Prediction of complete remission and survival in acute myeloid leukemia using supervised machine learning.

Achievement of complete remission signifies a crucial milestone in the therapy of acute myeloid leukemia (AML) while refractory disease is associated with dismal outcomes. Hence, accurately identifying patients at risk is essential to tailor treatment concepts individually to disease biology. We used nine machine learning (ML) models to predict complete remission and 2-year overall survival in a large multicenter cohort of 1,383 AML patients who received intensive induction therapy. Clinical, laboratory, cytogenetic and molecular genetic data were incorporated and our results were validated on an external multicenter cohort. Our ML models autonomously selected predictive features including established markers of favorable or adverse risk as well as identifying markers of so-far controversial relevance. De novo AML, extramedullary AML, double-mutated CEBPA, mutations of CEBPA-bZIP, NPM1, FLT3-ITD, ASXL1, RUNX1, SF3B1, IKZF1, TP53, and U2AF1, t(8;21), inv(16)/t(16;16), del(5)/del(5q), del(17)/del(17p), normal or complex karyotypes, age and hemoglobin concentration at initial diagnosis were statistically significant markers predictive of complete remission, while t(8;21), del(5)/del(5q), inv(16)/t(16;16), del(17)/del(17p), double-mutated CEBPA, CEBPA-bZIP, NPM1, FLT3-ITD, DNMT3A, SF3B1, U2AF1, and TP53 mutations, age, white blood cell count, peripheral blast count, serum lactate dehydrogenase level and hemoglobin concentration at initial diagnosis as well as extramedullary manifestations were predictive for 2-year overall survival. For prediction of complete remission and 2-year overall survival areas under the receiver operating characteristic curves ranged between 0.77-0.86 and between 0.63-0.74, respectively in our test set, and between 0.71-0.80 and 0.65-0.75 in the external validation cohort. We demonstrated the feasibility of ML for risk stratification in AML as a model disease for hematologic neoplasms, using a scalable and reusable ML framework. Our study illustrates the clinical applicability of ML as a decision support system in hematology.

Different treatment strategies versus a common standard arm (CSA) in patients with newly diagnosed AML over the age of 60 years: a randomized German inter-group study.

A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60-87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45-64)) and the study group arms (53% (95%CI: 47-60) and 59% (95%CI: 58-63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7-14.0) in the CSA, 7.6% (95%CI: 4.5-12.8) in study group A and 11.1% (95%CI: 9.0-13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0-26.9), 17.0% (95%CI: 2.0-23.9), and 19.5% (95%CI: 16.7-22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA.

Asymmetry-index and orthodontic facial analysis of children with foetal alcohol syndrome using 3D-facial scans.

BACKGROUND: The foetal alcohol spectrum disorder (FASD) is a complex and heterogenic disorder, caused by gestational exposure to alcohol. Patients with foetal alcohol syndrome (FAS-most severe form) show abnormal facial features. Our study aims at finding additional reliable and objective parameters for FAS diagnosis. METHODS: Facial three-dimensional scans of 30 children with FAS and 30 controls were analysed. Orthodontic profile analysis (concerning position of upper and lower jaw) was performed. Vertical facial proportions were taken and facial asymmetry index (right to left side) was calculated. RESULTS: Profile type was significantly different for children with FAS (p = 0.001) with lower jaws more frequently in a retral position. Profile angle was significantly larger in the group with FAS (p = 0.009). Children with FAS had shorter middle thirds and longer lower thirds of the face (p < 0.001). Stomion (point between upper and lower lip) was located significantly more caudally in the FAS group (p < 0.001). Facial asymmetry index was not significantly different. CONCLUSIONS: Children with FAS differ significantly from controls in vertical and sagittal facial measurements. Profile analysis and measurement of vertical proportions are easy to apply standard procedures in everyday orthodontic practice and could be time-saving and objective means for additional verification of FAS.

Variability in the decision-making process of acute ischemic stroke in difficult clinical and radiological constellations: analysis based on a cross-sectional interview-administered stroke questionnaire.

BACKGROUND AND PURPOSE: Notwithstanding guidelines, indications for mechanical thrombectomy (MT) in acute ischemic stroke are multifactorial and can be complex. Our aim was to exploratively evaluate decision-making on the advisability of performing MT in cases presented as an interview-administered questionnaire. METHODS: Fifty international raters assessed 12 cases and decided to recommend or exclude MT. Each case contained a brief summary of clinical information and eight representative images of the initial multimodal CT. The demographic characteristics and stroke protocols were recorded for raters. For each case, the reasons for excluding MT were recorded. Uni- and multivariate logistic regression analysis were performed for the different demographic and case characteristics to identify factors that might influence decision-making. RESULTS: All raters performed MT (median MTs/hospital/year [IQR], 100 [50-141]) with a median of 7 years of experience as first operator (IQR, 4-12). Per case, diversity in decision-making ranged between 1 (case 6, 100% yes MT) and 0.50 (case 12, 54.2% yes MT and 45.8% no MT). The most common reasons for excluding MT were small CBV/CBF mismatch (17%, 102/600), size of infarct core on the CBV map (15.2%, 91/600), and low NIHSS score (National Institute of Health Stroke Scale, 8.3%, 50/600). All clinical and radiological characteristics significantly affected the decision regarding MT, but the general characteristics of the raters were not a factor. CONCLUSIONS: Clinical and imaging characteristics influenced the decision regarding MT in stroke. Nevertheless, a consensus was reached in only a minority of cases, revealing the current divergence of opinion regarding therapeutic decisions in difficult cases. KEY POINTS: • This is the first study to explore differences in decision-making in respect of mechanical thrombectomy in ischemic stroke with complex clinical and radiological constellations. • Fifty experienced international neurointerventionalists answered this interview-administered stroke questionnaire and made decisions as to whether to recommend or disadvise thrombectomy in 12 selected cases. • Diversity in decision-making for thrombectomy ranged from 1 (100% of raters offered the same answer) to 0.5 (50% indicated mechanical thrombectomy). There was a consensus in only a minority of cases, revealing the current disparity of opinion regarding therapeutic decisions in difficult cases.

Malocclusion Can Give Additional Hints for Diagnosis of Fetal Alcohol Spectrum Disorder.

AIMS: Fetal alcohol spectrum disorder (FASD) is a developmental disorder caused by maternal alcohol intake (prevalence: 0.77%). Malocclusion has been described in case reports of patients with FASD, but reliable evidence for associations between FASD and malocclusion is not documented. Malocclusion is defined as tooth irregularity (prevalence: 14.6%) or incorrect relationship between the jaws such as lateral crossbites (prevalence: 3.1%). The purpose of this study was to investigate possible associations between malocclusion and FASD. SHORT SUMMARY: FASD prevalence is high and diagnosis is very difficult; Malocclusions can give additional hints for FASD diagnosis; Patients with FASD show growth deficits concerning the maxilla; Early and consistent orthodontic supervision and therapy can prevent facial asymmetries in FASD patients. METHODS: Thirty patients with FASD and 30 patients of a healthy control group were examined. Inclusion criteria were mixed dentition, verified FASD/absence of FASD (control group), exclusion criteria were orthodontic treatment and disorders other than FASD. The extent and type of malocclusion were quantified with the peer assessment rating (PAR) index based on an analysis of orthodontic plaster models. In addition, anthropometric data such as gestational age, body weight and height at birth as well as present body weight, height and head circumference at examination date were assessed. RESULTS: The PAR index showed a significant increase in malocclusions in FASD patients compared to the group that were not diagnosed with FASD (P = 0.002). FASD patients showed particular differences in the upper transversal dimension with a higher prevalence of crossbites (P = 0.018) and a lower head circumference (P < 0.001). Body weight (P < 0.001) and height (P < 0.001) were significantly lower for FASD patients at time of birth, but not at the present examination date (weight: P = 0.329; height: P = 0.496). When relating weight and height measures to age using percentile curves of physiological growth, clinically relevant discrepancies could be found for FASD patients. CONCLUSIONS: Our results show that malocclusion can provide additional evidence for FASD diagnosis. When FASD is diagnosed in a child, early referral to an orthodontist is advisable to stimulate maxillary growth and consequently prevent further malocclusions.

3D Analysis of Philtrum Depth in Children with Fetal Alcohol Syndrome.

AIMS: Diagnosis of fetal alcohol spectrum disorder (FASD) is complex and difficult. The estimated number of unreported FASD is thus assumed to be substantial. In our cross-sectional study, we aimed to identify possible metric differences in philtrum depth in children with fetal alcohol syndrome (FAS) compared to healthy controls based on non-invasive 3D facial scanning in order to provide an objective, metrical tool improving FASD diagnosis. METHODS: Twenty-five children with confirmed FAS and 30 healthy school children without FAS, both in the mixed dentition, were prospectively recruited and 3D facial scans were performed after recording body length, weight and head circumference. Philtrum surface data were extracted and metric philtrum depth was determined at four geometrically defined measuring points (P1-P4) along the vertical length of the philtrum. RESULTS: Philtrum depths at P1 (P = 0.025), P2 (P = 0.001), P3 (P < 0.001) and P4 (P = 0.001) as well as mean philtrum depth P1-P4 (P < 0.001) differed significantly between patients with and without FAS. Compared to controls, the philtrum was shallower in patients with FAS by on average 0.4 mm at each of the respective points. Whereas no differences could be determined for body height and weight, head circumference was significantly smaller in patients with FAS (P = 0.001), particularly in girls (P = 0.008). CONCLUSIONS: Apart from head circumference, philtrum depth is significantly reduced in children with FAS and can thus be used as diagnostic indicator to aid and confirm FAS diagnosis. In contrast to visual assessments, 3D face scan methods allow a more objective quantification and can thus provide additional evidence in FAS diagnosis.

Frontline therapy of acute promyelocytic leukemia: Randomized comparison of ATRA and intensified chemotherapy versus ATRA and anthracyclines.

OBJECTIVES: Randomized comparison of two treatment strategies in frontline therapy of acute promyelocytic leukemia (APL): all-trans retinoic acid (ATRA) and double induction intensified by high-dose cytosine arabinoside (HD ara-C) (German AMLCG) and therapy with ATRA and anthracyclines (Spanish PETHEMA, LPA99). PATIENTS AND RESULTS: Eighty of 87 adult patients with genetically confirmed APL of all risk groups were eligible. The outcome of both arms was similar: AMLCG vs PETHEMA: hematological complete remission 87% vs 83%, early death 13% vs 17% (P = .76), overall survival, event-free survival, leukemia-free survival, cumulative incidence of relapse at 6 years 75% vs 78% (P = .92); 75% vs 68% (P = .29); 86% vs 81% (P = .28); and 0% vs 12% (P = .04, no relapse vs four relapses), respectively. The median time to achieve molecular remission (RT-PCR negativity of PML-RARA) was 60 days in both arms (P = .12). The AMLCG regimen was associated with a longer duration of neutropenia (P = .02) and a higher rate of WHO grade ≥3 infections. CONCLUSIONS: The small number of patients limits the reliability of conclusions. With these restrictions, the outcomes of both approaches were similar and show the limitations of ATRA and chemotherapy. The HD ara-C-containing regimen was associated with a lower relapse rate in high-risk APL.

Quantification of macular perfusion using optical coherence tomography angiography: repeatability and impact of an eye-tracking system.

BACKGROUND: The aim of the study was to evaluate the impact of integration of the eye-tracking system (ET) on the repeatability of flow density measurements using optical coherence tomography (OCT) angiography. METHODS: 20 healthy subjects were included in this study. OCT-angiography was performed using RTVue XR Avanti (Optovue Inc., Fremont, California, USA). The macula was imaged using a 3 × 3 mm scan twice with and twice without activation of the ET. Flow density data of the macular in the superficial and deep OCT angiograms were extracted and analyzed. RESULTS: The difference between the flow density (whole en face) in the first session and second session with and without ET was statistically non-significant (with ET: superficial retinal OCT angiogram: p = 0.50; deep retinal OCT angiogram: p = 0.89; without ET: superficial retinal OCT angiogram: p = 0.81; deep retinal OCT angiogram: p = 0.24). There was no significant difference in the coefficients of repeatability for measurements with and without ET in the superficial retinal OCT angiogram (adjusted p-value = 0.176), whereas the difference was significant for the deep retinal OCT angiogram (adjusted p-value = 0.008). CONCLUSIONS: Integration of the ET improved the repeatability of flow density measurements in the deep OCT angiogram; this needs to be considered when evaluating the long-term changes of flow density and when comparing data of different studies and different devices.

The Simpson grading in meningioma surgery: does the tumor location influence the prognostic value?

In meningiomas, location-specific differences of the prognostic value of the Simpson classification are sparsely investigated but can influence strategy of surgery. We therefore compared the prognostic value of the Simpson classification in different tumor locations. Progression was compared with Simpson grade in 826 meningioma patients (median age 58 years, female:male ratio 2.4) in location-specific uni- and multivariate analyses. Simpson grade strongly correlated with tumor location (p < .001). Within a median follow-up of 50 months, recurrence was observed in 107 of 803 patients (13%). In general, increasing Simpson grade (p = .002) and subtotal resection (STR, ≥grade III) were correlated with tumor recurrence [hazard ratio (HR): 1.87; p = .004]. In 268 convexity meningiomas, frequency of tumor recurrence correlated with Simpson grade (p = .034). Risk of recurrence was similar after grade I and II resections, tended to increase after grade III (HR: 2.35; p = .087) but was higher after grade IV resections (HR: 7.35; p = .003). Risk of recurrence was higher after STR (HR: 4.21; p = .001) than after gross total resection (GTR, ≤grade II). Contrarily, increasing Simpson grade and STR were not correlated with progression in 102 falx, 38 posterior fossa and nine intraventricular meningiomas. In 325 skull base lesions, risk of recurrence was similar after GTR and STR (p = .198) and was only increased after grade IV resections (HR: 3.26; p = .017). Simpson grading and extent of resection were not equally prognostic in all locations. Lower impact of extent of resection should be considered during surgery for skull base, posterior fossa and falx meningiomas.

Dexmedetomidine sedation combined with caudal anesthesia for lower abdominal and extremity surgery in ex-preterm and full-term infants.

BACKGROUND: Awake caudal anesthesia is a potentially attractive option, because the administration of general anesthesia is associated with a high rate of respiratory complications and hemodynamic disturbances and potential neurotoxic effects. To facilitate the caudal puncture and subsequent surgical intervention, additional sedatives are commonly administered. AIM: We aimed to establish a new, safe, and effective anesthetic procedure for very young children with comorbidities. METHODS: We retrospectively analyzed 23 children who underwent lower abdominal or lower extremity surgery with dexmedetomidine sedation and caudal anesthesia from January 2015 to August 2015. Dexmedetomidine was initiated with a total bolus infusion of 0.7-1.1 µg·kg-1 followed by a continuous infusion of 1 µg·kg-1 ·h-1 . Bupivacaine (2.5 mg·kg-1 ) was supplemented with 5-10 µg·kg-1 epinephrine to strengthen and prolong motor block. According to maturity at birth, two groups were defined: ex-preterm and full-term infants. RESULTS: There were 12 ex-preterm and 10 full-term infants available for analysis. The median postmenstrual age was 44 (38-52) weeks in ex-preterm and 46.5 (40-72) weeks in full-term infants. Without any additional intervention, surgery was successfully accomplished in 82% of all cases. While respiratory complications were not a problem, hemodynamic disturbances commonly occurred. Maximum decreases in heart rate (HR) of 30% were accompanied by maximum decreases in mean arterial pressure (MAP) of 38%. No infant had a heart rate below 100 bpm. MAP declined in one ex-preterm infant to a minimum value of 32 mmHg. CONCLUSION: Caudal anesthesia combined with dexmedetomidine sedation is an effective anesthetic technique for lower abdominal and extremity surgery in ex-preterm and full-term infants with severe comorbidities.

Thorax-to-head ratio and defect diameter-to-head ratio in giant omphaloceles as predictor for fetal outcome.

PURPOSE: To investigate the relationship between the thorax diameter and defect diameter of giant omphaloceles as a predictor for fetal outcome. METHODS: In a retrospective study, 17 fetuses with isolated giant omphaloceles were included for evaluation. The anterior-posterior thorax diameter and the defect diameter were measured from ultrasound images. For analysis, the thorax-to-head ratio (T/HC), the defect diameter-to-head ratio (DD/HC), and the quotient of the defect diameter and the thorax diameter (DD/T) were calculated. The days of ventilation (t ventilation), the duration until hospital discharge (t hospital), and the type of treatment were recorded as outcome parameters. RESULTS: No relationship was found between the calculated ratios (T/HC, DD/HC, or DD/T) and neither t hospital (r = -0.418, p = 0.095; r = -0.153, p = 0.556; and r = -0.023, p = 0.929; respectively) nor t ventilation (r = -0.391, p = 0.121; r = 0.041, p = 0.875; and r = 0.121, p = 0.645, respectively). The type of postnatal treatment was not associated with the three calculated ratios or t hospital (r = 0.155, p = 0.553; r = 0.019, p = 0.942; and r = 0.012, p = 0.965; r = -0.009, p = 0.973, respectively). In 53% of cases, t hospital was delayed due to additional and independent postnatal complications. CONCLUSION: Thorax diameter or defect diameter of giant omphaloceles is not predictive for fetal outcome. The perinatal care of these abdominal wall defects still remains a multidisciplinary challenge, but the outcome of giant omphaloceles is favorable at experienced centers.

Resilience in patients after allogeneic stem cell transplantation.

PURPOSE: After undergoing allogeneic stem cell transplantation (alloSCT), patients adapt in very different ways to their taxing situation. Some patients cope very well; others almost seem to fail. Psychosocial variables are important factors for successful reintegration. Besides quality of life, resilience may help to understand the variance in individual differences in adaptation after alloSCT. METHODS: A pilot study at the University Hospital Muenster, Germany, assessed resilience in patients after alloSCT. The sample included 75 patients (leukemia, lymphoma, myeloma, aplastic anemia) aged 20-76 years. The instruments Resilience Scale RS-25, Hospital Anxiety and Depression Scale, General Self-efficacy Scale, and EORTC QLQ-C30 were used. RESULTS: Resilience is positively correlated with quality of life (Spearman's rho 0.587) and social functioning (0.472), negatively with anxiety (-0.491) and depression (-0.577). Dividing the sample at the median resilience score of 144 reveals that high-resilience patients report less anxiety (p = 0.008) and depression (p < 0.001); higher physical (p = 0.041), emotional (p = 0.030), and social functioning (p = 0.003); and a better quality of life (p < 0.001) than low-resilience patients. No effects on resilience were found for age, gender, and primary disease entity. The high correlation of resilience and self-efficacy (r = 0.698) shows the strong relationship between the two concepts. Our results indicate a potential influence of the time span from alloSCT on patients' resilience. CONCLUSIONS: Resilience should be considered as a protective psychosocial factor for patients after alloSCT. A high degree of resilience can help patients to adapt to their situation and to resume their everyday life.

In vivo assessment of number of milk duct orifices in lactating women and association with parameters in the mother and the infant.

BACKGROUND: In vitro and in vivo analyses differ between the number of milk ducts found in the lactating breast, and there is a lack of knowledge as to whether or not external factors in the mother or the child affect the number of ductal orifices. The aim of this study was to determine the number of milk duct orifices in vivo and to investigate the possible influence of variable parameters in mother and infant. STUDY DESIGN: Prospective clinical trial. In 98 breastfeeding women we investigated the nipple surface in order to identify the number of milk duct orifices using Marmet's manual milk expression technique. In addition mothers were interviewed on different parameters of birth and breastfeeding. RESULTS: Every nipple had 3.90 ± 1.48 milk duct orifices on average. There was no significant difference between left and right breasts. The use of a breast pump in addition to breastfeeding did not have any effect on the number of ductal orifices. Multiparous women exhibited more ductal orifices (8.5 ± 3.0) as compared to primipara (7.1 ± 2.7). Boys were associated with significantly more ductal orifices in their mother's right breast (4.2 ± 1.7) than girls (3.5 ± 1.4). Furthermore boys were breastfed for longer per session. A shorter birth height of males correlated with more ductal orifices in left nipples. Fluid intake of mothers was associated with a higher number of ductal orifices. Restless infant behavior could not be explained by less milk duct orifices. Pain in the breast during breastfeeding did not have an influence on ductal orifices either. Psychological criteria, such as duration of maternity leave and total intended breastfeeding period, did not affect the number of orifices in the papilla mammaria of breasts during lactation. CONCLUSION: For the first time an in vivo investigation of the number of ductal orifices in lactating women was conducted non-invasively and associations with variables in the mother and the child, birth parameters in infants, and breastfeeding parameters in mothers and children were assessed. We conclude that the number of activated ductal orifices on the surface of the nipple is primarily associated with functional aspects.

Exploring the relationship between embolic acute stroke distribution and supra-aortic vessel patency: key findings from an in vitro model study.

BACKGROUND: We investigated differences in intracranial embolus distribution through communicating arteries in relation to supra-aortic vessel (SAV) patency. METHODS: For this experimental analysis, we created a silicone model of the extracranial and intracranial circulations using a blood-mimicking fluid under physiological pulsatile flow. We examined the sequence of embolus lodgment on injecting 104 frangible clot analogues (406 emboli) through the right internal carotid artery (CA) as SAV patency changed: (a) all SAV patent (baseline), (b) emboli from a CA occlusion, (c) emboli contralateral to a CA occlusion and (d) occlusion of the posterior circulation. The statistical analysis included a descriptive analysis of thrombi location after occlusion (absolute and relative frequencies). Sequences of occlusions were displayed in Sankey flow charts for the four SAV conditions. Associations between SAV conditions and occlusion location were tested by Fisher's exact test. Two-sided p values were compared with a significance level of 0.05. RESULTS: The total number of emboli was 406 (median fragments/clot: 4 (IQR: 3-5)). Embolus lodgment was dependent on SAV patency (p<0.0001). In all scenarios, embolism lodging in the anterior cerebral artery (ACA) occurred after a previous middle cerebral artery (MCA) embolism (MCA first lodge: 96%, 100/104). The rate of ipsilateral ACA embolism was 28.9% (28/97) at baseline, decreasing significantly when emboli originated from an occluded CA (16%, 14/88). There were more bihemispheric embolisations in cases of contralateral CA occlusion (37%, 45/122), with bilateral ACA embolisms preceding contralateral MCA embolism in 56% of cases (14/25 opposite MCA and ACA embolism). CONCLUSIONS: All emboli in the ACA occurred after a previous ipsilateral MCA embolism. Bihemispheric embolisms were rare, except when there was a coexisting occlusion in either CA, particularly in cases of a contralateral CA occlusion.

Making acute ischemic stroke thrombi visible in MRI imaging.

Knowledge of thrombus behavior and visualization on MRI in acute ischemic stroke is less than optimal. However, MRI sequences could be enhanced based on the typical T1 and T2 relaxation times of the target tissues, which mainly determine their signal intensities on imaging. We studied the relaxation times of a broad spectrum of clot analogs along with their image characteristics of three sequences analyzed: a T1-weighted turbo inversion-recovery sequence (T1w Turbo IR), a T1-weighted turbo spin echo with fat suppression (T1w TSE SPIR), and a T2-weighted 3D TSE with magnetization refocusing to remove T1 dependence (T2w TSE DRIVE). We compared their imaging behavior with the intensity values of normal brain tissue using the same imaging protocols as for clots. Each histological and biochemical clot component contributed to each of the relaxation times. Overall, histological composition correlated strongly with T1 times, and iron content, specifically, with T2 relaxation time. Using decision trees, fibrin content was selected as the primary biomarker for T1 relaxation times, inducing an increase. Up to four clot subgroups could be defined based on its distinctive T1 relaxation time. Clot signal intensity in the T1 and T2-weighted images varied significantly according to T1 and T2 relaxation times. Moreover, in comparison with normal brain tissue intensity values, T2w DRIVE images depict thrombi according to the principle of the more fibrin, the higher the intensity, and in T1w TSE, the more erythrocytes, the higher the intensity. These findings could facilitate improvements in MRI sequences for clot visualization and indicate that T2w DRIVE and T1w TSE sequences should depict the vast majority of acute ischemic stroke thrombi as more hyperintense than surrounding tissues.

High expression of the Ets-related gene (ERG) is an independent prognostic marker for relapse-free survival in patients with acute promyelocytic leukemia.

In acute promyelocytic leukemia (APL), relapse occurs in about 15 % of cases and is a major cause for death. Molecular markers identifying patients at high risk for relapse are not well established. High expression of the transcription factor Ets-related gene (ERG) is associated with inferior overall survival (OS) and disease-free survival in different types of hematologic malignancies. There are no data available about the impact of ERG expression in APL. ERG expression levels were analyzed in bone marrow samples of 86 APL patients at initial diagnosis. High ERG expression was significantly associated with an inferior OS in patients who had reached first complete remission. It was also significantly correlated with inferior relapse-free survival (RFS) and time to relapse (i.e., relapse-free interval, RFI). In multivariate analysis, high ERG expression had an independent negative impact on RFS and RFI. High ERG expression was significantly associated with inferior OS, RFS, and RFI. Moreover, in multivariate analysis, it maintained its value as an independent negative prognostic factor with regard to RFS and RFI. Therefore, ERG expression might serve as a molecular marker for risk stratification in APL and might identify patients who could benefit from intensified treatment regimens.

Outcome of elderly patients with acute promyelocytic leukemia: results of the German Acute Myeloid Leukemia Cooperative Group.

Despite improvement of prognosis, older age remains a negative prognostic factor in acute promyelocytic leukemia (APL). Reports on disease characteristics and outcome of older patients are conflicting. We therefore analyzed 91 newly diagnosed APL patients aged 60 years or older (30 % of 305 adults with APL) registered by the German AML Cooperative Group (AMLCG) since 1994; 68 patients (75 %) were treated in studies, 23 (25 %) were non-eligible, and 31 % had high-risk APL. Fifty-six patients received induction therapy with all-trans retinoic acid and TAD (6-thioguanine, cytarabine, daunorubicin), and consolidation and maintenance therapy. Treatment intensification with a second induction cycle (high dose cytarabine, mitoxantrone; HAM) was optional (n = 14). Twelve patients were randomized to another therapy not considered in this report. The early death rate was 48 % in non-eligible and 19 % in study patients. With the AMLCG regimen, 7-year overall, event-free and relapse-free survival (RFS) and cumulative incidence of relapse were 45 %, 40 %, 48 %, and 24 %, respectively. In patients treated with TAD-HAM induction, 7-year RFS was superior (83 %; p = 0.006) compared to TAD only, and no relapse was observed. In our registered elderly patients, we see a high rate of non-eligibility for treatment in studies and of high-risk APL. In patients who can undergo a curative approach, intensified chemotherapy is highly effective, but is restricted to a selection of patients. Therefore, new less toxic treatment approaches with broader applicability are needed. Elderly patients might be a particular target group for concepts with arsenic trioxide.

Validation and refinement of the 2022 European LeukemiaNet genetic risk stratification of acute myeloid leukemia.

The revised 2022 European LeukemiaNet (ELN) AML risk stratification system requires validation in large, homogeneously treated cohorts. We studied 1118 newly diagnosed AML patients (median age, 58 years; range, 18-86 years) who received cytarabine-based induction chemotherapy between 1999 and 2012 and compared ELN-2022 to the previous ELN-2017 risk classification. Key findings were validated in a cohort of 1160 mostly younger patients. ELN-2022 reclassified 15% of patients, 3% into more favorable, and 12% into more adverse risk groups. This was mainly driven by patients reclassified from intermediate- to adverse-risk based on additional myelodysplasia-related mutations being included as adverse-risk markers. These patients (n = 79) had significantly better outcomes than patients with other adverse-risk genotypes (5-year OS, 26% vs. 12%) and resembled the remaining intermediate-risk group. Overall, time-dependent ROC curves and Harrel's C-index controlling for age, sex, and AML type (de novo vs. sAML/tAML) show slightly worse prognostic discrimination of ELN-2022 compared to ELN-2017 for OS. Further refinement of ELN-2022 without including additional genetic markers is possible, in particular by recognizing TP53-mutated patients with complex karyotypes as "very adverse". In summary, the ELN-2022 risk classification identifies a larger group of adverse-risk patients at the cost of slightly reduced prognostic accuracy compared to ELN-2017.

Unsupervised meta-clustering identifies risk clusters in acute myeloid leukemia based on clinical and genetic profiles.

BACKGROUND: Increasingly large and complex biomedical data sets challenge conventional hypothesis-driven analytical approaches, however, data-driven unsupervised learning can detect inherent patterns in such data sets. METHODS: While unsupervised analysis in the medical literature commonly only utilizes a single clustering algorithm for a given data set, we developed a large-scale model with 605 different combinations of target dimensionalities as well as transformation and clustering algorithms and subsequent meta-clustering of individual results. With this model, we investigated a large cohort of 1383 patients from 59 centers in Germany with newly diagnosed acute myeloid leukemia for whom 212 clinical, laboratory, cytogenetic and molecular genetic parameters were available. RESULTS: Unsupervised learning identifies four distinct patient clusters, and statistical analysis shows significant differences in rate of complete remissions, event-free, relapse-free and overall survival between the four clusters. In comparison to the standard-of-care hypothesis-driven European Leukemia Net (ELN2017) risk stratification model, we find all three ELN2017 risk categories being represented in all four clusters in varying proportions indicating unappreciated complexity of AML biology in current established risk stratification models. Further, by using assigned clusters as labels we subsequently train a supervised model to validate cluster assignments on a large external multicenter cohort of 664 intensively treated AML patients. CONCLUSIONS: Dynamic data-driven models are likely more suitable for risk stratification in the context of increasingly complex medical data than rigid hypothesis-driven models to allow for a more personalized treatment allocation and gain novel insights into disease biology.

There are various ways in which clinicians can predict the risk of disease progression in patients with leukemia, helping them to treat the patients accordingly. However, these approaches are usually designed by human experts and might not fully capture the complexity of a patient's disease. Here, with a large cohort of patients with acute myeloid leukemia, we design an unsupervised machine learning model ­ a type of computer model that learns from patterns in data without human input­to separate these patients into subgroups according to risk. We identify four distinct groups which differ with regards to patient genetics, laboratory values, and clinical characteristics. These groups have differences in response to treatment and patient survival, and we validate our findings in another dataset. Our approach might help clinicians to better predict outcomes in patients with leukemia and make decisions on treatment.