The impact of radiation therapy in patients with diffuse large B-cell lymphoma with positive post-chemotherapy FDG-PET or gallium-67 scans.

BACKGROUND: 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography (PET) and gallium-67 citrate (gallium) response after chemotherapy are powerful prognostic factors in diffuse large B-cell lymphoma (DLBCL). However, clinical outcomes when consolidation radiation therapy (RT) is administered are less defined. PATIENTS AND METHODS: We reviewed 99 patients diagnosed with DLBCL from 1996 to 2007 at Duke University who had a post-chemotherapy response assessment with either PET or gallium and who subsequently received consolidation RT. Clinical outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Median follow-up was 4.4 years. Stage distribution was I-II in 70% and III-IV in 30%. Chemotherapy was R-CHOP or CHOP in 88%. Median RT dose was 30 Gy. Post-chemotherapy PET (n = 79) or gallium (n = 20) was positive in 21 of 99 patients and negative in 78 of 99 patients. Five-year in-field control was 95% with a negative PET/gallium scan versus 71% with a positive scan (P < 0.01). Five-year event-free survival (EFS; 83% versus 65%, P = 0.04) and overall survival (89% versus 73%, P = 0.04) were also significantly better when the post-chemotherapy PET/gallium was negative. CONCLUSIONS: A positive PET/gallium scan after chemotherapy is associated with an increased risk of local failure and death. Consolidation RT, however, still results in long-term EFS in 65% of patients.

A comparison of randomized concurrent control groups with matched historical control groups: are historical controls valid?

The use of a historical control group is predicated on the assumption that survival and relapse-free survival in the historical control group closely approximate the survival and relapse-free survival in a randomized concurrent control group. This assumption has never been tested. This study compares survival and relapse-free survival in randomized control groups with historical control groups matched for disease, stage, and follow-up. Of the 43 matched control groups, 42% varied by more than 10 percentage points, 21% varied by more than 20 percentage points, and 5% varied by more than 30 percentage points. Of the 18 that varied by greater than 10 percentage points, 17 had superior survival or relapse-free survival in the randomized concurrent control group. This study indicates that the assumption that historical control groups may replace randomized concurrent control groups is not valid.

The pattern of intrathoracic Hodgkin's disease assessed by computed tomography.

Computed tomography (CT) was used to define the sites of intrathoracic abnormality in Hodgkin's disease, determine a pattern of progression of disease in the thorax, and establish the place of this pattern of spread in the differential diagnosis of thoracic abnormalities. One hundred eight patients with newly diagnosed Hodgkin's disease were studied by chest CT. Seventy-seven patients had intrathoracic abnormalities. The pattern seen was one of contiguous spread from the anterior mediastinal/paratracheal area to the other mediastinal lymph node groups (aortopulmonary, subcarinal, posterior mediastinal, and internal mammary), to the hila, and then into the lung by extension or as discrete nodules. Involvement of the pleura, pericardium, or chest wall occurred only after the anterior mediastinal/paratracheal mass had enlarged to greater than 30% of the thoracic diameter. The probability that this pattern of contiguous lymph node spread occurred by chance alone was very small. Hodgkin's disease spreads from the anterior mediastinal/paratracheal area in a contiguous manner. Exceptions are unusual enough that when they occur, diagnoses other than Hodgkin's disease are more likely.

Hemolytic anemia after fludarabine therapy for chronic lymphocytic leukemia.

PURPOSE: A report of the clinical features, treatment, and outcome of patients who developed hemolytic anemia (HA) temporally associated with fludarabine (Fludara; Berlex Laboratories, Richmond, CA) therapy for chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Data on 24 patients who developed HA related to fludarabine therapy were collected from the Spontaneous Reporting System of the Food and Drug Administration (FDA) and the Walter Reed Army Medical Center (Washington, DC). RESULTS: Seventeen (71%) patients developed HA after either the first, second, or third cycle of this drug. The longest duration of fludarabine therapy before HA occurred was six cycles. The median decline in hematocrit from baseline during the hemolytic episode was 14.1 (range, 8.0 to 28.9) for the 18 patients for whom this information was available. For the 11 patients for whom transfusion requirements were known, the number of transfusions administered ranged between three and 36. Seven (29%) patients died of medical complications associated with the HA. Seven of eight patients who were re-challenged with fludarabine after an episode of HA developed recurrent HA, and three of these patients died. CONCLUSION: HA associated with fludarabine therapy appears to be uncommon, but it can be severe and fatal, especially if a patient is re-treated with this drug after a previous episode of HA. The mechanism of this toxicity is unknown, but it may be caused by the release of a suppressed auto-antibody to a native red cell antigen.

Leukopenia, neutropenia, and reduced hemoglobin levels in healthy American blacks.

Hematologic profiles of 462 persons, mostly active-duty service members, were studied to determine whether hematologic differences between blacks and whites exist in a healthy population. Whites had significantly greater mean concentrations of leukocytes (6.73 vs 5.95 x 10(9)/L), neutrophils (3.96 vs 3.16 x 10(9)/L), and hemoglobin (153 vs 135 g/L for men, 147 vs 125 g/L for women). The mean differences were largely due to relatively symmetric shifts in the frequency distributions for these cell concentrations. No significant correlation was found between neutrophil count and morbidity from infection as measured by a standardized questionnaire. The use of separate hematologic reference values for blacks and whites should be considered.

Autoimmune disease and chronic lymphocytic leukemia: autoimmune hemolytic anemia, pure red cell aplasia, and autoimmune thrombocytopenia.

Immune dysregulation, a hallmark of chronic lymphocytic leukemia (CLL), manifests itself in three autoimmune diseases: warm autoimmune hemolytic anemia (AIHA); idiopathic thrombocytopenia (ITP); and, pure red cell aplasia (PRCA). AIHA occurs in 11% of advanced stage CLL patients. Prednisone is the first treatment of choice, with 90% responses and 65% complete responses. More than 60% of patients relapse when treatment is stopped. Intravenous immunoglobulin, the next line of treatment, causes responses in 40% of patients. While the data are very limited, cyclosporine A is a reasonable choice for third-line therapy. Alkylating agents, danazol, plasma exchange, immunoabsorption, vincristine-loaded platelets, splenectomy, and splenic irradiation are also reported to cause responses. The data on mechanisms of AIHA are most consistent with immune dysregulation leading to loss of tolerance to a self antigen which in turn leads to the immune-based hemolytic anemia. PRCA is underrecognized in CLL with 6% of CLL patients having PRCA when tested for it. Unlike AIHA, PRCA often occurs in early stage disease. Anemia, reticulocytopenia, and a marrow virtually devoid of red blood cell precursors are hallmarks of PRCA. Corticosteroid therapy is the first line of treatment. If a response is not obtained in 4 weeks, cyclosporine A should be added. Although the data on pathophysiology are very limited, PRCA appears to be the result of an abnormal T cell that both fails in its normal function to support growth and inhibits the growth of erythroid progenitor cells. ITP occurs in 2-3% of CLL patients, occurs in early stage disease and may be a presenting manifestation. Initial therapy for ITP mirrors the guidelines for primary ITP. Initial therapy should consist of prednisone. Seventy percent of patients respond. Splenectomy is a reasonable second-line treatment. Autoimmune phenomena, largely related to blood cells, are based in the immune dysregulation of CLL. Longer survivals in CLL patients, more treatment regimens per patient, and more immunosuppression with modern treatments, allow us to predict an increasing incidence of autoimmune blood cell diseases in CLL.

Transient abnormalities in serum bilirubin and lactate dehydrogenase levels following red blood cell transfusions in adults.

BACKGROUND: The effect of transfusion of small amounts of packed red blood cells (PRBC) on serum chemistry values is not known. METHODS: We studied 73 adult patients without evidence of bleeding who received 2-unit PRBC transfusions. In study 1 (n=39), we examined multiple laboratory values pretransfusion and 15 minutes, 1 hour, 2 hours, and 24 hours posttransfusion. In study 2 (n=34), we examined changes in fractionated bilirubin, lactate dehydrogenase, and haptoglobin prior to and 1 hour following the transfusion. RESULTS: Total bilirubin increased from a median pretransfusion baseline of 0.7 mg/dL to 1.4 mg/dL shortly after transfusion (P <0.0005), and then returned to normal 24 hours later. Of the 36 patients with normal pretreatment total bilirubin levels, 17 (47%) became transiently abnormal. The lactate dehydrogenase level increased similarly 15 minutes after transfusion, but returned to baseline 24 hours later. The unconjugated bilirubin level increased from a median baseline pretransfusion value of 0.3 mg/dL to 1.1 mg/dL at 1 hour posttransfusion (P <0.0005). No significant changes were noted in conjugated bilirubin levels or haptoglobin concentration following transfusion. CONCLUSIONS: Transient increases in serum bilirubin and lactate dehydrogenase are seen following transfusion of PRBC. These data should be considered when interpreting laboratory values during the first few hours after a transfusion.

Life expectancy benefits of cancer screening in the end-stage renal disease population.

Health maintenance includes secondary prevention through cancer screening. There are no established guidelines for cancer screening patients with end-stage renal disease (ESRD). Using an established method of estimating life expectancy, published literature on cancer screening, and information from databases on mortality and malignancy (US Renal Data System 1997 Annual Data Report and the SEER Cancer and Statistical Review, 1973-1994), a "real-time life expectancy calculator" was developed to guide the primary help provider in making informed decisions on the benefits of cancer screening in individual patients. Potential days of life saved by each screening method can be calculated using the difference in life expectancy per the DEALE (declining exponential approximation of life expectancy) method with and without cancer screening. Using two sets of assumptions (one to enhance any bias toward support for screening and one to limit this bias), a range of potential days of life saved with screening for breast and colon cancer can be calculated in individual patients with ESRD. In breast cancer, for example, a 50-year-old black woman with ESRD and multiple risk factors would have 41 to 291 potential days of life saved with screening. A 60-year-old white woman with ESRD and diabetes mellitus (DM) would have only 1 to 16 days of life saved. This life expectancy calculator can guide the primary health care provider in making clinical decisions concerning screening in the ESRD population. In addition to assisting in patient education, the calculator can be updated as new information becomes available regarding relative risk, treatment, and mortality.

Mediastinal bulk in Hodgkin disease. Method of measurement versus prognosis.

The presence of a large mediastinal mass (bulk disease) in patients with newly diagnosed Hodgkin disease is believed by many to predict a poorer prognosis and to warrant more aggressive treatment. These masses are formed by an aggregate of mediastinal lymph nodes. The determination of bulk disease is confusing, with at least 27 definitions having been proposed. This study seeks to determine the best definition, and determine the role of thoracic computed tomography (CT) versus chest radiographs in the evaluation of mediastinal bulk disease. One hundred seven consecutive newly diagnosed adult patients with Hodgkin disease were evaluated using 13 commonly used definitions of mediastinal bulk. Of the 76 patients with mediastinal disease, 73 had bulk disease as defined by at least one definition. Of the 16 patients who had recurrence of mediastinal disease, only the presence of bulk disease according to one definition (hilar adenopathy, greater than or equal to 2 cm) was statistically significant in its prediction (P = .05). No definition based on the size of the mediastinal nodal mass reliably predicted those patients with recurrence. No differences in our data were found for differing stages or disease cell types, the presence of extension, or with differing treatment regimens. This study highlights the confusion and controversy surrounding the use of bulk disease of the mediastinum as an adverse prognostic indicator. The numerous methods of measuring mediastinal bulk in patients with newly diagnosed Hodgkin disease are confusing, overlap, and are not statistically reliable in predicting recurrence. Efforts to create a standard or ideal definition were unsuccessful. Thoracic CT was useful in those patients whose bulk disease distorted only one side of the mediastinal silhouette on chest radiographs.

D-dimer assay predicts mortality in critically ill patients without disseminated intravascular coagulation or venous thromboembolic disease.

OBJECTIVE: To determine if D-dimer predicts outcomes in critically ill patients. DESIGN: Observational, cohort study. SETTING: Medical intensive care unit (MICU) of a tertiary care hospital. PATIENTS AND PARTICIPANTS: Seventy-four patients consecutively admitted to the MICU. INTERVENTIONS: D-dimer was measured by latex agglutination within 12 h of admission to the MICU. MEASUREMENTS AND RESULTS: Of the study population, 43.2% had positive D-dimers. The in-hospital mortality rate in D-dimer positive patients was 28.1% as compared to 7.1% in D-dimer negative subjects (p = 0.024). D-dimer positive patients had significantly greater frequencies of venous thromboses (21.9% vs 4.8%, p = 0.035). CONCLUSIONS: The D-dimer assay identifies patients at increased risk for mortality and may be a more sensitive test to determine the presence of underlying microvascular pathology in critically ill patients. A positive D-dimer at admission to the MICU is associated with an increased risk for the later development of a venous thromboembolic event (VTE).

Fatal esorubicin-induced cardiomyopathy: report of a case and review of the literature.

A case of fatal dilated cardiomyopathy induced by esorubicin (ESO) at a total dose of 740 mg/m2, given in 27 doses over 650 days, is reported. The sudden onset, rapid clinical deterioration, and fatal outcome are detailed. The outcome was not predicted by serial rest ejection fractions or clinical signs. The data from animal studies, phase 1 and phase 2 clinical testing, are reviewed, demonstrating the almost complete absence of reports of ESO-induced cardiotoxicity. Studies reviewing ejection fractions and myocardial biopsy scores show that ESO can be cardiotoxic and may produce fatal dilated cardiomyopathy.

Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function.

Chronic lymphocytic leukemia (CLL) can be immunosuppressive in humans and mice, and CLL cells share multiple phenotypic markers with regulatory B cells that are competent to produce interleukin (IL)-10 (B10 cells). To identify functional links between CLL cells and regulatory B10 cells, the phenotypes and abilities of leukemia cells from 93 patients with overt CLL to express IL-10 were assessed. CD5(+) CLL cells purified from 90% of the patients were IL-10-competent and secreted IL-10 following appropriate ex vivo stimulation. Serum IL-10 levels were also significantly elevated in CLL patients. IL-10-competent cell frequencies were higher among CLLs with IgV(H) mutations, and correlated positively with TCL1 expression. In the TCL1-transgenic (TCL1-Tg) mouse model of CLL, IL-10-competent B cells with the cell surface phenotype of B10 cells expanded significantly with age, preceding the development of overt, CLL-like leukemia. Malignant CLL cells in TCL1-Tg mice also shared immunoregulatory functions with mouse and human B10 cells. Serum IL-10 levels varied in TCL1-Tg mice, but in vivo low-dose lipopolysaccharide treatment induced IL-10 expression in CLL cells and high levels of serum IL-10. Thus, malignant IL-10-competent CLL cells exhibit regulatory functions comparable to normal B10 cells that may contribute to the immunosuppression observed in patients and TCL1-Tg mice.

LMP-420: a novel purine nucleoside analog with potent cytotoxic effects for CLL cells and minimal toxicity for normal hematopoietic cells.

B-cell chronic lymphocytic leukemia (CLL) is characterized by slow accumulation of malignant cells, which are supported in the microenvironment by cell-cell interactions and soluble cytokines such as tumor necrosis factor (TNF). We evaluated the effect of the small molecule TNF inhibitor LMP-420 on primary CLL cells. The mean concentration of LMP-420 required to induce 50% cytotoxicity (ED50) at 72 h was 245 n. LMP-420-induced time- and dose-dependent apoptosis, as shown by annexin V staining, caspase activation and DNA fragmentation. These changes were associated with decreased expression of anti-apoptotic proteins Mcl-1, Bcl-xL and Bcl-2. CLL cells from patients with poor prognostic indicators showed LMP-420 sensitivity equal to that for cells from patients with favorable characteristics. In addition, LMP-420 potentiated the cytotoxic effect of fludarabine and inhibited in vitro proliferation of stimulated CLL cells. Gene expression profiling indicated that the mechanism of action of LMP-420 may involve suppression of nuclear factor-kappaB and immune response pathways in CLL cells. LMP-420 had minimal effects on normal peripheral blood mononuclear cell, B- and T-cell function, and hematopoietic colony formation. Our data suggest that LMP-420 may be a useful treatment for CLL with negligible hematologic toxicities.

Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia.

Survival of chronic lymphocytic leukemia (CLL) cells requires sustained activation of the antiapoptotic PI-3-K/Akt pathway, and many therapies for CLL cause leukemia cell death by triggering apoptosis. Blood lipoprotein particles are either pro- or antiapoptotic. High-density lipoprotein particles are antiapoptotic through sphingosine-1-phosphate receptor 3-mediated activation of the PI-3-K/Akt pathway. Apolipoprotein E4 (apoE4)-very low density lipoproteins (VLDL) increase apoptosis, but the apoE2-VLDL and apoE3-VLDL isoforms do not. As increased B-cell apoptosis favors longer survival of CLL patients, we hypothesized that APOE4 genotype would beneficially influence the clinical course of CLL. We report here that women (but not men) with an APOE4 genotype had markedly longer survival than non-APOE4 patients. VLDL is metabolized to low-density lipoprotein through lipoprotein lipase. Higher levels of lipoprotein lipase mRNA in these CLL patients correlated with shorter survival. The beneficial effect of APOE4 in CLL survival is likely mediated through APOE4 allele-specific regulation of leukemia cell apoptosis. The APOE allele and genotype distribution in these CLL patients is the same as in unaffected control populations, suggesting that although APOE genotype influences CLL outcome and response to therapy, it does not alter susceptibility to developing this disease.

Radiation and chemotherapy in the treatment of esophageal cancer.

Patients with esophageal cancer present with a cancer that is locally aggressive in a critical area and that readily metastasizes. Neither surgery nor radiotherapy alone can control local disease, and chemotherapy alone cannot control local or disseminated disease. Combined modalities yield better results. Surgery or radiotherapy is the standard primary treatment. Chemotherapy may help to control local disease and microscopic metastatic disease. Prospective randomized trials indicate that chemotherapy added to surgery and radiotherapy and chemotherapy added to radiotherapy prolong survival.

Mean platelet volume improves upon the megathrombocyte index but cannot replace the blood film examination in the evaluation of thrombocytopenia.

The measurement of the number of platelets larger than 3 microns (megathrombocyte index) is the first element in the evaluation of thrombocytopenia. This is currently performed by counting the number of large platelets on the peripheral blood film. The MPV (mean platelet volume) is an automated measurement of the platelet volume. This study examines the mean values, correlations, sensitivity, specificity and the receiver operating characteristic curve (comparison of two tests) to determine which of these tests better separates the production state. For increased vs. decreased production, the MPV was 10.0 + 1.9 fL and 8.0 + 1.5 fL (P < .0001) respectively and the megathrombocyte index (MEGA) was 19.0 + 17.6% and 11.5 + 14.9% (P < .007) respectively. The correlation with the state of production was better for MPV (R = .47) than for MEGA (R = .20). For the MPV a sensitivity of 80% occurred with the MPV > or = 8.4 fL with a specificity of 71%. For a MEGA > or = 6%, the sensitivity was 80% but the specificity was 43%. For any MPV the sensitivity and specificity were better than for any MEGA. The Receiver Operating Characteristic Curve demonstrated that the MPV is a better test than the MEGA for separating the production into increased and decreased states. The MPV is a better test than the MEGA and will add to, but not replace, examination of the peripheral blood film in the diagnosis of thrombocytopenia.

Ambulatory use of high-dose intravenous morphine for severe pain.

A case is presented that describes the use of an intravenous morphine infusion to treat severe pain in an outpatient setting. The patient had severe pain secondary to tumor involvement of the brachial plexus. Morphine was administered as a concentrated solution (50 mg/ml), using an autosyringe (model AS-2F) via a Hickman catheter. The dose was titrated to pain relief. A dose of 200-250 mg/h was required.