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.

Darbepoetin alfa 300 or 500 µg once every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia.

This study evaluated efficacy and safety of darbepoetin alfa administered every 3 weeks (Q3W) at fixed doses of 300 or 500 µg with or without intravenous (IV) iron in treating anemia in patients receiving multicycle chemotherapy. This Phase 2, double-blind, 2 × 2 factorial study randomized patients to one of four treatment arms; darbepoetin alfa 300 µg (n = 62), darbepoetin alfa 300 µg plus IV iron (n = 60), darbepoetin alfa 500 µg (n = 60), or darbepoetin alfa 500 µg plus IV iron (n = 60). Patients had nonmyeloid malignancies, hemoglobin levels ≤10 g dL(-1), and no iron deficiency. Primary endpoint was achievement of target hemoglobin (≥11 g dL(-1)). Secondary endpoints included incidence of transfusions and change in Functional Assessment of Cancer Therapy Fatigue (FACT-F) score from baseline to end of study. Safety was evaluated by incidence of adverse events. No evidence of a statistically significant interaction between darbepoetin alfa dose received and IV iron usage was observed, therefore, results are provided separately comparing darbepoetin alfa doses and comparing IV iron usage groups. Similar proportions of patients receiving darbepoetin alfa 300 or 500 µg achieved target hemoglobin (75 and 78%, respectively); Kaplan-Meier median time to target hemoglobin was 10 and 8 weeks, respectively. More patients receiving IV iron (82%) than not receiving IV iron (72%) achieved hemoglobin target. Adverse events profiles were similar for darbepoetin alfa treatment groups. Transient anaphylactoid reactions were reported in two patients receiving IV iron. Darbepoetin alfa at 300 µg Q3W and 500 µg Q3W showed similar benefit, while added IV iron improved treatment response in these patients.

Kidney transplant from sickle cell trait donor to sickle cell trait recipient.

There have been concerns about using kidneys from potential donors with sickle cell trait because kidneys from these donors may not concentrate urine properly. We report a case of living-related renal transplant, in which both the recipient and the donor had sickle cell trait, and the postoperative course for both was uneventful.

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.

Molecular assessment of erythroid lineage chimerism following nonmyeloablative allogeneic stem cell transplantation.

OBJECTIVE: Nonmyeloablative conditioning regimens for allogeneic stem cell transplantation are now commonly used in the treatment of patients with hematologic malignancies. Since this treatment often results in the establishment of mixed hematopoietic chimerism, this approach may also prove to be useful in the treatment of nonmalignant disorders, such as sickle cell disease and thalassemia major. To apply this approach to these diseases, it will be necessary to determine the levels of donor erythropoiesis required to correct hemolysis and ameliorate disease symptoms. Current methods for measuring hematopoietic chimerism are based on DNA polymorphisms that distinguish recipient from donor. These methods accurately measure donor leukocyte engraftment but do not quantify the relative contributions of recipient and donor erythropoiesis following transplant. METHODS: To specifically measure erythroid-lineage chimerism, we used pyrosequencing of the sickle cell mutation to quantify the relative levels of normal and sickle beta-globin mRNA in patient samples. Results of beta-globin RNA chimerism were compared to assessment of beta-globin DNA chimerism as well as analysis of short tandem repeat (STR) polymorphisms, cytogenetics, and hemoglobin electrophoresis. RESULTS: Donor engraftment was measured in two adult patients following nonmyeloablative stem cell transplant for sickle cell disease. In Patient 1, 25 to 30% of peripheral leukocytes were donor derived after day 41. In contrast, more than 55% of peripheral blood beta-globin mRNA was of donor origin, and these results correlated with posttransplant clinical improvement. Patient 2 achieved 40 to 50% donor leukocyte engraftment from day 33 onward. This was associated with 70 to 100% peripheral blood donor beta-globin mRNA. CONCLUSIONS: These studies demonstrate that relatively low levels of donor leukocyte engraftment can be associated with higher levels of donor erythropoiesis and with significant clinical improvement. Pyrosequencing of lineage-specific mRNA directly measures functional reconstitution of donor cells and provides valuable information that can affect clinical decisions in patients with nonmalignant diseases following allogeneic transplant.

Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment.

CONTEXT: Hydroxyurea increases levels of fetal hemoglobin (HbF) and decreases morbidity from vaso-occlusive complications in patients with sickle cell anemia (SCA). High HbF levels reduce morbidity and mortality. OBJECTIVE: To determine whether hydroxyurea attenuates mortality in patients with SCA. DESIGN: Long-term observational follow-up study of mortality in patients with SCA who originally participated in the randomized, double-blind, placebo-controlled Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), conducted in 1992-1995, to determine if hydroxyurea reduces vaso-occlusive events. In the MSH Patients' Follow-up, conducted in 1996-2001, patients could continue, stop, or start hydroxyurea. Data were collected during the trial and in the follow-up period. SETTING: Inpatients and outpatients in 21 sickle cell referral centers in the United States and Canada. PATIENTS: Two-hundred ninety-nine adult patients with frequent painful episodes enrolled in the follow-up. Follow-up data through May 2001 were complete for 233 patients. INTERVENTION: In the MSH, patients were randomly assigned to receive hydroxyurea (n = 152) or placebo (n = 147). MAIN OUTCOME MEASURE: Mortality, HbF levels, painful episodes, acute chest syndrome, and blood cell counts. The randomized trial was not designed to detect specified differences in mortality. RESULTS: Seventy-five of the original 299 patients died, 28% from pulmonary disease. Patients with reticulocyte counts less than 250 000/mm3 and hemoglobin levels lower than 9 g/dL had increased mortality (P =.002). Cumulative mortality at 9 years was 28% when HbF levels were lower than 0.5 g/dL after the trial was completed compared with 15% when HbF levels were 0.5 g/dL or higher (P =.03 ). Individuals who had acute chest syndrome during the trial had 32% mortality compared with 18% of individuals without acute chest syndrome (P =.02). Patients with 3 or more painful episodes per year during the trial had 27% mortality compared with 17% of patients with less frequent episodes (P =.06). Taking hydroxyurea was associated with a 40% reduction in mortality (P =.04) in this observational follow-up with self-selected treatment. There were 3 cases of cancer, 1 fatal. CONCLUSIONS: Adult patients taking hydroxyurea for frequent painful sickle cell episodes appear to have reduced mortality after 9 of years follow-up. Survival was related to HbF levels and frequency of vaso-occlusive events. Whether indications for hydroxyurea treatment should be expanded is unknown.

Genetics in primary care: a USA faculty development initiative.

The Genetics in Primary Care (GPC) project is a USA national faculty development initiative with the goal of enhancing the training of medical students and primary care residents by developing primary care faculty expertise in genetics. Educational strategies were developed for the project by an executive committee with input from an advisory committee, comprising individuals with primary care, medical education and genetics expertise. These committees identified the key issues in genetics education for primary care as (1) considering inherited disease in the differential diagnosis of common disorders; (2) using appropriate counseling strategies for genetic testing and diagnosis, and (3) understanding the implications of a genetic diagnosis for family members. The group emphasized the importance of a primary care perspective, which suggests that the clinical utility of genetic information is greatest when it has the potential to improve health outcomes. The group also noted that clinical practice already incorporates the use of family history information, providing a basis for discussing the application of genetic concepts in primary care. Genetics and primary care experts agreed that educational efforts will be most successful if they are integrated into existing primary care teaching programs, and use a case-based teaching format that incorporates both clinical and social dimensions of genetic disorders. Three core clinical skills were identified: (1) interpreting family history; (2) recognizing the variable clinical utility of genetic information, and (3) acquiring cultural competency. Three areas of potential controversy were identified as well: (1) the role of nondirective counseling versus shared decision-making in discussions of genetic testing; (2) the intrinsic value of genetic information when it does not influence health outcomes, and (3) indications for a genetics referral. The project provides an opportunity for ongoing discussion about these important issues.

Acute occlusion of an abdominal aortic aneurysm complicated by bilateral lower extremity venous thrombosis: A case report.

Acute occlusion of an abdominal aortic aneurysm is a rare phenomenon. Its possible complications include distal spasm followed by arterial thrombosis, ischemia of the distal limbs, distal embolization, acidosis, hyperkalemia, and the development of venous thrombosis of the lower limbs. Surgical correction is often complicated by cardiac decompensation, renal failure, fatal pulmonary embolism, and metabolic derangements related to toxins released from the revascularized limb. Unless contraindicated, immediate systemic heparinization must be undertaken when the diagnosis is first suspected. We present a case of sudden occlusion of an abdominal aortic aneurysm complicated by venous thrombosis involving both lower extremities. After undergoing surgical revascularization, the patient sustained massive fatal pulmonary emboli. Prophylactic interruption of the inferior vena cava may be indicated in patients who present with this complication of abdominal aortic aneurysm.