Complications associated with erythropoietin-stimulating agents in patients with metastatic breast cancer: a Surveillance, Epidemiology, and End Results-Medicare study.

BACKGROUND: The authors evaluated the patterns of use and the risk of thromboembolic events (TEE) associated with erythropoietin-stimulating agents (ESAs) in older patients with metastatic breast cancer who were receiving chemotherapy. METHODS: The study was retrospective and used the SEER-Medicare linked database. Stage IV breast cancer patients diagnosed from 1995-2005, treated with chemotherapy, ≥66 years old, with full coverage of Medicare A and B were included. The World Health Organization's International Classification of Diseases (ICD-9) and the Healthcare Common Procedure Coding System (HCPCS) were used to identify the use of ESAs, chemotherapy, and complications of therapy. Analyses included descriptive statistics and logistic regression. RESULTS: Of 2266 women, 980 (43.3%) received ESAs, and 1286 (56.7%) did not. Patients diagnosed after 1999 or who received treatment with taxanes, anthracyclines, or vinorelbine were more likely to receive ESAs. Patients receiving ESAs had higher rates of stroke (18.5% vs 15.1%, P = .031); deep-vein thrombosis (DVT; 21.3% vs 14.4%, P<.001), other/unspecified thromboembolic event (TEE; 19.8% vs 14.7%, P = .001), and any clot (31.3% vs 23.4%, P<.0001). In multivariate analysis, patients receiving ESAs had increased risk for DVT (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.05-1.75), and any clot (OR, 1.26; 95% CI, 1.02-1.57). A dose-dependent effect was evident for stroke, DVT, other TEE, and any clot. CONCLUSIONS: In this cohort of patients, the use of ESAs increased the risk of TEEs, with a dose-dependent effect for stroke, DVT, other TEE, and any clot. The data show that among patients treated with chemotherapy and ESAs for metastatic breast cancer, TEEs are a common event. Therefore, caution is recommended when using these agents.

Pixantrone dimaleate in combination with fludarabine, dexamethasone, and rituximab in patients with relapsed or refractory indolent non-Hodgkin lymphoma: phase 1 study with a dose-expansion cohort.

BACKGROUND: Pixantrone dimaleate (pixantrone) has been shown to have antitumor activity in leukemia and lymphoma in vitro models and to lack delayed cardiotoxicity associated with mitoxantrone in animal models. FND-R, a combination regimen of fludarabine, mitoxantrone, dexamethasone, and rituximab, has been shown to be an effective regimen for low-grade lymphomas. METHODS: This dose-escalation study, with an expansion cohort, was conducted to evaluate the safety and preliminary efficacy of FPD-R, in which pixantrone was substituted for mitoxantrone in the FND-R regimen, in patients with relapsed or refractory indolent non-Hodgkin lymphoma (NHL). Escalated doses of pixantrone were administered to newly enrolled patients on day 2 of each 28-day cycle of FPD-R. RESULTS: Twenty-eight of 29 enrolled patients received at least 1 cycle of FPD-R (median, 5 cycles). Pixantrone 120 mg/m(2) was identified as the recommended dose in this regimen. Grade 3-4 adverse events were primarily hematologic; grade 3-4 lymphopenia occurred in 89% of patients and leukopenia in 79%. No patients developed congestive heart failure or grade 3-4 cardiac adverse events. Left ventricular ejection fraction decreases occurred in 8 (29%) patients, and most were grade 1 or 2, transient, and asymptomatic. The overall response rate was 89%. Estimated survival was 96% after 1 year and 92% after 3 years. CONCLUSIONS: The FPD-R regimen was well-tolerated and highly active in patients with relapsed or refractory indolent NHL.

Fractional Fokker-Planck equation for Lévy flights in nonhomogeneous environments.

The fractional Fokker-Planck equation, which contains a variable diffusion coefficient, is discussed and solved. It corresponds to the Lévy flights in a nonhomogeneous medium. For the case with the linear drift, the solution is stationary in the long-time limit and it represents the Lévy process with a simple scaling. The solution for the drift term in the form lambda sgn(x) possesses two different scales which correspond to the Lévy indexes micro and micro+1 (micro<1) . The former component of the solution prevails at large distances but it diminishes with time for a given x . The fractional moments, as a function of time, are calculated. They rise with time and the rate of this growth increases with lambda .

Lévy flights in nonhomogeneous media: distributed-order fractional equation approach.

A jumping process, defined in terms of the Lévi distributed jumping size and the Poissonian, position-dependent waiting time with the algebraic jumping rate, is discussed on the assumption that parameters of both distributions are themselves random variables which are determined from given probability distributions. The fractional equation for the distributed Lévy order parameter mu is derived and solved. The solution is of the form of a combination of the Fox functions and simple scaling is lacking. The problem of accelerated diffusion is also discussed. The case of the distributed waiting time parameter theta is similarly solved and the solution offers a possibility to manage processes which are characterized by more general forms of the jumping rate, not only algebraic. Moreover, we mention a possibility that the parameters mu and theta are mutually dependent.

Random walk in nonhomogeneous environments: A possible approach to human and animal mobility.

The random walk process in a nonhomogeneous medium, characterized by a Lévy stable distribution of jump length, is discussed. The width depends on a position: either before the jump or after that. In the latter case, the density slope is affected by the variable width and the variance may be finite; then all kinds of the anomalous diffusion are predicted. In the former case, only the time characteristics are sensitive to the variable width. The corresponding Langevin equation with different interpretations of the multiplicative noise is discussed. The dependence of the distribution width on position after jump is interpreted in terms of cognitive abilities and related to such problems as migration in a human population and foraging habits of animals.

Escape process in systems characterized by stable noises and position-dependent resting times.

Stochastic systems characterized by a random driving in a form of the general stable noise are considered. The particle experiences long rests due to the traps the density of which is position dependent and obeys a power-law form attributed to the underlying self-similar structure. Both the one- and two-dimensional cases are analyzed. The random walk description involves a position-dependent waiting time distribution. On the other hand, the stochastic dynamics is formulated in terms of the subordination technique where the random time generator is position dependent. The first passage time problem is addressed by evaluating a first passage time density distribution and an escape rate. The influence of the medium nonhomogeneity on those quantities is demonstrated; moreover, the dependence of the escape rate on the stability index and the memory parameter is evaluated. Results indicate essential differences between the Gaussian case and the case involving Lévy flights.

Anomalous diffusion in stochastic systems with nonhomogeneously distributed traps.

The stochastic motion in a nonhomogeneous medium with traps is studied and diffusion properties of that system are discussed. The particle is subjected to a stochastic stimulation obeying a general Lévy stable statistics and experiences long rests due to nonhomogeneously distributed traps. The memory is taken into account by subordination of that process to a random time; then the subordination equation is position dependent. The problem is approximated by a decoupling of the medium structure and memory and exactly solved for a power-law position dependence of the memory. In the case of the Gaussian statistics, the density distribution and moments are derived: depending on geometry and memory parameters, the system may reveal both the subdiffusion and enhanced diffusion. The similar analysis is performed for the Lévy flights where the finiteness of the variance follows from a variable noise intensity near a boundary. Two diffusion regimes are found: in the bulk and near the surface. The anomalous diffusion exponent as a function of the system parameters is derived.

Lévy flights and nonhomogenous memory effects: Relaxation to a stationary state.

The non-Markovian stochastic dynamics involving Lévy flights and a potential in the form of a harmonic and nonlinear oscillator is discussed. The subordination technique is applied and the memory effects, which are nonhomogeneous, are taken into account by a position-dependent subordinator. In the nonlinear case, the asymptotic stationary states are found. The relaxation pattern to the stationary state is derived for the quadratic potential: the density decays like a linear combination of the Mittag-Leffler functions. It is demonstrated that in the latter case the density distribution satisfies a fractional Fokker-Planck equation. The densities for the nonlinear oscillator reveal a complex picture, qualitatively dependent on the potential strength, and the relaxation pattern is exponential at large time.

Expression and localization of GRP75 in human epithelial tumors and normal tissues.

Using differential display mRNA techniques, the authors found cDNA of the heat shock 70 protein known as GRP75 overexpressed in ovarian cancer cell lines. In the current study, the authors used immunohistochemistry to characterize the expression pattern of GRP75 in ovarian carcinomas and compared it with epithelial tumors originating from the female reproductive tract, epithelial neoplasms from non-gynecologic sites (colon, pancreas, breast, and lung), and various normal tissues. The authors also developed an antigen capture ELISA assay to determine if GRP75 can be detected in tumors, ascites, or sera of patients with advanced mullerian adenocarcinomas. All epithelial tumors from the ovary and the female reproductive tract were positive for GRP75 expression with moderate to strong staining intensity; stromal expression of GRP75 was generally weak or absent. Adenocarcinomas from the colon, lung, pancreas, and breast also stained strongly positive for GRP75. The epithelial cells of all normal tissues examined were positive for GRP75, and strong staining was also seen in the corpora lutea, hepatocytes, enteric neural plexus of the esophagus and colon, and placental cytotrophoblast and syncytiotrophoblast, and in subpopulations of pancreatic acinar cells. The ELISA assay detected GRP75 in tumor lysates and ascitic fluid, but not sera, of patients with mullerian adenocarcinomas. The authors conclude that GRP75 is highly expressed in both benign and malignant epithelium, as well as cells of specialized function from a variety of tissues.

Anomalous diffusion in nonhomogeneous media: time-subordinated Langevin equation approach.

Diffusion in nonhomogeneous media is described by a dynamical process driven by a general Lévy noise and subordinated to a random time; the subordinator depends on the position. This problem is approximated by a multiplicative process subordinated to a random time: it separately takes into account effects related to the medium structure and the memory. Density distributions and moments are derived from the solutions of the corresponding Langevin equation and compared with the numerical calculations for the exact problem. Both subdiffusion and enhanced diffusion are predicted. Distribution of the process satisfies the fractional Fokker-Planck equation.

Anomalous diffusion in systems driven by the stable Lévy noise with a finite noise relaxation time and inertia.

Dynamical systems driven by a general Lévy stable noise are considered. The inertia is included and the noise, represented by a generalized Ornstein-Uhlenbeck process, has a finite relaxation time. A general linear problem (the additive noise) is solved: the resulting distribution converges with time to the distribution for the white-noise, massless case. Moreover, a multiplicative noise is discussed. It can make the distribution steeper and the variance, which is finite, depends sublinearly on time (subdiffusion). For a small mass, a white-noise limit corresponds to the Stratonovich interpretation. On the other hand, the distribution tails agree with the Itô interpretation if the inertia is very large. An escape time from the potential well is calculated.

Nonlinear stochastic equations with multiplicative Lévy noise.

The Langevin equation with a multiplicative Lévy white noise is solved. The noise amplitude and the drift coefficient have a power-law form. A validity of ordinary rules of the calculus for the Stratonovich interpretation is discussed. The solution has the algebraic asymptotic form and the variance may assume a finite value for the case of the Stratonovich interpretation. The problem of escaping from a potential well is analyzed numerically; predictions of different interpretations of the stochastic integral are compared.

Multiplicative Lévy processes: Itô versus Stratonovich interpretation.

Langevin equation with a multiplicative stochastic force is considered. That force is uncorrelated, it has the Lévy distribution and the power-law intensity. The Fokker-Planck equations, which correspond both to the Itô and Stratonovich interpretation, are presented. They are solved for the case without drift and for the harmonic oscillator potential. The variance is evaluated; it is always infinite for the Itô case whereas for the Stratonovich one it can be finite and rise with time slower that linearly, which indicates subdiffusion. Analytical results are compared with numerical simulations.

Impact of diabetes mellitus on complications and outcomes of adjuvant chemotherapy in older patients with breast cancer.

PURPOSE: To evaluate whether diabetes affects patterns of adjuvant chemotherapy use, toxic effects of chemotherapy, and breast cancer outcomes. PATIENTS AND METHODS: By using the Surveillance, Epidemiology, and End Results-Medicare database, we identified patients aged 66 years or older who had stages I through III breast cancer that was diagnosed between 1992 and 2002. Multivariable regression analyses were performed to determine the effect of diabetes on use of chemotherapy, toxicities, and outcomes. The risks of all-cause mortality and breast cancer-specific (BCS) mortality were estimated with the Kaplan-Meier method. RESULTS: Our cohort had 70,781 men and women, of whom 14,414 (20.36%) had diabetes. Among people who received chemotherapy (n = 11,826), 21.0% were diabetics. In this group, diabetics had lower odds of receiving anthracyclines (odds ratio [OR], 0.78; 95% CI, 0.71 to 0.87) and taxanes (OR, 0.86; 95% CI, 0.75 to 0.99). Diabetes was associated with increased odds of being hospitalized for any chemotherapy toxicity (OR, 1.38; 95% CI, 1.23 to 1.56), for infection or fever (OR, 1.43; 95% CI, 1.2 to 1.7), for neutropenia (OR, 1.22; 95% CI, 1.03 to 1.45), for anemia (OR, 1.24; 95% CI, 1.05 to 1.47), and for any cause (OR, 1.32; 95% CI, 1.19 to 1.46). Patients with diabetes had higher all-cause mortality (hazard ratio [HR], 1.35; 95% CI, 1.31 to 1.39). There was a significant interaction between diabetes and chemotherapy use for BCS mortality. Diabetic and nondiabetic patients who did not receive chemotherapy had similar BCS mortality, but diabetic patients who did receive chemotherapy had higher BCS mortality than nondiabetic patients (OR, 1.20; 95% CI, 1.07 to 1.35). CONCLUSION: In this observational, hypothesis-generating study, patients who have breast cancer and diabetes are at increased risk of chemotherapy-related toxicities compared with nondiabetic patients who are receiving chemotherapy and have higher all-cause mortality.

Completion of adjuvant radiation therapy among women with breast cancer.

BACKGROUND: Optimal treatment for breast cancer often involves lengthy multimodality care including 5 to 6 weeks of radiotherapy, but few studies have evaluated adherence to radiotherapy outside the context of a therapeutic clinical trial. METHODS: Using a SEER-Medicare database, the authors identified women age 66 years or older with Stage I to III breast cancer diagnosed between 1992 and 2002. They evaluated rates of completion of radiotherapy, defined as a minimum of 25 sessions. Multivariate logistic regression analyses were performed to determine factors associated with completion of radiotherapy, and Cox multivariate models were used to determine the impact of radiotherapy completion on local recurrence. RESULTS: Some 24,510 patients were included in the study. Eighty-seven percent of patients completed 25 or more radiotherapy sessions. In multivariate logistic regression models, mastectomy (HR 1.26, 95% CI 1.10-1.43), hospitalization during treatment (2.87, 2.49-3.31), earlier year of diagnosis, and black race (1.36, 1.14-1.63) were associated with increased risk of non-completion of radiotherapy. Among 21,269 patients treated with breast conservation, incomplete radiotherapy was associated with higher risk of local recurrence. A total of 96.6% [corrected] of patients who did not complete radiation therapy were free of recurrence at 5 years vs. 97.5% of patients who completed radiation therapy (HR 1.46, CI 1.09-1.95). CONCLUSION: This study demonstrates relatively high rates of completion of radiation therapy among a population of older woman with breast cancer. However, those who did not complete a full course of radiotherapy had small but statistically significant higher risk of breast cancer recurrence. Future efforts should focus on intervening with women at high risk of not receiving adjuvant radiotherapy and increasing rates of radiotherapy completion.