Reed E. Drews

Dying with cancer: patients' function, symptoms, and care preferences as death approaches.

OBJECTIVE: To characterize the dying experience of patients with cancer over the last 6 months of life.

Critical issues in hematology: anemia, thrombocytopenia, coagulopathy, and blood product transfusions in critically ill patients

Systematic evaluations of anemia, thrombocytopenia, and coagulopathy are essential to identifying and managing their causes successfully. In all cases, clinicians should evaluate RBC measurements alongside WBC and platelet counts and WBC differentials. Multiple competing factors may coexist; certain factors affect RBCs independent of those that affect WBCs or platelets. Ideally, clinicians should examine the peripheral blood smear for morphologic features of RBCs, WBCs, and platelets that provide important clues to the cause of the patients hematologic disorder. Thrombocytopenia arises from decreased platelet production, increased platelet destruction, or dilutional or distributional causes. Drug-induced thrombocytopenias present diagnostic challenges, because many medicines can cause thrombocytopenia and critically ill patients often receive multiple medications. If they suspect type II HIT, clinicians must promptly discontinue all heparin sources, including LMWHs, without awaiting laboratory confirmation, to avoid thrombotic sequelae. Because warfarin anticoagulation induces acquired protein C deficiency, thereby exacerbating the prothrombotic state of type II HIT, warfarin should be withheld until platelet counts increase to more than 100,000/microL and type II HIT is clearly resolving. The presence of a consumptive coagulopathy in the setting of thrombocytopenia supports a diagnosis of DIC, not TTP-HUS, and is demonstrated by decreasing serum fibrinogen levels, and increasing TTs, PTs, aPTTs, and fibrin degradation products. Increasing D-dimer, levels are the most specific DIC parameter and reflect fibrinolysis of cross-linked fibrin. Elevated PTs or a PTTs can result from the absence of factors or the presence of inhibitors. Clinicians should suspect factor inhibitors when the prolonged PT or aPTT does not correct or only partially corrects following an immediate assay of a 1:1 mix of patient and normal plasma. In addition to factor inhibitors, antiphospholipid antibodies (e.g., lupus anticoagulant) can produce a prolonged aPTT that does not correct with normal plasma but is overcome by adding excess phospholipid or platelets. Paradoxically, a tendency to thrombosis, not bleeding, accompanies lupus anticoagulants and the antiphospholipid antibody syndrome. Transfusion of red blood cells, platelets, or plasma products is sometimes warranted, but clinicians must carefully weigh potential benefits against known risks. In critically ill patients, administering RBCs can enhance oxygen delivery to tissues. Among euvolemic patients who do not have ischemic heart disease, guidelines recommend a transfusion threshold of HGB levels in the range of 6.0 to 8.0 g/dL; patients who have HGB that is at least 10.0 g/dL are unlikely to benefit from blood transfusion. The use of rHuEPO to increase erythropoiesis offers an alternative to RBC transfusion, assuming normal, responsive progenitor cells and adequate iron, folate, and cobalamin stores. Future research should examine whether clinical outcomes from rHuEPO use in critically ill patients are important and cost-effective. Because platelets play an instrumental role in primary hemostasis, platelet transfusions are often important in managing patients who are bleeding or at risk of bleeding with thrombocytopenia or impaired platelet function. Platelet transfusions carry risks, and decisions to transfuse platelets must consider clinical circumstances. Most important, platelet transfusions are generally contraindicated if the underlying disorder is TTP or type II HIT, because platelet transfusion in these settings may fuel thrombosis and worsen clinical signs and symptoms. Plasma products can correct hemostasis when bleeding arises from malfunction, consumption, or underproduction of plasma coagulation proteins. Choice of plasma product for transfusion depends on clinical circumstances. FFP is the most commonly used plasma product to correct clotting factor deficiencies, particularly coagulopathies that are attributable to multiple clotting factor deficiency states as in liver disease, DIC, or warfarin anticoagulation. PCC or rFVIIa that is administered in small volumes may provide advantages over FFP when coagulopathies require quick reversal without risk of volume overload. Factor concentrates can replace specific factor deficiencies. Recombinant FVIIa bypasses inhibitors to factors VIII and IX and vWF. Use of rFVIIa in managing hemostatic abnormalities from severe liver dysfunction; extensive surgery, trauma, or bleeding; excessive warfarin anticoagulation; and certain platelet disorders requires further study to determine optimal and cost-effective dosing regimens. Recombinant activated protein C reduces mortality from severe sepsis that is associated with organ dysfunction in adults who are at high risk for death (APACHE scores of at least 25). In severe sepsis, levels of protein C decrease, as do fibrinogen and platelet levels. Because of its anticoagulant effect, however, drotrecogin alfa may induce bleeding. Guidelines for drotrecogin alfa use must take into account bleeding risks.

Treatment Disparities for Disabled Medicare Beneficiaries With Stage I Non-Small Cell Lung Cancer

UNLABELLED Treatment disparities for disabled Medicare beneficiaries with stage I non-small cell lung cancer. OBJECTIVE To compare initial treatment and survival of nonelderly adults with and without disabilities newly diagnosed with non-small cell lung cancer. DESIGN Retrospective analyses; population-based cohorts. SETTING Eleven Surveillance, Epidemiology, and End Results cancer registries. PARTICIPANTS Persons with disability Medicare entitlement (n=1016) and nondisabled persons (n=8425) ages 21 to 64 years when diagnosed with stage I, pathologically confirmed, first primary non-small cell lung cancer between January 1, 1988, and December 31, 1999. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Initial cancer treatments (surgery, radiotherapy), survival (through December 31, 2001). Multivariable logistic regression and Cox proportional hazards regression estimated adjusted associations of disability status with treatments and survival. RESULTS Persons with disabilities were much more likely to be male, non-Hispanic black, and not currently married. Although 82.2% of nondisabled persons had surgery, 68.5% of disabled persons received operations. Adjusted relative risks (RRs) of receiving surgery were especially low for persons with respiratory disabilities (adjusted RR=.76; 95% confidence interval [CI], .67-.85), nervous system conditions (adjusted RR=.86; 95% CI, .76-.98), and mental health and/or mental retardation disorders (adjusted RR=.92; 95% CI, .86-.99). Persons with disabilities had significantly higher cancer-specific mortality rates (hazard ratio [HR]=1.37; 95% CI, 1.24-1.51) than persons without disabilities. Observed differences in cancer mortality persisted after adjusting for demographic and tumor characteristics (adjusted relative HR=1.23; 95% CI, 1.10-1.39). Further adjustment for surgery use eliminated statistically significant differences in cancer mortality between persons with and without disabilities across disabling conditions. CONCLUSIONS Persons with disabilities were much less likely than nondisabled Medicare beneficiaries to receive surgery; statistically significant cancer-specific mortality differences disappeared after accounting for these treatment differences. Future research must explore reasons for these findings and whether survival of disabled Medicare beneficiaries with early-stage, non-small cell lung cancer could improve if surgical treatment disparities were eliminated.

Early Stage Breast Cancer Treatments for Younger Medicare Beneficiaries with Different Disabilities

OBJECTIVE To explore how underlying disability affects treatments and outcomes of disabled women with breast cancer. DATA SOURCES Surveillance, Epidemiology, and End Results program data, linked with Medicare files and Social Security Administration disability group. STUDY DESIGN Ninety thousand two hundred and forty-three incident cases of early-stage breast cancer under age 65; adjusted relative risks and hazards ratios examined treatments and survival, respectively, for women in four disability groups compared with nondisabled women. PRINCIPAL FINDINGS Demographic characteristics, treatments, and survival varied among four disability groups. Compared with nondisabled women, those with mental disorders and neurological conditions had significantly lower adjusted rates of breast conserving surgery and radiation therapy. Survival outcomes also varied by disability type. CONCLUSIONS Compared with nondisabled women, certain subgroups of women with disabilities are especially likely to experience disparities in care for breast cancer.

POEMS syndrome with myocardial infarction: Observations concerning pathogenesis and review of the literature

A 27-year-old white man with no significant risk factors for coronary artery disease presented with a 9-month history of progressive impotence, gynecomastia, lower extremity paresthesias, and extensive myocardial infarction and subsequently developed ulcerative proctitis. A diagnosis of POEMS syndrome was made based on the clinical presentation; additional physical findings of papilledema, clubbing, and hyperpigmentation; and laboratory findings of an immunoglobulin G M component of the lambda subtype, elevated cerebrospinal fluid protein, and typical sclerotic bone lesions. Abnormal in vitro binding of the patients serum immunoglobulin to testicular tissue was also seen. Cardiac catheterization showed evidence of diffuse coronary artery narrowing and left ventricular wall motion abnormalities. Diffuse coronary involvement and ulcerative proctitis have not been previously described in POEMS syndrome. It is hypothesized that an abnormal immunoglobin (or fragment) is responsible for both findings. Furthermore, the detection of antitesticular autoantibodies suggests the possibility of an interaction between the antibody and Leydig cells, leading to an alteration in the synthesis and release of sex steroids and thereby explaining the gonadal failure seen in this syndrome. Long-term glucocorticoid therapy for the past 5 years has resulted in marked subjective and objective improvement.

Oncogenes result in genomic alterations that activate a transcriptionally silent, dominantly selectable reporter gene (neo).

Although oncogenes and tumor suppressor genes have been implicated in carcinogenesis and tumor progression, their relationship to the development of genomic instability has not been elucidated. To examine this role, we transfected oncogenes (polyomavirus middle [Py] and large T [MT and LT]) and adenovirus serotype 5 E1A) into two NIH 3T3-derived cell lines, EN/NIH 2-4 and EN/NIH 2-20. Both cell lines contain two stable integrants of a variant of the retrovirus vector pZipNeoSV(x)1 that has been modified by deletion of the enhancer elements from the long terminal repeats. DNA rearrangements activating the silent neomycin phosphotransferase gene (neo) present in these integrants were identified by selection of cells in the antibiotic G418. Whereas control-transfected EN/NIH cell lines do not yield G418-resistant subclones (GRSs), a fraction of oncogene-transfected EN/NIH 2-4 (8 of 19 Py MT, 5 of 17 Py LT, and 11 of 19 E1A) and 2-20 (7 of 15 Py MT) cell lines gave rise to GRSs at differing frequencies (0.33 x 10(-6) to 46 x 10(-6) for line 2-4 versus 0.11 x 10(-6) to 1.3 x 10(-6) for line 2-20) independent of cell generation time. In contrast, a distinctly smaller fraction of mutant Py MT-transfected EN/NIH cell lines (1 of 10 MT23, 1 of 10 MT1015, and 0 of 10 MT59b) resulted in GRSs. Southern analysis of DNA from selected oncogene-transfected GRSs demonstrated genomic rearrangements of neo-containing cellular DNA that varied in type (amplification and/or novel fragments) and frequency depending on the specific oncogene and EN/NIH cell line used in transfection. Furthermore, only one of the two neo-containing genomic loci present in both EN/NIH cell lines appeared to be involved in these genomic events. In addition to effects related to the genomic locus, these observations support a role for oncogenes in the development of genetic changes associated with tumor progression.

Update in Hematology and Oncology

This Update in Hematology and Oncology features 16 articles published in 2009 that the authors judged to be of high clinical relevance. Hematology topics include the use of dabigatran, anticoagulation in patients with deep venous thrombosis, estimation of warfarin dose, use of oral vitamin K to counter overanticoagulation, and adverse effects of erythropoiesis-stimulating agents. Oncology topics include screening for prostate and breast cancer, hormone replacement therapy and risk for breast cancer, cancer genomics and targeted therapies, short- and long-term cardiac effects of cancer treatment, and palliative care for patients with cancer.

Complete pathologic response of metastatic cutaneous squamous cell carcinoma and allograft rejection after treatment with combination immune checkpoint blockade

cSCC: cutaneous squamous cell carcinoma DICB: dual immune checkpoint blockade ICB: immune checkpoint blockade ipi/nivo: ipilimumab and nivolumab mcSCC: metastatic cSCC INTRODUCTION Roughly 1.1 million cases of cutaneous squamous cell carcinoma (cSCC) occur annually. Although most cases can be cured with local therapy, up to 8,000 deaths from metastatic cSCC (mcSCC) occur each year, a number similar to that of melanoma. With no US Food and Drug Administrationeapproved options available for mcSCC, common approaches include platinumbased chemotherapy and off-label cetuximab. These strategies lack durability, and overall survival for mcSCC is only 10.9 months. Clinical responses in mcSCC have recently been reported with the use of PD-1 antibodies, pembrolizumab and nivolumab. Here we report a complete pathologic response after 4 cycles of nivolumab and the antieCTLA-4 antibody, ipilimumab, in a patient with mcSCC.

Emerging Treatment Options for Advanced-Stage Mycosis Fungoides

A 72-year-old man with a 3-year history of hypersensitivity skin reaction managed with topical steroids and ultraviolet B (UVB) radiation develops skin tumors chiefly involving his face. After a diagnosis of stage IIB mycosis fungoides (MF), he begins oral low-dose weekly methotrexate with partial response lasting 5 months. Subsequently, he receives six cycles of weekly gemcitabine and achieves a partial response with resolution of skin tumors but persistence of scattered patches and plaques (Fig 1). He begins daily bexarotene and interferon alfa (IFN-α) three times per week while continuing topical steroids. When scattered patches and plaques progress 7 months later, UVB radiation is added to his regimen. His disease remains well controlled until 17 months later, when he develops pneumonia complicated by pericarditis, requiring discontinuation of IFN-α. Over the next year, he continues bexarotene maintenance therapy and topical steroids but requires localized radiation therapy to isolated patch and tumor...

A primer on anemia evaluation withcase presentations

Anemia represents a common problem encountered in daily clinical practice, affecting 3.4 million Americans. Hence, a structured approach to evaluating anemia is highly relevant in primary care. Multichannel automated analyzers have revolutionized the work of performing complete blood counts (CBCs). However, when interpreting results, clinicians must be aware of limitations encountered with these technologies, which can yield spurious red blood cell (RBC) values in certain clinical circumstances. Automated analyzers identify subpopulations of RBCs that are unexpectedly small or large or have unexpectedly low or high hemoglobin concentrations, thereby signifying aberrant RBC morphologies for review on peripheral blood smear. Results of various blood chemistries help to refine or confirm diagnostic considerations suggested by the CBC, reticulocyte count, and peripheral blood smear. Although tempo of anemia development may strongly support bleeding or hemolysis as the cause of anemia, kinetic changes in RBC mass, even due to these mechanisms, are often more subtle, suggesting possible underproduction causes of anemia. Abnormalities in white blood cell (WBC) counts, platelet counts, and WBC differentials may suggest disorders of trilineage hematopoiesis, although multiple competing factors may coexist, with certain factors affecting RBCs independent of those affecting WBCs and/or platelets. To focus diagnostic considerations, clinicians should consider anemia etiologies categorized by RBC size (mean cell volume, MCV) and morphology (eg, spherocytes, bite cells, schistocytes, target cells, teardrops). These categories include the microcytic, normocytic, and macrocytic anemias. Each of these categories are briefly reviewed, and case presentations are provided to illustrate specific points.