Imaging breast malignancies with the Twente Photoacoustic Mammoscope 2.

Clinical measurements on breast cancer patients were performed with a three-dimensional tomographic photoacoustic prototype imager (PAM 2). Patients with a suspicious lesion, visiting the center for breast care of a local hospital, were included in the study. The acquired photoacoustic images were compared to conventional clinical images. Of 30 scanned patients, 19 were diagnosed with one or more malignancies, of which a subset of four patients was selected for detailed analysis. Reconstructed images were processed to enhance image quality and the visibility of blood vessels. Processed photoacoustic images were compared to contrast-enhanced magnetic resonance images where available, which aided in localizing the expected tumoral region. In two cases, spotty high-intensity photoacoustic signals could be seen in the tumoral region, attributable to the tumor. One of these cases also displayed a relatively high image entropy at the tumor site, likely related to the chaotic vascular networks associated with malignancies. For the other two cases, it was not possible to identify features indicative of malignancy, because of limitations in the illumination scheme and difficulties in locating the region of interest in the photoacoustic image.

Assessment of microcirculation in the diabetic foot with laser speckle contrast imaging.

OBJECTIVE: A major challenge for treating diabetic foot ulcers is estimating the severity of ischemia, as the currently used non-invasive diagnostic techniques provide relatively poor prognostic values. Laser speckle contrast imaging (LSCI) is a promising non-invasive technique to assess microcirculation. Our aim was to investigate the stability and reproducibility of LSCI for the assessment of microcirculation in the diabetic foot, the relation of LSCI results to currently used non-invasive blood pressure measurements, and the ability of LSCI to discriminate between the degrees of ischemia. APPROACH: Thirty-three participants with diabetic foot ulcers were included in this prospective, single centre, observational cohort study that was conducted in the Netherlands. They were classified as non-ischemic, ischemic or critical-ischemic based on criteria formulated in the international guidelines. Two clinicians performed LSCI scans of the foot, consisting of baseline measurements, followed by two stress tests (post-occlusion peak and elevation test). With three measurement conditions and five regions of interest of the foot per patient, a total of 15 measurements were available for analyses. MAIN RESULTS: The intra-observer agreement of LSCI was high (interclass correlation coefficient (ICC) = 0.711-0.950; p  < 0.001) for all 15 measurements. The inter-observer agreement was high (ICC = 0.728-0.861; p  ⩽ 0.001) for 10 measurements and moderate (ICC = 0.476-0.570; p  ⩽ 0.005) for the remaining five measurements. The inter-assessor agreement was high and significant (ICC = 0.857-0.996; p  ⩽ 0.001) for all measurements. Correlation between LSCI and non-invasive blood pressure measurements was low (ICC = -0.272-0.582). During both stress tests, microcirculation was significantly lower in critical-ischemic feet compared to non-ischemic feet (67.5 perfusion units (PU) versus 96.3 PU and 41.0 PU versus 63.9 PU; p  < 0.05). SIGNIFICANCE: LSCI is a stable and reproducible technique for assessment of microcirculation in people with diabetic foot ulcers and shows significant differences between non-ischemic, ischemic and critical-ischemic patient populations.

The Belgian national registry on chronic pancreatitis: A prospective multi-centre study covering more than 800 patients in one year.

BACKGROUND/OBJECTIVES: The epidemiology, natural history, complications, and therapeutic management of chronic pancreatitis (CP) are not well described at the national level. This multi-centre prospective observational study involving eight Belgian hospitals aimed to improve the understanding of these aspects of CP in Belgium. METHODS: All patients with a diagnosis of CP based on imaging were eligible for this study. Data were gathered regarding epidemiology, etiology, CP complications, and treatment modalities. RESULTS: A total of 809 patients were included between 1/9/2014 and 31/8/2015. Most patients (794) were adults ≥16-years old, 74% were male, the median age at symptom onset was 47 (38-57) years, the median disease duration was 7 (3-13) years, and the median Izbicki pain score (IPS) was 96 (0-195). The main etiological risk factors according to the TIGAR-O classification were alcohol and tobacco (67%). Current drinkers had lower body mass index (BMI) (21.4 kg/m2 vs 24.1 kg/m2), higher IPS (110 vs 56), and longer inability to work than non-drinkers. Current smokers had lower BMI (21.5 kg/m2 vs 25 kg/m2) and higher IPS (120 vs 30) than non-smokers. Endocrine insufficiency and/or clinical steatorrhea was recorded in 41% and 36% of patients, respectively. The highest IPS was reported in patients with ongoing endotherapy (166 vs 50 for patients who completed endoscopy). CONCLUSION: This multicentric study on CP patients showed that current alcohol drinking and smoking are associated with pain and malnutrition. Pain scores were higher in patients with ongoing endotherapy, independently of surgery.

Patients with large-duct primary sclerosing cholangitis and Crohn's disease have a better outcome than those with ulcerative colitis, or without IBD.

BACKGROUND: Approximately 20% of primary sclerosing cholangitis (PSC) patients with concomitant inflammatory bowel disease (IBD) have Crohn's disease (CD). AIM: To compare PSC/CD with other PSC patients. METHODS: Retrospective study of 240 PSC patients diagnosed between 1975 and 2012 (median follow-up 12 years). Activity of PSC at diagnosis was assessed by liver biopsy, Mayo risk and ERC scores. Survival without liver transplantation, number of transplantations and liver-related death were endpoints. RESULTS: Sixty-three per cent of patients had IBD: 105 UC, 32 CD and 14 IBD unclassified (IBDu). IBD was diagnosed before PSC in 50%. The yearly development of PSC after diagnosing IBD was similar in UC, CD or IBDu. Small-duct PSC was present in 28% of PSC/CD compared to 3% of PSC/UC. Small-duct PSC had a markedly better survival than large-duct PSC: no patient developed cholangiocarcinoma or liver-related death, but colorectal cancer occurred in three patients. In large-duct PSC, a more favourable outcome was evident in patients with CD. The liver disease was less progressive: one patient underwent liver transplantation compared to 28% and liver-related deaths were absent compared to 7% in the other PSC groups. CONCLUSIONS: The prevalence of PSC with concomitant Crohn's disease is relatively rare, but the outcome is more benign than PSC with UC or without IBD. Approximately one-fourth has small-duct PSC. In large-duct PSC/CD, liver disease is less aggressive and the outcome is much better. The outcome of PSC patients with UC resembled that of PSC without IBD.

Tandem pulsed acousto-optics: obtaining the tagged light fraction from modulated non-ideal speckle patterns.

Recently we presented novel methods for acousto-optic (AO) imaging of biological tissues, taking (1) the mean square difference of speckle patterns (subtraction method) or (2) the contrast of the summation of speckle patterns (summation method) acquired from nanosecond pulses of coherent light, fired at different ultrasound phases. In this study we relate the two methods both analytically and experimentally. We experimentally show that these two methods are nearly identical provided that the maximum achievable speckle contrast is determined correctly. We show with simulations that after correction the outcome is independent of experimental detection parameters. This makes the AO methods in this study reliable, allowing quantifying speckle observations in terms of the ultrasonically tagged fractions of light. The use of tandem nanosecond pulses in one burst of ultrasound overcomes the challenge of tissue dynamics.

A Method for Delineation of Bone Surfaces in Photoacoustic Computed Tomography of the Finger.

Photoacoustic (PA) imaging of interphalangeal peripheral joints is of interest in the context of using the synovial membrane as a surrogate marker of rheumatoid arthritis. Previous work has shown that ultrasound (US) produced by absorption of light at the epidermis reflects on the bone surfaces within the finger. When the reflected signals are backprojected in the region of interest, artifacts are produced, confounding interpretation of the images. In this work, we present an approach where the PA signals known to originate from the epidermis are treated as virtual US transmitters, and a separate reconstruction is performed as in US reflection imaging. This allows us to identify the bone surfaces. Furthermore, the identification of the joint space is important as this provides a landmark to localize a region-of-interest in seeking the inflamed synovial membrane. The ability to delineate bone surfaces allows us to identify not only the artifacts but also the interphalangeal joint space without recourse to new US hardware or a new measurement. We test the approach on phantoms and on a healthy human finger.

Review of photoacoustic flow imaging: its current state and its promises.

Flow imaging is an important method for quantification in many medical imaging modalities, with applications ranging from estimating wall shear rate to detecting angiogenesis. Modalities like ultrasound and optical coherence tomography both offer flow imaging capabilities, but suffer from low contrast to red blood cells and are sensitive to clutter artefacts. Photoacoustic imaging (PAI) is a relatively new field, with a recent interest in flow imaging. The recent enthusiasm for PA flow imaging is due to its intrinsic contrast to haemoglobin, which offers a new spin on existing methods of flow imaging, and some unique approaches in addition. This review article will delve into the research on photoacoustic flow imaging, explain the principles behind the many techniques and comment on their individual advantages and disadvantages.

Budd-Chiari syndrome: reassessment of a step-wise treatment strategy.

BACKGROUND AND STUDY AIMS: The Budd-Chiari syndrome is a rare disorder characterized by hepatic venous outflow obstruction. A step-wise management was recently proposed. The aim of this study is to reassess our treatment approach and long-term outcome. PATIENTS AND METHODS: The data of 37 Budd-Chiari patients, seen in our unit, were critically analyzed and compared with the ENVIE (European Network For Vascular Disorders of the Liver) data. RESULTS: Most patients had multiple prothrombotic conditions (41%), of which an underlying myeloproliferative neoplasm was the most frequent (59%). The JAK2V617F mutation was associated with more complete occlusion of all hepatic veins (JAK2 mutation +: 70% vs JAK2 mutation -: 23% and a higher severity score. The step-wise treatment algorithm used in our unit, in function of the severity of the liver impairment and the number and the extension of hepatic veins occluded, resulted in the following treatments: only anticoagulation (n = 7.21%), recanalization procedure (n = 4.21%), portosystemic shunts (n = 9.26%) and liver transplantation (n = 14.44%). This resulted in a 10 year survival rate of 90%. Treatment of the underlying hemostatic disorder offered a low recurrence rate. None of the 21 patients with a myeloproliferative neoplasm died in relation to the hematologic disorder. CONCLUSIONS: An individualized treatment regimen consisting of anticoagulation and interventional radiology and/or transplantation when necessary and strict follow-up of the underlying hematologic disorder, provided an excellent long-term survival, which confirm the data of the ENVIE study.

Photoacoustic image patterns of breast carcinoma and comparisons with Magnetic Resonance Imaging and vascular stained histopathology.

Photoacoustic (optoacoustic) imaging can visualize vasculature deep in tissue using the high contrast of hemoglobin to light, with the high-resolution possible with ultrasound detection. Since angiogenesis, one of the hallmarks of cancer, leads to increased vascularity, photoacoustics holds promise in imaging breast cancer as shown in proof-of-principle studies. Here for the first time, we investigate if there are specific photoacoustic appearances of breast malignancies which can be related to the tumor vascularity, using an upgraded research imaging system, the Twente Photoacoustic Mammoscope. In addition to comparisons with x-ray and ultrasound images, in subsets of cases the photoacoustic images were compared with MR images, and with vascular staining in histopathology. We were able to identify lesions in suspect breasts at the expected locations in 28 of 29 cases. We discovered generally three types of photoacoustic appearances reminiscent of contrast enhancement types reported in MR imaging of breast malignancies, and first insights were gained into the relationship with tumor vascularity.

Tandem-pulsed acousto-optics: an analytical framework of modulated high-contrast speckle patterns.

Recently we presented acousto-optic (AO) probing of scattering media using addition or subtraction of speckle patterns due to tandem nanosecond pulses. Here we present a theoretical framework for ideal (polarized, noise-free) speckle patterns with unity contrast that links ultrasound-induced optical phase modulation, the fraction of light that is tagged by ultrasound, speckle contrast, mean square difference of speckle patterns and the contrast of the summation of speckle patterns acquired at different ultrasound phases. We derive the important relations from basic assumptions and definitions, and then validate them with simulations. For ultrasound-generated phase modulation angles below 0.7 rad (assuming uniform modulation), we are now able to relate speckle pattern statistics to the acousto-optic phase modulation. Hence our theory allows quantifying speckle observations in terms of ultrasonically tagged fractions of light for near-unity-contrast speckle patterns.

Clearing of psoriasis documented by laser Doppler perfusion imaging contrasts remaining elevation of dermal expression levels of CD31.

BACKGROUND: Vascular modifications represent a key feature in psoriatic plaques. Previous research with Laser Doppler Perfusion Imaging (LDPI) revealed a remarkable heterogeneity in the cutaneous perfusion within homogenous-appearing psoriatic lesions. Insights in the relation between perfusion during treatment and related biological changes are lacking. OBJECTIVES: To study the effect of calcipotriol-betamethasone dipropionate ointment on the microcirculation and the expression levels of immunohistochemical markers in psoriatic lesions compared to the distant uninvolved skin. METHODS: Psoriatic lesions of fourteen patients were treated once a day during 8 weeks. Clinical SUM scores and the perfusion intensity by means of LDPI were assessed every 2 weeks. After 8 weeks, a biopsy from the target lesion and one from the distant uninvolved skin were taken and stained for psoriasis-related markers, like IL-17 and CD31. RESULTS: After 8 weeks, seven patients reached a SUM score of 0 or 1, and were classified as good-responders. The other patients were classified moderate-responders. The perfusion intensity decreased in all lesions during therapy. In the good-responders, all investigated psoriasis-related proteins within the treated lesions reached the expression level found within the distant uninvolved skin. The expression of CD31, however, was significantly higher in the treated lesions as compared to the distant uninvolved skin (p = 0.0156). In the moderate responders, almost all expression levels remained significantly elevated compared to the uninvolved skin. CONCLUSIONS: In the skin of good-responders the expression of dermal CD31(+) endothelium remains significantly elevated within the treated lesions compared with the distant uninvolved skin, whereas a marked reduction in the perfusion intensity and SUM score was found. This indicates that clinical improvement might outrun endothelial changes.

Handheld probe integrating laser diode and ultrasound transducer array for ultrasound/photoacoustic dual modality imaging.

Ultrasound and photoacoustics can be utilized as complementary imaging techniques to improve clinical diagnoses. Photoacoustics provides optical contrast and functional information while ultrasound provides structural and anatomical information. As of yet, photoacoustic imaging uses large and expensive systems, which limits their clinical application and makes the combination costly and impracticable. In this work we present and evaluate a compact and ergonomically designed handheld probe, connected to a portable ultrasound system for inexpensive, real-time dual-modality ultrasound/photoacoustic imaging. The probe integrates an ultrasound transducer array and a highly efficient diode stack laser emitting 130 ns pulses at 805 nm wavelength and a pulse energy of 0.56 mJ, with a high pulse repetition frequency of up to 10 kHz. The diodes are driven by a customized laser driver, which can be triggered externally with a high temporal stability necessary to synchronize the ultrasound detection and laser pulsing. The emitted beam is collimated with cylindrical micro-lenses and shaped using a diffractive optical element, delivering a homogenized rectangular light intensity distribution. The system performance was tested in vitro and in vivo by imaging a human finger joint.

Towards acousto-optic tissue imaging with nanosecond laser pulses.

We present a way to generate acousto-optical signals in timovssue-like media with nanosecond laser pulses. Our method is based on recording and analyzing speckle patterns formed by interaction of nanosecond laser pulses with tissue, without and with simultaneous application of ultrasound. Stroboscopic application allows visualizing the temporal behavior of speckles while the ultrasound is propagating through the medium. We investigate two ways of quantifying the acousto-optic effect, viz. adding and subtracting speckle patterns obtained at various ultrasound phases. Both methods are compared with the existing speckle contrast method using a 2D scan and are found to perform similarly. Our method gives outlook on overcoming the speckle decorrelation problem in acousto-optics, and therefore brings in-vivo acousto-optic measurements one step closer. Furthermore it enables combining acousto-optics and photoacoustics in one setup with a single laser.

Spontaneous life-threatening hemobilia during acute liver failure successfully treated with transarterial embolization.

A 28-year-old patient admitted with jaundice, vomiting and deteriorating coagulopathy was diagnosed with acute liver failure. After listing for urgent transplantation, he developed Boerhaave's syndrome and massive hemobilia, two life-threatening complications. Massive hemobilia secondary to a fistula between the right hepatic artery and the right bile duct occurred several days after transjugular biopsy and was controlled with fluid resuscitation, transfusion and arterial embolization. Two days later he was transplanted successfully, and is currently doing well after more than 72 months. Aggressive treatment of potentially reversible complications during acute liver failure whilst awaiting transplantation is mandatory to allow survival of these patients.

Risk factors for bleeding and clinical implications in patients undergoing liver transplantation.

INTRODUCTION: Advanced liver disease is characterized by prolonged global coagulation tests such as prothrombin time (PT). Using Model of End-stage Liver Disease (MELD) score-based allocation, many current transplant recipients show advanced end-stage liver disease with an elevated international normalized ratio (INR). The relationship between abnormalities in coagulation tests and the risk of bleeding has been recently challenged among liver disease patients. In this study we reassessed risk factors for bleeding and the clinical implications for patients who underwent orthotopic liver transplantation (OLT). METHODS: We studied OLT patients between 2005 and 2011 excluding combined transplantations, retransplantations, or cases due to acute liver failure. We collected prospectively pre-OLT, during OLT, and post-OLT clinical and biochemical data to assess the risk for bleeding using linear regression models. RESULTS: The strongest predictor of overall survival among 286 patients with a mean follow-up of 32 months was the number of blood transfusions (P = .005). The risk factor for bleeding during surgery investigated by multivariate analysis only showed the INR (P < .001) and the presence of ascites (P = .003) to independently correlate with the amount of blood transfusion. Receiver operation characteristics (ROC) analysis performed to determine the risk for massive blood transfusion (more than 6 units) revealed a cut-off value for INR ≥ 1.6. Appreciation of the operative field by the surgeon during the intervention as "wet" versus "dry", amounts of blood transfusion and fresh frozen plasma, and stay in the intensive care unit (ICU) and in the hospital were all significantly different (P < .001) for patients with INR <1.6 versus INR ≥ 1.6. CONCLUSIONS: Bleeding during OLT affects the outcome. The risk is independently influenced by the presence of ascites (probably reflecting the degree portal hypertension) and an INR ≥ 1.6. To improve survival after OLT therapeutic interventions should be further explored to reduce the need for blood transfusions.

Septuagenarian and octogenarian donors provide excellent liver grafts for transplantation.

BACKGROUND: Wider utilization of liver grafts from donors ≥ 70 years old could substantially expand the organ pool, but their use remains limited by fear of poorer outcomes. We examined the results at our center of liver transplantation (OLT) using livers from donors ≥ 70 years old. METHODS: From February 2003 to August 2010, we performed 450 OLT including 58 (13%) using donors ≥ 70 whose outcomes were compared with those using donors <70 years old. RESULTS: Cerebrovascular causes of death predominated among donors ≥ 70 (85% vs 47% in donors <70; P < .001). In contrast, traumatic causes of death predominated among donors <70 (36% vs 14% in donors ≥ 70; P = .002). Unlike grafts from donors <70 years old, grafts from older individuals had no additional risk factors (steatosis, high sodium, or hemodynamic instability). Both groups were comparable for cold and warm ischemia times. No difference was noted in posttransplant peak transaminases, incidence of primary nonfunction, hepatic artery thrombosis, biliary strictures, or retransplantation rates between groups. The 1- and 5-year patient survivals were 88% and 82% in recipients of livers <70 versus 90% and 84% in those from ≥ 70 years old (P = .705). Recipients of older grafts, who were 6 years older than recipients of younger grafts (P < .001), tended to have a lower laboratory Model for End-Stage Liver Disease score (P = .074). CONCLUSIONS: Short and mid-term survival following OLT using donors ≥ 70 yo can be excellent provided that there is adequate donor and recipient selection. Septuagenarians and octogenarians with cerebrovascular ischemic and bleeding accidents represent a large pool of potential donors whose wider use could substantially reduce mortality on the OLT waiting list.

Outcomes of liver transplantations using donations after circulatory death: a single-center experience.

INTRODUCTION: Orthotopic liver transplantation (OLT) (LTx) using donation after circulatory death (DCD) donors is increasingly performed, but still considered to risk of poorer outcomes compared with standard donations after brain death (DBD)-OLT. Therefore we reviewed our results of DCD-OLT. PATIENTS AND METHODS: Between 2003 and 2010, we performed 30 DCD-OLT (6% of all OLT). We retrospectively reviewed medical records of donors and recipients after DCD versus DBD-OLT to analyze biliary complications, retransplantation rates, and patient/graft survivals. RESULTS: Median donor age was similar for DCD and DBD-OLT: 51 versus 53 years (P = .244). Median donor warm ischemia time (stop ventilation to cold perfusion in DCD donors) was 24 minutes. Median cold ischemia time was shorter for DCD (6 hours 54 minutes) compared with DBD-OLT (8 hours 36 minutes; P < .0001). Median laboratory model of end-stage liver disease score was 15 for DCD, and 16 for DBD-OLT (P = .59). Median post-OLT Aspartate Aminotransferase (AST) peak was higher after DCD: 1178 versus DBD-OLT 651 IU/L (P = .005). The incidence of nonanastomotic strictures was different: 33.3% for DCD versus 12.5% for DBD-OLT (P = .001). The overall retransplantation rate was 3% after both DCD and DBD-OLT. After DCD-LTx actuarial 1, 3- and 5-year patient survivals were 93, 85 and 85%, and corresponding graft survivals, 90%, 82%, and 82% respectively, and not different compared with DBD-OLT: 88%, 78%, and 72% (P = .348) and 85%, 74%, and 68% (P = .524) respectively. CONCLUSION: Despite substantial ischemic injury (high peak AST and biliary strictures) short- and long-term survival after DCD-OLT was comparable to DBD-OLT. Rapid donor surgery, careful donor and recipient selection, as well as short warm and cold ischemia times are key factors to optimize outcomes after DCD-OLT. However, strategies to reduce biliary complications remain warranted.

First experiences of photoacoustic imaging for detection of melanoma metastases in resected human lymph nodes.

BACKGROUND AND OBJECTIVE: Excision and histological assessment of the first draining node (sentinel lymph node) is a frequently used method to assess metastatic lymph node involvement related to cutaneous melanoma. Due to the time required for accurate histological assessment, nodal status is not immediately available to the surgeon. Hence, in case histological examination shows metastases, the patient has to be recalled to perform additional lymphadenectomy. To overcome these drawbacks we studied the applicability of photoacoustic tomographic imaging as an intra-operative modality for examining the status of resected lymph nodes. MATERIALS AND METHODS: In melanoma patients undergoing lymphadectomy for metastatic disease, six suspect lymph nodes were photoacoustically (PA) imaged using multiple wavelengths. Histopathologal examination showed three nodes without tumor cells (benign nodes) and three nodes with melanoma cells (malignant nodes). PA images were compared with histology and anatomical features were analyzed. In addition, PA spectral analysis was performed on areas of increased signal intensity. RESULTS: After correlation with histopathology, multiple areas containing melanoma cells could be identified in the PA images due to their increased response. Malignant nodes showed a higher PA response and responded differently to an increase in excitation wavelength than benign nodes. In addition, differences in anatomical features between the two groups were detected. CONCLUSIONS: Photoacoustic detection of melanoma metastases based on their melanin content proves to be possible in resected human lymph nodes. The amount of PA signal and several specific anatomical features seem to provide additional characteristics for nodal analysis. However, it is as yet preliminary to designate a highly accurate parameter to distinguish between malignant and benign nodes. We expect to improve the specificity of the technique with a future implementation of an adjusted illumination scheme and depth correction for photon fluence.

An unusual case of rectal perforation after liver transplantation.

We present the case of a 50-year-old patient in whom an anastomotic biliary stricture after liver transplantation was treated endoscopically by sphincterotomy, dilatation and stenting using a plastic biliary stent. A distal migration of the stent caused a perforation of the rectum which was treated following stent extraction per anum -- conservatively with antibiotics and temporary bowel rest.

Visualizing breast cancer using the Twente photoacoustic mammoscope: what do we learn from twelve new patient measurements?

We acquired images of breast malignancies using the Twente photoacoustic mammoscope (PAM), to obtain more information about the clinical feasibility and limitations of photoacoustic mammography. Results were compared with conventional imaging and histopathology. Ten technically acceptable measurements on patients with malignancies and two measurements on patients with cysts were performed. In the reconstructed volumes of all ten malignant lesions, a confined region with high contrast with respect to the background could be seen. In all malignant cases, the PA contrast of the abnormality was higher than the contrast on x-ray mammography. The PA contrast appeared to be independent of the mammographically estimated breast density and was absent in the case of cysts. Technological improvements to the instrument and further studies on less suspicious lesions are planned to further investigate the potential of PAM.