Enhanced resting-state dynamics of the hemoglobin signal as a novel biomarker for detection of breast cancer.

PURPOSE: The work presented here demonstrates an application of diffuse optical tomography (DOT) to the problem of breast-cancer diagnosis. The potential for using spatial and temporal variability measures of the hemoglobin signal to identify useful biomarkers was studied. METHODS: DOT imaging data were collected using two instrumentation platforms the authors developed, which were suitable for exploring tissue dynamics while performing a simultaneous bilateral exam. For each component of the hemoglobin signal (e.g., total, oxygenated), the image time series was reduced to eight scalar metrics that were affected by one or more dynamic properties of the breast microvasculature (e.g., average amplitude, amplitude heterogeneity, strength of spatial coordination). Receiver-operator characteristic (ROC) analyses, comparing groups of subjects with breast cancer to various control groups (i.e., all noncancer subjects, only those with diagnosed benign breast pathology, and only those with no known breast pathology), were performed to evaluate the effect of cancer on the magnitudes of the metrics and of their interbreast differences and ratios. RESULTS: For women with known breast cancer, simultaneous bilateral DOT breast measures reveal a marked increase in the resting-state amplitude of the vasomotor response in the hemoglobin signal for the affected breast, compared to the contralateral, noncancer breast. Reconstructed 3D spatial maps of observed dynamics also show that this behavior extends well beyond the tumor border. In an effort to identify biomarkers that have the potential to support clinical aims, a group of scalar quantities extracted from the time series measures was systematically examined. This analysis showed that many of the quantities obtained by computing paired responses from the bilateral scans (e.g., interbreast differences, ratios) reveal statistically significant differences between the cancer-positive and -negative subject groups, while the corresponding measures derived from individual breast scans do not. ROC analyses yield area-under-curve values in the 77%-87% range, depending on the metric, with sensitivity and specificity values ranging from 66% to 91%. An interesting result is the initially unexpected finding that the hemodynamic-image metrics are only weakly dependent on the tumor burden, implying that the DOT technique employed is sensitive to tumor-induced changes in the vascular dynamics of the surrounding breast tissue as well. Computational modeling studies serve to identify which properties of the vasomotor response (e.g., average amplitude, amplitude heterogeneity, and phase heterogeneity) principally determine the values of the metrics and their codependences. Findings from the modeling studies also serve to clarify the influence of spatial-response heterogeneity and of system-design limitations, and they reveal the impact that a complex dependence of metric values on the modeled behaviors has on the success in distinguishing between cancer-positive and -negative subjects. CONCLUSIONS: The authors identified promising hemoglobin-based biomarkers for breast cancer from measures of the resting-state dynamics of the vascular bed. A notable feature of these biomarkers is that their spatial extent encompasses a large fraction of the breast volume, which is mainly independent of tumor size. Tumor-induced induction of nitric oxide synthesis, a well-established concomitant of many breast cancers, is offered as a plausible biological causal factor for the reported findings.

Artesunate-related fever and delayed hemolysis in a returning traveler.

Malaria is a serious and sometimes fatal disease caused by an intraerythrocytic parasite, and is commonly seen in developing countries. Approximately 1500 cases of malaria are diagnosed in the United States each year, mostly in travelers and immigrants returning from endemic areas [1]. There are many different regimens used to treat malaria, some of which are not approved in the USA. The side effects of these medications may not be familiar to physicians in the USA. We report a case of a returning traveler from Nigeria presenting with fever and hemolytic anemia caused by a delayed response to artesunate given 3 weeks earlier while in Nigeria. To our knowledge, there are few cases reported in the United States of hemolytic anemia secondary to artesunate therapy [2].

A critical analysis of prognostic factors in North American patients with human T-cell lymphotropic virus type-1-associated adult T-cell leukemia/lymphoma: a multicenter clinicopathologic experience and new prognostic score.

BACKGROUND: To define the clinicopathologic and prognostic features of patients with human T-cell lymphotropic virus type-1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATLL) in North America, standard criteria were used to identify patients with ATLL. METHODS: Statistical analyses used included descriptive statistics, Kaplan-Meir survival analysis, and recursive partitioning. RESULTS: Eighty-nine patients were identified between August 1992 and May 2007, including 37 (41.6%) males and 52 (58.4%) females with a median age of 50 years (range, 22-82 years). All but 6 patients had immigrated to the United States from the Caribbean, Latin America, or Africa. The acute subtype predominated (68.5%). The majority of patients received a combination-alkylator-based chemotherapy regimen in the front-line setting (72.6%). The most common regimen was cyclophosphamide, doxorubicin, vincristine, and prednisone at standard doses or attenuated and/or with methotrexate (CHOP-like), which produced an overall response rate of 64.1%. Despite initial responses to therapy, the median overall survival for all subtypes was 24 weeks (range, 0.9-315 weeks). Although the International Prognostic Index and Prognostic Index for peripheral T-cell lymphoma unspecified identified subsets of patients, these models were not completely predictive. A recursive partitioning analysis was performed on the data, which successfully identified 3 prognostic categories based on Eastern Cooperative Oncology Group performance status, stage, age, and calcium level at diagnosis. CONCLUSIONS: This series proposed a new prognostic model for patients with HTLV-1-associated ATLL and confirmed a poor outcome for these patients in North America.

Design and implementation of dynamic near-infrared optical tomographic imaging instrumentation for simultaneous dual-breast measurements.

Dynamic near-infrared optical tomographic measurement instrumentation capable of simultaneous bilateral breast imaging, having a capability of four source wavelengths and 32 source-detector fibers for each breast, is described. The system records dynamic optical data simultaneously from both breasts, while verifying proper optical fiber contact with the tissue through implementation of automatic schemes for evaluating data integrity. Factors influencing system complexity and performance are discussed, and experimental measurements are provided to demonstrate the repeatability of the instrumentation. Considerations in experimental design are presented, as well as techniques for avoiding undesirable measurement artifacts, given the high sensitivity and dynamic range (1:10(9)) of the system. We present exemplary clinical results comparing the measured physiologic response of a healthy individual and of a subject with breast cancer to a Valsalva maneuver.