A retrospective analysis to examine factors associated with mortality in Medicare beneficiaries newly diagnosed with multiple myeloma.

OBJECTIVE: Population-based data on mortality and associated factors in patients with multiple myeloma (MM) are limited. We examined the association between all-cause mortality and demographic and clinical characteristics in newly diagnosed MM patients treated with guideline-recommended chemotherapeutic agents. RESEARCH DESIGN AND METHODS: This retrospective cohort analysis used Medicare 20% data to create a cohort of adult (aged ≥18 years) newly diagnosed MM patients who received chemotherapy 2008-2011 and had no MM diagnosis in the 12 months before the disease index date. Patients were followed from treatment initiation through the earliest of death, loss of insurance coverage, or study end (December 2011). Modified Charlson Comorbidity Index scores and MM-related comorbid conditions (anemia, hypercalcemia, skeletal-related events) were identified in the 6 month pre-index-date period. All-cause mortality and associated factors were examined using multivariable Cox proportional hazard models. RESULTS: We identified 2419 newly diagnosed patients who received MM therapy during follow-up. Mean (SD) and median follow-up were 1.51 (1.0) and 1.37 years. Of the cohort, 55% were female, 78% white, and 92% aged ≥65 years. Pre-index, 54%, 9%, and 5% were diagnosed with anemia, hypercalcemia, and skeletal-related events. Overall, 942 (39%) patients died during follow-up. Factors associated with increased risk of death were older age (≥65 vs. 18-64 years; hazard ratio 1.49, 95% confidence interval 1.13-1.99), higher comorbidity score (≥4 vs. 0; 1.78, 1.43-2.21), anemia (1.23, 1.06-1.42), and hypercalcemia (1.45, 1.19-1.76); female sex (0.86, 0.75-0.98) was associated with decreased risk. CONCLUSIONS: Older age, male sex, high comorbidity burden, anemia, and hypercalcemia were risk factors for death in newly diagnosed Medicare MM patients. Study limitations included non-causal observational design, non-validated MM algorithm, potential treatment misclassification, and non-availability of prognostic factors including disease staging information, biomarkers, and other laboratory variables. Additional analyses are warranted to understand the relationship between treatments and death.

Impact of Centers for Medicare & Medicaid Services national coverage determination on erythropoiesis-stimulating agent and transfusion use in chemotherapy-treated cancer patients.

PURPOSE: In July 2007, the Centers for Medicare & Medicaid Services released a national coverage determination (NCD) for erythropoiesis-stimulating agent (ESA) use in cancer patients, mandating payment restrictions likely to reduce ESA use and possibly increase red blood cell transfusions. We aimed to quantify ESA and transfusion use pre-NCD and post-NCD. METHODS: Medicare 5% sample data, 2005-2007, were used. Patients were 66 years or older, had lung, breast, or colorectal cancer or lymphomas, and initiated chemotherapy in pre-NCD and post-NCD periods (September-November 2006, September-November 2007). ESA use and transfusions were identified from claims. Differences in proportions of patients using ESAs and receiving transfusions pre-NCD and post-NCD were evaluated using logistic regression; differences in transfusion event rates were evaluated using a Poisson model. RESULTS: The pre-NCD cohort included 1897 patients and the post-NCD cohort 1877. In the pre-NCD cohort, 31% of patients had lung cancer, 29% lymphoma, 20% colorectal cancer, and 20% breast cancer; distribution was similar in the post-NCD cohort. Overall, ESA use decreased from 35.0% pre-NCD to 15.2% post-NCD. Transfusion use increased from 9.3% to 10.4%, and transfusion event rates from 19.0 to 21.8 per 100 patient-quarters. Results adjusted for baseline characteristics and comorbid conditions were similar. ESA use reduction achieved statistical significance; transfusion use and rate increases did not. CONCLUSIONS: ESA use decreased sharply post-NCD. This was accompanied by an estimated 1.1% (95% confidence interval -0.8% to 3.0%) absolute increase in transfusion use.

Nitric oxide reduces sickle hemoglobin polymerization: potential role of nitric oxide-induced charge alteration in depolymerization.

We previously demonstrated that inhaling nitric oxide (NO) increases the oxygen affinity of sickle red blood cells (RBCs) in patients with sickle cell disease (SCD). Our recent studies found that NO lowered the P(50) values of sickle hemoglobin (HbS) hemolysates but did not increase methemoglobin (metHb) levels, supporting the role of NO, but not metHb, in the oxygen affinity of HbS. Here we examine the mechanism by which NO increases HbS oxygen affinity. Because anti-sickling agents increase sickle RBC oxygen affinity, we first determined whether NO exhibits anti-sickling properties. The viscosity of HbS hemolysates, measured by falling ball assays, increased upon deoxygenation; NO treatment reduced the increment. Multiphoton microscopic analyses showed smaller HbS polymers in deoxygenated sickle RBCs and HbS hemolysates exposed to NO. These results suggest that NO inhibits HbS polymer formation and has anti-sickling properties. Furthermore, we found that HbS treated with NO exhibits an isoelectric point similar to that of HbA, suggesting that NO alters the electric charge of HbS. NO-HbS adducts had the same elution time as HbA upon high performance liquid chromatography analysis. This study demonstrates that NO may disrupt HbS polymers by abolishing the excess positive charge of HbS, resulting in increased oxygen affinity.

The acute box cis-element in human heavy ferritin mRNA 5'-untranslated region is a unique translation enhancer that binds poly(C)-binding proteins.

Intracellular levels of the light (L) and heavy (H) ferritin subunits are regulated by iron at the level of message translation via a modulated interaction between the iron regulatory proteins (IRP1 and IRP2) and a 5'-untranslated region. Iron-responsive element (IRE). Here we show that iron and interleukin-1beta (IL-1beta) act synergistically to increase H- and L-ferritin expression in hepatoma cells. A GC-rich cis-element, the acute box (AB), located downstream of the IRE in the H-ferritin mRNA 5'-untranslated region, conferred a substantial increase in basal and IL-1beta-stimulated translation over a similar time course to the induction of endogenous ferritin. A scrambled version of the AB was unresponsive to IL-1. Targeted mutation of the AB altered translation; reverse orientation and a deletion of the AB abolished the wild-type stem-loop structure and abrogated translational enhancement, whereas a conservative structural mutant had little effect. Labeled AB transcripts formed specific complexes with hepatoma cell extracts that contained the poly(C)-binding proteins, iso-alphaCP1 and -alphaCP2, which have well defined roles as translation regulators. Iron influx increased the association of alphaCP1 with ferritin mRNA and decreased the alphaCP2-ferritin mRNA interaction, whereas IL-1beta reduced the association of alphaCP1 and alphaCP2 with H-ferritin mRNA. In summary, the H-ferritin mRNA AB is a key cis-acting translation enhancer that augments H-subunit expression in Hep3B and HepG2 hepatoma cells, in concert with the IRE. The regulated association of H-ferritin mRNA with the poly(C)-binding proteins suggests a novel role for these proteins in ferritin translation and iron homeostasis in human liver.