The genomic and biological complexity of mixed phenotype acute leukemia.

Mixed phenotype acute leukemia (MPAL) is a heterogeneous group of leukemias that are defined immunophenotypically by antigen expression on blasts of both myeloid and lymphoid lineage. With the exception of BCR-ABL positive and KMT2A rearranged MPAL, the biology of the majority of MPAL remains uncertain. Several recent studies have explored the genomic and epigenetic landscape of MPAL and have suggested a further refinement of the WHO classification to emphasize the genomic heterogeneity of MPAL. Further studies including single cell analysis, whole exome sequencing and time of flight cytometry will provide for further biological characterization. Treatment decisions are complicated due to this lack of classification and the dearth of prospective randomized studies. Acute lymphoblastic leukemia-type therapy appears to achieve higher remission rates, and allogenic stem cell transplantation may be beneficial in a select group of patients in first complete remission. Multi-center collaborations may answer these questions more conclusively. Our review aims to discuss the diagnostic challenges, recent genomic studies and therapeutic strategies in this poorly understood disease.

Outcomes and adverse events in older acute lymphoblastic Leukemia patients treated with a pediatric-inspired protocol with Pegylated or native Asparaginase.

This retrospective report presents the outcomes and adverse events (AEs) observed in 73 patients aged 60 years or older diagnosed with Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia (Ph-negative ALL) treated with a pediatric-inspired protocol incorporating either Pegylated (PEG-ASP) or Native Asparaginase (EC-ASP). Notably, 61% of patients experienced AEs of Grade III-IV severity. The most prevalent AEs included thrombosis (35.6%), febrile neutropenia (38.4%), and transaminitis (34.2%). AEs did not translate into significant differences concerning overall survival, leukemia-free survival, or early mortality. Furthermore, we observed a reduction in early mortality rates (11% vs. 20%) and an increase in median overall survival (54 vs. 48 months) compared to our previous data. These findings suggest that the utilization of a pediatric-inspired chemotherapy protocol, with ASP, is an effective and well-tolerated therapeutic option for older patients with Ph-negative ALL. However, it emphasizes the importance of diligent monitoring and close follow-up throughout treatment.

CPX-351 in FLT3-mutated acute myeloid leukemia.

CPX-351, a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a 1:5 molar ratio, is approved for the treatment of newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes. In a pivotal phase III trial, CPX-351 significantly improved overall survival compared with standard-of-care 7 + 3 chemotherapy (7 days cytarabine; 3 days daunorubicin) in adults aged 60-75 years with newly diagnosed high-risk or secondary AML (median = 9.56 months vs. 5.95 months; hazard ratio = 0.69; 95% confidence interval = 0.52-0.90; p = 0.003). Approximately 30% of patients with newly diagnosed AML have mutations in the FLT3 gene, which may be associated with poor outcomes. Here, we review the current in vitro, clinical, and real-world evidence on the use of CPX-351 in patients with AML and mutations in FLT3. Additionally, we review preliminary data from clinical trials and patient case reports that suggest the combination of CPX-351 with FLT3 inhibitors may represent another treatment option for patients with FLT3 mutation-positive AML.

Molecular diagnostic criteria of myeloproliferative neoplasms.

INTRODUCTION: Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell neoplasms characterized by the driver mutations JAK2, CALR, and MPL. These mutations cause constitutive activation of JAK-STAT signaling, which is central to pathogenesis of MPNs. Next-generation sequencing has further expanded the molecular landscape allowing for improved diagnostics, prognostication, and targeted therapy. AREAS COVERED: This review aims to address current understanding of the molecular diagnosis of MPN not only through improved awareness of the driver mutations but also the disease modifying mutations. In addition, other genetic factors such as clonal hematopoiesis of indeterminate potential (CHIP), order of mutation, and mutation co-occurrence are discussed and how these factors influence disease initiation and ultimately progression. How this molecular information is incorporated into risk stratification models allowing for earlier intervention and targeted therapy in the future will be addressed further. EXPERT OPINION: The genomic landscape of the MPN has evolved in the last 15 years with integration of next-generation sequencing becoming the gold standard of MPN management. Although diagnostics and prognostication have become more personalized, additional studies are required to translate these molecular findings into targeted therapy therefore improving patient outcomes.

Safety of re-challenging adults with acute lymphoblastic leukemia with PEG-asparaginase-induced severe hypertriglyceridemia when treated with a pediatric-inspired regimen.

PEG-asparaginase is used as a treatment for Philadelphia-negative acute lymphoblastic leukemia. In pediatric studies, triglycerides (TGs) were affected more by PEG-asparaginase than by native L-asparaginase (10.0% vs. 5.5%). We conducted a retrospective study to determine the safety of re-challenging adult patients with PEG-asparaginase after experiencing an episode of severe hypertriglyceridemia (>1000 mg/dl or 11.4 mmol/L). The incidence of hypertriglyceridemia associated with PEG-asparaginase in adult patients was high (67.5%). Therefore, checking TGs at baseline and monitoring levels while receiving PEG-asparaginase need to be considered and studied in prospective studies. However, in patients with hypertriglyceridemia not complicated by acute pancreatitis, re-challenging is safe once TG levels normalize.

Genome sequencing with gene panel-based analysis for rare inherited conditions in a publicly funded healthcare system: implications for future testing.

NHS genetics centres in Scotland sought to investigate the Genomics England 100,000 Genomes Project diagnostic utility to evaluate genome sequencing for in rare, inherited conditions. Four regional services recruited 999 individuals from 394 families in 200 rare phenotype categories, with negative historic genetic testing. Genome sequencing was performed at Edinburgh Genomics, and phenotype and sequence data were transferred to Genomics England for variant calling, gene-based filtering and variant prioritisation. NHS Scotland genetics laboratories performed interpretation, validation and reporting. New diagnoses were made in 23% cases - 19% in genes implicated in disease at the time of variant prioritisation, and 4% from later review of additional genes. Diagnostic yield varied considerably between phenotype categories and was minimal in cases with prior exome testing. Genome sequencing with gene panel filtering and reporting achieved improved diagnostic yield over previous historic testing but not over now routine trio-exome sequence tests. Re-interpretation of genomic data with updated gene panels modestly improved diagnostic yield at minimal cost. However, to justify the additional costs of genome vs exome sequencing, efficient methods for analysis of structural variation will be required and / or cost of genome analysis and storage will need to decrease.

WT1 expression in salivary gland pleomorphic adenomas: a reliable marker of the neoplastic myoepithelium.

Pleomorphic adenoma is a benign salivary gland neoplasm with a diverse morphology. This is considered to be a function of the neoplastic myoepithelium, which shows histological and immunophenotypical variability. Wilms' tumor 1 gene (WT1) protein, involved in bidirectional mesenchymal-epithelial transition, has been detected by reverse transcription PCR in salivary gland tumors showing myoepithelial-epithelial differentiation. The aim of this study was to investigate the immunoreactivity of WT1 in pleomorphic adenomas and to compare the pattern of staining with p63 and calponin, two reliable markers of myoepithelial cells. A total of 31 cases of pleomorphic adenoma were selected. The myoepithelium was classified as myoepithelial-like (juxtatubular and spindled), modified myoepithelium (myxoid, chondroid and plasmacytoid) and transformed myoepithelium (solid epithelioid, squamous and basaloid cribriform). Immunohistochemistry for WT1, p63 and calponin was assessed in each myoepithelial component, as well as in nonneoplastic myoepithelial cells and inner tubular epithelial cells. There was no immunostaining of tubular epithelial cells by any of the markers. In contrast to p63 and calponin, WT1 did not react with normal myoepithelial cells. Cytoplasmic WT1 staining was present in all pleomorphic adenomas, and in 29 cases (94%), >50% of neoplastic myoepithelial cells were highlighted. p63 and calponin stained the myoepithelium in 30 tumors. In comparison, 50% of cells were positive in 21 (68%) and 9 (29%) cases of p63 and calponin, respectively. Staining with WT1 showed less variability across the spectrum of myoepithelial differentiation with the difference most marked in the transformed myoepithelium. WT1 is a sensitive marker of the neoplastic myoepithelial cell in pleomorphic adenomas. The role of this protein in influencing the mesenchymal-epithelial state of cells suggests that WT1 and the myoepithelial cell have an important role in the histogenesis of pleomorphic adenomas.

Comparison of advanced and intermediate 200-m backstroke swimmers' dominant and non-dominant shoulder entry angles across various swimming speeds.

During backstroke, an optimum shoulder entry angle of 180° has been anecdotally suggested; however, this has yet to be investigated biomechanically. The aim of this study was to quantify shoulder entry angles for advanced and intermediate backstroke swimmers. Six advanced (season's best <150 s) and six intermediate (season's best >160 s) 200-m backstroke swimmers had markers applied to the medial humeral epicondyles and glenoid cavities. Following a familarization period, participants completed backstroke swimming trials (90 s each) in a swimming flume at 50%, 60%, 70%, and 80% of their season's best 200-m velocity. A camera positioned above the flume recorded frontal plane motion, which was digitized and analysed in Simi Motion Systems. The mean peak angle between the upper arm and the line of progression was established in ten strokes for each participant. The results showed backstroke shoulder entry angles for advanced swimmers (170°) were significantly closer to the suggested optimum 180° compared with those of intermediate swimmers (161°). The non-dominant arm displayed values closer to the optimum (171°), while swimming speed had no effect on backstroke shoulder entry angle. In conclusion, backstroke shoulder entry angle may help discriminate between advanced and intermediate backstroke swimmers and may be influenced by laterality dominance, being independent of swimming speed.

Venous thromboembolism incidence in the Ireland east hospital group: a retrospective 22-month observational study.

OBJECTIVES: To determine the incidence of venous thromboembolism (VTE) and the incidence of hospital-acquired VTE (HA-VTE) arising within the population served by the Ireland East Hospital Group (IEHG). DESIGN: /home/user/Documents/Sathish Kumar G/RFO/June/21-06-2019/bmjopen_iss_9_7_20190621_1/ A retrospective observational study was conducted using hospital discharge data obtained from the hospital inpatient enquiry data reporting system. In this system, VTE events recorded as 'primary diagnosis' represented the reason for initial hospital admission, whereas VTE recorded as a 'secondary diagnosis' occurred following admission and were therefore used as an approximation of HA-VTE. These data were used to estimate the overall incidence of VTE and the proportion of these events which were hospital-acquired. SETTING: The IEHG is the largest hospital group in the Irish healthcare system and serves a population of over 1 million individuals. PARTICIPANTS: Data were generated from records pertaining to the 2727 patient admission episodes where a diagnosis of VTE was made during the 22-month study period. RESULTS: During the study period, 2727 VTE events were recorded within the IEHG (which serves a population of 1 036 279) corresponding to an incidence of 1.44 (95% CI 1.36 to 1.51) per 1000 per annum. 1273 (47%) of VTE events were recorded as secondary VTE. The incidence of VTE was highest among individuals over 85 years of age (16.03 per 1000;95% CI 12.81 to 19.26) and was more common following emergency hospital admission. CONCLUSION: These data suggest that HA-VTE accounts for at least 47% of all VTE events arising within a hospital group serving a population of over 1 million individuals within the Ireland. Given that HA-VTE is a well-recognised source of (potentially preventable) hospital deaths, these findings provide a compelling argument for prioritising strategies directed at reducing the risk of VTE among hospital patients served by the IEHG and within the Ireland as a whole.

Total contact casting as part of an adaptive care approach: a case study.

Although total contact casting provides pressure relief and a moist wound-healing modality that allows patients to resume mobility while the wound is healing, it is not as widely used as it should be, in part because Board-certified pedorthists with relevant skills are scarce. As a result, clinicians may not appreciate the positive impact total contact casting has on the patient's overall condition. This case study of a 75-year-old woman with a potentially life-threatening diabetic foot ulcer offers a comprehensive picture of pervasive physiological changes in a context of challenging comorbidities. This multifaceted case is presented against a backdrop of Sister Callista Roy's nursing theory of adaptation and a total patient care approach to illustrate the cascading effects of diabetes on the patient's well-being, as well as to show that total contact casting is not only an effective intervention in the management of the patient's diabetic foot ulcer, but also a way to improve the patient's overall condition by maximizing the benefits of mobility.

Late Emergence of an Imatinib-Resistant ABL1 Kinase Domain Mutation in a Patient with Chronic Myeloid Leukemia.

The introduction of the tyrosine kinase inhibitor (TKI) imatinib has revolutionised the outlook of chronic myeloid leukemia (CML); however, a significant proportion of patients develop resistance through several mechanisms, of which acquisition of ABL1 kinase domain mutations is prevalent. In chronic-phase patients, these mutations become evident early in the disease course. A case is described of a chronic-phase CML patient who achieved a sustained, deep molecular response but who developed an Y253H ABL1 kinase domain mutation nearly nine years after commencing imatinib. Switching therapy to bosutinib resulted in a rapid reachievement of a major molecular response. Long-term TKI treatment impacts on quality of life and late losses of responses are usually due to lack of adherence. This case highlights the requirement for ABL1 kinase domain mutation analysis in those CML patients on long-term imatinib who lost their molecular response, regardless of whether nonadherence is suspected.

Acute Lymphoblastic Leukemia Arising in CALR Mutated Essential Thrombocythemia.

The development of acute lymphoblastic leukemia in an existing myeloproliferative neoplasm is rare with historical cases unable to differentiate between concomitant malignancies or leukemic transformation. Molecular studies of coexisting JAK2 V617F-positive myeloproliferative neoplasms and mature B cell malignancies indicate distinct disease entities arising in myeloid and lymphoid committed hematopoietic progenitor cells, respectively. Mutations of CALR in essential thrombocythemia appear to be associated with a distinct phenotype and a lower risk of thrombosis yet their impact on disease progression is less well defined. The as yet undescribed scenario of pro-B cell acute lymphoblastic leukemia arising in CALR mutated essential thrombocythemia is presented. Intensive treatment for the leukemia allowed for expansion of the original CALR mutated clone. Whether CALR mutations in myeloproliferative neoplasms predispose to the acquisition of additional malignancies, particularly lymphoproliferative disorders, is not yet known.

Maternal race/ethnicity and predictors of pregnancy and infant outcomes.

OBJECTIVE: To examine predictors of pregnancy and infant outcomes, including maternal race/ethnicity. DESIGN: Prospective and observational follow-up of high-risk pregnancies and births. PARTICIPANTS: Three hundred fifty-four mothers and their preterm and/or high-risk live-born neonates were closely followed in three tertiary care centers from the prenatal to postnatal periods for potential high-risk and/or preterm births that required neonatal resuscitations. MAJOR OUTCOME MEASURES: Pregnancy complications, birth complications, and infant outcomes were examined in conjunction with maternal factors, including preexisting health problems, health behaviors (smoking, alcohol consumption, prenatal visits), and the birth setting (tertiary care centers or community hospitals). RESULTS: About 22% of these infants were transferred into the tertiary care centers from the community hospitals right after birth; the rest were born in the centers. According to regression analyses, predictors of the birth setting were race (White vs. non-White), maternal health behaviors, pregnancy complications, fetal distress, and the presence of congenital defects for infants (p < .001). Predictors for fetal distress included race (Whites) and pregnancy-induced hypertension (p < .003). Predictors for lower birth weight included race (non-Whites), maternal cigarette smoking, pregnancy complications, fetal distress, and congenital defects (p < .001). Infant mortality rate was 3.9% for these high-risk infants, with the highest rate in infants born to Black mothers (8%). CONCLUSIONS: There are obvious health disparities among White and non-White women experiencing high-risk pregnancies and births. Future studies are needed to develop interventions targeted to different racial/ethnic groups during pregnancy to reduce preterm and high-risk births.

Physical theory as a basis for successful rotation of fetal malpositions and conversion of fetal malpresentations.

Maternal posturing, in which a pregnant or laboring woman assumes specific postures with the intention of altering the position and/or presentation of the fetus within the uterus, is a safe alternative to operative procedures recommended in cases of fetal malpositions and malpresentations. Clinicians and researchers are more likely to help pregnant women understand and perform posturing correctly if they comprehend the theoretical underpinnings of the technique. In maternal posturing, the forces of gravity and buoyancy combine to form a couple that overcomes frictional forces and/or obstructions to allow the fetus to rotate within the uterus to an optimal position or presentation. Integrating an understanding of these physical processes into clinical practice and research according to the recommendations provided here should lead to greater success in correcting malpositions and converting malpresentations.

The level of importance and level of confidence that midwives in the United States attach to using genetics in practice.

INTRODUCTION: The clinical application of genetic advances has the potential to transform preconception and pregnancy care and improve pregnancy outcomes. The study aim was to evaluate the level of importance and level of confidence that midwives in the United States attach to using genetics in practice. METHODS: The study was a descriptive, cross-sectional, online survey with a convenience sample of certified nurse-midwives who were active members of the American College of Nurse-Midwives (ACNM) and provided midwifery care in the United States. The survey contained genetic case studies and questions related to genetic activities that occur in clinical practice. Participants were asked to rate how important each genetic activity is to midwifery practice generally and their personal level of confidence in carrying out the stated activity at the present time; questions were rated on a Likert-type scale of 1 (not at all important, not at all confident) to 4 (essential, confident to teach). RESULTS: There were 612 survey responses from among the 4244 active members of ACNM (14.42%). Most midwives believed that genetics-related activities were very important or essential to their clinical practices, but they were only moderately confident in their abilities to perform these activities. The average importance survey score was 88%, and the average confidence survey score was 70%. Some midwives (17.5%) thought that taking a 3-generation family history was essential, and some midwives (20.9%) were extremely confident in their abilities to perform this activity. Almost all midwives (98.5%) indicated that they wanted to learn more about genetics and genomics. DISCUSSION: Genetics education programs need to be developed and made available to midwives to increase their confidence levels in using genetics in clinical practice.