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Abstract Background: In essential thrombocythemia (ET), homozygosity for the JAK2 V617F mutant allele is rare despite the frequent (23–57%) occurrence of the heterozygous state. This is in direct contrast with the situation in polycythemia vera (PV) where homozygosity for the mutation is seen in 25–33% of the cases. The particular observation is consistent with what has been observed in vitro as well as in animal studies where JAK2 V617F has been associated with induction of erythropoietin hypersensitivity in cell lines and erythrocytosis in mice (James et al. Nature2005;434:1144). Therefore, regardless of whether or not JAK2 V617F represents a primary event in myeloproliferative disorders, it is probable that it promotes a PV phenotype. In the current study, we explore this hypothesis as well as investigate the long-term prognostic relevance of the mutation in a well defined cohort of patients with ET seen at a single institution. Methods: The diagnosis of ET was according to the WHO classification of tumors (Jaffe ES et al. Lyon, IARC press, 2001). All patients were seen at the Mayo Clinic and patient characteristics and subsequent clinical events were determined both retrospectively (chart review) and prospectively (by means of a questionnaire sent both to patients and their primary doctors). In addition date and cause of death were confirmed by probing both the social security index and the national death index. DNA for mutation screening was derived and sequenced from either archived unsorted cells from the bone marrow or prospectively collected peripheral blood granulocytes according to previously published methods (Levine et al. Cancer Cell, 2005;7:387). Results: The study cohort consisted of 150 consecutive patients with ET including 99 females and 51 males (median age 49.8 years; range 16.8–98). Overall, JAK2 V617F was detected in 73 patients (48.7%) but none were homozygous for the mutant allele. At diagnosis, ET patients with JAK2 V617F were significantly older (median age of 53.5 vs. 42.3; p=0.02) and also displayed higher readings of both hemoglobin level (p=0.0002) and leukocyte count (p=0.005). All study patients have now been followed for a median of 11.4 years from diagnosis (range 0–32.7) and follow-up period was similar between the two mutational categories (p=0.53). During this period, 32 patients have died and the median survival for the entire group was 19.3 years; 21.9 and 17.7 years in the absence and presence of the mutation, respectively (p=0.09). Disease transformation into acute leukemia, myelofibrosis, and PV occurred in 6 (4%), 15 (10%), and 8 (5.3%) patients, respectively, and the only significant difference between the two mutational categories in this regard was the higher incidence of transformation into PV in patients with the mutation (p=0.02). Multivariate analysis identified age, hemoglobin level, and thrombosis history at diagnosis but not JAK2 V617F mutational status as independent risk factors for survival. Conclusion: Although the presence of JAK2 V617F in ET appears to promote a PV phenotype, it might not carry treatment-relevant information.

Abstract Background Estrogen-based hormone treatment (EBHT), in the form of either oral contraceptives or hormone replacement therapy, is generally felt to be associated with an increased risk of thrombosis in women with essential thrombocythemia (ET). However, there is insufficient evidence to support or refute such a concern. Methods Data was abstracted from medical records of a consecutive cohort of women with ET seen at the Mayo Clinic. Thrombotic risk was determined by the occurrence of a major thrombotic event namely myocardial infarction, angina, cerebrovascular accident, transient ischemic attack, peripheral arterial thrombosis, pulmonary embolism, or deep venous thrombosis at or after diagnosis of ET. Results i. Information regarding EBHT at or after the diagnosis of ET The study cohort included 307 women with ET (median age, 55 years; range 16–88) with a median follow-up of 133 months from diagnosis (range, 0.2–397). EBHT at or after diagnosis was documented in 93 women (30%); 59 patients were on EBHT at time of diagnosis and treatment was initiated after diagnosis in 34 patients. Among the 59 patients who were receiving EBHT at the time of diagnosis, treatment was discontinued within one month of their ET diagnosis in 17 patients but continued in the other 42 patients for a median of 48 months (range, 2–168). In the 34 patients with EBHT that was initiated after the diagnosis of ET, median treatment period was 44 months (range, 1–144). ii. Correlation between EBHT and thrombosis at diagnosis At diagnosis, major thrombosis was documented in a total of 74 patients (24%) that included 11 of the 59 patients (19%) on EBHT and 63 of 248 patients (25%) that were not receiving such therapy at the time of diagnosis (p=0.28). iii. Correlation between EBHT and thrombosis after diagnosis A total of 95 patients (31%) experienced a subsequent (i.e. post-diagnosis) thrombotic episode during the study period. These occurred in 65 of 214 patients (30%) that were not exposed to EBHT at or after diagnosis, 5 of 17 patients (29%) in whom EBHT was discontinued with the diagnosis of ET, 13 of 42 patients (31%) in whom EBHT was continued despite the diagnosis of ET, and 12 of 34 patients (35%) in whom EBHT was started after the diagnosis of ET (p=0.95). Furthermore, duration of EBHT, using a cutoff value of 1 year, did not significantly affect the incidence of thrombotic events (p=0.67). The different comparative groups were similar in age distribution as well as frequency of other cardiovascular risk factors including smoking, diabetes mellitus, hypertension, and hyperlipidemia. Conclusion The current study addresses the important issue of safety pertaining to the use of estrogen-based hormones in women with ET and did not reveal a significant alteration of thrombosis risk as a result of hormone therapy.

Abstract Background: The FIP1L1-PDGFRA fusion, an imatinib-sensitive molecular target, is detected in a subset of cases with moderate-to-severe eosinophilia (eosinophil count ≥1500/μL). Using 2 FISH strategies to detect loss of the CHIC2 locus as a surrogate marker of the FIP1L1-PDGFRA fusion, we previously found 14% of cases to be CHIC2-deleted when studying bone marrow smears from 81 adult patients with moderate-to-severe, non-reactive eosinophilia at our institution (Blood 2004, 104:3038–3045). Since then, the FISH test has been made available for routine clinical use both within our institution, and to external physicians as a mail-in test, for the workup of patients with eosinophilic disorders, including systemic mast cell disease (SMCD). Study design: FISH data, subsequent to the test’s introduction into routine clinical practice (from Nov. 2003), were retrospectively analyzed for CHIC2-deletion. Data from the initial pilot study of 81 patients was not used in this analysis (Table). The imatinib treatment analysis, however, included all CHIC2-deleted patients treated at our institution, including those from the pilot study (Table). Results: A total of 741 patients were studied in the post-pilot phase. Of these, 20 cases were found to be CHIC2-deleted, with an overall prevalence of 2.7% (Table). Of the 219 patients seen at our institution, 13 (all male) were found to be CHIC2-deleted (Table) (prevalence=5.9%), and of these, 10 have been treated with imatinib (100 mg/day starting dose) to date. Nine patients are evaluable for response - all achieved a complete clinical and histological remission (7 patients were tested by FISH post-treatment - all achieved cytogenetic remission). One patient received concomitant corticosteroids for co-morbidities and could not be evaluated for response. After a median follow-up of 24 months (range 17 to 39 months), all 9 patients continue to be in remission, with a normal eosinophil count. At last follow-up, one patient had discontinued imatinib and the others were on maintenance therapy at the following dose: 100mg/wk (n=1), 100mg BIW (n=1), 100mg TIW (n=2), 50mg QOD (n=1), and 100 mg/day (n=3). Conclusions: FIP1L1-PDGFRA prevalence in non-selected patients with eosinophilia is lower than anticipated from prior studies. Patients with FIP1L1-PDGFRA exhibit durable responses to imatinib therapy. It may be feasible to maintain some patients in remission on an empirically derived, intermittent schedule of low-dose imatinib. Pilot Data Post-pilot Data (n=741) Total Mayo samples Mayo samples Mail-in samples Number of Patients 81 138 603 822 Number CHIC2-deleted 11 2 18 31 Prevalence 14% 1.4% 3.0% 3.8% Number Imatinib treated 8 2 n/a 10

Abstract Background: Paroxysmal Nocturnal Hemoglobinuria (PNH) is a clonal stem cell disorder characterized by intravascular hemolysis, thrombosis, bone marrow failure and reduced survival. In this current single institution study of patients with PNH, we investigate the risk factors predictive of survival and thrombosis. Methods: Data were abstracted from medical records of a consecutive cohort of patients with PNH seen at the Mayo Clinic. Diagnosis was confirmed by the presence of intravascular Hemolysis and either a positive Ham’s test, and/or by the presence of a GPI-deficient hematopoietic clone. Follow-up data were obtained by contacting the patients and by reviewing the social security death index. Results: i. Patients and treatment: The study cohort included 68 patients with PNH (median age 32 years, range 10–77; 33 females) with a median follow up of 84.5 months (range, 1–538 months). Presenting features included infection (n=9), thrombosis (n=9), neutropenia (absolute neutrophil count (ANC) < 1000) (n=32) severe intravascular hemolysis (n=16) and splenomegaly (n=11). Prior to the diagnosis of PNH, 6 patients (8.8%) carried a diagnosis of aplastic anemia (AA) and 2 (2.9%) myelodysplastic syndrome (MDS). Complications documented after diagnosis included major thrombosis (n=11), major hemorrhage (n=4), and development of AA (n=7), MDS (n=4), and non-hematologic cancer (n=4) but none experienced leukemic transformation. Treatment included prednisone (n=30), other immunosuppressive agents (n=6), androgens (n=10), and bone marrow transplantation (n=4). Review of treatment with systemic anticoagulation disclosed only 2 patients that were receiving prophylactic warfarin therapy and both patients remain free of thrombosis after 1 and 2 years of therapy. ii. Thrombotic events and risk factors: Overall, 20 patients (29.4 %) experienced one or more episodes of major thrombosis. Among several clinical and laboratory parameters evaluated at presentation, only the detection of urine hemoglobin and infection were found to be significantly associated with the occurrence of thrombosis (p=0.05) iii. Risk factors for survival To date, 18 patients (27%) have died and median survival for the study cohort is projected at 21.1 years. Multivariate analysis identified thrombosis (p=0.003) and an ANC of > 1000 (p= 0.05) at presentation as independent risk factors for inferior survival. In addition, the occurrence of major hemorrhage was significantly associated with poor survival (p= 0.04). Conclusion The current study provides natural history information in a relatively large cohort of patients with PNH and identifies certain disease features that could be further explored for their potential as risk factors for both thrombosis and survival.

Abstract Background: Leukocytosis has recently been implicated as an adverse prognostic feature for thrombosis in both ET and PV. Such an association would be therapeutically most relevant in the context of “low-risk” disease. In the current study, we sought to clarify the relationship between leukocytosis at diagnosis and the subsequent occurrence of either arterial or venous thrombosis, in “low-risk” patients with ET or PV. Methods: Data was abstracted from the medical records of a consecutive cohort of patients with WHO-defined ET or PV seen at the Mayo Clinic. Low-risk disease was defined by the absence of both thrombosis history and age 3 60 years. Cox proportional hazards model was utilized to determine the impact of clinical and laboratory variables on thrombosis-free survival (TFS). Arterial- or venous-specific TFS curves were constructed by Kaplan-Meier method. Results: i) Patient characteristics and outcome A total of 407 “low-risk” patients were studied; 153 had PV (median age 48 years; females 43%) and 254 ET (median age 42 years; females 71%). A total of 46 thrombotic events (22 arterial and 24 venous) were recorded in 41 (27%) patients with PV during a median follow up of 130 months (range 2–562 months). The corresponding figures in ET were 54 total thrombotic events (41 arterial and 14 venous) in 47 (19%) patients at a median follow up of 104 months (range 0.25–424 months). Cytoreductive therapy was avoided in the presence of < 1000 x 109/L platelet count but, at the discretion of the treating physician, some patients with higher platelet counts received prophylactic cytoreductive therapy. ii) Correlation between leukocytosis and thrombosis A leukocyte count of 3 15 x 109/L at diagnosis was documented in 42 (27%) patients with PV and 21 (8%) patients with ET; 102 patients (40%) with ET had > 9.4 x 109/L leukocyte count. Leukocyte count considered as either a continuous or categorical variable (using cutoff levels of 15 x 109/L for PV and either 15 x 109/L or 9.4 x 109/L for ET) was not significantly associated with either arterial or venous thrombosis (Figure 1). iii) Correlation between other risk factors and thrombosis In univariate analysis, presence of the JAK2V617F was significantly associated with arterial thrombosis in ET (p=0.049) but significance was lost during multivariable analysis that included age as a covariate. Only advanced age was found to be significantly associated with arterial thrombosis in PV (p=0.04) and higher hemoglobin level with venous thrombosis in ET (p<0.0001). Conclusion: The current study does not identify leukocyte count at diagnosis as a marker of increased thrombosis risk in low-risk patients with either ET or PV. Instead, the study found an association between arterial thrombosis and advanced age in PV and venous thrombosis and higher hemoglobin level in ET. Figure Figure

Abstract Background: Essential thrombocythemia (ET) frequently occurs in women of childbearing age. Recently, an increased risk of pregnancy complications was reported in patients with ET carrying the JAK2V617F mutation (Passamonti et al. Blood. 2007;110:485). In the current study, we sought to validate this observation as well as identify other predictors of pregnancy loss in ET. Methods: Data was abstracted from the medical records of a consecutive cohort of patients with WHO-defined ET seen at the Mayo Clinic. Patient characteristics and pregnancy outcome are summarized using descriptive statistics. The analysis of risk factors associated with pregnancy complications was carried out by both univariate and multivariate analyses. Results: i) Patient characteristics at ET diagnosis A total of 63 pregnancies were recorded in 36 women at or after their diagnosis of ET. At diagnosis of ET, median (range) values were: age 26 years (15–36), platelet count 1350 x 109/L (683–3300), hemoglobin level 13.3 g/dL (10.5–16) and leukocyte count 9.3 x109/L (5–26.9). JAK2V617F mutation analysis was performed in 20 patients; half were positive. Only 5 patients had a history of thrombosis at diagnosis. Follow-up after ET diagnosis was for a median of 82.9 months (range, 6.5–340.8 months). ii) Outcome of first pregnancy at or after diagnosis of ET A total of 36 first pregnancies were documented at or after the diagnosis of ET. At the time, median (range) values were: time from diagnosis 25.5 months (0–155), age 28 years (20–36), platelet count 840 x 109/L (255–1998), hemoglobin 12.9 g/dl (9–16.6) and leukocyte count 8.4 x109/L (6.6–19.8). Seven of the 36 (19%) women were receiving cytoreductive therapy at time of conception: anagrelide (n=4), interferon (n=1), hydroxyurea (n=1) and radiophosphorus (n=1). Aspirin therapy was documented in 53% of the women at time of conception and in 69% during the first trimester of their pregnancy. Among the 36 first pregnancies, 61% (n=22) resulted in live birth and 39% (n=14) in fetal loss. Twelve of the 14 pregnancy losses occurred during the first trimester (10 spontaneous miscarriages, 1 ectopic pregnancy and 1 therapeutic abortion) and the remaining two during the second trimester. Maternal complications occurred in 11% (n=4) of pregnancies and included pre-eclampsia (n=1), hematoma after Cesarean-section (n=2) and post-partum hemorrhage (n=1). iii) Predictors of first pregnancy outcome in ET Pregnancy outcome, in terms of live birth versus miscarriage did not correlate with age (p=0.27), presence of cardiovascular risk factor (p=0.76), platelet count (p=0.49), leukocyte count (p=0.67) or hemoglobin level (p=0.31). Similarly, pregnancy loss was similar between JAK2V617F-positive (4 of 10 pregnancies) and JAK2V617F-negative (4 of 10 pregnancies) patients (p>0.9). Furthermore, among 5 cases of 3 consecutive miscarriages, 4 were JAK2V617F-negative. Interestingly, the rate of pregnancy loss was only 21% among 24 patients receiving aspirin therapy during the first trimester as compared to 75% among the 12 patients in whom no such treatment was documented (p=0.002). iv) Second and subsequent pregnancy outcome Seventeen second pregnancies were recorded; 71% (n=12) resulted in live birth that included 8 of 9 patients with successful and 4 of 8 with unsuccessful first pregnancies (p=0.07). The trend was similar among 7 third pregnancies, which resulted in only one live birth; 5 of the 6 fetal losses occurred in women with history of first pregnancy loss (p=0.09). Conclusion: The current study does not support the recently communicated association between the presence of JAK2V617F and increased risk of pregnancy loss in ET. Instead, two parameters of potential importance for predicting pregnancy outcome in ET were identified; the occurrence of a miscarriage might be a marker for a similar event during subsequent pregnancies whereas aspirin therapy during the first trimester might be beneficial.

BACKGROUND: Risk factors for pouch survival may or may not have a linear relationship with pouch loss over time. Conditional survival is a method to describe these nonlinear time-to-event relationships by reporting the expected survival at various time points. OBJECTIVE: The aim of this study was to calculate conditional pouch survival based on occurrence of risk factors for pouch loss. DESIGN: This was a retrospective study from an institutional database. SETTINGS: The study was conducted at the Cleveland Clinic Foundation. PATIENTS: Patients with ulcerative or indeterminate colitis who underwent index IPAA construction between 1986 and 2016 were included. MAIN OUTCOME MEASURES: Patients were stratified based on postoperative anastomotic leak, abscess, or fistula occurrence. The Kaplan–Meier method with conditional survival was used to estimate overall and cause-specific survival at 10 years. RESULTS: A total of 3468 patients underwent IPAA during the study period. The overall 10-year pouch survival rate was 0.94 (95% CI, 0.93–0.95), and after 1 year the conditional pouch survival increased to 0.95 (95% CI, 0.94–0.96), after 3 years to 0.97 (95% CI, 0.96–0.98), and after 5 years to 0.98 (95% CI, 0.98–0.99). A total of 122 patients (3.5%) developed anastomotic leak, and the 10-year IPAA survival in patients with leak was 0.85 (95% CI, 0.77–0.93). In this group, after 1 year of pouch survival, the conditional pouch survival increased to 0.89 (95% CI, 0.82–0.96) and after 3 years to 0.98 (95% CI, 0.94–1.00). A similar pattern was seen for IPAA with postoperative abscess. The conditional survival curve was stable over time for patients with a fistula. LIMITATIONS: This was a retrospective, single-institution study. CONCLUSIONS: Overall conditional pouch survival improved over time for patients with postoperative anastomotic leak and abscess. These novel findings can be useful to counsel patients regarding expectations for long-term pouch survival even if they develop leaks and abscesses. See Video Abstract at http://links.lww.com/DCR/B217. SUPERVIVENCIA CONDICIONAL DESPUÉS DE ANASTOMOSIS CON BOLSA ÍLEO ANAL, PARA COLITIS ULCERATIVA E INDETERMINADA: ¿LA SOBREVIDA DE LA BOLSA A LARGO PLAZO, MEJORA O EMPEORA CON EL TIEMPO? ANTECEDENTES: Los factores de riesgo para la sobrevida de la bolsa, pueden o no tener una relación lineal con la pérdida de la bolsa y con el tiempo. La supervivencia condicional es un método para describir estas relaciones no lineales de tiempo, hasta el evento informando la supervivencia esperada en varios puntos de tiempo. OBJETIVO: El objetivo de este estudio fue calcular la supervivencia condicional de la bolsa, en función de aparición de factores de riesgo para la pérdida de bolsa. DISEÑO: Estudio retrospectivo de una base de datos institucional. AJUSTES: Cleveland Clinic Foundation. PACIENTES: Pacientes con colitis ulcerativa o indeterminada, sometidos a una anastomosis de bolsa íleo anal, de 1986 a 2016. PRINCIPALES MEDIDAS DE RESULTADO: Los pacientes fueron estratificados en función de la fuga anastomótica postoperatoria, absceso o aparición de fístula. El método de Kaplan Meier con supervivencia condicional, se utilizó para estimar la supervivencia general y la causa específica a los 10 años. RESULTADOS: Un total de 3.468 pacientes fueron sometidos a anastomosis ileal con bolsa anal durante el período de estudio. La tasa de supervivencia global de la bolsa a 10 años, fue de 0,94 (0,93 a 0,95), y después de 1 año, la supervivencia condicional de la bolsa aumentó a 0,95 (0,94 a 0,96), después de 3 años a 0,97 (0,96 a 0,98) y después de 5 años a 0.98 (0.98 - 0.99). Un total de 122 (3,5%) pacientes desarrollaron fuga anastomótica, y la supervivencia de la anastomosis de bolsa íleo anal a 10 años en pacientes con fuga fue de 0,85 (IC del 95%: 0,77 a 0,93). En este grupo, después de 1 año de supervivencia de la bolsa, la supervivencia condicional de la bolsa aumentó a 0,89 (IC del 95%: 0,82 a 0,96), y después de 3 años a 0,98 (IC del 95%: 0,94 a 1). Se observó un patrón similar para la anastomosis de bolsa íleo anal con absceso postoperatorio. La curva de supervivencia condicional fue estable en el tiempo para los pacientes con una fístula. LIMITACIONES: Estudio retrospectivo, de una sola institución. CONCLUSIONES: La supervivencia condicional global de la bolsa, mejoró con el tiempo para pacientes con fuga anastomótica postoperatoria y absceso. Estos nuevos hallazgos pueden ser útiles para aconsejar a los pacientes con respecto a las expectativas de supervivencia de la bolsa a largo plazo, incluso si desarrollan fugas y abscesos. Consulte Video Resumen http://links.lww.com/DCR/B217. (Traducción—Dr Fidel Ruiz Healy)

Abstract Aims Takotsubo syndrome (TTS) is an acute heart failure syndrome, which shares many features with acute coronary syndrome (ACS). Although TTS was initially described with angiographically normal coronary arteries, smaller studies recently indicated a potential coexistence of coronary artery disease (CAD) in TTS patients. This study aimed to determine the coexistence, features, and prognostic role of CAD in a large cohort of patients with TTS. Methods and results Coronary anatomy and CAD were studied in patients diagnosed with TTS. Inclusion criteria were compliance with the International Takotsubo Diagnostic Criteria for TTS, and availability of original coronary angiographies with ventriculography performed during the acute phase. Exclusion criteria were missing views, poor quality of angiography loops, and angiography without ventriculography. A total of 1016 TTS patients were studied. Of those, 23.0% had obstructive CAD, 41.2% had non-obstructive CAD, and 35.7% had angiographically normal coronary arteries. A total of 47 patients (4.6%) underwent percutaneous coronary intervention, and 3 patients had acute and 8 had chronic coronary artery occlusion concomitant with TTS, respectively. The presence of CAD was associated with increased incidence of shock, ventilation, and death from any cause. After adjusting for confounders, the presence of obstructive CAD was associated with mortality at 30 days. Takotsubo syndrome patients with obstructive CAD were at comparable risk for shock and death and nearly at twice the risk for ventilation compared to an age- and sex-matched ACS cohort. Conclusions Coronary artery disease frequently coexists in TTS patients, presents with the whole spectrum of coronary pathology including acute coronary occlusion, and is associated with adverse outcome. Trial registration ClinicalTrials.gov number: NCT01947621.