Cytogenetic risk grouping by the monosomal karyotype classification is superior in predicting the outcome of acute myeloid leukemia undergoing allogeneic stem cell transplantation in complete remission

We retrospectively analyzed the impact of cytogenetic abnormalities grouped according to the monosomal karyotype (MK) classification or the Southwest Oncology/Eastern Cooperative Oncology Group (SWOG/ECOG) definition in 263 patients with acute myeloid leukemia (AML) who underwent allogeneic stem cell transplantation (alloSCT) in complete remission (CR) at our center. Risk grouping using the MK criteria shows a highly significant difference in 5‐yr overall survival (OS) ranging between 67%, for the most favorable, and 32%, for the poorest risk group (P = 0.001). Although similarly precise in predicting OS, the MK scheme better separates patients with respect to relapse incidence as compared to the SWOG/ECOG grouping (P = 0.0001 vs. P = 0.01). Notably, patients displaying non‐MK abnormalities (MK?) had a 5‐yr relapse incidence identical to those cytogenetically normal (CN), that is 24%. Multivariate analysis revealed that the MK classification is an independent prognosticator and superior in predicting OS (hazard ratios, HR 3.74, P = 0.01) and relapse incidence (HR 3.74, P = 0.005) as compared to the SWOG/ECOG criteria. Finally, subgroup analysis revealed that the prognostic capacity of the MK classification is highly significant in patients treated with standard myeloablative conditioning prior to alloSCT (P = 0.0011 for OS, P = 0.0007 for relapse). In contrast, the MK grouping failed to predict OS or relapse incidence in patients treated with reduced intensity conditioning. Taken together, these results indicate that the MK classification is superior in predicting the overall outcome of patients with AML undergoing alloSCT in CR. Furthermore, our data suggest that the genetic risk profile of MK? and CN patients is mostly overlapping in this setting.     

Infants use relative numerical group size to infer social dominance

Detecting dominance relationships, within and across species, provides a clear fitness advantage because this ability helps individuals assess their potential risk of injury before engaging in a competition. Previous research has demonstrated that 10- to 13-mo-old infants can represent the dominance relationship between two agents in terms of their physical size (larger agent = more dominant), whereas younger infants fail to do so. It is unclear whether infants younger than 10 mo fail to represent dominance relationships in general, or whether they lack sensitivity to physical size as a cue to dominance. Two studies explored whether infants, like many species across the animal kingdom, use numerical group size to assess dominance relationships and whether this capacity emerges before their sensitivity to physical size. A third study ruled out an alternative explanation for our findings. Across these studies, we report that infants 6–12 mo of age use numerical group size to infer dominance relationships. Specifically, preverbal infants expect an agent from a numerically larger group to win in a right-of-way competition against an agent from a numerically smaller group. In addition, this is, to our knowledge, the first study to demonstrate that infants 6–9 mo of age are capable of understanding social dominance relations. These results demonstrate that infants’ understanding of social dominance relations may be based on evolutionarily relevant cues and reveal infants’ early sensitivity to an important adaptive function of social groups.Competition for valuable resources such as mates, food, and territory (1) is commonplace across the animal kingdom. To minimize the cost of fighting (e.g., energy spent and personal injury or death), natural selection appears to have favored the emergence of cognitive adaptations that help individuals predict whether they stand a chance against an opponent (2–5). For example, many species, including ants, bees, birds, chimpanzees, and humans, appear to represent dominance relationships among conspecifics and use this information to decide whether to engage in or avoid a physical conflict (6–10). One such cue often associated with dominance ranking is physical size, with larger individuals often benefiting from greater strength and power over smaller individuals. Natural selection has also favored adaptations that exploit this inference, such that under threat, certain species adopt postures that make them appear bigger (11, 12) in order to intimidate an opponent.Underscoring the possibility that representations of social dominance may be part of humans’ evolved psychology, recent evidence has demonstrated that preverbal human infants infer social dominance relationships by comparing the physical size of two competing agents (13). In this earlier study, infants were introduced to two agents (one twice as large as the other), each with the goal of crossing to the opposite side of a platform. When both agents tried to cross the platform at the same time, their paths conflicted. Infants were shown two scenarios: one in which the larger agent yielded to the smaller agent, and one in which the smaller agent yielded to the larger agent. Although 10–13 mo olds expected a smaller agent to yield to a larger agent, younger infants (8–9 mo) failed to show any systematic belief about which agent should prevail. Therefore, only older infants were able to use the relative physical size of two competing agents to infer which one would get the right of way.Because younger infants did not reliably use physical size as a cue to social dominance, it remains unclear whether the younger infants were incapable of representing dominance relationships in general, or if they lacked sensitivity to this particular cue. To address this issue, the present study examined whether infants’ understanding of social dominance extends to cues beyond physical size—namely, to numerical group size, and if so, whether such a sensitivity emerges earlier in development.For many group-living animals, including social insects (7), wolves (14), hyenas (15), lions (16), primates (6), and human children and adults (5, 10), the ability to infer social dominance by assessing the numerical size of one’s own group relative to another is particularly important for survival (15, 17). The importance of this capacity to evaluate one’s own group size relative to another is illustrated by groups of chimpanzees patrolling their territory borders. To advertise the numerical strength of their group to others (18, 19) and deter opposing groups from approaching (20, 21), both males and females will engage noisy pant-hoot calling. In general, both chimpanzees and lions are more likely to approach if they outnumber intruders, but will stay silent and refrain from engaging in intergroup conflict if they do not (6, 16, 22, 23). Consequently, a group’s decision to engage in competition is more likely to occur if there are more individuals in one’s own group than in the opposing group (22, 24). Further, the relationship between numerical group size and inferences about social dominance has also been recently observed among children ages 6–8 y (5). School-aged children predicted that alliance strength would determine the likelihood of success in a conflict, such that two individuals aligned together were expected to win against a single individual. Coupled with the evidence reviewed from behavioral ecology, numerical group size may serve as an evolutionarily relevant cue to social dominance that humans are sensitive to within the first few years of life.Indeed, if young human infants have core knowledge of social relationships, as some have argued (13, 25), along with the capability to track the numerical size of small groups (26), it is possible that infants may be able to draw on both capacities to support inferences about the social dominance relationship between groups that differ in numerical size. If infants infer that individuals from larger groups are more dominant than individuals from smaller groups, this would demonstrate that infants’ understanding of social dominance can extend beyond the direct relationship between two competing individuals. Specifically, such a finding may shed light on whether infants already have an understanding of how social alliances operate—namely, that group members may help their own during a conflict, which confers a benefit to having more alliance members in close proximity during a conflict (10).Here, we explored whether infants can infer the dominance relationship between two agents from groups that differ in numerical size by modifying the methodology designed by Thomsen et al. (13). In our study, infants were first introduced to two groups that differed in numerical size (but equated for total surface area) and color. Next, infants were familiarized to an agent from each group independently achieving their goal of crossing a platform. When both of these agents attempted to cross the platform simultaneously, they bumped into one another. Therefore, the only way an agent could continue along their goal path was if one agent yielded to the other by moving out of the way.In study 1, we investigated whether 9- to 12-mo-old infants use numerical group size as a cue to social dominance. In study 2, we examined whether 6- to 9-mo-old infants (who have not yet been shown to represent social dominance relationships between individuals) would also be sensitive to the cue of numerical group size. Infants in studies 1 and 2 viewed the same sequence of events.     

The fludarabine,cytarabine, and granulocyte colony‐stimulating factor (FLAG) chemotherapy regimen is an alternative to anthracycline‐based therapy for the treatment of acute myeloid leukemia for patients with pre‐existing cardiac disease

We conducted a retrospective study assessing FLAG (fludarabine, cytarabine, and granulocyte colony‐stimulating factor) as first‐line treatment in 56 newly diagnosed acute myeloid leukemia patients considered ineligible for anthracycline‐based treatment due to advanced age, significant comorbidities, or pre‐existing cardiac disease. The median age was 69 (21–80); 46% received FLAG for pre‐existing cardiac disease and others due to age (32%), non‐cardiac comorbidities (20%), or previous anthracycline exposure (2%). The induction mortality was 16% and, among evaluable patients, 48% achieved a complete remission after the first induction course with an additional patient achieving a remission after a second course for a total complete remission rate of 50%. Four patients proceeded to an allogeneic stem cell transplant including two with pre‐existing cardiac disease. Among non‐transplanted patients, the relapse rate (RR) was 47%. When censored at time of stem cell transplant, the median relapse‐free survival was 14.7 months. The median overall survival was 9.3 months with 1‐ and 2‐yr survivals of 44% and 22%, respectively. There was no difference in clinical outcomes between patients treated with FLAG for cardiac reasons vs. other reasons. In conclusion, FLAG is a useful alternative to anthracycline‐based induction for Acute myeloid leukemia in those with significant comorbidities including pre‐existing cardiac disease.     

Utility of clinical comprehensive genomic characterization for diagnostic categorization in patients presenting with hypocellular bone marrow failure syndromes

Bone marrow failure (BMF) related to hypoplasia of hematopoietic elements in the bone marrow is a heterogeneous clinical entity with a broad differential diagnosis including both inherited and acquired causes. Accurate diagnostic categorization is critical to optimal patient care and detection of genomic variants in these patients may provide this important diagnostic and prognostic information. We performed real-time, accredited (ISO15189) comprehensive genomic characterization including targeted sequencing and whole exome sequencing in 115 patients with BMF syndromes (median age 24 years, range: 3 months - 81 years). In patients with clinical diagnoses of inherited BMF syndromes, acquired BMF syndromes or clinically unclassifiable BMF we detected variants in 52% (12 of 23), 53% (25 of 47) and 56% (25 of 45) respectively. Genomic characterization resulted in a change of diagnosis in 30 of 115 (26%) including the identification of germline causes for 3 of 47 and 16 of 45 cases with pre-test diagnoses of acquired and clinically unclassifiable BMF respectively. The observed clinical impact of accurate diagnostic categorization included choice to perform allogeneic stem cell transplantation, disease-specific targeted treatments, identification of at-risk family members and influence of sibling allogeneic stem cell donor choice. Multiple novel pathogenic variants and copy number changes were identified in our cohort including in TERT, FANCA, RPS7 and SAMD9. Whole exome sequence analysis facilitated the identification of variants in two genes not typically associated with a primary clinical manifestation of BMF but also demonstrated reduced sensitivity for detecting low level acquired variants. In conclusion, genomic characterization can improve diagnostic categorization of patients presenting with hypoplastic BMF syndromes and should be routinely performed in this group of patients.     

Low vision perspectives on glaucoma

Introduction : Glaucoma is one of the major causes of visual impairment, especially in the older population. The aim of this paper is to examine the demographics of patients with glaucoma-induced visual impairment. Method : Visual rehabilitation information was analysed for 590 visually impaired patients attending the multi-disciplinary low vision clinic at Kooyong in Melbourne. Data collected included age, subjective assessment of glare, mobility and visual needs, visual acuity (at distance and near), contrast sensitivity, visual field loss or disruption and magnifiers prescribed. An assessment was also made of the patients' psychological status and the members of the multi-disciplinary team involved in their rehabilitation was noted. Results : Glaucoma was the primary cause of visual loss in 8.5 per cent of patients and was a secondary contributor to visual impairment in 5.9 per cent. The mean distance visual acuity was 6/38 and peak contrast sensitivity was 10 dB. Sixty-four per cent of glaucoma patients had magnifiers prescribed to help them achieve their visual needs, which were to read newspapers in the majority of cases.