Prognostic impact of SF3B1 mutation and multilineage dysplasia in myelodysplastic syndromes with ring sideroblasts: a Mayo Clinic study of 170 informative cases.

The revised 4th edition of the World Health Organization (WHO4R) classification lists myelodysplastic syndromes with ring sideroblasts (MDS-RS) as a separate entity with single lineage (MDS-RS-SLD) or multilineage (MDS-RS-MLD) dysplasia. The more recent International Consensus Classification (ICC) distinguishes between MDS with SF3B1 mutation (MDS-SF3B1) and MDS-RS without SF3B1 mutation; the latter is instead included under the category of MDS not otherwise specified. The current study includes 170 Mayo Clinic patients with WHO4R-defined MDS-RS, including MDS-RS-SLD (N=83) and MDS-RS-MLD (N=87); a subset of 145 patients were also evaluable for the presence of SF3B1 and other mutations, including 126 with (87%) and 19 (13%) without SF3B1 mutation. Median overall survival for all 170 patients was 6.6 years with 5- and 10-year survival rates of 59% and 25%, respectively. A significant difference in overall survival was apparent between MDS-RS-MLD and MDS-RS-SLD (p<0.01) but not between MDS-RS with and without SF3B1 mutation (p=0.36). Multivariable analysis confirmed the independent prognostic contribution of MLD (HR 1.8, 95% CI 1.1-2.8; p=0.01) and also identified age (p<0.01), transfusion need at diagnosis (p<0.01), and abnormal karyotype (p<0.01), as additional risk factors; the impact from SF3B1 or other mutations was not significant. Leukemia-free survival was independently affected by abnormal karyotype (p<0.01), RUNX1 (0.02) and IDH1 (p=0.01) mutations, but not by MLD or SF3B1 mutation. Exclusion of patients not meeting ICC-criteria for MDSSF3B1 did not change the observations on overall survival. MLD-based, as opposed to SF3B1 mutationbased, disease classification for MDS-RS might be prognostically more relevant.

A dynamic 3-factor survival model for acute myeloid leukemia that accounts for response to induction chemotherapy.

The current study was approached with the assumption that response to induction chemotherapy, in acute myeloid leukemia (AML), overshadows pre-treatment risk variables in predicting survival and therefore be used as an anchor for a simplified risk model. We considered 759 intensively-treated patients with AML, not promyelocytic: median age 60 years; primary 66%, secondary 25%, and therapy-related 9%; European LeukemiaNet cytogenetic risk category favorable 8%, intermediate 61%, and adverse 31%. Complete remission with (CR) or without (CRi) count recovery was achieved in 608 (80%) patients. After a median follow-up of 22 months, 503 deaths, 272 relapses, and 257 allogeneic hematopoietic stem cell transplants (AHSCTs) were recorded. Multivariable analysis identified failure to achieve CR/CRi (HR 3.8, 95% CI 3.1-4.8), adverse karyotype (2.2, 1.8-2.8), and age >55 years (2.1, 1.6-2.7) as main risk factors for survival. HR-weighted scoring resulted in four-tiered risk stratification: low (0 points; N = 183), intermediate-1 (1 point; N = 331), intermediate-2 (2 points; N = 117), and high (≥3 points; N = 128), with respective median survival (5-year rate) not reached (68%), 34 (37%), 13 (20%), and 5 (5%) months (p < .001). FLT3-ITD mutation was associated with inferior survival in intermediate-1 (p = .004) and TP53 in intermediate-2 (p = .06) and high (p = .02) risk disease; the latter was fully accounted for by the close association between TP53 mutation and complex/monosomal karyotype while the observations regarding FLT3-ITD were not affected by treatment with midostaurin. AHSCT had a favorable impact on survival, most apparent in intermediate-1 (p < .001), intermediate-2 (p = .03), and high (p = .01) risk disease. The proposed 3-factor survival model offers a novel prototype that is amenable to further enhancement by molecular information and was validated in an external cohort of 1032 intensively-treated AML patients.

A long way to go: engagement of men and boys in country family planning commitments and implementation plans.

Background: To reach global goals related to women and girls' access to modern family planning (FP) and gender equality, evidence shows that it is critical to understand and account for the role of men and boys as users of reproductive health services, as partners for millions of women & girls around the world, and as advocates in their communities. Under the Family Planning 2020 (FP2020) partnership, countries were encouraged to develop costed implementation plans and action plans in an effort to provide 120 million additional women and girls with contraception. As FP2020 becomes FP2030, reviewing these previously-developed strategies helps understand the extent to which countries considered the engagement of men as an important aspect of their family planning portfolios. Methods: We conducted textual analysis on commitments and implementation plans related to achieving FP2020 commitments in six countries in Africa and one in Asia to determine the extent to which male engagement was incorporated into country or subnational family planning goals, with particular focus on FP policy, program, and financial commitments.  Results: Some of the documents analyzed included robust plans for including male engagement in their efforts to expand access to FP.  The strongest aspects of male engagement programming were those that sought to engage men as advocates for women's access to and use of FP services, and improve their knowledge and attitudes related to contraception and reproduction. The weakest aspects were engaging men as users of services and, vitally, tackling underlying gender norms which hamper men's and women's health-seeking behaviors and attitudes. Conclusions: Developing FP programs that target men and boys as people deserving of reproductive health services, as partners with women in building their families, and as social activists in their communities, will complement and strengthen existing FP programs as well as promote broader goals related to gender equality.

De novo isolated myeloid sarcoma: comparative analysis of survival in 19 consecutive cases.

Institutional database search (1999-2020) for acute myeloid leukaemia (AML) identified 109 cases of myeloid sarcoma (MS), of which 19 were isolated and presented de novo. The latter displayed longer survival (median 78 months), compared to MS with synchronous intramedullary AML (n = 32; median 16 months) and de novo AML without MS (n = 729; median 22 months; P = 0·13). However, the difference in survival was no longer apparent after accounting for bone marrow cytogenetic risk status (P = 0·67). Treatment-induced MS tumour resolution was not affected by the presence of intramedullary disease (P = 0·61). The current study clarifies the prognosis of de novo isolated MS, in the context of AML.

Health services for women, children and adolescents in conflict affected settings: experience from North and South Kivu, Democratic Republic of Congo.

BACKGROUND: Insecurity has characterized the Eastern regions of the Democratic Republic of Congo for decades. Providing health services to sustain women's and children's health during protracted conflict is challenging. This mixed-methods case study aimed to describe how reproductive, maternal, newborn, child, adolescent health and nutrition (RMNCAH+N) services have been offered in North and South Kivu since 2000 and how successful they were. METHODS: We conducted a case study using a desk review of publicly available literature, secondary analysis of survey and health information system data, and primary qualitative interviews. The qualitative component provides insights on factors shaping RMNCAH+N design and implementation. We conducted 49 interviews with government officials, humanitarian agency staff and facility-based healthcare providers, and focus group discussions with community health workers in four health zones (Minova, Walungu, Ruanguba, Mweso). We applied framework analysis to investigate key themes across informants.The quantitative component used secondary data from nationwide surveys and the national health facility information system to estimate coverage of RMNCAH+N interventions at provincial and sub-provincial level. The association between insecurity on service provision was examined with random effects generalized least square models using health facility data from South Kivu. RESULTS: Coverage of selected preventive RMNCAH+N interventions seems high in North and South Kivu, often higher than the national level. Health facility data show a small negative association of insecurity and preventive service coverage within provinces. However, health outcomes are poorer in conflict-affected territories than in stable ones. The main challenges to service provisions identified by study respondents are the availability and retention of skilled personnel, the lack of basic materials and equipment as well as the insufficient financial resources to ensure health workers' regular payment, medicaments' availability and facilities' running costs. Insecurity exacerbates pre-existing challenges, but do not seem to represent the main barrier to service provision in North and South Kivu. CONCLUSIONS: Provision of preventive schedulable RMNCAH+N services has continued during intermittent conflict in North and South Kivu. The prolonged effort by non-governmental organizations and UN agencies to respond to humanitarian needs was likely key in maintaining intervention coverage despite conflict. Health actors and communities appear to have adapted to changing levels and nature of insecurity and developed strategies to ensure preventive services are provided and accessed. However, emergency non-schedulable RMNCAH+N interventions do not appear to be readily accessible. Achieving the Sustainable Development Goals will require increased access to life-saving interventions, especially for newborn and pregnant women.

Clinical outcomes of adults with hemophagocytic lymphohistiocytosis treated with the HLH-04 protocol: a retrospective analysis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome of pathologic immune activation in children that is increasingly being recognized in adults. Efficacy data for the HLH-04 protocol in adults is lacking. This study retrospectively analyzed 31 adult patients, median age 46 years, who received HLH-04 from 1/1/2004 to 5/1/2018. HLH etiology included malignancy (n = 9), autoimmune (n = 8), infection (n = 8), and idiopathic (n = 6). Eighteen patients were evaluable for response at week 4 with 7 having no response, 11 reaching partial response, and 0 reaching complete response (CR). Six patients eventually achieved CR at a median 195 days. The 1-year overall survival (OS) was 35% and median OS was 3.2 months. Univariate analysis showed shorter survival for hemoglobin <9 g/dL (HR 4.29, p = 0.003), platelets <100 × 109/L (HR 4.06, p = 0.027), ANC <1 × 109/L (HR 5.24, p = 0.001), and total bilirubin >1.2 mg/dL (HR 3.30, p = 0.022). Outcomes of adults treated with HLH-04 remain dismal and newer treatment modalities are needed.

Etiologies of Extreme Thrombocytosis: A Contemporary Series.

OBJECTIVE: To describe the multifactorial etiologies of extreme thrombocytosis (EXT) in different care settings and the frequency of finding an occult malignancy. PATIENTS AND METHODS: We conducted a retrospective chart review at Mayo Clinic from January 1, 2011, through December 31, 2016. Adult patients who had at least 2 readings of platelet counts greater than 1000×109/L within 30 days of each other were included. We determined the causes of EXT on the basis of preset definitions of precipitating factors and identified the dominant causes on the basis of the trend of platelet counts. RESULTS: A total of 44,490 patients had thrombocytosis, and 305 patients (0.7%) had EXT. In 242 patients (79.3%), EXT was multifactorial. Surgical complications (54.1%) and hematologic malignancies (27.9%) were the 2 most dominant causes. Thirty-eight patients (12.5%) had new diagnoses of malignancies, mostly myeloproliferative neoplasms. In inpatients, surgical complications (71.9%), concurrent/previous splenectomy (50.5%), and infections (44.9%) were the most common causes, whereas hematologic malignancies (56.9%), iron deficiency (36.7%), and previous splenectomy (28.4%) were the most common causes in outpatients. Hematologic malignancy was 3.4 times more likely to be the cause of EXT in outpatients than in inpatients (56.9% vs 16.8%), and a new diagnosis of hematologic malignancy was 1.9 times more likely to be made in outpatients (15.6% vs 8.2%). Eighty-four percent of patients had resolution of EXT within 30 days. One patient died during the period of EXT. Nonsurgical patients with hematologic malignancies had the most prolonged period of EXT. CONCLUSION: Extreme thrombocytosis is a multifactorial hematologic condition, and its etiology differs substantially between inpatients and outpatients. Occult hematologic malignancies are uncommon in EXT when other major causes are present.

Successful Percutaneous Nephrolithotomy in Patients with Immune-Mediated Thrombocytopenia Treated with Romiplostim.

BACKGROUND: Percutaneous nephrolithotomy (PCNL) for large stone burden can be problematic in patients with significant risk of bleeding complications, specifically thrombocytopenia. This report demonstrates effective correction of two patients' thrombocytopenia, subsequently leading to removal of large stone burden through PCNL. CASE PRESENTATION: We present two Middle Eastern patients who presented with medical histories significant for thrombocytopenia, secondary to splenomegaly and hepatic vein thrombosis, and large volume nephrolithiasis. Patient 1 is a 65-year-old female with a right 5 cm stone and a platelet count of 34,000. Patient 2 is a 45-year-old female with a 3 cm left staghorn stone and a platelet count of 44,000. After consultation with hematology, both underwent therapy with prednisone and intravenous immunoglobulin without improvement in their platelet count. They then received 3 µg/kg/dose of romiplostim weekly that improved their platelet counts to 133,000 and 195,000 in 2 weeks, respectively. Patient 1's PCNL was completed in a single-stage procedure with stone-free status shown on CT postoperative day 1. Patient 2 underwent PCNL and a secondary ureteroscopy for residual stone fragments on postoperative day 2. Both patients experienced no complication during the procedure, hospital stay, or postoperative course. Both continued romiplostim for 20 days postoperatively with platelet levels returning to their baseline range after 1 month. CONCLUSION: In the appropriately selected patient, romiplostim can correct thrombocytopenia enough to safely and effectively perform PCNL in patients with underlying hematologic disorders. Close coordination between urology and hematology is imperative to ensure an effective outcome in this challenging patient population.

Effect of the UK's revised paracetamol poisoning management guidelines on admissions, adverse reactions and costs of treatment.

AIMS: In September 2012 the UK's Commission on Human Medicines (CHM) recommended changes in the management of paracetamol poisoning: use of a single '100 mg l(-1) ' nomogram treatment line, ceasing risk assessment, treating all staggered/uncertain ingestions and increasing the duration of the initial acetylcysteine (NAC) infusion from 15 to 60 min. We evaluated the effect of this on presentation, admission, treatment, adverse reactions and costs of paracetamol poisoning. METHODS: Data were prospectively collected from adult patients presenting to three large UK hospitals from 3 September 2011 to 3 September 2013 (year before and after change). Infusion duration effect on vomiting and anaphylactoid reactions was examined in one centre. A cost analysis from an NHS perspective was performed for 90 000 patients/annum with paracetamol overdose. RESULTS: There were increases in the numbers presenting to hospital (before 1703, after 1854; increase 8.9% [95% CI 1.9, 16.2], P = 0.011); admitted (1060/1703 [62.2%] vs. 1285/1854 [69.3%]; increase 7.1% [4.0, 10.2], P < 0.001) and proportion treated (626/1703 [36.8%] vs. 926/1854 [50.0%]; increase: 13.2% [95% CI 10.0, 16.4], P < 0.001). Increasing initial NAC infusion did not change the proportion of treated patients developing adverse reactions (15 min 87/323 [26.9%], 60 min 145/514 [28.2%]; increase: 1.3% [95% CI -4.9, 7.5], P = 0.682). Across the UK the estimated cost impact is £8.3 million (6.4 million-10.2 million) annually, with a cost-per-life saved of £17.4 million (13.4 million-21.5 million). CONCLUSIONS: The changes introduced by the CHM in September 2012 have increased the numbers of patients admitted to hospital and treated with acetylcysteine without reducing adverse reactions. A safety and cost-benefit review of the CHM guidance is warranted, including novel treatment protocols and biomarkers in the assessment of poisoning.

Therapy-related acute promyelocytic leukemia: observations relating to APL pathogenesis and therapy.

Therapy-related acute promyelocytic leukemia (t-APL) is a well-recognized form of APL for which the underlying etiology has been well characterized. The pathogenesis of de novo (dn-APL) remains unknown; but epidemiologic studies have consistently identified increased body mass index (BMI), younger age, and ethnicity as possible risk factors. We analyzed demographics, clinical features, and treatment responses in a contemporary series of 64 patients treated with all-trans-retinoic acid and anthracycline-based therapy to assess for differences in these two etiologically distinct patient groups. Compared with patients with t-APL (n = 11), those with dn-APL (n = 53) had a greater median BMI (31.33 vs. 28.48), incidence of obesity (60.4% vs. 27.3%) (P = 0.04), and history of hyperlipidemia (45.3% vs. 18.2%) (P = 0.01). Fewer t-APL than dn-APL patients achieved complete remission at 63.6% vs. 92.5% respectively (P = 0.008). This was the result of a higher induction mortality rate of 36.4% vs. 7.5% respectively (P = 0.008). No cases of leukemic resistance were seen in either group. Overall survival (OS) was inferior in t-APL compared with dn-APL at 51% vs. 84%, respectively (P < 0.005), primarily as a result of higher induction mortality. Relapse occurred in nine patients (16.1%) overall, but no relapses occurred in the t-APL cohort. Our observations provide further support for the hypothesis that abnormalities in lipid homeostasis may in some way be of pathogenic importance in dn-APL. Therapy-related APL is sensitive to standard therapy with no cases of resistance or relapse seen. The inferior OS of the t-APL was due to induction mortality, possibly reflecting prior therapy.

Assessing attitudes about genetic testing as a component of continuing medical education.

OBJECTIVE: To investigate the attitudes among mental health professionals regarding the use of genetic testing. METHODS: Psychiatrists and other mental health professionals (N=41) who were enrolled in a week-long course in psychiatric genomics completed questionnaires before and after the course designed to assess how diagnostic genetic tests should be used and the value of pharmacogenomic testing for clinical practice. RESULTS: Only 5% of the course participants knew their genotype for the CYP 2D6 and CYP 2C19 genes at the time they participated in the course. However, after completing the course, 95% of the participants who had not been tested responded that they would be tested if genotyping was provided at no cost. Most of the participants reported that adults have the right to know their genotypes. Specifically, a majority of participants also reported that adults should have access to information regarding their genetic predispositions to both Huntington's disease and Alzheimer's disease. A majority of participants believed that parents had the right to know the genotypes of their children and that adolescents should have access to their genotypes if they had parental permission or were emancipated minors. However, only 29% of participants reported that children ages 6 to 12 should have access to the results of their genotyping. CONCLUSION: Continuing medical educational programs can provide an effective and informative opportunity to develop a better understanding of contemporary perspectives of practicing clinicians. Despite some variability in beliefs regarding the implications of age and diagnosis for making genetic testing decisions, a majority of course participants reported that they would choose to be genotyped for two drug metabolizing enzyme genes. Furthermore, they felt that, in most circumstances, adults should be permitted to know their genotype.

Report of 255 clinical ethics consultations and review of the literature.

OBJECTIVE: To review clinical ethics consultations at a tertiary care academic medical center. METHODS: We retrospectively reviewed all ethics consultations (and associated patient medical records) conducted at the Mayo Clinic in Rochester, Minn, between April 6, 1995, and December 31, 2005. RESULTS: Of the 255 consultations, 101 (40%) reviewed intensive care unit care, 103 (40%) involved patients who died during hospitalization, and 174 (68%) were requested by physicians. The most common primary diagnoses of the patients involved were malignancy (18%, n=47), neurologic disease (18%, n=47), and cardiovascular disease (17%, n=43). Most cases involved multiple issues: patient competency and decision-making capacity (82%, n=208), staff member disagreement with care plans (76%, n=195), end-of-life and quality-of-life issues (60%, n=154), and goals of care and futility (54%, n=138). Withholding or withdrawing measures was the focus of 132 (52%) of the consultations. We also identified previously published reports of ethics consultations and compared the findings of those reports with ours. CONCLUSIONS: Despite advances in medicine, the nature of ethical dilemmas remains relatively unchanged. Issues of communication, family conflict, and futility continue to give rise to ethical quandaries.