Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma.

FcRH5 is a cell surface marker enriched on malignant plasma cells when compared to other hematologic malignancies and normal tissues. DFRF4539A is an anti-FcRH5 antibody-drug conjugated to monomethyl auristatin E (MMAE), a potent anti-mitotic agent. This phase I study assessed safety, tolerability, maximum tolerated dose (MTD), anti-tumor activity, and pharmacokinetics of DFRF4539A in patients with relapsed/refractory multiple myeloma. DFRF4539A was administered at 0.3-2.4 mg/kg every 3 weeks or 0.8-1.1 mg/kg weekly as a single-agent by intravenous infusion to 39 patients. Exposure of total antibody and antibody-conjugate-MMAE analytes was linear across the doses tested. There were 37 (95%) adverse events (AEs), 8 (21%) serious AEs, and 15 (39%) AEs ≥ grade 3. Anemia (n = 10, 26%) was the most common AE considered related to DFRF4539A. Two cases of grade 3 acute renal failure were attributed to DFRF4539A. There were no deaths; the MTD was not reached. DFRF4539A demonstrated limited activity in patients at the doses tested with 2 (5%) partial response, 1 (3%) minimal response, 18 (46%) stable disease, and 16 (41%) progressive disease. FcRH5 was confirmed to be expressed and occupied by antibody post-treatment and thus remains a valid myeloma target. Nevertheless, this MMAE-based antibody-drug-conjugate targeting FcRH5 was unsuccessful for myeloma.

The Application of Gene Expression Profiling in Predictions of Occult Lymph Node Metastasis in Colorectal Cancer Patients.

A key factor in determining the likely outcome for a patient with colorectal cancer is whether or not the tumour has metastasised to the lymph nodes-information which is also important in assessing any possibilities of lymph node resection so as to improve survival. In this review we perform a wide-range assessment of literature relating to recent developments in gene expression profiling (GEP) of the primary tumour, to determine their utility in assessing node status. A set of characteristic genes seems to be involved in the prediction of lymph node metastasis (LNM) in colorectal patients. Hence, GEP is applicable in personalised/individualised/tailored therapies and provides insights into developing novel therapeutic targets. Not only is GEP useful in prediction of LNM, but it also allows classification based on differences such as sample size, target gene expression, and examination method.

GJA4/Connexin 37 Mutations Correlate with Secondary Lymphedema Following Surgery in Breast Cancer Patients.

Lymphedema is a condition resulting from mutations in various genes essential for lymphatic development and function, which leads to obstruction of the lymphatic system. Secondary lymphedema is a progressive and incurable condition, most often manifesting after surgery for breast cancer. Although its causation appears complex, various lines of evidence indicate that genetic predisposition may play a role. Previous studies show that mutations in connexin 47 are associated with secondary lymphedema. We have tested the hypothesis that connexin 37 gene mutations in humans are associated with secondary lymphedema following breast cancer surgery. A total of 2211 breast cancer patients were screened and tested for reference single nucleotide polymorphisms (SNPs) of the GJA4 gene (gap junction protein alpha 4 gene). The results presented in this paper indicate that two SNPs in the 3' UTR (the three prime untranslated region) of the GJA4 gene are associated with an increased risk of secondary lymphedema in patients undergoing breast cancer treatment. Our results provide evidence of a novel genetic biomarker for assessing the predisposition to secondary lymphedema in human breast cancer patients. Testing for the condition-associated alleles described here could assist and inform treatment and post-operative care plans of breast cancer patients, with potentially positive outcomes for the management of disease progression.

High-resolution seismic event detection using local similarity for Large-N arrays.

We develop a novel method for seismic event detection that can be applied to large-N arrays. The method is based on a new detection function named local similarity, which quantifies the signal consistency between the examined station and its nearest neighbors. Using the 5200-station Long Beach nodal array, we demonstrate that stacked local similarity functions can be used to detect seismic events with amplitudes near or below noise levels. We apply the method to one-week continuous data around the 03/11/2011 Mw 9.1 Tohoku-Oki earthquake, to detect local and distant events. In the 5-10 Hz range, we detect various events of natural and anthropogenic origins, but without a clear increase in local seismicity during and following the surface waves of the Tohoku-Oki mainshock. In the 1-Hz low-pass-filtered range, we detect numerous events, likely representing aftershocks from the Tohoku-Oki mainshock region. This high-resolution detection technique can be applied to both ultra-dense and regular array recordings for monitoring ultra-weak micro-seismicity and detecting unusual seismic events in noisy environments.

Reprogramming of primary human Philadelphia chromosome-positive B cell acute lymphoblastic leukemia cells into nonleukemic macrophages.

BCR-ABL1(+) precursor B-cell acute lymphoblastic leukemia (BCR-ABL1(+) B-ALL) is an aggressive hematopoietic neoplasm characterized by a block in differentiation due in part to the somatic loss of transcription factors required for B-cell development. We hypothesized that overcoming this differentiation block by forcing cells to reprogram to the myeloid lineage would reduce the leukemogenicity of these cells. We found that primary human BCR-ABL1(+) B-ALL cells could be induced to reprogram into macrophage-like cells by exposure to myeloid differentiation-promoting cytokines in vitro or by transient expression of the myeloid transcription factor C/EBPα or PU.1. The resultant cells were clonally related to the primary leukemic blasts but resembled normal macrophages in appearance, immunophenotype, gene expression, and function. Most importantly, these macrophage-like cells were unable to establish disease in xenograft hosts, indicating that lineage reprogramming eliminates the leukemogenicity of BCR-ABL1(+) B-ALL cells, and suggesting a previously unidentified therapeutic strategy for this disease. Finally, we determined that myeloid reprogramming may occur to some degree in human patients by identifying primary CD14(+) monocytes/macrophages in BCR-ABL1(+) B-ALL patient samples that possess the BCR-ABL1(+) translocation and clonally recombined VDJ regions.

Seismocardiography-Based Detection of Cardiac Quiescence.

Cardiac-computed tomography angiography (CTA) is a minimally invasive imaging technology for characterizing coronary arteries. A fundamental limitation of CTA imaging is cardiac movement, which can cause artifacts and reduce the quality of the obtained images. To mitigate this problem, current approaches involve gating the image based on the electrocardiogram (ECG) to predict the timing of quiescent periods of the cardiac cycle. This paper focuses on developing a foundation for using a mechanical alternative to the ECG for finding these quiescent periods: the seismocardiogram (SCG). SCG was used to determine beat-by-beat systolic and diastolic quiescent periods of the cardiac cycle for nine healthy subjects, and 11 subjects with various cardiovascular diseases. To reduce noise in the SCG, and quantify these quiescent periods, a Kalman filter was designed to extract the velocity of chest wall movement from the recorded SCG signals. The average systolic and diastolic quiescent periods were centered at 29% and 76% for the healthy subjects, and 33% and 79% for subjects with cardiovascular disease. Both inter and intrasubject variability in the quiescent phases were observed compared to ECG-predicted phases, suggesting that the ECG may be a suboptimal modality for predicting quiescence, and that the SCG provides complementary data to the ECG.

Characterization of cardiac quiescence from retrospective cardiac computed tomography using a correlation-based phase-to-phase deviation measure.

PURPOSE: Accurate knowledge of cardiac quiescence is crucial to the performance of many cardiac imaging modalities, including computed tomography coronary angiography (CTCA). To accurately quantify quiescence, a method for detecting the quiescent periods of the heart from retrospective cardiac computed tomography (CT) using a correlation-based, phase-to-phase deviation measure was developed. METHODS: Retrospective cardiac CT data were obtained from 20 patients (11 male, 9 female, 33-74 yr) and the left main, left anterior descending, left circumflex, right coronary artery (RCA), and interventricular septum (IVS) were segmented for each phase using a semiautomated technique. Cardiac motion of individual coronary vessels as well as the IVS was calculated using phase-to-phase deviation. As an easily identifiable feature, the IVS was analyzed to assess how well it predicts vessel quiescence. Finally, the diagnostic quality of the reconstructed volumes from the quiescent phases determined using the deviation measure from the vessels in aggregate and the IVS was compared to that from quiescent phases calculated by the CT scanner. Three board-certified radiologists, fellowship-trained in cardiothoracic imaging, graded the diagnostic quality of the reconstructions using a Likert response format: 1 = excellent, 2 = good, 3 = adequate, 4 = nondiagnostic. RESULTS: Systolic and diastolic quiescent periods were identified for each subject from the vessel motion calculated using the phase-to-phase deviation measure. The motion of the IVS was found to be similar to the aggregate vessel (AGG) motion. The diagnostic quality of the coronary vessels for the quiescent phases calculated from the aggregate vessel (PAGG) and IVS (PIV S) deviation signal using the proposed methods was comparable to the quiescent phases calculated by the CT scanner (PCT). The one exception was the RCA, which improved for PAGG for 18 of the 20 subjects when compared to PCT (PCT = 2.48; PAGG = 2.07, p = 0.001). CONCLUSIONS: A method for quantifying the motion of specific coronary vessels using a correlation-based, phase-to-phase deviation measure was developed and tested on 20 patients receiving cardiac CT exams. The IVS was found to be a suitable predictor of vessel quiescence. The diagnostic quality of the quiescent phases detected by the proposed methods was comparable to those calculated by the CT scanner. The ability to quantify coronary vessel quiescence from the motion of the IVS can be used to develop new CTCA gating techniques and quantify the resulting potential improvement in CTCA image quality.

Detection of quiescent cardiac phases in echocardiography data using nonlinear filtering and boundary detection techniques.

We describe an algorithm to detect cardiac quiescence within a heartbeat using nonlinear filtering and boundary detection techniques in echocardiography images. The motivation for detection of these quiescent phases is to provide improved cardiac gating to obtain motion-artifact-free images of the heart at cardiac computed tomography (CT). Currently, cardiac gating is provided through electrocardiography (ECG), which does not provide information about the instantaneous mechanical state of the heart. Our goal is to test if information about the actual mechanical motion of the heart obtained from B-mode echocardiographic data could potentially be used for gating purposes. The nonlinear filtering algorithm presented involves anisotropic diffusion to smoothen the homogeneous regions of the B-mode images while preserving image edges that represent myocardial boundaries. Following this, we detect the boundary of a particular region of interest (ROI) using a thresholding step. The positional changes of this ROI are then observed for quiescent phases over multiple cardiac cycles using the ECG's R-R interval. In a pilot study, seven subjects were imaged in the apical, four-chamber view, and quiescence of the interventricular septum was primarily observed in the diastolic region of the ECG signal. However, the position and length of quiescence vary across multiple heartbeats for the same individual and for different individuals as well. The center of quiescence for the seven patients ranged from 51 to 84 % and did not show a trend with heart rates, which ranged from 54 to 83 beats per minute. The gating intervals based on such analysis of echocardiographic signals could potentially optimize cardiac CT gating.

Seismocardiography-based detection of cardiac quiescence for cardiac computed tomography angiography.

As a measure of chest wall acceleration caused by cardiac motion, the seismocardiogram (SCG) has the potential to supplement the electrocardiogram (ECG) to more accurately trigger cardiac computed tomography angiography (CTA) data acquisition during periods of cardiac quiescence. The SCG was used to identify the systolic and diastolic quiescent periods of the cardiac cycle on a beat-by-beat basis and from composite velocity signals for nine healthy subjects. The cardiac velocity transmitted to the chest wall was calculated using a Kalman filter. The average systolic and diastolic quiescent periods were centered at 30% and 76%, respectively. Inter- and intra-subject variability of the quiescent phases with respect to the ECG was observed, suggesting that the ECG may be a suboptimal modality for predicting cardiac quiescence.

Novel Tool for Complete Digitization of Paper Electrocardiography Data.

OBJECTIVE: We present a Matlab-based tool to convert electrocardiography (ECG) information from paper charts into digital ECG signals. The tool can be used for long-term retrospective studies of cardiac patients to study the evolving features with prognostic value. METHODS AND PROCEDURES: To perform the conversion, we: 1) detect the graphical grid on ECG charts using grayscale thresholding; 2) digitize the ECG signal based on its contour using a column-wise pixel scan; and 3) use template-based optical character recognition to extract patient demographic information from the paper ECG in order to interface the data with the patients' medical record. To validate the digitization technique: 1) correlation between the digital signals and signals digitized from paper ECG are performed and 2) clinically significant ECG parameters are measured and compared from both the paper-based ECG signals and the digitized ECG. RESULTS: The validation demonstrates a correlation value of 0.85-0.9 between the digital ECG signal and the signal digitized from the paper ECG. There is a high correlation in the clinical parameters between the ECG information from the paper charts and digitized signal, with intra-observer and inter-observer correlations of 0.8-0.9 (p < 0.05), and kappa statistics ranging from 0.85 (inter-observer) to 1.00 (intra-observer). CONCLUSION: The important features of the ECG signal, especially the QRST complex and the associated intervals, are preserved by obtaining the contour from the paper ECG. The differences between the measures of clinically important features extracted from the original signal and the reconstructed signal are insignificant, thus highlighting the accuracy of this technique. CLINICAL IMPACT: Using this type of ECG digitization tool to carry out retrospective studies on large databases, which rely on paper ECG records, studies of emerging ECG features can be performed. In addition, this tool can be used to potentially integrate digitized ECG information with digital ECG analysis programs and with the patient's electronic medical record.

Detection of Cardiac Quiescence from B-Mode Echocardiography Using a Correlation-Based Frame-to-Frame Deviation Measure.

Two novel methods for detecting cardiac quiescent phases from B-mode echocardiography using a correlation-based frame-to-frame deviation measure were developed. Accurate knowledge of cardiac quiescence is crucial to the performance of many imaging modalities, including computed tomography coronary angiography (CTCA). Synchronous electrocardiography (ECG) and echocardiography data were obtained from 10 healthy human subjects (four male, six female, 23-45 years) and the interventricular septum (IVS) was observed using the apical four-chamber echocardiographic view. The velocity of the IVS was derived from active contour tracking and verified using tissue Doppler imaging echocardiography methods. In turn, the frame-to-frame deviation methods for identifying quiescence of the IVS were verified using active contour tracking. The timing of the diastolic quiescent phase was found to exhibit both inter- and intra-subject variability, suggesting that the current method of CTCA gating based on the ECG is suboptimal and that gating based on signals derived from cardiac motion are likely more accurate in predicting quiescence for cardiac imaging. Two robust and efficient methods for identifying cardiac quiescent phases from B-mode echocardiographic data were developed and verified. The methods presented in this paper will be used to develop new CTCA gating techniques and quantify the resulting potential improvement in CTCA image quality.

Cryptococcal osteomyelitis and meningitis in a patient with non-hodgkin's lymphoma treated with PEP-C.

The authors present the first case report of a patient with lymphoma who developed disseminated cryptococcal osteomyelitis and meningitis while being treated with the PEP-C (prednisone, etoposide, procarbazine and cyclophosphamide) chemotherapy regimen. During investigation of fever and new bony lesions, fungal culture from a rib biopsy revealed that the patient had cryptococcal osteomyelitis. Further evaluation demonstrated concurrent cryptococcal meningitis. The patient's disseminated cryptococcal infections completely resolved after a full course of antifungal treatment. Cryptococcal osteomyelitis is itself an extremely rare diagnosis, and the unique presentation with concurrent cryptococcal meningitis in our patient with lymphoma was likely due to his PEP-C treatment. It is well recognised that prolonged intensive chemotherapeutic regimens place patients at risk for atypical infections; yet physicians should recognise that even chronic low-dose therapies can put patients at risk for fungal infections. Physicians should consider fungal infections as part of the infectious investigation of a lymphopaenic patient on PEP-C.

A system for seismocardiography-based identification of quiescent heart phases: implications for cardiac imaging.

Seismocardiography (SCG), a representation of mechanical heart motion, may more accurately determine periods of cardiac quiescence within a cardiac cycle than the electrically derived electrocardiogram (EKG) and, thus, may have implications for gating in cardiac computed tomography. We designed and implemented a system to synchronously acquire echocardiography, EKG, and SCG data. The device was used to study the variability between EKG and SCG and characterize the relationship between the mechanical and electrical activity of the heart. For each cardiac cycle, the feature of the SCG indicating Aortic Valve Closure was identified and its time position with respect to the EKG was observed. This position was found to vary for different heart rates and between two human subjects. A color map showing the magnitude of the SCG acceleration and computed velocity was derived, allowing for direct visualization of quiescent phases of the cardiac cycle with respect to heart rate.

An active contour based method for analyzing cardiac quiescence from echocardiography.

A semi-automated method for analyzing cardiac quiescence of anatomical cardiac features from two-dimensional echocardiographic cine data is presented. The method utilizes both active contour and optical flow techniques for feature identification and tracking. A curvature-based potential surface was used in the active contour calculations to attract the contour to regions of inflection on the image surface rather than the standard gradient-based surface that attracts the contour to strong edges. After identifying the feature in each frame, the frame-to-frame correlation matrix of the feature was calculated with correlation values corresponding to how well the feature matched between frames. Therefore prolonged regions of high correlation correspond to periods of cardiac quiescence. The location and duration of these periods were automatically identified from the correlation matrix by finding the largest region around each time index with a mean correlation above a specified threshold. In parallel, the position of the feature was calculated for each frame by finding the centroid of the pixel locations inside the contour. From this trajectory, the magnitude of the two-dimensional velocity was calculated. These methods were used to analyze the quiescence of the interventricular septum from an apical four-chamber echocardiogram performed on a human subject. Correlation-derived quiescent phases were observed to coincide with periods of the cardiac cycle with minimal velocity magnitude.

Treatment advances have not improved the early death rate in acute promyelocytic leukemia.

Early mortality in acute promyelocytic leukemia has been reported to occur in less than 10% of patients treated in clinical trials. This study reports the incidence and clinical features of acute promyelocytic leukemia patients treated at Stanford Hospital, CA, USA since March 1997, focusing on early mortality. We show that the risk of early death in acute promyelocytic leukemia patients is higher than previously reported. In a cohort of 70 patients who received induction therapy at Stanford Hospital, 19% and 26% died within seven and 30 days of admission, respectively. High early mortality was not limited to our institution as evaluation of the Surveillance, Epidemiology and End Results Database demonstrated that 30-day mortality for acute promyelocytic leukemia averaged 20% from 1977-2007 and did not improve significantly over this interval. Our findings show that early death is now the greatest contributor to treatment failure in this otherwise highly curable form of leukemia.

A trimodal system for the acquisition of synchronous echocardiography, electrocardiography, and seismocardiography data.

A novel system was developed to acquire synchronous echocardiography, electrocardiography (EKG), and seismocardiography (SCG) data. The system was developed to facilitate the study of the relationship between the mechanical and electrical characteristics of the heart. The system has both a hardware and software component. The hardware component consists of an application-specific device designed and built to acquire both SCG and EKG signals simultaneously. The software component consists of a package developed to record and synchronize data from both the device and a clinical ultrasound machine. A feasibility test was performed by simultaneous acquisition of a synchronous dataset from a human subject.

Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema.

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency is characterized by recurrent acute attacks of swelling that can be painful and sometimes life-threatening. METHODS: We conducted two randomized trials to evaluate nanofiltered C1 inhibitor concentrate in the management of hereditary angioedema. The first study compared nanofiltered C1 inhibitor concentrate with placebo for treatment of an acute attack of angioedema. A total of 68 subjects (35 in the C1 inhibitor group and 33 in the placebo group) were given one or two intravenous injections of the study drug (1000 units each). The primary end point was the time to the onset of unequivocal relief. The second study was a crossover trial involving 22 subjects with hereditary angioedema that compared prophylactic twice-weekly injections of nanofiltered C1 inhibitor concentrate (1000 units) with placebo during two 12-week periods. The primary end point was the number of attacks of angioedema per period, with each subject acting as his or her own control. RESULTS: In the first study, the median time to the onset of unequivocal relief from an attack was 2 hours in the subjects treated with C1 inhibitor concentrate but longer than 4 hours in those given placebo (P=0.02). In the second study, the number of attacks per 12-week period was 6.26 with C1 inhibitor concentrate given as prophylaxis, as compared with 12.73 with placebo (P<0.001); the subjects who received the C1 inhibitor concentrate also had significant reductions in both the severity and the duration of attacks, in the need for open-label rescue therapy, and in the total number of days with swelling. CONCLUSIONS: In subjects with hereditary angioedema, nanofiltered C1 inhibitor concentrate shortened the duration of acute attacks. When used for prophylaxis, nanofiltered C1 inhibitor concentrate reduced the frequency of acute attacks. (Funded by Lev Pharmaceuticals; ClinicalTrials.gov numbers, NCT00289211, NCT01005888, NCT00438815, and NCT00462709.)

A-form DNA structure is a determinant of transcript levels from the Xenopus gata2 promoter in embryos.

We have previously shown that a critical region of the gata2 promoter contains an inverted CCAAT box and adopts a partial A-form DNA structure in vitro. At gastrula stages of development transcription requires binding of CBTF (CCAAT box transcription factor), a multi-subunit transcription factor, to this region. Xilf3 is one component of CBTF and the double stranded RNA binding domains (dsRBDs) of Xilf3 must be active for both binding to, and transcription from, this promoter. Here we determine the contribution of DNA sequence and structure at the gata2 promoter to transcriptional activity. In all the constructs we tested a CCAAT box was a requirement for full activity. However, base substitutions that increase B-form structure propensity in the sequences flanking the CCAAT box are equally able to decrease activity even if a CCAAT box is present. In contrast, mutations that maintain A-form propensity in these regions also maintain, or increase, transcription factor binding and transcriptional activity. We propose a two-component model for the interaction of CBTF with the gata2 promoter, requiring both a CCAAT sequence and flanking A-form DNA structures. These results support a novel role for dsRBDs in transcriptional regulation and suggest a function for A-form DNA in vivo.