Deep-Learning-Based High-Intensity Focused Ultrasound Lesion Segmentation in Multi-Wavelength Photoacoustic Imaging.

Photoacoustic (PA) imaging can be used to monitor high-intensity focused ultrasound (HIFU) therapies because ablation changes the optical absorption spectrum of the tissue, and this change can be detected with PA imaging. Multi-wavelength photoacoustic (MWPA) imaging makes this change easier to detect by repeating PA imaging at multiple optical wavelengths and sampling the optical absorption spectrum more thoroughly. Real-time pixel-wise classification in MWPA imaging can assist clinicians in monitoring HIFU lesion formation and will be a crucial milestone towards full HIFU therapy automation based on artificial intelligence. In this paper, we present a deep-learning-based approach to segment HIFU lesions in MWPA images. Ex vivo bovine tissue is ablated with HIFU and imaged via MWPA imaging. The acquired MWPA images are then used to train and test a convolutional neural network (CNN) for lesion segmentation. Traditional machine learning algorithms are also trained and tested to compare with the CNN, and the results show that the performance of the CNN significantly exceeds traditional machine learning algorithms. Feature selection is conducted to reduce the number of wavelengths to facilitate real-time implementation while retaining good segmentation performance. This study demonstrates the feasibility and high performance of the deep-learning-based lesion segmentation method in MWPA imaging to monitor HIFU lesion formation and the potential to implement this method in real time.

A Handheld Imaging Probe for Acoustic Angiography With an Ultrawideband Capacitive Micromachined Ultrasonic Transducer (CMUT) Array.

This article presents an imaging probe with a 256-element ultrawideband (UWB) 1-D capacitive micromachined ultrasonic transducer (CMUT) array designed for acoustic angiography (AA). This array was fabricated on a borosilicate glass wafer with a reduced bottom electrode and an additional central plate mass to achieve the broad bandwidth. A custom 256-channel handheld probe was designed and implemented with integrated low-noise amplifiers and supporting power circuitry. This probe was used to characterize the UWB CMUT, which has a functional 3-dB frequency band from 3.5 to 23.5 MHz. A mechanical index (MI) of 0.33 was achieved at 3.5 MHz at a depth of 11 mm. These promising measurements are then combined to demonstrate AA. The use of alternate amplitude modulation (aAM) combined with a frequency analysis of the measured transmit signal demonstrates the suitability of the UWB CMUT for AA. This is achieved by measuring only a low level of unwanted high-frequency harmonics in both the transmit signal and the reconstructed image in the areas other than the contrast bubbles.

A Row-Column (RC) Addressed 2-D Capacitive Micromachined Ultrasonic Transducer (CMUT) Array on a Glass Substrate.

This article presents a row-column (RC) capacitive micromachined ultrasonic transducer (CMUT) array fabricated using anodic bonding on a borosilicate glass substrate. This is shown to reduce the bottom electrode-to-substrate capacitive coupling. This subsequently improves the relative response of the elements when top or bottom electrodes are used as the "signal" (active) electrode. This results in a more uniform performance for the two cases. Measured capacitance and resonant frequency, pulse-echo signal amplitude, and frequency response are presented to support this. Biasing configurations with varying ac and dc arrangements are applied and subsequently explored. Setting the net dc bias voltage across an off element to zero is found to be most effective to minimize spurious transmission. To achieve this, a custom switching circuit was designed and implemented. This circuit was also used to obtain orthogonal B-mode cross-sectional images of a rotationally asymmetric target.

An Improved CMUT Structure Enabling Release and Collapse of the Plate in the Same Tx/Rx Cycle for Dual-Frequency Acoustic Angiography.

This study demonstrates, in detail, the potential of using capacitive micromachined ultrasonic transducers (CMUTs) for acoustic angiography of the microvasculature. It is known that when ultrasound contrast agents (microbubbles) are excited with moderate acoustic pressure around their resonance (2-4 MHz), they produce higher order harmonics (greater than third harmonic) due to their nonlinear behavior. To date, the fundamental challenge has been the availability of a transducer that can generate the transmit signals to excite the microbubbles at low frequencies and, in the same cycle, confocally detect harmonics in the higher frequencies. We present a novel device structure and dual-mode operation of a CMUT that operates with a center frequency of 4.3 MHz and 150% bandwidth in the conventional mode for transmitting and a center frequency of 9.8 MHz and a 125.5% bandwidth in collapse mode for receiving. Output pressure of 1.7 MPapp is achieved on the surface of a single unfocused transducer. The mechanical index at the transducer surface is 0.56. FEM simulations are performed first to show the functionality of the proposed device, and then, the device fabrication is described in detail. Finally, we experimentally demonstrate the ability to detect the microbubble signals with good contrast, and the background reflection is adequately suppressed, indicating the feasibility of the presented approach for acoustic angiography.

An FPGA-Based Backend System for Intravascular Photoacoustic and Ultrasound Imaging.

The integration of intravascular ultrasound (IVUS) and intravascular photoacoustic (IVPA) imaging produces an imaging modality with high sensitivity and specificity which is particularly needed in interventional cardiology. Conventional side-looking IVUS imaging with a single-element ultrasound (US) transducer lacks forward-viewing capability, which limits the application of this imaging mode in intravascular intervention guidance, Doppler-based flow measurement, and visualization of nearly, or totally blocked arteries. For both side-looking and forward-looking imaging, the necessity to mechanically scan the US transducer limits the imaging frame rate, and therefore, array-based solutions are desired. In this paper, we present a low-cost, compact, high-speed, and programmable imaging system based on a field-programmable gate array suitable for dual-mode forward-looking IVUS/IVPA imaging. The system has 16 US transmit and receive channels and functions in multiple modes including interleaved photoacoustic (PA) and US imaging, hardware-based high-frame-rate US imaging, software-driven US imaging, and velocity measurement. The system is implemented in the register-transfer level, and the central system controller is implemented as a finite-state machine. The system was tested with a capacitive micromachined ultrasonic transducer array. A 170-frames-per-second (FPS) US imaging frame rate is achieved in the hardware-based high-frame-rate US imaging mode while the interleaved PA and US imaging mode operates at a 60-FPS US and a laser-limited 20-FPS PA imaging frame rate. The performance of the system benefits from the flexibility and efficiency provided by the low-level implementation. The resulting system provides a convenient backend platform for research and clinical IVPA and IVUS imaging.

A Row-Column (RC) Addressed 2D Capacitive Micromachined Ultrasonic Transducer (CMUT) Array on a Glass Substrate: Preliminary Results.

In this work, we present preliminary characterization results from a 32 x 32 row-column (RC) addressed 2D capacitive micromachined ultrasonic transducer (CMUT) array. The device was fabricated using anodic bonding on a borosilicate glass substrate, which eliminates the substrate - bottom electrode coupling previously observed in traditional CMUT RC arrays fabricated on silicon substrates. The characterization results were compared for the top and bottom electrodes and include impedance measurements, pulseecho impulse responses, and 2D scans of the pressure field using a calibrated hydrophone. The results showed that the array elements behave similarly when ground and hot electrodes were switched between the top and bottom electrodes for all of the measured parameters including device capacitance, center frequency, and pulse-echo response amplitude. The pressure scans verified the highly customizable nature of RC arrays by showing multiple active element configurations. A sample cross-sectional image of a metal target was also demonstrated.

Late Effects after Umbilical Cord Blood Transplantation in Very Young Children after Busulfan-Based, Myeloablative Conditioning.

Infants and young children who undergo allogeneic cord blood transplantation (CBT) are at increased risk for late effects because of exposure of developing organs to chemotherapy and radiation therapy typically used in transplant conditioning regimens. Busulfan (Bu)-based myeloablative regimens were developed to eliminate radiation exposure in these young children with the hope that late effects would be minimized. We now describe the late effects in 102 consecutive patients surviving a minimum of 5 years (median follow-up, 12.9 years) post-CBT. Patients were conditioned with high-dose chemotherapy using Bu-containing regimens. No patient received total body irradiation. The median age at transplant was 1 year (range, .1 to 2). Diagnoses included inherited metabolic diseases (59.8%), leukemia (17.6%), congenital immune deficiency (20.2%), bone marrow failure/myelodysplastic syndrome (3.9%), and hemoglobinopathy (2%). Among patients surviving 5 years, the overall survival rate at 10 years post-CBT was 93% (95% CI, 84.9 to 96.8). Virtually all patients (98%) experienced at least 1 significant late effect. Most (83.3%) experienced 2 or more late effects, and more than half of the patients (64.7%) experienced 3 or more late effects. The most commonly observed late effects included dental problems (92.2%), short stature (55.9%), cognitive deficits (53.6%), pulmonary dysfunction (18.6%), and abnormal pubertal development (27.9%). This is the first report of late effects of Bu-based conditioning in a cohort of very young patients at the time of transplant. These results will inform clinical care guidelines for long-term follow-up and add to the growing information regarding outcomes of hematopoietic stem cell transplantation.

Photoacoustic-imaging-based temperature monitoring for high-intensity focused ultrasound therapy.

Temperature monitoring during high-intensity focused ultrasound (HIFU) application is necessary to ensure effective therapy while minimizing thermal damage to adjacent tissue. In this study, we demonstrate a noninvasive approach for temperature measurement during HIFU therapy based on photoacoustic imaging (PAI). Because of the dependence of photoacoustic (PA) signal amplitude on temperature of the source tissue and the linearity of the PAI system, changes in temperature will cause changes in PA image intensity. Experiments have been conducted in ex-vivo bovine tissue to characterize the linear dependence of PA image pixel values on temperature and subsequently to convert the PA image to a real-time temperature map.

Intestinal decontamination of multidrug-resistant Klebsiella pneumoniae after recurrent infections in an immunocompromised host.

Multidrug-resistant (MDR) Enterobacteriaceae infections are associated with increased morbidity. We describe a 20-year-old hematopoietic cell transplantation recipient with recurrent MDR Klebsiella pneumoniae infection, prolonged intestinal colonization, and subsequent intestinal decontamination. Further study should evaluate stool surveillance, molecular typing, and fecal microbiota transplantation for patients with intestinal MDR Enterobacteriaceae carriage.

Training practices of hematopoietic progenitor cell-apheresis and -cord blood collection staff: analysis of a survey by the Alliance for Harmonisation of Cellular Therapy Accreditation.

BACKGROUND: As hematopoietic stem cell transplantation expands globally, identification of the key elements that make up high-quality training programs will become more important to optimizing collection practices and quality of the products collected. STUDY DESIGN AND METHODS: Multiple-choice and open questions to identify training practices of those collecting hematopoietic progenitor cell-apheresis [HPC(A)] and -cord blood [HPC(CB)] products were distributed via an electronic survey tool worldwide. Data were collected on facility demographics, job descriptions, and the content of training programs including general practices, staff assessment, retraining, and unique program features. RESULTS: Respondents from more than 50 countries predominantly associating with facilities in North America and Europe represented transplant centers or transfusion services also performing collections. For the majority of staff performing HPC(A) collections (50%), initial training required as many procedures as necessary be done until competency was achieved. Competency was evaluated by direct observation comparing performance to written procedures or protocol steps (47%), combination of written assessment and observation (45%), evaluation of product quality (40%), and written assessment alone (12%). Staff retraining was customized on a case-by-case basis (42%). Similar criteria were placed on HPC(CB) training, with an emphasis on product quality measured by sterility, CD34+ cell collection efficiency, hematocrit, volume, and mononuclear cell count. CONCLUSION: Observation, practice, evaluation, and retraining until competency is achieved marked the training programs. Success was based on the ability of staff to execute procedures ultimately measured in product quality. Identified features may assist facilities in further developing and strengthening their own training programs.

Success of allogeneic marrow transplantation for children with severe aplastic anaemia.

Allogeneic marrow transplantation offers curative therapy for children with severe aplastic anaemia (SAA). We report the outcomes of 148 children with SAA who received human leucocyte antigen (HLA)-matched related marrow grafts between 1971 and 2010. Patients were divided into three groups, reflecting changes in conditioning and graft-versus-host disease (GVHD) prophylaxis regimens that occurred over time. Patients in Group 1 were conditioned with cyclophosphamide (CY; 200 mg/kg) followed by 'long' (102 d) methotrexate (MTX). Patients in Groups 2 and 3 received CY alone (Group 2) or combined with anti-thymocyte globulin (Group 3) followed by 'short' (days 1, 3, 6, and 11) MTX and ciclosporin (until day 180). With a median follow-up of 25 years, the 5-year survivals were 66%, 95%, and 100% for Groups 1, 2, and 3, respectively (overall P < 0·0001). The 3-year estimates of graft rejection were 22%, 32%, and 7%, respectively. The probabilities of grades III-IV acute and 2-year chronic GVHD were 15%, 0%, and 3%, and 21%, 21%, and 10%, respectively. Advances in preparative and GVHD prophylaxis regimens, and supportive care during the past 40 years have led to improved outcomes for children with SAA. These results confirm the use of allogeneic marrow transplantation for children with SAA who have HLA-matched related donors.

National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow Transplantation Consortium First International Consensus Conference on late effects after pediatric hematopoietic cell transplantation: the need for pediatric-specific long-term follow-up guidelines.

Existing standards for screening and management of late effects occurring in children who have undergone hematopoietic cell transplantation (HCT) include recommendations from pediatric cancer networks and consensus guidelines from adult-oriented transplantation societies applicable to all HCT recipients. Although these approaches have significant merit, they are not pediatric HCT-focused, and they do not address post-HCT challenges faced by children with complex nonmalignant disorders. In this article we discuss the strengths and weaknesses of current published recommendations and conclude that pediatric-specific guidelines for post-HCT screening and management would be beneficial to the long-term health of these patients and would promote late effects research in this field. Our panel of late effects experts also provides recommendations for follow-up and therapy of selected post-HCT organ and endocrine complications in pediatric patients.

Randomized trial of hydroxychloroquine for newly diagnosed chronic graft-versus-host disease in children: a Children's Oncology Group study.

The Children's Oncology Group conducted a multicenter Phase III trial for chronic graft-versus-host disease (cGVHD). The double-blind, placebo-controlled, randomized study evaluated hydroxychloroquine added to standard therapy for children with newly diagnosed cGVHD. The study also used a novel grading and response scoring system and evaluated clinical laboratory correlates of cGVHD. The primary endpoint was complete response (CR) after 9 months of therapy. Fifty-four patients (27 on each arm) were enrolled before closure because of slow accrual. The CR rate was 28% in the hydroxychloroquine arm versus 33% in the placebo arm (odds ratio [OR] = 0.77, 95% confidence interval [CI]: 0.20-2.93, P = .75) for 42 evaluable patients. For 41 patients with severity assessment at enrollment, 20 (49%) were severe and 18 (44%) moderate according to the National Institutes of Health Consensus Conference global scoring system. The CR rate was 15% for severe cGVHD and 44% for moderate cGVHD (OR = 0.24, 95% CI: 0.05-1.06, P = .07). Although the study could not resolve the primary question, it provided important information for future cGVHD study design in this population.

NCI, NHLBI/PBMTC first international conference on late effects after pediatric hematopoietic cell transplantation: endocrine challenges-thyroid dysfunction, growth impairment, bone health, & reproductive risks.

The endocrine system is highly susceptible to damage by high-dose chemotherapy and/or irradiation before hematopoietic cell transplantation (HCT) during childhood. The specific endocrine organs most affected by HCT include the thyroid gland, the pituitary, and the gonads. In addition, hormones that support development and stability of the skeletal system are also affected. Insufficiency of thyroid hormone is 1 of the most common late sequelae of HCT, and occurs more often in young children. Deficiency in the pituitary's production of growth hormone is a problem of unique concern to the pediatric population. The reproductive risks of HCT depend on the patient's gender and pubertal status at the time of HCT. Pubertal or gonadal failure frequently occurs, especially in females. Infertility risks for both genders remain high, whereas methods of fertility preservation are limited in all but postpubertal males. Bone health post-HCT can be compromised by low bone mineral density as well as avascular necrosis, but the data on both problems in the pediatric HCT population are limited. In this paper, the current state of knowledge, gaps in that knowledge, and recommendations for future research are addressed in detail for each of these systems.

Late effects among pediatric patients followed for nearly 4 decades after transplantation for severe aplastic anemia.

Aplastic anemia (AA), a potentially fatal disease, may be cured with marrow transplantation. Survival in pediatric patients has been excellent early after transplantation, but only limited data are available regarding late effects. This study evaluates late effects among 152 patients followed 1-38 years (median, 21.8 years). Transplantation-preparative regimes were mostly cyclophosphamide with or without antithymocyte globulin. Survival at 30 years for the acquired AA patients is 82%, and for the Fanconi anemia patients it is 58% (P = .01). Multivariate analysis demonstrated that chronic GVHD (P = .02) and Fanconi anemia (P = .03) negatively impacted survival. Two Fanconi patients and 18 acquired AA patients developed a malignancy that was fatal for 4. There was an increased incidence of thyroid function test abnormalities among those who received total body irradiation. Cyclophosphamide recipients demonstrated normal growth, basically normal development, and pregnancies with mostly normal offspring. Quality-of-life studies in adult survivors of this pediatric transplantation cohort indicated that patients were comparable with control patients except for difficulty with health and life insurance. These data indicate that the majority of long-term survivors after transplantation for AA during childhood can have a normal productive life.

Significant 25-hydroxyvitamin D deficiency in child and adolescent survivors of acute lymphoblastic leukemia: treatment with chemotherapy compared with allogeneic stem cell transplant.

BACKGROUND: 25-hydroxyvitamin D insufficiency is common in healthy children and adolescents. There have been limited studies of the 25-hydroxyvitamin D status of survivors of pediatric and adolescent acute lymphoblastic leukemia (ALL). PROCEDURE: In a cohort of 78 ALL survivors (52 chemotherapy-treated and 26 HCT-treated), we determined the prevalence of, and host, treatment and environmental risk factors for 25-hydroxyvitamin D insufficiency and deficiency. RESULTS: There were no differences in serum 25-hydroxyvitamin D levels between ALL survivors treated with conventional chemotherapy and those treated with HCT (median 26.0 vs 25.5 ng/ml). Fifty-three percent of pediatric ALL survivors were 25-hydroxyvitamin D insufficient (15-29 ng/dl), and 12% were deficient (<15 ng/dl). Younger age, higher reported dietary vitamin D intake, use of vitamin D supplementation, and increased ambient ultraviolet light were associated with higher serum 25-hydroxyvitamin D levels. There was not enough evidence to suggest treatment type, gender, race, years since diagnosis or BMI were associated with serum 25-hydroxyvitamin D levels. Only 27% of conventional chemotherapy-treated ALL survivors and 8% of HCT-treated ALL survivors met RDA for dietary vitamin D intake. CONCLUSIONS: The prevalence of vitamin D deficiency and insufficiency in ALL survivors is similar to that of the general pediatric population in the United States, and there is no difference in serum 25-hydroxyvitamin D status between chemotherapy-treated and HCT-treated ALL survivors. ALL survivors rarely meet the RDA requirements for vitamin D. Further studies are needed to determine whether dietary and behavioral interventions can improve the vitamin D status of ALL survivors.

A simulation-based comparison of two methods for determining relaxation rates from relaxometry images.

When assessing liver iron content using relaxometry, an average relaxation rate (R1, R2 or R2*) is usually determined from a region of interest or the entire liver. This is commonly performed by fitting the signal decay in individual voxels to an appropriate relaxation function. The voxel-level parameters resulting from the fits are combined to determine the average relaxation rate, and an empirically derived calibration curve is used to convert this single value to iron content. The goal of this study was to compare the precision and accuracy of this voxel-wise fitting to an alternative method that relies on first averaging the signals from all voxels within the region of interest and then determining the relaxation rate from a single fit. Systematic differences were observed when both methods were applied to clinical images. Mathematical simulations were employed to determine which method provided more robust estimates of the true relaxation rate. The mathematical simulations were then expanded to include a range of conditions expected in typical relaxometry images. The results show that voxel-wise fitting skews the relaxation rate estimates and increases variance, particularly when the true relaxation rate is moderate to fast, as it would be in liver with high iron content. The potential impact of these results on clinical decisions is discussed.

Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria.

Risk factors for grades 2-4 acute graft-versus-host disease (GVHD) and for chronic GVHD as defined by National Institutes of Health consensus criteria were evaluated and compared in 2941 recipients of first allogeneic hematopoietic cell transplantation at our center. In multivariate analyses, the profiles of risk factors for acute and chronic GVHD were similar, with some notable differences. Recipient human leukocyte antigen (HLA) mismatching and the use of unrelated donors had a greater effect on the risk of acute GVHD than on chronic GVHD, whereas the use of female donors for male recipients had a greater effect on the risk of chronic GVHD than on acute GVHD. Total body irradiation was strongly associated with acute GVHD, but had no statistically significant association with chronic GVHD, whereas grafting with mobilized blood cells was strongly associated with chronic GVHD but not with acute GVHD. Older patient age was associated with chronic GVHD, but had no effect on acute GVHD. For all risk factors associated with chronic GVHD, point estimates and confidence intervals were not significantly changed after adjustment for prior acute GVHD. These results suggest that the mechanisms involved in acute and chronic GVHD are not entirely congruent and that chronic GVHD is not simply the end stage of acute GVHD.

A phase I/II study of chemotherapy followed by donor lymphocyte infusion plus interleukin-2 for relapsed acute leukemia after allogeneic hematopoietic cell transplantation.

The efficacy of donor lymphocyte infusion (DLI) for treatment of relapsed acute leukemia after allogeneic hematopoietic cell transplantation is limited. We hypothesized that interleukin-2 (IL-2) combined with DLI after chemotherapy might augment graft-versus-leukemia effects. To identify a safe and effective IL-2 regimen, a phase I/II study of DLI plus IL-2 therapy was performed for such patients. After chemotherapy, 17 patients received DLI (1 × 10(8) CD3/kg for patients with related donors, and 0.1 × 10(8) CD3/kg for those with unrelated donors) and an escalating dose of induction IL-2 (1.0, 2.0, or 3.0 × 10(6) IU/m(2)/day representing levels I [n = 7], Ia [n = 9], and II [n = 1]) for 5 days followed by maintenance (1.0 × 10(6) IU/m(2)/day) for 10 days as a continuous intravenous infusion. Unacceptable IL-2-related toxicities developed in 1 patient at level I, 2 at level Ia, and 1 at level II. Grades III-IV acute graft-versus-host disease (aGVHD) developed in 5 patients, and extensive chronic GVHD (cGVHD) developed in 8. Eight patients had a complete remission after chemotherapy prior to DLI, and 2 additional patients had a complete remission after DLI plus IL-2 therapy. In conclusion, the maximal tolerated induction dose of IL-2 combined with DLI appears to be 1.0 × 10(6) IU/m(2)/day. IL-2 administration after DLI might increase the incidence of cGVHD.