Adherence to a Mediterranean diet and health-related quality of life: a cross-sectional analysis of overweight and obese middle-aged and older adults with and without type 2 diabetes mellitus.

The relationship between adherence to a Mediterranean diet (MedDiet) and health-related quality of life (HRQoL) is unclear, particularly in vulnerable older adults. This cross-sectional analysis explored the association between adherence to a MedDiet and subscales of HRQoL in two independent cohorts of overweight and obese middle-aged to older adults with and without type 2 diabetes mellitus (T2DM). Both cohorts were community-dwelling (T2DM aged ≥ 50 years; non-T2DM aged ≥ 60 years) with a BMI ≥ 25 kg/m2. Adherence to a MedDiet was assessed using the Mediterranean Diet Adherence Screener, and HRQoL was determined using the 36-item short-form health survey. Multiple regression analysis was used to examine the association between adherence to a MedDiet and HRQoL subscales. A total of 152 middle-aged to older adults were included (T2DM: n 87, 71·2 (sd 8·2) years, BMI: 29·5 (sd 5·9) kg/m2; non-T2DM: n 65, 68·7 (sd 5·6) years, BMI: 33·7 (sd 4·9) kg/m2). Mean adherence scores for the entire cohort were 5·3 (sd 2·2) (T2DM cohort: 5·6(sd 2·3); non-T2DM cohort: 4·9 (sd 2·0)). In the adjusted model, using pooled data from both study cohorts, adherence to a MedDiet was significantly associated with the general health subscale of HRQoL (ß = 0·223; 95 % CI 0·006, 0·044; P = 0·001). Similar findings were also observed in the T2DM cohort (ß = 0·280; 95 % CI 0·007, 0·054; P = 0·001). However, no additional significant associations between adherence to a MedDiet and HRQoL subscales were observed. We showed that adherence to a MedDiet was positively associated with the general health subscale of HRQoL in middle-aged to older adults with T2DM. However, larger longitudinal data in older adults with a wider range of adherence scores, particularly higher adherence, are required to better understand the direction of this relationship.

Protein intake is not associated with functional biomarkers of physical frailty: A cross-sectional analysis of community-dwelling older adults with type 2 diabetes mellitus.

BACKGROUND AND AIM: Frailty has emerged as a third category of complication in patients with type 2 diabetes mellitus (T2DM). It has been suggested that adequate protein intake is an important dietary strategy for counteracting frailty. Therefore, we explored the association between protein intake and functional biomarkers of frailty in older adults with T2DM. METHODS AND RESULTS: Frailty was operationalized as the presence of three of the following: exhaustion, low muscle strength, low physical activity, slow gait speed, and weight loss. Functional biomarkers included handgrip strength (HGS), chair stands, the short physical performance battery and gait speed. Eighty-seven older adults (71.2 ± 8.2 years; 66.7% males) were included. A total of n = 6 (~7%) and n = 32 (~37%) participants were identified as frail and pre-frail respectively. No significant difference was observed for protein intake across staging of frailty (pre-frail/frail: 1.3 ± 0.4 g/kg BW; non-frail: 1.4 ± 0.4 g/kg BW; P = 0.320). A significant association was observed for total protein intake and HGS (ß = 0.44; 95% CI: 0.23-1.8; P = 0.01). However, this was no longer significant after adjusting for age, gender, physical activity, energy intake and total appendicular lean muscle (ß = 0.03; 95% CI: -0.45-0.60; P = 0.78). Nil other associations were observed between total protein intake and functional biomarkers of frailty. CONCLUSION: Adequate protein intake was not associated with functional biomarkers in older adults with T2DM. Future research should focus on the efficacy of protein on attenuating functional decline in vulnerable older adults with low protein intake.

Mucosal CD30-positive T-cell lymphoproliferations of the head and neck show a clinicopathologic spectrum similar to cutaneous CD30-positive T-cell lymphoproliferative disorders.

CD30-positive T-cell lymphoproliferative disorders are classified as cutaneous (primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis) or systemic. As extent of disease dictates prognosis and treatment, patients with skin involvement need clinical staging to determine whether systemic lymphoma also is present. Similar processes may involve mucosal sites of the head and neck, constituting a spectrum that includes both neoplasms and reactive conditions (eg, traumatic ulcerative granuloma with stromal eosinophilia). However, no standard classification exists for mucosal CD30-positive T-cell lymphoproliferations. To improve our understanding of these processes, we identified 15 such patients and examined clinical presentation, treatment and outcome, morphology, phenotype using immunohistochemistry, and genetics using gene rearrangement studies and fluorescence in situ hybridization. The 15 patients (11 M, 4 F; mean age, 57 years) had disease involving the oral cavity/lip/tongue (9), orbit/conjunctiva (3) or nasal cavity/sinuses (3). Of 14 patients with staging data, 7 had mucosal disease only; 2 had mucocutaneous disease; and 5 had systemic anaplastic large cell lymphoma. Patients with mucosal or mucocutaneous disease only had a favorable prognosis and none developed systemic spread (follow-up, 4-93 months). Three of five patients with systemic disease died of lymphoma after 1-48 months. Morphologic and phenotypic features were similar regardless of extent of disease. One anaplastic lymphoma kinase-positive case was associated with systemic disease. Two cases had rearrangements of the DUSP22-IRF4 locus on chromosome 6p25.3, seen most frequently in primary cutaneous anaplastic large cell lymphoma. Our findings suggest mucosal CD30-positive T-cell lymphoproliferations share features with cutaneous CD30-positive T-cell lymphoproliferative disorders, and require clinical staging for stratification into primary and secondary types. Primary cases have clinicopathologic features closer to primary cutaneous disease than to systemic anaplastic large cell lymphoma, including indolent clinical behavior. Understanding the spectrum of mucosal CD30-positive T-cell lymphoproliferations is important to avoid possible overtreatment resulting from a diagnosis of overt T-cell lymphoma.

Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies.

The prognostic heterogeneity of the World Health Organization category of "systemic mastocytosis with associated clonal hematologic nonmast cell lineage disease" (SM-AHNMD) has not been systematically validated by primary data. Among 138 consecutive cases with SM-AHNMD, 123 (89%) had associated myeloid neoplasm: 55 (45%) myeloproliferative neoplasm (SM-MPN), 36 (29%) chronic myelomonocytic leukemia, 28 (23%) myelodysplastic syndrome (SM-MDS), and 4 (3%) acute leukemia. Of the myeloid subgroups, SM-MPN displayed a 2- to 3-fold better life expectancy (P = .003), whereas leukemic transformation was more frequent in SM-MDS (29%; P = .02). The presence of eosinophilia, although prevalent (34%), was prognostically neutral, and the overall results were not affected by exclusion of FIP1L1-PDGFRA-positive cases. We conclude that it is clinically more useful to consider specific entities, such as SM-MPN, systemic mastocytosis with chronic myelomonocytic leukemia, SM-MDS, and systemic mastocytosis with-acute leukemia, rather than their broad reference as SM-AHNMD.

Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors.

Clinical phenotype in systemic mastocytosis (SM) is markedly variable, which complicates prognostication and decision making regarding the choice and timing of therapy. In a retrospective study of 342 consecutive adult patients with SM seen at the Mayo Clinic between 1976 and 2007, disease subdesignation according to the World Health Organization (WHO) proposal was indolent (ISM) in 159 (46%), with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD) in 138 (40%), aggressive (ASM) in 41 (12%), and mast cell leukemia in 4 (1%). KITD816V was detected in bone marrow-derived DNA by allele-specific polymerase chain reaction (PCR) in 68% of 165 patients evaluated (ISM, 78%; ASM, 82%; SM-AHNMD, 60%; P = .03); JAK2V617F was detected in 4%, all in SM-AHNMD. Compared with those with nonindolent SM, life expectancy in ISM was superior and not significantly different from that of the age- and sex-matched US population. In addition, multivariable analysis identified advanced age, weight loss, anemia, thrombocytopenia, hypoalbuminemia, and excess bone marrow blasts as independent adverse prognostic factors for survival. The current study validates the prognostic relevance of the WHO subclassification of SM and provides additional information of value in terms of both risk stratification and interpretation of clinical presentation and laboratory results.

The Alpha-1 Association Genetic Counseling Program: an innovative approach to service.

In an era of specialty medicine, genetic counselors are becoming increasingly focused in their service provision. The Alpha-1 Association Genetic Counseling Program, established in September 2007, specializes in confidential toll-free genetic counseling provided by a certified genetic counselor for Alpha-1 Antitrypsin deficiency, a co-dominant condition associated with lung and/or liver disease. The program received more than 600 callers in its first 2 years. Sixty-seven percent of new callers were family members, carriers, or health professionals. The number of callers increased between the first 2 years, with the greatest increases being family members and health professionals. Testing options and explanation of results encompassed 60% of initial reasons for calls. Seventy-two percent of referrals came from family and friends, test result letters, and the Alpha-1 Association. Between year 1 and 2 family member referrals showed the largest increase. This disease-specific genetic counseling program provides a model that may be useful for other rare disease communities.

Multisite verification of the accuracy of a multi-gene next generation sequencing panel for detection of mutations and copy number alterations in solid tumours.

Molecular variants including single nucleotide variants (SNVs), copy number variants (CNVs) and fusions can be detected in the clinical setting using deep targeted sequencing. These assays support low limits of detection using little genomic input material. They are gaining in popularity in clinical laboratories, where sample volumes are limited, and low variant allele fractions may be present. However, data on reproducibility between laboratories is limited. Using a ring study, we evaluated the performance of 7 Ontario laboratories using targeted sequencing panels. All laboratories analysed a series of control and clinical samples for SNVs/CNVs and gene fusions. High concordance was observed across laboratories for measured CNVs and SNVs. Over 97% of SNV calls in clinical samples were detected by all laboratories. Whilst only a single CNV was detected in the clinical samples tested, all laboratories were able to reproducibly report both the variant and copy number. Concordance for information derived from RNA was lower than observed for DNA, due largely to decreased quality metrics associated with the RNA components of the assay, suggesting that the RNA portions of comprehensive NGS assays may be more vulnerable to variations in approach and workflow. Overall the results of this study support the use of the OFA for targeted sequencing for testing of clinical samples and suggest specific internal quality metrics that can be reliable indicators of assay failure. While we believe this evidence can be interpreted to support deep targeted sequencing in general, additional studies should be performed to confirm this.

Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication.

Ibrutinib inhibits Bruton tyrosine kinase while venetoclax is a specific inhibitor of the anti-apoptotic protein BCL2. Both drugs are highly effective as monotherapy against chronic lymphocytic leukemia (CLL), and clinical trials using the combination therapy have produced remarkable results in terms of rate of complete remission and frequency of undetectable minimal residual disease. However, the laboratory rationale behind the success of the drug combination is still lacking. A better understanding of how these two drugs synergize would eventually help develop other rational combination strategies. Using an ex vivo model that promotes CLL proliferation, we show that modeled ibrutinib proliferative responses, but not viability responses, correlate well with patients' actual clinical responses. Importantly, we demonstrate for the first time that ibrutinib and venetoclax act on distinct CLL subpopulations that have different proliferative capacities. While the dividing subpopulation of CLL responds to ibrutinib, the resting subpopulation preferentially responds to venetoclax. The combination of these targeted therapies effectively reduced both the resting and dividing subpopulations in most cases. Our laboratory findings help explain several clinical observations and contribute to the understanding of tumor dynamics. Additionally, our proliferation model may be used to identify novel drug combinations with the potential of eradicating residual disease.

PAX5-positive T-cell anaplastic large cell lymphomas associated with extra copies of the PAX5 gene locus.

Cell lineage is the major criterion by which lymphomas are classified. Immunohistochemistry has greatly facilitated lymphoma diagnosis by detecting expression of lineage-associated antigens. However, loss or aberrant expression of these antigens may present diagnostic challenges. Anaplastic large cell lymphoma is a T-cell lymphoma that shows morphologic and phenotypic overlap with classical Hodgkin's lymphoma, which is a tumor of B-cell derivation. Staining for the B-cell transcription factor, paired box 5 (PAX5), has been suggested to be helpful in this differential, as it is positive in most classical Hodgkin's lymphomas, but absent in anaplastic large cell lymphomas. In this study we report four systemic T-cell anaplastic large cell lymphomas that were positive for PAX5 by immunohistochemistry, with weak staining intensity similar to that observed in classical Hodgkin's lymphoma. All diagnoses were confirmed by a combination of morphologic, phenotypic, and molecular criteria. Three cases were anaplastic lymphoma kinase (ALK) negative and one was ALK positive. PAX5 immunohistochemistry was negative in 198 additional peripheral T-cell lymphomas, including 66 anaplastic large cell lymphomas. Unexpectedly, although PAX5 translocations were absent, all evaluable PAX5-positive anaplastic large cell lymphomas showed extra copies of the PAX5 gene locus by fluorescence in situ hybridization (FISH). In contrast, only 4% of PAX5-negative peripheral T-cell lymphomas had extra copies of PAX5. We conclude that aberrant expression of PAX5 occurs rarely in T-cell anaplastic large cell lymphomas, and may be associated with extra copies of the PAX5 gene. PAX5-positive lymphomas with morphologic features overlapping different lymphoma types should be evaluated with an extensive immunohistochemical panel and/or molecular studies to avoid diagnostic errors that could lead to inappropriate treatment. As PAX5 overexpression causes T-cell neoplasms in experimental models, PAX5 may have contributed to lymphomagenesis in our cases.

Adiposity is inversely associated with strength in older adults with type 2 diabetes mellitus.

BACKGROUND AND PURPOSE: Several biological mechanisms describing the pathway to mobility disability and functional decline in older adults with type 2 diabetes mellitus (T2DM) have been postulated, including skeletal muscle atrophy and the concurrent accumulation of fat mass. Therefore, we explored the association between adiposity, muscle strength and physical performance in community-dwelling older adults with T2DM. METHODS: Adiposity was measured by waist circumference (WC) or body fat percentage (BF %) derived from dual-energy X-ray absorptiometry (DXA). The Short Physical Performance Battery (SPPB) and gait speed were used to evaluate lower extremity physical function. Muscle strength was assessed using hand-grip strength (HGS) or chair stands. Multiple regression analysis was used to examine the association between measures of adiposity, SPPB score, gait speed, HGS and chair stands adjusted for age, gender and total appendicular skeletal muscle (ASM). RESULTS: A total of n = 87 participants (71.2 ± 8.2 years; BMI 29.5 ± 5.8 kg/m2; BF % 37.8 ± 7.3%) were included in this cross-sectional analysis. Pearson's correlation coefficients revealed that BF% was negatively associated with hand-grip strength (r = - 0.430; P < 0.001) and total ASM (r = - 0.223; P = 0.03), but positively associated with increased time to compete chair stands (r = 0.366; P < 0.001). After adjusting for age, gender and total ASM, WC and BF% were inversely associated with HGS (WC: ß = -0.385; P = 0.001; BF% ß = - 0.487; P < 0.001). Similarly, in the adjusted model, both WC and BF% were positively associated with increased time to complete chair stands (WC: ß = 0.479; P < 0.001; BF% ß = 0.415; P = 0.002). CONCLUSION: Adiposity, independent of the criteria used, was inversely associated with muscle strength, suggesting that adiposity negatively influences muscle quality in older adults with T2DM. Screening for poor muscle strength and quality has the potential to facilitate early exercise and dietary interventions aimed at preserving muscle function in older adults with T2DM.

Diagnostic differences and agreement between the original and revised European Working Group (EWGSOP) consensus definition for sarcopenia in community-dwelling older adults with type 2 diabetes mellitus.

AIM: We aimed to compare diagnostic differences for identification of sarcopenia using the original operational definition developed by the European Working Group on Sarcopenia in Older People (EWGSOP1) and the most recently revised EWGSOP2 definition in community dwelling older adults with type 2 diabetes mellitus (T2DM). METHODS: Appendicular Lean Mass (ALM) corrected for height (ALM/m2) was assessed by dual energy X-ray absorptiometry. Muscle strength was assessed using hand-grip strength (HGS) or chair stands, and the Short Physical Performance Battery (SPPB) and gait speed were used to evaluate lower extremity physical function. Cohen's kappa (κ) statistic was applied to determine the degree of agreement between the two definitions. Chi-square analysis with Bonferroni post hoc corrections were applied to determine differences in the prevalence of sarcopenic case-findings. RESULTS: A total of n = 87 older adults (71.2 ±â€¯8.2 years; 66.7% males; BMI: 29.5 ±â€¯5.8 kg/m2) were included. Agreement between the two definitions was low and non-significant (κ value = 0.118; P =  0.144). Significantly more cases of sarcopenia were identified when applying the EWGSOP1 definition (EWGSOP1: n = 6 (7%); EWGSOP2: n = 2 (2%); P = 0.004). No sex specific differences were observed. Only 2 of the 6 (33.3%) cases of sarcopenia identified by EWGSOP1 were also identified as sarcopenic when applying the EWGSOP2 diagnostic criteria. CONCLUSIONS: We showed significant discordance and limited overlap in the number of sarcopenic case-findings when applying both EWGSOP definitions. It is unknown as to whether the new diagnostic criteria are better at identifying adverse clinical outcomes in patients with T2DM. Future investigation is therefore warranted.

Activation of the pattern recognition receptor NOD1 augments colon cancer metastasis.

While emerging data suggest nucleotide oligomerization domain receptor 1 (NOD1), a cytoplasmic pattern recognition receptor, may play an important and complementary role in the immune response to bacterial infection, its role in cancer metastasis is entirely unknown. Hence, we sought to determine the effects of NOD1 on metastasis. NOD1 expression in paired human primary colon cancer, human and murine colon cancer cells were determined using immunohistochemistry and immunoblotting (WB). Clinical significance of NOD1 was assessed using TCGA survival data. A series of in vitro and in vivo functional assays, including adhesion, migration, and metastasis, was conducted to assess the effect of NOD1. C12-iE-DAP, a highly selective NOD1 ligand derived from gram-negative bacteria, was used to activate NOD1. ML130, a specific NOD1 inhibitor, was used to block C12-iE-DAP stimulation. Stable knockdown (KD) of NOD1 in human colon cancer cells (HT29) was constructed with shRNA lentiviral transduction and the functional assays were thus repeated. Lastly, the predominant signaling pathway of NOD1-activation was identified using WB and functional assays in the presence of specific kinase inhibitors. Our data demonstrate that NOD1 is highly expressed in human colorectal cancer (CRC) and human and murine CRC cell lines. Clinically, we demonstrate that this increased NOD1 expression negatively impacts survival in patients with CRC. Subsequently, we identify NOD1 activation by C12-iE-DAP augments CRC cell adhesion, migration and metastasis. These effects are predominantly mediated via the p38 mitogen activated protein kinase (MAPK) pathway. This is the first study implicating NOD1 in cancer metastasis, and thus identifying this receptor as a putative therapeutic target.

Greater adherence to a Mediterranean Diet is associated with better gait speed in older adults with type 2 diabetes mellitus.

BACKGROUND & AIMS: Older adults with type 2 diabetes mellitus (T2DM) are vulnerable to the physical frailty phenotype. Adherence to a Mediterranean Diet (MedDiet) is emerging as a potential dietary strategy to attenuate physical disability with age. This cross-sectional analysis aimed to explore the association between adherence to a MedDiet and characteristics of the physical frailty phenotype in older adults with T2DM. METHODS: Adherence to a MedDiet was assessed using two dietary adherence tools: [1] alternate Mediterranean Food Score (MED); [2] Mediterranean Diet Adherence Screener (MEDAS). The short physical performance battery (SPPB) and gait speed was used to evaluate lower extremity physical function. Frailty was defined as having three of the following: exhaustion, low muscle strength, low physical activity, slow gait speed, and weight loss. Multiple regression analysis was used to summarise associations between dietary adherence, SPPB score, gait speed and muscle strength adjusted for age, physical activity and time since T2DM diagnosis. RESULTS: A total of n = 87 participants (71.2 ± 8.2 years) were included. A total of n = 6 (∼7%) and n = 32 (∼37%) participants were identified as frail and pre-frail respectively. After adjustment for age, physical activity and time since T2DM diagnosis, greater adherence to a MedDiet, using both adherence tools, was significantly associated with better gait speed (MED: ß = 0.365; P = 0.002; MEDAS: ß = 0.313; P = 0.007). When assessing the individual dietary elements included in the MED score, fish and seafood consumption was the single significant contributor to better gait speed (ß = 0.229; P = 0.05). Nil associations were observed when assessing adherence against muscle strength. CONCLUSIONS: Greater adherence to a MedDiet was associated with better lower extremity physical performance in older adults with T2DM. Future studies should investigate the efficacy of a MedDiet intervention for attenuation of physical frailty characteristics in older adults with T2DM.

20+ yr without leukemic or fibrotic transformation in essential thrombocythemia or polycythemia vera: predictors at diagnosis.

OBJECTIVES: The current study identified patients with either essential thrombocythemia (ET) or polycythemia vera (PV) who have survived for at least 20 yr without the development of either acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) or myelofibrosis (MF) and compared their presenting features with those in whom these complications occurred in the first 10 yr of disease. METHODS: The study patients were selected from an institutional database of 1061 patients with either ET (n = 603) or PV (n = 458). In both instances, three distinct groups were delineated and their presenting features compared; group A included patients who have remained AML/MDS/MF free after a minimum follow-up of 20 yr; groups B and C included patients who developed either AML/MDS or MF, respectively, in the first decade of their disease. RESULTS: The respective number of patients who fulfilled the above-mentioned criteria for inclusion in groups A, B and C were 40, 12 and 8 for ET and 23, 18 and 12 for PV. In ET, compared with both groups B and C, group A displayed significantly fewer patients with less than normal hemoglobin level (P < 0.0001 and =0.02) or male sex (P = 0.005 and 0.05), respectively. On multivariable analysis, only anemia sustained its significance. A similar analysis in PV revealed an association between group B and leukocytosis using a leukocyte count threshold of either 10 or 15 x 10(9)/L (P = 0.02). CONCLUSION: The current study identifies PV patients with leukocytosis and ET patients with anemia as the most likely to undergo leukemic or fibrotic transformation.

Barriers to genetic testing among persons at risk for alpha-1 antitrypsin deficiency.

The alpha coded testing (ACT) study offers free and confidential testing for alpha-1 antitrypsin deficiency (AATD) and includes surveys to provide data to study the psychosocial correlates of genetic testing. The purpose of the current study is to better understand reasons why some individuals complete genetic testing while others do not. Survey measures were compared between participants who requested and returned a genetic test for AATD (n = 703), and a random sample of individuals who requested a test kit, but did not return it within 3 months of their request (n = 83). Increasing decile of age (odds ratio [OR] = 0.74 [95% confidence interval = 0.60-0.82]) and fingerstick fear (OR = 0.74 [0.60-0.93]) were associated with a decreased likelihood of returning the test, while assurance of confidentiality was associated with an increased likelihood (OR = 1.26 [1.01-1.57]) of returning the genetic test. General anxiety as measured by the Beck Anxiety Inventory, family functioning as measured by the general functioning subscale of the Family Assessment Device, and stress induced by genetic testing as measured by the Impact of Events Scale did not significantly differ between responder groups (p = not significant). Results of this study help characterize factors driving genetic testing in AATD and may offer insight into population responses with other genetic tests.

Clinical Significance of DNA Variants in Chronic Myeloid Neoplasms: A Report of the Association for Molecular Pathology.

To address the clinical relevance of small DNA variants in chronic myeloid neoplasms (CMNs), an Association for Molecular Pathology Working Group comprehensively reviewed published literature, summarized key findings that support clinical utility, and defined critical gene inclusions for high-throughput sequencing testing panels. This review highlights the biological complexity of CMNs [including myelodysplastic syndromes, myeloproliferative neoplasms, entities with overlapping features (myelodysplastic syndromes/myeloproliferative neoplasms), and systemic mastocytosis], the genetic heterogeneity within diagnostic categories, and similarities between apparently disparate diagnostic entities. The founding variant's hematopoietic differentiation compartment, specific genes and variants present, order of variant appearance, individual subclone dynamics, and therapeutic intervention all contribute to the clinicopathologic features of CMNs. Selection and efficacy of targeted therapies are increasingly based on DNA variant profiles present at various time points; therefore, high-throughput sequencing remains critical for patient management. The following genes are a minimum recommended list to provide relevant clinical information for the management of most CMNs: ASXL1, BCOR, BCORL1, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PPM1D, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, and ZRSR2. This list is not comprehensive for all myeloid neoplasms and will evolve as insights into effects of combinations of relevant biomarkers on specific clinicopathologic characteristics of CMNs accumulate.

Oxytetracycline does not cause growth promotion in finfish.

Until recently, use of antibiotics to enhance terrestrial animal growth performance was a common, U.S. Food and Drug Administration (FDA)-approved, but controversial practice. There are no FDA-approved production claims for antibiotic drug use in fish, but it is a common misconception that antibiotics are widely used for this purpose in U.S. aquaculture. Antibiotics are not thought to be effective growth promoters in fish, but there is little quantitative data available to address whether there are growth-promoting effects that might incentivize the use of antibiotics in this way, despite legal prohibitions. Therefore, this study was conducted to determine if oral administration of oxytetracycline, an antibiotic with known growth-promoting effects in terrestrial livestock, has a similar effect when applied to channel catfish Ictalurus punctatus, hybrid striped bass Morone chrysops × M. saxatilis, Nile tilapia Oreochromis niloticus, or rainbow trout Oncorhynchus mykiss. Oxytetracycline products with production claims are typically applied at doses substantially lower than the approved therapeutic doses for the same products. Medication (0, 0.24, or 1.2 g oxytetracycline dihydrate kg-1 feed) and feeding rates (3% BW d-1) were selected to achieve target daily doses of 0, 16, or 80 mg kg-1 fish representing control, subtherapeutic, and therapeutic treatments. Replicate groups of fish (N = 4) were fed accordingly for 8 wk. Overall, oral administration of oxytetracycline did not affect survival or promote growth of the selected taxa, with no significant differences observed for weight gain, feed conversion ratio, or specific growth rate (P > 0.05 in all cases). Few differences were observed in organosomatic indices and in the frequency of tissue abnormalities; where present, these differences tended to suggest a negative effect of long-term dietary exposure to oxytetracycline. These data demonstrate that there is no benefit to dietary supplementation with oxytetracycline for nontherapeutic purposes in a range of economically important finfish species. As such, our results indicate there is little incentive to misuse oxytetracycline products for purposes of growth promotion in U.S. aquaculture.

Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors.

OBJECTIVE: To describe the long-term natural history of essential thrombocythemia (ET) in terms of life expectancy, risk of disease transformation Into a more aggressive myeloid disorder, and prognostic factors for both survival and disease complications. PATIENTS AND METHODS: The study population consisted of a consecutive cohort of patients seen at the Mayo Clinic In Rochester, Minn, in whom a diagnosis of ET was established before 1992, thus allowing a minimum of 10 years of potential follow-up. The conventional criteria-based diagnosis was confirmed by bone marrow biopsy in all Instances. RESULTS: A total of 322 patients were studied (median age, 54 years; median follow-up, 13.6 years). With a median survival time of 18.9 years, survival in the first decade of disease was similar to that of the control population (risk ratio, 0.72; 95% confidence interval, 0.50-0.99) but became significantly worse thereafter (risk ratio, 2.21; 95% confidence Interval, 1.74-2.76). Multivariable analysis identified age at diagnosis of 60 years or older, leukocytosis, tobacco use, and diabetes mellitus as Independent predictors of poor survival. A 2-variable model based on an age cutoff of 60 years and leukocyte count of 15 x 10(9)/L resulted in 3 risk groups with significant difference in survival. In addition, age at diagnosis of 60 years or older, leukocytosis, and history of thrombosis were independent predictors of major thrombotic events. The risk of leukemic or any myeloid disease transformation was low in the first 10 years (1.4% and 9.1%, respectively) but increased substantially in the second (8.1% and 28.3%, respectively) and third (24.0% and 58.5%, respectively) decades of the disease. CONCLUSION: Life expectancy in patients with ET is significantly worse than that of the control population. Leukocytosis is identified as a novel independent risk factor for both inferior survival and thrombotic events.

JAK2(V617F) and leukemic transformation in myelofibrosis with myeloid metaplasia.

Amongst 42 consecutive patients with leukemic transformation (LT) from myelofibrosis with myeloid metaplasia (MMM) 72% carried the JAK2(V617F) mutation. The mutation was observed at expected frequencies in all subtypes of MMM and acute myeloid leukemia. Although the patients with the mutation were younger and had a shorter interval to LT there was no difference in survival. Additionally, both the lack of mutation status progression in serial analysis (available in nine patients) and the low frequency of patients with high mutated allele burden suggest that LT arising from MMM is probably not dependent on changes in JAK2(V617F) mutation status.