Barry K. Moser

Noninvasive evaluation of hepatic fibrosis using acoustic radiation force-based shear stiffness in patients with nonalcoholic fatty liver disease

BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease in developed countries, may progress to nonalcoholic steatohepatitis (NASH) in a minority of people. Those with NASH are at increased risk for cirrhosis and hepatocellular carcinoma. The potential risk and economic burden of utilizing liver biopsy to stage NAFLD in an overwhelmingly large at-risk population are enormous; thus, the discovery of sensitive, inexpensive, and reliable noninvasive diagnostic modalities is essential for population-based screening. METHODS Acoustic Radiation Force Impulse (ARFI) shear wave imaging, a noninvasive method of assessing tissue stiffness, was used to evaluate liver fibrosis in 172 patients diagnosed with NAFLD. Liver shear stiffness measures in three different imaging locations were reconstructed and compared to the histologic features of NAFLD and AST-to-platelet ratio indices (APRI). RESULTS Reconstructed shear stiffnesses were not associated with ballooned hepatocytes (p=0.11), inflammation (p=0.69), nor imaging location (p=0.11). Using a predictive shear stiffness threshold of 4.24kPa, shear stiffness distinguished low (fibrosis stage 0-2) from high (fibrosis stage 3-4) fibrosis stages with a sensitivity of 90% and a specificity of 90% (AUC of 0.90). Shear stiffness had a mild correlation with APRI (R(2)=0.22). BMI>40kg/m(2) was not a limiting factor for ARFI imaging, and no correlation was noted between BMI and shear stiffness (R(2)=0.05). CONCLUSIONS ARFI imaging is a promising imaging modality for assessing the presence or absence of advanced fibrosis in patients with obesity-related liver disease.

Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710

Arsenic trioxide (As(2)O(3)) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age ≥ 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As(2)O(3) consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As(2)O(3) consolidation, 80% compared with 63% at 3 years (stratified log-rank test, P < .0001). Survival, a secondary end point, was better in the As(2)O(3) arm, 86% compared with 81% at 3 years (P = .059). Disease-free survival, a secondary end point, was significantly better in the As(2)O(3) arm, 90% compared with 70% at 3 years (P < .0001). The addition of As(2)O(3) consolidation to standard induction and consolidation therapy significantly improves event-free and disease-free survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934).

Number of children associated with obesity in middle-aged women and men: results from the health and retirement study.

OBJECTIVE To study associations between number of children and obesity in middle-aged women and men. METHODS In the Health and Retirement Study, a national survey of households, we tested the association between increasing number of children and obesity (body mass index [BMI] >or= 30) in 9046 middle-aged women and men (4523 couples). RESULTS Women (n = 4523) who were obese were more frequently nonwhite, reported lower household income, were more frequently employed outside the home, were less frequently covered by health insurance, and were more frequently less educated compared with nonobese women. Men (n = 4523) who were obese were younger, were more frequently African American, and were more frequently less educated and poorer compared with nonobese men. Among women, a 7% increase in risk of obesity was noted for each additional child, adjusting for age, race, household income, work status, physical activity, tobacco use, and alcohol use. Among men, a 4% increase in risk of obesity was noted for each additional child, adjusting for the same covariates. These sex differences were not significantly different. CONCLUSIONS Previous research has demonstrated an association between number of children and obesity among women. These results suggest a similar association among men. Public health interventions focused on obesity prevention should target both parents, especially those parents with several children.

Bortezomib Added to Daunorubicin and Cytarabine During Induction Therapy and to Intermediate-Dose Cytarabine for Consolidation in Patients With Previously Untreated Acute Myeloid Leukemia Age 60 to 75 Years: CALGB (Alliance) Study 10502

PURPOSE The purpose of this study was to determine remission induction frequency when bortezomib was combined with daunorubicin and cytarabine in previously untreated older adults with acute myeloid leukemia (AML) and safety of bortezomib in combination with consolidation chemotherapy consisting of intermediate-dose cytarabine (Int-DAC). PATIENTS AND METHODS Ninety-five adults (age 60 to 75 years; median, 67 years) with previously untreated AML (including therapy-related and previous myelodysplastic syndrome) received bortezomib 1.3 mg/m(2) intravenously (IV) on days 1, 4, 8, and 11 with daunorubicin 60 mg/m(2) on days 1 through 3 and cytarabine 100 mg/m(2) by continuous IV infusion on days 1 through 7. Patients who achieved complete remission (CR) received up to two courses of consolidation chemotherapy with cytarabine 2 gm/m(2) on days 1 through 5 with bortezomib. Three cohorts with escalating dose levels of bortezomib were tested (0.7, 1.0, and 1.3 mg/m(2)). Dose-limiting toxicities were assessed during the first cycle of consolidation. The relationship between cell surface expression of CD74 and clinical outcome was assessed. RESULTS Frequency of CR was 65% (62 of 95), and 4% of patients (four of 95) achieved CR with incomplete platelet recovery (CRp). Eleven patients developed grade 3 sensory neuropathy. Bortezomib plus Int-DAC proved tolerable at the highest dose tested. Lower CD74 expression was associated with CR/CRp (P = .04) but not with disease-free or overall survival. CONCLUSION The addition of bortezomib to standard 3 + 7 daunorubicin and cytarabine induction chemotherapy for AML resulted in an encouraging remission rate. The maximum tested dose of bortezomib administered in combination with Int-DAC for remission consolidation was 1.3 mg/m(2) and proved tolerable. Further testing of this regimen is planned.

Thymic output, T-cell diversity, and T-cell function in long-term human SCID chimeras

Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T, B, and sometimes NK-cell function. Nonablative human leukocyte antigen-identical or rigorously T cell-depleted haploidentical parental bone marrow transplantation (BMT) results in thymus-dependent genetically donor T-cell development in the recipients, leading to long-term survival. We reported previously that normal T-cell numbers, function, and repertoire developed by 3 to 4 months after transplantation in SCID patients, and the repertoire remained highly diverse for the first 10 years after BMT. The T-cell receptor diversity positively correlated with T-cell receptor excision circle levels, a reflection of thymic output. However, the fate of thymic function in SCID patients beyond 10 to 12 years after BMT remained to be determined. In this greater than 25-year follow-up study of 128 patients with 11 different molecular types of SCID after nonconditioned BMT, we provide evidence that T-cell function, thymic output, and T-cell clonal diversity are maintained long-term.

Partner-assisted emotional disclosure for patients with gastrointestinal cancer†

For patients with cancer who are married or in an intimate relationship, their relationships with their partners play a critical role in their adaptation to illness. However, cancer patients and their partners often have difficulty in talking with each other about their cancer‐related concerns. Difficulties in communication ultimately may compromise both the patient‐partner relationship and the patients psychological adjustment. The current study tested the efficacy of a novel partner‐assisted emotional disclosure intervention in a sample of patients with gastrointestinal (GI) cancer.

Post-Transplantation B Cell Function in Different Molecular Types of SCID

PurposeSevere combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T, B and sometimes NK cell function. Non-ablative HLA-identical or rigorously T cell-depleted haploidentical parental bone marrow transplantation (BMT) results in thymus-dependent genetically donor T cell development in the recipients, leading to a high rate of long-term survival. However, the development of B cell function has been more problematic. We report here results of analyses of B cell function in 125 SCID recipients prior to and long-term after non-ablative BMT, according to their molecular type.MethodsStudies included blood immunoglobulin measurements; antibody titers to standard vaccines, blood group antigens and bacteriophage Φ X 174; flow cytometry to examine for markers of immaturity, memory, switched memory B cells and BAFF receptor expression; B cell chimerism; B cell spectratyping; and B cell proliferation.ResultsThe results showed that B cell chimerism was not required for normal B cell function in IL7Rα-Def, ADA-Def and CD3-Def SCIDs. In X-linked-SCID, Jak3-Def SCID and those with V-D-J recombination defects, donor B cell chimerism was necessary for B cell function to develop.ConclusionThe most important factor determining whether B cell function develops in SCID T cell chimeras is the underlying molecular defect. In some types, host B cells function normally. In those molecular types where host B cell function did not develop, donor B cell chimerism was necessary to achieve B cell function. 236 words

Partner-assisted emotional disclosure for patients with gastrointestinal cancer: Results from a randomized controlled trial

For patients with cancer who are married or in an intimate relationship, their relationships with their partners play a critical role in their adaptation to illness. However, cancer patients and their partners often have difficulty in talking with each other about their cancer‐related concerns. Difficulties in communication ultimately may compromise both the patient‐partner relationship and the patients psychological adjustment. The current study tested the efficacy of a novel partner‐assisted emotional disclosure intervention in a sample of patients with gastrointestinal (GI) cancer.

Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia

Mutations in the all-trans retinoic acid (ATRA)-targeted ligand binding domain of PML-RARα (PRα/LBD+) have been implicated in the passive selection of ATRA-resistant acute promyelocytic leukemia clones leading to disease relapse. Among 45 relapse patients from the ATRA/chemotherapy arm of intergroup protocol C9710, 18 patients harbored PRα/LBD+ (40%), 7 of whom (39%) relapsed Off-ATRA selection pressure, suggesting a possible active role of PRα/LBD+. Of 41 relapse patients coanalyzed, 15 (37%) had FMS-related tyrosine kinase 3 internal tandem duplication mutations (FLT3-ITD+), which were differentially associated with PRα/LBD+ depending on ATRA treatment status at relapse: positively, On-ATRA; negatively, Off-ATRA. Thirteen of 21 patients (62%) had additional chromosome abnormalities (ACAs); all coanalyzed PRα/LBD mutant patients who relapsed off-ATRA (n = 5) had associated ACA. After relapse Off-ATRA, ACA and FLT3-ITD+ were negatively associated and were oppositely associated with presenting white blood count and PML-RARα type: ACA, low, L-isoform; FLT3-ITD+, high, S-isoform. These exploratory results suggest that differing PRα/LBD+ activities may interact with FLT3-ITD+ or ACA, that FLT3-ITD+ and ACA are associated with different intrinsic disease progression pathways manifest at relapse Off-ATRA, and that these different pathways may be short-circuited by ATRA-selectable defects at relapse On-ATRA. ACA and certain PRα/LBD+ were also associated with reduced postrelapse survival.

FLT3 mutation status is a predictor of early death in pediatric acute promyelocytic leukemia: A report from the Children's Oncology Group†‡

FLT3 mutations (FLT3/Mut) are prevalent in de novo AML and are associated with early relapse. The prevalence and prognostic significance of FLT3/Mut have not been well defined in childhood acute promyelocytic leukemia (APL).