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.

Decreased survival and increased rate of fibrotic progression in essential thrombocythemia chronicled after the FDA approval date of anagrelide.

First-line cytoreductive drug of choice in high risk essential thrombocythemia (ET) is currently hydroxyurea, a practice based on the results of a randomized study; second-line drugs of choice include pegylated interferon-α, busulfan and anagrelide. Anagrelide clinical trials were pioneered by the late Murray N. Silverstein (1928-1998) of the Mayo Clinic whose studies led to FDA approval in March 1997. The current study represents a retrospective examination of the potential impact of anagrelide therapy on survival and disease complications in ET. 1076 patients with ET were considered (median age 58 years; females 63%); risk distribution, according to the international prognostic score for ET (IPSET), was 28% high, 42% intermediate, and 30% low. Overall (OS), myelofibrosis-free (MFFS) and thrombosis-free survival data were compared for ET patients diagnosed before and after the 1997 FDA approval date for anagrelide; a significant difference was apparent in OS (P = .006; HR 1.4, 95% CI 1.1-1.7) and MFFS (P < .001; HR 4.2, 95% CI 2.7-6.5), in favor of patients diagnosed prior to 1997; the difference was sustained during multivariable analysis that included IPSET. Similarly stratified survival data in polycythemia vera (n = 665) and primary myelofibrosis (n = 1282) showed no similar impact on survival (P = .3 and .17, respectively). The current study represents a retrospective analysis and suggests significantly decreased OS and MFFS in ET patients diagnosed after the FDA approval date of anagrelide. Whether or not anagrelide therapy was to blame for the worsening of OS and MFFS over time cannot be assumed and requires validation in a prospective study.

The Impact of a Required Longitudinal Stress Management and Resilience Training Course for First-Year Medical Students.

BACKGROUND: Although psychological distress is common among medical students, little remains known about effective interventions. One promising individual-focused approach is mindfulness-based stress management interventions; however, studies to date have relied on volunteers. OBJECTIVE: To determine whether a required longitudinal stress management and resilience course improves well-being among first-year medical students. DESIGN: A quasi-experimental study. PARTICIPANTS: Two cohorts of medical students who participated in a required stress management and resilience course and completed pre and post questionnaires. MAIN MEASURES: Validated instruments were used to examine the effects on burnout, quality of life (QOL), stress, resilience, happiness, and empathy. Paired analysis was conducted to explore changes from baseline. KEY RESULTS: On paired analysis of individual students, mean mental QOL and happiness declined (mental QOL: -5.63 [P < 0.001] and -5.15 [P = 0.015] and happiness: -0.31 [P = 0.02] and -0.4 [P = 0.01], cohorts 1 and 2, respectively) over the course of the year. Similarly, stress scores increased by 4.22 (P < 0.0001) and 3.62 (P = 0.03) in cohorts 1 and 2, respectively. Cognitive and emotive empathy declined in both cohorts but was only statistically significant for cohort 1 (-1.64 and -2.07, P < 0.01). No statistically significant differences in burnout or resilience were seen. CONCLUSIONS: The required longitudinal mindfulness-based stress management course tested in first-year medical students did not lead to measurable improvements in medical student well-being or empathy. These findings contrast with those of studies using volunteer medical students or physicians, which suggested a reduction in burnout and stress using a similar curriculum. Medical schools should consider offering a variety of effective options so that students can select activities they want to engage in.

Science of health care delivery milestones for undergraduate medical education.

BACKGROUND: The changing healthcare landscape requires physicians to develop new knowledge and skills such as high-value care, systems improvement, population health, and team-based care, which together may be referred to as the Science of Health Care Delivery (SHCD). To engender public trust and confidence, educators must be able to meaningfully assess physicians' abilities in SHCD. We aimed to develop a novel set of SHCD milestones based on published Accreditation Council for Graduate Medical Education (ACGME) milestones that can be used by medical schools to assess medical students' competence in SHCD. METHODS: We reviewed all ACGME milestones for 25 specialties available in September 2013. We used an iterative, qualitative process to group the ACGME milestones into SHCD content domains, from which SHCD milestones were derived. The SHCD milestones were categorized within the current ACGME core competencies and were also mapped to Association of American Medical Colleges' Entrustable Professional Activities (AAMC EPAs). RESULTS: Fifteen SHCD sub-competencies and corresponding milestones are provided, grouped within ACGME core competencies and mapped to multiple AAMC EPAs. CONCLUSIONS: This novel set of milestones, grounded within the existing ACGME competencies, defines fundamental expectations within SHCD that can be used and adapted by medical schools in the assessment of medical students in this emerging curricular area. These milestones provide a blueprint for SHCD content and assessment as ongoing revisions to milestones and curricula occur.

Pruritus in primary myelofibrosis: management options in the era of JAK inhibitors.

Primary myelofibrosis (PMF)-associated pruritus is often severe and requires treatment. Fifty-one patients with bone marrow-proven PMF with associated pruritus were identified from a primary cohort of patients with PMF (n = 566) seen at our institution. We conducted a retrospective review of the clinical characteristics, severity of pruritus, type of treatment, and response of these patients. Thirty-two out of 51 patients (63 %) reported severe PMF-associated pruritus and required a total of 108 treatment episodes, with complete response (CR), partial response (PR) and no response (NR) observed in 22, 23, and 55 % of episodes, respectively. The most common treatment categories included JAK inhibitors (n = 19), anti-depressants (n = 18), and antihistamines (n = 17). Highest CR rates were observed in patients treated with a JAK inhibitor (53 %) and immunomodulatory drugs (IMiDS (50 %)). Emerging targeted therapies may result in better symptom control and higher response rates in patients suffering from severe PMF-associated pruritus.

Mutations and thrombosis in essential thrombocythemia: prognostic interaction with age and thrombosis history.

BACKGROUND: Vascular events in essential thrombocythemia (ET) are associated with advanced age and thrombosis history. Recent information suggests additional effect from the presence of specific mutations. OBJECTIVES: To examine the influence of age and thrombosis history on the reported association between mutational status and thrombosis-free survival in ET. PATIENTS AND METHODS: Analysis was performed using a Mayo Clinic cohort of 300 ET patients, and key findings were reanalyzed by including additional 102 Italian patients. RESULTS: Among 300 Mayo patients with ET (median age 55 yr, 60% females), mutational frequencies were 53% JAK2, 32% CALR, 3% MPL, and 12% JAK2, CALR and MPL wild type. One hundred and six (35%) patients experienced arterial (n = 75) or venous (n = 43) events, before (n = 55) or after (n = 71) diagnosis. In univariate analysis, compared to JAK2-mutated cases, JAK2, CALR and MPL wild type (HR 0.31, 95% CI 0.11-0.86), and CALR-mutated (0.53, 95% CI 0.30-0.92) patients displayed better thrombosis-free survival. JAK2, CALR, and MPL wild type remained significant (P = 0.03; HR 0.32, 95% CI 0.11-0.9) during multivariable analysis that included age (P = 0.01) and thrombosis history (P = 0.0006); a favorable impact from CALR mutations was of borderline significance (P = 0.1; HR 0.62, 95% CI 0.35-1.1), but became significant (P = 0.02) when multivariable analysis including thrombosis history (P = 0.02) was performed on patients younger than 60 yr of age. CONCLUSIONS: The favorable impact of mutational status on thrombosis-free survival in ET might be most evident for JAK2, CALR, and MPL wild type patients, whereas the favorable effect from CALR mutations might be confined to young patients.

Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: a collaborative study of 1027 patients.

CALR (calreticulin) trails JAK2 as the second most mutated gene in essential thrombocythemia (ET). Mutant CALR in ET is a result of frameshift mutations, caused by exon 9 deletions or insertions; type-1, 52-bp deletion (p.L367fs*46), and type-2, 5-bp TTGTC insertion (p.K385fs*47) variants constitute more than 80% of these mutations. The current study includes a total of 1027 patients divided into test (n = 402) and validation (n = 625) cohorts. Among the 402 ET patients in the test cohort, 227 (57%) harbored JAK2, 11 (3%) Myeloproliferative leukemia virus oncogene (MPL), and 114 (28%) CALR mutations; 12% were wild-type for all three mutations (i.e., triple-negative). Among the 114 patients with CALR mutations, 51 (45%) displayed type-1 and 44 (39%) type-2 variants; compared to mutant JAK2, both variants were associated with higher platelet and lower hemoglobin and leukocyte counts. However, male sex was associated with only type-1 (P = 0.005) and younger age with type-2 (P = 0.001) variants. Notably, platelet count was significantly higher in type-2 vs. type-1 CALR-mutated patients (P = 0.03) and the particular observation was validated in the validation cohort that included 111 CALR-mutated ET patients (P = 0.002). These findings, coupled with the recent demonstration of preferential expression of mutant and wild-type CALR in megakaryocytes, suggest differential effects of CALR variants on thrombopoiesis.

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.

Pruritus in primary myelofibrosis: clinical and laboratory correlates.

Recent clinical trials with JAK or mammalian target of rapamycin (mTOR) inhibitors in primary myelofibrosis (PMF) have identified pruritus as one of the most treatment-responsive disease traits. However, little is known about the prevalence of pruritus in PMF or its clinical and laboratory correlates. Among 566 consecutive patients with PMF seen at our institution, the presence or absence of pruritus was documented in 90 (16%) and 146 (26%) patients, respectively. Patients with pruritus were less likely to express MPLW515 (0% vs. 10%; P = 0.02) or leukopenia (8% vs. 24%; P = 0.002). The latter association was more pronounced in the absence of JAK2 or MPL mutations. Pruritus also clustered with marked leukocytosis (23% vs. 11%; P = 0.01) and JAK2V617F (71% vs. 59%; P = 0.08). Pruritus did not correlate with karyotype (P = 0.33), risk category per the Dynamic International Prognostic Scoring System (DIPSS)-plus (P = 0.37), DIPSS-plus-adjusted survival (P = 0.41), or leukemic transformation (P = 0.13). Plasma levels of 20 cytokines, which are known to be abnormally expressed in PMF, including IL-1b, IL-2R, IL-6, IL-8, and VEGF, were measured in 63 informative cases and showed no correlations with history of pruritus. We conclude that pruritus is relatively frequent in PMF and is prognostically irrelevant. The pathogenesis of PMF-associated pruritus is not necessarily linked to proinflammatory cytokines but may instead involve molecules that are either granulocyte-derived or influence granulopoiesis. The apparently differential effect of MPL vs. JAK2 mutations on pruritus requires further investigation.

The arduous journey to find a portrait of Beauchêne fils: a famous anatomist and surgeon.

Earlier publications by our group have reported the major contributions of Beauchêne fils, Edme François Chauvot de Beauchêne (1778-1830), a prosector, and surgeon in Paris. These included a variety of firsts: the finding of an intraneural ganglion cyst, the description of the exploded skull (Beauchêne) technique, and the case of air pulmonary embolism. This article describes the exhaustive efforts necessary to locate a portrait of him. Information obtained along the circuitous journey through 13 generations over five centuries will clarify the important medical accomplishments by individuals of a noble family. The discovered portraits will allow scholars to honor accurately the individuals, particularly Beauchêne fils, in the future.

Lack of efficacy of pyridoxine (vitamin B6) treatment in acquired idiopathic sideroblastic anaemia, including refractory anaemia with ring sideroblasts.

Pyridoxine, or vitamin B6, is commonly used to treat acquired idiopathic sideroblastic anaemia (AISA, including refractory anaemia with ring sideroblasts), but the efficacy of this therapy in an unselected AISA population (i.e. patients without confirmed ALAS2 or other pyridoxine-responsive germline mutations) has not been established. We reviewed clinical data from 231 patients with AISA and found that 42% of 203 evaluable patients had been treated with pyridoxine. Only 6.8% of pyridoxine-treated patients experienced a haemoglobin improvement (≥ 1.5 g/dL) meeting 2006 International Working Group for Myelodysplastic Syndromes standardised response criteria. As some patients received combination therapy with erythropoietin or other agents, improvement could be attributed to pyridoxine monotherapy in only one patient (1.4%). Smaller, less meaningful increments in haemoglobin levels of 0.5 g/dL were observed in 13.5% of patients. Response to therapy did not correlate with International Prognostic Scoring System (IPSS) risk group or multilineage vs unilineage dysplasia. New symptomatic peripheral neuropathy was noted in 2.3% of patients treated with pyridoxine. In this large series of unselected patients with sideroblastic anaemia, pyridoxine therapy was ineffective and was associated with a risk of adverse effects. Pyridoxine therapy should be reserved for patients with known or suspected pyridoxine-responsive mutations.

Discovering the elusive Beauchêne: the originator of the disarticulated anatomic technique.

The identity of the Beauchêne bearing the name of the widely used disarticulated anatomic technique has remained elusive over the years. This article traces the skull technique to its originator, Edmé François Chauvot de Beauchêne (ca. 1780-1830), an anatomist and surgeon. In addition to pioneering this innovative anatomic preparation, Edmé François reported the first known case of an intraneural cyst in 1810 and pulmonary air embolism in 1818. The credit has been incorrectly attributed to Claude Beauchêne, an imaginary anatomist in Paris in the 1850s, or to his famous father, Edmé Pierre Chauvot de Beauchêne (1749-1825), a psychologist and physician. The significant accomplishments of Edmé François Chauvot de Beauchêne (Beauchêne fils or Beauchêne son) in medicine have been overshadowed by those of his distinguished father and should be fully recognized.

Predictors of pregnancy outcome in essential thrombocythemia: a single institution study of 63 pregnancies.

An increased risk of pregnancy complications was recently reported in JAK2V617F-positive essential thrombocythemia (ET). In the current study of 63 pregnancies among 36 women with ET, we sought to appraise this association and identify other predictors of outcome. Overall outcome included 38 (60%) births and 20 (35%) first trimester spontaneous abortions. Among 36 first pregnancies, 22 (61%) resulted in live birth. Twelve of the 14 pregnancy losses occurred during the first trimester. Rate of pregnancy loss was 21% among 24 patients receiving aspirin therapy during the first trimester vs. 75% among 12 patients not receiving such treatment (P = 0.002). Pregnancy outcome was not influenced by platelet count, leukocyte count or presence of JAK2V617F; four pregnancy losses each were documented in 10 mutated and 10 unmutated patients. Among 17 second pregnancies, 12 (71%) resulted in live birth; these included eight from nine patients with successful and four from eight with unsuccessful first pregnancies (P = 0.07). Maternal complications were infrequent (11%): pre-eclampsia (n = 1), hematoma after Cesarean-section (n = 2) and post-partum hemorrhage (n = 1). This study suggests a salutary role for aspirin therapy in pregnant women with ET. Furthermore, the occurrence of a miscarriage in ET might be a marker for a similar event during subsequent pregnancies.

Cytogenetic abnormalities in essential thrombocythemia: prevalence and prognostic significance.

OBJECTIVES: In the current study we describe cytogenetic findings as well as clinical correlates and long-term prognostic relevance of abnormal cytogenetics at the time of diagnosis of essential thrombocythemia (ET). PATIENTS AND METHODS: The study cohort consisted of a consecutive group of patients with ET who fulfilled the World Health Organization diagnostic criteria, and in whom cytogenetic analysis was performed at diagnosis. RESULTS: A total of 402 patients were studied (median age, 56 yrs; median follow-up 70 months). The prevalence of abnormal cytogenetics at diagnosis was 7% (28 of 402). The most common cytogenetic anomalies were trisomy 9 (four patients), abnormal chromosome 1 (three patients) and trisomy 8 (two patients). Parameters at diagnosis that were significantly associated with abnormal cytogenetics included palpable splenomegaly (P = 0.03), current tobacco use (P = 0.04); venous thrombosis (P = 0.02), and anemia with a hemoglobin of <10 g/dL (P = 0.02); but did not include JAK2V617F mutation status, or advanced age. During follow up, patients with abnormal cytogenetics did not have shorter survival, or increased transformation to acute leukemia or myelofibrosis. CONCLUSION: Cytogenetic anomalies at diagnosis are relatively uncommon in ET, and do not predict evolution into more aggressive myeloid disorders, or inferior survival.