods and results We analysed outcome of 2833 patients from the Mitral Regurgitation International Database registry undergoing surgical correction of DMR. Patients were stratified by surgical indications: Class I trigger (symptoms, left ventricular end-systolic diameter ≥ 40 mm, or left ventricular ejection fraction &lt; 60%, n = 1677), isolated Class IIa trigger [atrial fibrillation (AF), pulmonary hypertension (PH), or left atrial diameter ≥ 55 mm, n = 568], or no trigger (n = 588). Postoperative survival was compared after matching for clinical differences. Restricted mean survival time (RMST) was analysed. During a median 8.5-year follow-up, 603 deaths occurred. Long-term postoperative survival was lower with Class I trigger than in Class IIa trigger and no trigger (71.4 ± 1.9, 84.3 ± 2.3, and 88.9 ± 1.9% at 10 years, P &lt; 0.001). Having at least one Class I criterion led to excess mortality (P &lt; 0.001), while several Class I criteria conferred additional death risk [hazard ratio (HR): 1.53, 95% confidence interval (CI): 1.42–1.66]. Isolated Class IIa triggers conferred an excess mortality risk vs. those without (HR: 1.46, 95% CI: 1.00–2.13, P = 0.05). Among these patients, isolated PH led to decreased postoperative survival vs. those without (83.7 ± 2.8% vs. 89.3 ± 1.6%, P = 0.011), with the same pattern observed for AF (81.8 ± 5.0% vs. 88.3 ± 1.5%, P = 0.023). According to RMST analysis, compare to those operated on without triggers, operating on Class I trigger patients led to 9.4-month survival loss (P &lt; 0.001) and operating on isolated Class IIa trigger patients displayed 4.9-month survival loss (P = 0.001) after 10 years. Conclusion Waiting for the onset of Class I or isolated Class IIa triggers before operating on DMR patients is associated with postoperative survival loss. These data encourage an early surgical strategy.

Background: Left atrial (LA) size increases in atrial fibrillation (AF). How changes in mitral annulus and atrial volume over time relate to severity of mitral regurgitation (MR) is unknown. Methods: This cohort study included 160 patients with a history of permanent AF who had at least 2 transthoracic echocardiograms (TTE) performed between 2005 and 2010 at Vancouver General Hospital (British Columbia, Canada). Patients with structural mitral valve disease, congenital heart disease, more than mild-moderate mitral/tricuspid regurgitation on their first TTE were excluded from analyses. LA volume was determined using biplane area-length method, averaged over 3 cardiac cycles. The mitral annulus diameter (MAD), defined as the distance between the hinge points of the anterior and posterior mitral leaflets from the apical 4-chamber view, was measured during end-systole and end-diastole. Linear mixed effects modeling was used in analyzing the above measurements for change over time. Mitral regurgitation was classified into 3 grades (mild, moderate, or severe) using standard color Doppler and PISA easurements where available. Results: Of the 160 subjects included in this analysis, 100 were men (62.5%). The mean age at study entry was 74±10 years. The median number of TTE performed was 3 (range 2 - 6). All 160 patients showed a progressive increase in MAD over time. There was a significant increase in MAD at end-systole and end-diastole over a mean follow-up of 3.2 ± 2.8 years; the increases were 0.48 mm/year (95% CI 0.124 -0.75, P=0.0037) and 0.45 mm/year (95% CI 0.102-0.716, P=0.0029) respectively. LA volume increased from a mean of 43 mL/m2 to 75 mL/m2 for the cohort, or 10 mL/m2 per year. Adjusting for age, sex, and left ventricular ejection fraction, an increase in MR severity by at least 1 grade was strongly and independently associated with an increase in MAD. A 15% increment in MAD was associated with an increase in MR severity by 1 grade. Conclusion: Permanent AF was associated with significant increases in MAD and LA volume over time. Severity of MR also significantly increased over time, and was independently related to the change in MAD. Further investigations as to whether this represents a mechanism for left heart failure in patients with permanent AF are warranted.

Background: Anecdotal cases of rapidly progressing dementia in patients with dural arteriovenous fistulas (dAVFs) and cortical venous drainage have been reported in small series. However, a comprehensive description of the angiographic features of this dAVFs is lacking. We conducted an analysis of the largest cohort of dAVFs presenting with cognitive impairment (dAVFs-CI), aiming to provide a better characterization of this subset of dAVFs. Methods: The CONDOR Consortium, a multicenter repository comprising 1077 dAVFs, served as the study population. Among the dAVFs, patients with dAVFs-CI were analyzed. A propensity scores matching analysis was conducted to compare dAVFs-CI with Borden type II and type III dAVFs without cognitive impairment (controls). Logistic regression was employed to identify angiographic characteristics specific to dAVFs-CI. Post-treatment outcomes were analyzed. Results: A total of 60 patients with dAVFs-CI and 60 control dAVFs were included. Outflow obstruction leading to venous hypertension was observed in all dAVFs-CI. Sinus stenosis was significantly associated with dAVFs-CI (OR 2.85, 95% CI: 1.16-7.55, p = 0.027). dAVFs-CI were more likely to have a higher number of arterial feeders (OR 1.56, 95% CI 1.22-2.05, p < 0.001) and draining veins (OR 2.05, 95% CI 1.05-4.46, p = 0.004). Venous ectasia increased the risk of dAVFs-CI (OR 2.38, 95% CI 1.13-5.11, p = 0.024). A trend toward achieving asymptomatic status at follow-up was observed in patients with successful closure of dAVFs (OR 2.86, 95% CI 0.85-9.56, p = 0.09). Discussion: Venous hypertension is a key angiographic feature dAVFs-CI. dAVFs-CI exhibit a complex angioarchitecture characterized by an increased number of arteriovenous connections and stenosed sinuses. The presence of venous ectasia further exacerbates the impaired drainage and contributes to the development of dAVFs-CI. Notably, closure of the dAVF has the potential to reverse symptoms in certain cases (Figure).

BACKGROUND AND OBJECTIVES: Anecdotal cases of rapidly progressing dementia in patients with dural arteriovenous fistulas (dAVFs) have been reported in small series. However, large series have not characterized these dAVFs. We conducted an analysis of the largest cohort of dAVFs presenting with cognitive impairment (dAVFs-CI), aiming to provide a detailed characterization of this subset of dAVFs. METHODS: Patients with dAVFs-CI were analyzed from the CONDOR Consortium, a multicenter repository comprising 1077 dAVFs. A propensity score matching analysis was conducted to compare dAVFs-CI with Borden type II and type III dAVFs without cognitive impairment (controls). Logistic regression was used to identify angiographic characteristics specific to dAVFs-CI. Furthermore, post-treatment outcomes were analyzed. RESULTS: A total of 60 patients with dAVFs-CI and 60 control dAVFs were included. Outflow obstruction leading to venous hypertension was observed in all dAVFs-CI. Sinus stenosis was significantly associated with dAVFs-CI (OR 2.85, 95% CI: 1.16-7.55, P = .027). dAVFs-CI were more likely to have a higher number of arterial feeders (OR 1.56, 95% CI 1.22-2.05, P < .001) and draining veins (OR 2.05, 95% CI 1.05-4.46, P = .004). Venous ectasia increased the risk of dAVFs-CI (OR 2.38, 95% CI 1.13-5.11, P = .024). A trend toward achieving asymptomatic status at follow-up was observed in patients with successful closure of dAVFs (OR 2.86, 95% CI 0.85-9.56, P = .09) CONCLUSION: Venous hypertension is a key angiographic feature of dAVFs-CI. Moreover, these fistulas present at a mean age of 58 years-old, and exhibit a complex angioarchitecture characterized by an increased number of arteriovenous connections and stenosed sinuses. The presence of venous ectasia further exacerbates the impaired drainage and contributes to the development of dAVFs-CI. Notably, in certain cases, closure of the dAVF has the potential to reverse symptoms.

While the cure rate of pediatric acute lymphoblastic leukemia (ALL) now exceeds ~90% with contemporary combination chemotherapy, the prognosis for adults with ALL remains significantly inferior with long-term overall survival ranging from 50% to 70%. Recent studies have uncovered marked differences in ALL genomics between children and adults, with some high-risk subtypes becoming more prevalent with age. However, the underlying biology of age-related disparities in ALL is not fully understood, especially with regard to differences in leukemia sensitivity to chemotherapy. To address this knowledge gap, we performed ex vivo drug sensitivity profiling (i.e., pharmacotyping) of 21 anti-leukemia agents on primary B-ALL diagnostic samples from 767 pediatric (age, 0-18 years) and 309 adult (19-84 years) patients. Drug sensitivity was measured as LC 50: the concentration of drug required to kill 50% of the leukemia cells (PMID: 36604538). A total of 7,975 unique LC 50 values were experimentally determined. RNA-seq was used for subtype classification and gene expression analysis. Among 21 drugs, seven showed significant differences in overall LC 50 between children and adults ( P&lt;0.05 after Bonferroni correction): children displayed higher sensitivity to asparaginase, prednisolone, mercaptopurine, daunorubicin, and inotuzumab, while adults showed higher sensitivity to dasatinib and nelarabine. In multivariate models adjusting for 23 ALL molecular subtypes, only mercaptopurine remained significantly associated with age ( P=1.5×10 -5), suggesting that age-related differences in drug sensitivity can be primarily attributed to the variation in ALL subtypes between children and adults. For mercaptopurine, within KMT2A, CRLF2, and DUX4 subtypes, pediatric samples consistently showed a lower LC 50 than adults carrying the same genomic abnormality ( P=0.032, 0.0045, and 0.02, respectively). To explore intra-subtype heterogeneity, we performed unsupervised clustering using gene expression data for each of these three subtypes. Remarkably, within each of these subtypes, we identified two clusters with distinct transcriptomic profiles that were also largely segregated by age group, i.e., an adult-dominated cluster (C-a) and a pediatric-dominated cluster (C-p). In the KMT2A subtype, cases in C-a exhibited an over-representation of the KMT2A:: AFF1 fusion, and resistance to mercaptopurine ( P=0.029), prednisolone ( P=0.0039), vincristine ( P=0.046) and cytarabine ( P=0.0037). Within CRLF2 ALL, cases in C-a were associated with the presence of BCR:: ABL1-like signature and IGH:: CRLF2 rearrangements, and were more resistant to mercaptopurine ( P=0.0073) and prednisolone ( P=0.00036) compared to those in C-p. For DUX4 ALL, C-a was characterized by an under-representation of ERG deletions and resistance to mercaptopurine ( P=0.0056) and prednisolone ( P=0.0031), compared to C-p within DUX4. To explore the clinical relevance of this heterogeneity, we analyzed the in vivo treatment response of KMT2A (N=35), CRLF2 (N=59) and DUX4 (N=118) B-ALL enrolled in six frontline ALL trials. Compared to cases in C-p (usually drug-sensitive), those in C-a (usually drug-resistant) consistently had significantly poorer initial treatment responses as measured by persistent end-of-induction minimal residual disease (≥0.01%) in KMT2A (58% vs 9%; P=0.0063), CRLF2 (74% vs 41%; P=0.030), and DUX4 (66% vs 40%; P=0.0058) ALL. In conclusion, these studies have revealed important new insights into the pharmacogenomic basis of age-related differences in B-ALL treatment response. These results indicate that both inter- and intra-subtype heterogeneity contribute to inferior prognosis in adults with ALL, but also point to therapeutic opportunities to improve their outcomes.

Blinatumomab is an efficacious immunotherapeutic agent in B cell acute lymphoblastic leukemia (B-ALL). However, the pharmacogenomic basis of leukemia response to blinatumomab is unclear. Using genome-wide CRISPR, we comprehensively identified leukemia intrinsic factors of blinatumomab sensitivity, i.e., the loss of CD58 as a top driver for resistance, in addition to CD19 . Screening 1639 transcription factor genes, we then identified PAX5 as the key activator of CD58. ALL with the PAX5 P80R mutation also expressed the lowest level of CD58 among 20 ALL molecular subtypes in 1988 patients. Genome editing confirmed the effects of this mutation on CD58 expression and blinatumomab sensitivity in B-ALL, with validation in patient leukemic blasts. We described a PAX5-driven enhancer at the CD58 locus, which was disrupted by PAX5 P80R, and the loss of CD58 abolished blinatumomab-induced T cell activation with global changes in transcriptomic/epigenomic program. In conclusion, we identified previously unidentified genetic mechanisms of blinatumomab resistance in B-ALL, suggesting strategies for genomics-guided treatment individualization.

Abstract The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.