Search

Patients diagnosed with high-risk essential thrombocythemia (ET) have limited treatment options to reduce the risk of thrombosis and lessen the progression of the disease by targeting the molecular source. Hydroxyurea is the recommended treatment, but many patients experience resistance or intolerance. Anagrelide is an approved second-line option for ET, but concerns of a higher frequency of disease transformation may affect its role as a suitable long-term option. Interferons have been evaluated in myeloproliferative neoplasms for over 30 years, but early formulations had safety and tolerability issues. SURPASS-ET (NCT04285086) is a phase III, open-label, multicenter, global, randomized, active-controlled trial that will evaluate the safety, efficacy, tolerability and pharmacokinetics of ropeginterferon alfa-2b compared with anagrelide as second-line therapy in high-risk ET.Essential thrombocythemia (ET) is a condition characterized by having more platelets than normal. The high number of platelets increases the risk of a life-threatening blood clot and/or bleeding. Patients with ET and at a high risk for these events are usually treated first with hydroxyurea (HU), but some patients do not respond properly or may develop significant side effects. Anagrelide is an approved medication used in patients who do not respond to HU. Ropeginterferon alfa-2b is a disease-specific, long-acting interferon with a good safety profile approved in polycythemia vera, another type of myeloproliferative neoplasm. The SURPASS-ET clinical trial will evaluate the safety, efficacy, tolerability and pharmacokinetics of ropeginterferon alfa-2b compared with anagrelide in patients with ET who are resistant or cannot tolerate HU.

Low-dose aspirin with hydroxyurea (HU) is first-line therapy in high-risk essential thrombocythemia (ET). However, many patients become HU-intolerant or -resistant. Anagrelide (ANA) and peginterferon alfa-2a are second-line options for high-risk ET patients.To assess the long-term safety and efficacy of P1101 compared to ANA as a second-line option for ET patients with HU intolerance or resistance Design: Phase 3, open-label, multicenter, randomized, active-controlled study to assess the efficacy, safety, tolerability after 12 months of treatment with a 28-day screening and follow-up, for a total trial duration of 14 months. Study visits are scheduled every 2 weeks. Treatments are assigned in a 1:1 ratio and stratified according to baseline platelet count, TSS, and country.Results will impact the treatment of patients with high-risk ET.Subjects diagnosed with high-risk ET (either60 years and JAK2V617F-positive at screening or having thrombosis or hemorrhage in the past) and according to WHO 2016 criteria, documented resistance/intolerance to HU, and IFN naïve are eligible to participate. Key exclusion criteria include pregnant females, autoimmune disease, and history or presence of clinically significant depression.P1101 will be administered subcutaneously every 2 weeks at the starting dose of 250 mcg (Week 0), 350 mcg (Week 2), and target optimal dose of 500 mcg (Week 4) for the remainder of the treatment period. ANA will be dosed according to local country label. All subjects will receive low-dose aspirin unless contraindicated.The primary endpoint is durable modified European LeukemiaNet composite response at 9 and 12 months from start of dosing.The study involves 58 sites across the world. To date 101 patients have been randomized (45 men and 56 women). The mean and median age at recruitment was 58.9 years (SD: 13.4) and 62 years (range 21 to 80 years). 79 subjects had a TSS20. Study is overseen by a DSMB and the need to intervene was not identified.Results will provide the first evidence of a second-line ET treatment by comparing P1101 with the only approved treatment option, ANA. This study is sponsored by PharmaEssentia USA.

Background Evidence showed that early palliative care could have many benefits in clinical outcomes for patients living with advanced medical illnesses. In fact, most of these studies have not involved patients with advanced haematologic cancer (HC), which are known to be associated with significant physical and psychological symptoms. In Hong Kong, an Early Integrated Palliative Care (EIPC) collaboration involving both Heamatology unit of Queen Mary Hospital (QMH) and the Palliative Medical Unit of Grantham Hospital (GH) has been started since early 2018 as a better way to improve the service gap. The HC patients failed 2 or more lines of cancer treatment are identified during the joint round and hematology clinic. Some of these patients will be referred to our PC services. Our joint PC clinic has multidisciplinary input from palliative care physicians, hematologists, and clinical psychologists. The clinic program is well coordinated and structured. The HC patients are initially seen by the parent team for disease treatment and then by GH PC team for symptom control and psychosocial care. Methods This was a retrospective study with a review of the clinical charts and electronic healthcare records of all patients who attended the Hematology PC clinic from June 2018 to September 2020. For the inclusion criteria, patients were found eligible if they had prospectively completed Edmonton Symptom Assessment Scale (ESAS) assessments for at least the initial and follow-up visits within a range of ≥7 days and ≤60 days of the first visit. Results Thirty-eight patients ultimately agreed to the referral. The mean age was 70.5 (12.5) years old. Twenty-five patients (66%) had myelodysplastic syndrome (MDS); 10 (26%) had acute myeloid leukemia (AML). Around 50-60% of patients reported significant symptoms of fatigue, anxiety, drowsiness, and anorexia; 42% of patients had significantly depressed moods while 37% had pain. There were significant symptom improvements for pain, depression, and anxiety after follow-up visits. Conclusions The study showed that our EIPC program resulted in a significant reduction in some of the important symptom item scores, including pain, anorexia, anxiety, and depression, after the follow-up visits.

Recent advances have led to cure or long-term disease control for patients with hematological malignancy (HM). Unfortunately, some of them still have poor prognoses and are often associated with significant symptom burden and poor quality of life for patients and families. These patients usually require supportive care including red blood cell and platelet transfusion, due to disease itself and the oncological treatment, apart from their symptom management. However, there is currently lack of the literatures review in these aspects. The objective of this review is to summarize practical supportive care recommendations for physicians or nurses practicing in palliative care (PC)/hematology-oncology unit, starting with core approaches in use of blood products for anemia and thrombocytopenia, management of tumor lysis syndrome, PC and oncology nursing care.Evidence for this review was obtained from a search of the Cochrane database, PubMed, guidelines of European Society of Medical Oncology, British society of Hematology, American Society of Clinical Oncology, National Comprehensive Cancer Network and peer-reviewed journal articles.For asymptomatic cancer patients who are anaemic, a threshold of haemoglobin level of 7 g/dL is considered to be safe and generally favored for blood transfusion. 'Single-unit' red cell transfusion is safer and at least as effective as 'double-unit' transfusion. Prophylactic platelet transfusion should be given to stable patients without bleeding and with platelet count less than 10×109/L. In febrile patients, the threshold is lifted to 20×109/L. There are also recommendations for the use of blood products during COVID-19 pandemic. In general, HM patients were more prone to painful infections when compared with solid cancer patients. Thus, antibiotics to treat underlying infections should be applied whenever possible and as required to control pain.This narrative review showed the recent literatures in the supportive care and symptom management of advanced HM patients. However, it is limited by some of the 'evidence-based' recommendations for interventions (including symptom management) based on early phase of HM populations rather than those receiving end-of-life care.

BackgroundThe epidemiology and treatment of acute promyelocytic leukaemia (APL) are changing. We have incorporated oral arsenic trioxide (oral-ATO) into induction/maintenance.MethodsNewly-diagnosed APL from 1991 to 2021 divided into three 10-year periods were studied to define its epidemiology and how oral-ATO impacted on its outcome. Primary endpoints included APL incidence, early deaths (ED, first 30 days), and overall survival (OS). Secondary endpoints included post-30-day OS, relapse-free survival (RFS), and incidence of second cancers.ResultsAPL occurred in 374 males and 387 females at a median age of 44 (1–97) years. Annual incidences increased progressively, averaging 0.32 per 100,000 people. All-trans retinoic acid (ATRA)-based and oral-ATO-based regimens were used in 469 and 282 patients. There were 144 EDs, occurring almost exclusively in ATRA-based inductions (N = 139), being more with males, age > 50 years, leucocyte > 10 x 109/L, diagnosis during 1991–2009 and fewer with oral-ATO-based regimens. After a median of 75 (interquartile range: 14–161) months, 5-year and 10-year OS were 68.1% and 63.3%, inferior with males, age > 50 years, leucocyte > 10 x 109/L, high-risk Sanz score and superior with oral-ATO-based regimens. Factoring out EDs, 5-year and 10-year post-30-day OS were 84.0% and 78.1%, inferior with males and superior with oral-ATO-based regimens. In 607 CR1 patients, the 5-year RFS was 83.8%, superior with diagnosis in 2010–2021 and oral-ATO-based regimens. Second cancers developed in 21 patients, unrelated to oral-ATO-based regimens.This study formed part of the Acute Promyelocytic Leukaemia Asian Consortium Project (ClinicalTrials.gov identifier: NCT04251754).

Background KRAS (KRAS proto-oncogene, GTPase; OMIM: 190,070) encodes one of three small guanosine triphosphatase proteins belonging to the RAS family. This group of proteins is responsible for cell proliferation, differentiation and inhibition of apoptosis. Gain-of-function variants in KRAS are commonly found in human cancers. Non-malignant somatic KRAS variants underlie a subset of RAS-associated autoimmune leukoproliferative disorders (RALD). RALD is characterized by splenomegaly, persistent monocytosis, hypergammaglobulinemia and cytopenia, but can also include autoimmune features and lymphadenopathy. In this report, we describe a non-malignant somatic variant in KRAS with prominent clinical features of massive splenomegaly, thrombocytopenia and lymphopenia. Case presentation A now-11-year-old girl presented in early childhood with easy bruising and bleeding, but had an otherwise unremarkable medical history. After consulting for the first time at 5 years of age, she was discovered to have massive splenomegaly. Clinical follow-up revealed thrombocytopenia, lymphopenia and increased polyclonal immunoglobulins and C-reactive protein. The patient had an unremarkable bone marrow biopsy, flow cytometry showed no indication of expanded double negative T-cells, while malignancy and storage disorders were also excluded. When the patient was 8 years old, whole exome sequencing performed on DNA derived from whole blood revealed a heterozygous gain-of-function variant in KRAS (NM_004985.5:c.37G > T; (p.G13C)). The variant was absent from DNA derived from a buccal swab and was thus determined to be somatic. Conclusions This case of idiopathic splenomegaly in childhood due to a somatic variant in KRAS expands our understanding of the clinical spectrum of RAS-associated autoimmune leukoproliferative disorder and emphasizes the value of securing a molecular diagnosis in children with unusual early-onset presentations with a suspected monogenic origin.

Objectives In response to the observations that interprofessional education (IPE) is seemingly atheoretical or under-theorised, this quantitative research seeks to uncover students' motivational mechanisms which could explain their behavioral and collaborative outcomes using self-determination theory (SDT). While SDT has been studied in various contexts, its applicability to IPE remains underexplored. This study aims to integrate a new perspective in understanding students' motivation in IPE by exploring how the fulfillment of a need for sense of autonomy, competence, and relatedness is linked to desirable IPE outcomes. Methods Utilising quantitative methods, we involved 255 healthcare students in Hong Kong from the medical, nursing, and pharmacy disciplines enrolled in IPE anticoagulation therapy module. They were invited to respond to the Psychological Need Satisfaction Questionnaire and other measures as part of the post-test. Results Sense of autonomy emerged as the strongest positive predictor of behavioral (collective dedication, behavioral engagement) and collaboration outcomes (team effectiveness, goal achievement). There were no significant program-level differences across these outcomes except for behavioural engagement for which nursing students had a higher perception than medicine students. Conclusions We were able to demonstrate that SDT is a meaningful framework in understanding behavioral and collaboration outcomes in IPE. The major theoretical contribution of this study refers to the ability of students' motivation to explain variance in their behavioral outcomes. That is, sense of autonomy consistently predicted team effectiveness, collective dedication, behavioral engagement, and goal achievement. Autonomous motivation among a sample of healthcare students can explain behavioral outcomes. Theoretical, methodological, and practical implications are discussed.

In myelodysplastic syndrome (MDS), resistance to hypomethylating agents (HMA) portends a poor prognosis, underscoring the importance of understanding the molecular mechanisms leading to HMA-resistance. In this study, P39 and Kasumi-1 cells and their azacitidine-resistant and decitabine-resistant sublines were evaluated comparatively with transcriptomic and methylomic analyses. Expression profiling and genome-wide methylation microarray showed downregulation of

Myelodysplastic syndrome (MDS) is a clonal myeloid neoplasm characterized by ineffective hematopoiesis, cytopenia, dysplasia and clonal instability leading to leukemic transformation. Hypomethylating agents are the mainstay of treatment in higher-risk MDS. However, treatment resistance and disease transformation into acute myeloid leukemia (AML) is observed in the majority patients and portend a dismal outcome. The residual cell clones resistant to therapy or cell clones acquiring new genetic aberrations are two of the key events responsible for drug resistance. Bulk tumor sequencing often fail to detect these rare subclones that confer resistance to therapy. In this study, we employed a single-cell DNA (sc-DNA) sequencing approach to study the clonal heterogeneity and clonal evolution in two MDS patients refractory to HMA. In both patients, different single nucleotide variations (SNVs) or insertions and deletions (INDELs) were detected concordant with bulk tumor sequencing. Rare cell clones with mutations undetectable on bulk tumor sequencing, were detected on single-cell DNA sequencing. In addition to SNVs and short INDELs, this study also revealed the presence clonal copy number loss of DNMT3A, TET2, and GAT2 as standalone events or in associated with the small SNVs or INDELs detected during HMA resistance and disease progression.

BACKGROUND The role of arsenic trioxide (As2 O3 ) in the maintenance of first complete remission (CR1) in acute promyelocytic leukemia (APL) is unclear. METHODS A total of 129 consecutive adult patients with APL of all risk categories who achieved CR1 with conventional induction (all-trans retinoic acid [ATRA]/daunorubicin) and consolidation (daunorubicin/cytarabine [induction daunorubicin and consolidation omitted for age ≥70 years]) underwent maintenance comprising ATRA (45 mg/m2 /day), oral As2 O3 (10 mg/day), and ascorbic acid (1 g/day) (AAA) for 2 weeks every 2 months for 2 years. RESULTS Over a 17-year period from August 1, 2002, to July 31, 2019, 63 men and 66 women (median age, 46 years [range, 18-82 years]) received AAA maintenance, which was already completed in 117 patients. At a median follow-up of 100 months (range, 8-215 months), 17 patients (13%) developed first relapse (R1) (hematologic, n = 14; molecular, n = 3) after a median of 19 months (range, 7-96 months) from CR1. Two R1 patients had concomitant central nervous system (CNS) involvement. All patients achieved CR2 with oral As2 O3 -based salvage. Five patients had a subsequent relapse and died. Eight patients died of unrelated causes while still in CR1. The 5-year and 10-year rates of relapse-free survival (RFS) were 89% and 85%, respectively. The 5-year and 10-year rates of overall survival (OS) were 94% and 87%, respectively. Multivariate analysis showed that inferior RFS was associated with FLT3-ITD (P = .005) and CNS involvement on presentation (P = .004), and inferior OS was associated with therapy-related APL (P = .03), FLT3-ITD (P = .03), and relapse (P = .03). The safety profile was favorable, with no grade 3/4 organ toxicities. CONCLUSION CR1 maintenance with AAA is safe and results in favorable long-term survival in patients with APL.

Clofarabine is active in refractory/relapsed acute myeloid leukemia (AML). In this phase 2 study, we treated 18‐ to 65‐year‐old AML patients refractory to first‐line 3 + 7 daunorubicin/cytarabine induction or relapsing after 3 + 7 induction and high‐dose cytarabine consolidation, with clofarabine (30 mg/m2/d, Days 1‐5), cytarabine (750 mg/m2/d, Days 1‐5), and mitoxantrone (12 mg/m2/d, Days 3‐5) (CLAM). Patients achieving remission received up to two consolidation cycles of 50% CLAM, with eligible cases bridged to allogeneic hematopoietic stem cell transplantation (allo‐HSCT). The mutational profile of a 69‐gene panel was evaluated. Twenty‐six men and 26 women at a median age of 46 (22‐65) years were treated. The overall response rate after the first cycle of CLAM was 90.4% (complete remission, CR: 69.2%; CR with incomplete hematologic recovery, CRi: 21.2%). Twenty‐two CR/CRi patients underwent allo‐HSCT. The 2‐year overall survival (OS), relapse‐free survival (RFS), and event‐free survival (EFS) were 65.8%, 45.7%, and 40.2%, respectively. Multivariate analyses showed that superior OS was associated with CR after CLAM (P = .005) and allo‐HSCT (P = .005), and superior RFS and EFS were associated with allo‐HSCT (P, Fifty‐two patients with relapsed/refractory acute myeloid leukemia (AML) were treated with clofarabine, cytarabine, and mitoxantrone. The overall response rate (ORR) was 90.4% (complete remission, CR: 69.2%; CR with incomplete hematological recovery, CRi: 21.2%), with 22 CR/CRi patients undergoing allogeneic hematopoietic stem cell transplantation (allo‐HSCT), while in CR; resulting in a 2‐year OS of 84.3% in CR patients and 90% in patients receiving allo‐HSCT. Clofarabine, cytarabine, and mitoxantrone resulted in high ORR and was safe in refractory/relapsed AML.

Background:Posaconazole is superior to fluconazole/itraconazole in preventing invasive fungal diseases (IFDs) in neutropenic patients. Whether the higher cost of posaconazole is offset by decreases in IFDs in a given institute requires cost-effective analysis encompassing the spectrum of IFDs and socioeconomic factors specific to that geographic area.Methods:This study performed a cost-effective analysis of posaconazole prophylaxis for IFDs in an Asian teaching hospital, employing decision modeling and data of IFDs and medication costs specific to the institute, in neutropenic patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).Results:In the cost-effectiveness analysis, the higher cost of posaconazole was partially offset by a reduction in the cost of treating IFDs that were prevented, resulting in an incremental cost of 125,954 Hong Kong dollars/16,148 USD per IFD avoided. Over a lifetime horizon, assuming same case fatality rate of IFDs in both groups, use of posaconazole results in 0.07 discounted life years saved. This corresponds to an incremental cost of 116,023 HKD/14,875 USD per life year saved. This incremental cost per life year saved in posaconazole prophylaxis fulfilled the World Health Organization defined threshold for cost-effectiveness.Conclusion:Posaconazole prophylaxis was cost-effective in Hong Kong.

Activating heterozygous germline mutations in the signal transducer and activator of transcription 3 ( STAT3) gene are associated with the rare autoimmune disorder autoimmune disease, multisystem, infantile onset (ADMIO). The phenotype of ADMIO is typified by hypogammaglobulinemia and onset of autoimmune phenomena during early childhood that include diabetes and autoimmune enteritis. This case report describes in utero onset of precocious lymphocyte maturation, autoimmune enteropathy-like inflammation, and proximal renal tubular dysplasia associated with a novel de novo heterozygous STAT3 mutation. The findings expand the phenotype associated with activating STAT3 mutations and suggest that the impact of the immunological abnormalities associated with ADMIO can begin prior to birth.

Genome-wide sequencing (GWS) is a standard of care for diagnosis of suspected genetic disorders, but the proportion of patients found to have pathogenic or likely pathogenic variants ranges from less than 30% to more than 60% in reported studies. It has been suggested that the diagnostic rate can be improved by interpreting genomic variants in the context of each affected individual's full clinical picture and by regular follow-up and reinterpretation of GWS laboratory results. Trio exome sequencing was performed in 415 families and trio genome sequencing in 85 families in the CAUSES study. The variants observed were interpreted by a multidisciplinary team including laboratory geneticists, bioinformaticians, clinical geneticists, genetic counselors, pediatric subspecialists, and the referring physician, and independently by a clinical laboratory using standard American College of Medical Genetics and Genomics (ACMG) criteria. Individuals were followed for an average of 5.1 years after testing, with clinical reassessment and reinterpretation of the GWS results as necessary. The multidisciplinary team established a diagnosis of genetic disease in 43.0% of the families at the time of initial GWS interpretation, and longitudinal follow-up and reinterpretation of GWS results produced new diagnoses in 17.2% of families whose initial GWS interpretation was uninformative or uncertain. Reinterpretation also resulted in rescinding a diagnosis in four families (1.9%). Of the families studied, 33.6% had ACMG pathogenic or likely pathogenic variants related to the clinical indication. Close collaboration among clinical geneticists, genetic counselors, laboratory geneticists, bioinformaticians, and individuals’ primary physicians, with ongoing follow-up, reanalysis, and reinterpretation over time, can improve the clinical value of GWS.

Myelodysplastic syndrome (MDS) is a heterogeneous, clonal hematological disorder characterized by ineffective hematopoiesis, cytopenia, morphologic dysplasia, and predisposition to acute myeloid leukemia (AML). Stem cell genomic instability, microenvironmental aberrations, and somatic mutations contribute to leukemic transformation. The hypomethylating agents (HMAs), azacitidine and decitabine are the standard of care for patients with higher-risk MDS. Although these agents induce responses in up to 40–60% of patients, primary or secondary drug resistance is relatively common. To improve the treatment outcome, combinational therapies comprising HMA with targeted therapy or immunotherapy are being evaluated and are under continuous development. This review provides a comprehensive update of the molecular pathogenesis and immune-dysregulations involved in MDS, mechanisms of resistance to HMA, and strategies to overcome HMA resistance.

Genetic disorders are one of the leading causes of infant mortality and are frequent in neonatal intensive care units (NICUs). Rapid genome-wide sequencing (GWS; whole genome or exome sequencing (ES)), due to its diagnostic capabilities and immediate impacts on medical management, is becoming an appealing testing option in the NICU setting. RAPIDOMICS was a trio-based rapid ES pilot study of 25 babies with suspected genetic disorders in the BC Women's Hospital NICU. ES and bioinformatic analysis were performed after careful patient ascertainment. Trio analysis was performed using an in-house pipeline reporting variants in known disease-causing genes. Variants interpreted by the research team as definitely or possibly causal of the infant's phenotype were Sanger validated in a clinical laboratory. The average time to preliminary diagnosis was 7.2 days. Sanger validation was pursued in 15 patients for 13 autosomal dominant and 2 autosomal recessive disorders, with an overall diagnostic rate (partial or complete) of 60%.Conclusion: In total, 72% of patients enrolled had a genomic diagnosis achieved through ES, multi-gene panel testing or chromosomal microarray analysis. Among these, there was an 83% rate of significant and immediate impact on medical decision-making directly related to new knowledge of the diagnosis. Health service implementation challenges and successes are discussed. What is Known: • Rapid genome-wide sequencing in the neonatal intensive care setting has a greater diagnostic hit rate and impact on medical management than conventional genetic testing. However, the impact of consultation with genetics and patient ascertainment requires further investigation. What is New: • This study demonstrates the importance of genetic consultation and careful patient selection prior to pursuing exome sequencing (ES). • In total, 15/25 (60%) patients achieved a diagnosis through ES and 18/25 (72%) through ES, multi-gene panel testing or chromosomal microarray analysis with 83% of those having immediate effects on medical management.

Despite therapeutic advances, early death (ED) remains a major factor curtailing survival of acute promyelocytic leukemia (APL). Studies examining factors that cause early death (ED; within 30 days of admission) and the correlation of survival with the timing of administration of all-trans retinoic acid (ATRA) and hemostatic parameters are scarce. We performed a cohort analysis of nonselect patients with newly diagnosed APL who presented to the health care system in Hong Kong, where oral arsenic trioxide was used. From 1 January 2007 to 30 April 2020, 358 patients (median age, 47 [1-97] years) with newly diagnosed APL were identified. ED occurred in 56 patients (16%): 11 (3%) died in the first 2 days after admission (intracranial hemorrhage [ICH], n = 6; APL-differentiation syndrome [APL-DS], n = 4; infection, n = 1); 22 (6%) died within 3 to 7 days (ICH, n = 12; APL-DS, n = 8; infections, n = 2), and 23 (6%) died within 8 to 30 days (ICH, n = 7; APL-DS, n = 11; infection, n = 5). Factors significantly associated with ED by multivariate analysis included male sex (P = .01); presenting leukocyte count ≥10 × 109/L (P = .03); fibrinogen 24 hours after hospital admission (P < .001). After a median follow-up of 47 (0-166) months, the 5- and 10-year overall survival (OS) was 68.6% and 61.2%, respectively. Excluding EDs, the 5- and 10-year post–30-day OS improved to 81.3% and 72.5%. Early administration of ATRA (

Background Patients with acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) suffer from a significant symptom burden and psychological, spiritual, social needs comparable to patients with solid metastatic malignancy. Referral to palliative care services for these haematological patients remains limited or often confined to the last days of life. We pioneered a palliative care (PC) program integrated with standard haematological care. The purpose of this trial will study the interventions by the PC team and preliminary results in the clinical outcomes. Methods This project is a non-blinded, randomized, controlled trial. In this study, we examine the clinical outcomes of the integrated PC program for MDS/AML patients when the 2nd lines disease treatment failed and in the presence of prognostic indicators. In group 1, patients will receive standard haematological care associated with PC (i.e., intervention group). In contrast, in group 2, patients will receive standard haematological care only (i.e., control group) with PC service only on a request basis. Patients who join the program would have to complete a standardized questionnaire to assess their quality of life and their psychological and physical symptoms. Results This is to exam the impact of the early integrated palliative care with enhanced psychosocial interventions to both advanced MDS/AML patients and their primary family members in Hong Kong. Discussion This protocol will not display any result. If future results demonstrate that the enhanced PC interventions are effective, they will provide a quality treatment plan for patients with MDS/AML. Trial registration The Hong Kong University/Hospital Authority Hong Kong West Institutional Review Board (HKU/HA HKW IRB). The registration number is UW 19-824.

Identifying genetic mosaicism is important in establishing a diagnosis, assessing recurrence risk, and providing accurate genetic counseling. Next-generation sequencing has allowed for the identification of mosaicism at levels below those detectable by conventional Sanger sequencing or chromosomal microarray analysis. The CAUSES Clinic was a pediatric translational trio-based genome-wide (exome or genome) sequencing study of 500 families (531 children) with suspected genetic disease at BC Children's and Women's Hospitals. Here we present 12 cases of apparent mosaicism identified in the CAUSES cohort: nine cases of parental mosaicism for a disease-causing variant found in a child and three cases of mosaicism in the proband for a de novo variant. In six of these cases, there was no evidence of mosaicism on Sanger sequencing—the variant was not detected on Sanger sequencing in three cases, and it appeared to be heterozygous in three others. These cases are examples of six clinical manifestations of mosaicism: a proband with classical clinical features of mosaicism (e.g., segmental abnormalities of skin pigmentation or asymmetrical growth of bilateral body parts), a proband with unusually mild manifestations of a disease, a mosaic proband who is clinically indistinguishable from the constitutive phenotype, a mosaic parent with no clinical features of the disease, a mosaic parent with mild manifestations of the disease, and a family in which both parents are unaffected and two siblings have the same disease-causing constitutional mutation. Our data demonstrate the importance of considering the possibility of mosaicism whenever exome or genome sequencing is performed and that its detection via genome-wide sequencing can permit more accurate genetic counseling.

Contains fulltext : 237823.pdf (Publisher’s version ) (Open Access) PURPOSE: The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood. METHODS: Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed. RESULTS: Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID. CONCLUSION: We expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1.