The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%–2% of pregnant women and is characterized by increased bile acid levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown. We analyzed the Northern Finland birth cohort 1985–1986 database and found that 16-year-old children of mothers with ICP had altered lipid profiles. Males had increased BMI, and females exhibited increased waist and hip girth compared with the offspring of uncomplicated pregnancies. We further investigated the effect of maternal cholestasis on the metabolism of adult offspring in the mouse. Females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following a Western diet, whereas matched mice not exposed to cholestasis in utero did not. Female littermates were susceptible to metabolic disease before dietary challenge. Human and mouse studies showed an accumulation of lipids in the fetoplacental unit and increased transplacental cholesterol transport in cholestatic pregnancy. We believe this is the first report showing that cholestatic pregnancy in the absence of altered maternal BMI or diabetes can program metabolic disease in the offspring.
Progressive familial intrahepatic cholestasis, type 2 (PFIC2), characterized by cholestasis in infancy that may progress to cirrhosis, is caused by mutation in ABCB11, which encodes bile salt export pump (BSEP). We correlated histopathologic, immunohistochemical, and ultrastructural features in PFIC2 with specific mutations and clinical course. Twelve patients with clinical PFIC2 and ABCB11 mutations were identified, and 22 liver biopsy and explant specimens were assessed. All had hepatocellular cholestasis; most had canalicular bile plugs. At least 1 specimen from every patient had centrizonal/sinusoidal fibrosis, often with periportal fibrosis. Neonatal hepatitis-like features (inflammation, giant cells, necrosis) varied. In 2 of the 5 patients with paired specimens obtained > 6 months apart, lobular and portal fibrosis worsened. Transmission electron microscopy (EM) in all 9 patients studied showed canalicular dilatation, microvilli loss, abnormal mitochondrial internal structure, and varying intra-canalicular accumulation of finely granular bile. Canalicular staining for BSEP was absent in 10 patients and present in 2 patients, 1 of whom had intermittent symptoms. ABCB11 sequencing of all patients identified 6 novel and 10 previously described mutations, with nonsense, missense, and/or noncoding mutations in the 10 patients without immunohistochemically demonstrable BSEP. Missense and/or noncoding mutations were identified in the 2 patients with demonstrable BSEP, whose clinical course was more indolent. Mutations ending ABCB11 transcription appear linked, through hepatocellular necrosis and fibrosis, to worse outcome. In conclusion, light microscopy and electron microscopy findings in clinical PFIC2 can support diagnosis, but are variable and nonspecific. Therefore, no correlation between specific mutations and histopathology is yet possible.
PFIC2; progressive familial intrahepatic cholestasis; bile salt export pump; BSEP; ABCB11; neonatal hepatitis
Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.
Lymphedema-cholestasis syndrome (LCS; Aagenaes syndrome) is a rare autosomal recessive disorder, characterized by 1) neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age, and 2) severe chronic lymphedema, mainly lower limb. LCS was originally described in a Norwegian kindred in which a locus, LCS1, was mapped to a 6.6cM region on chromosome 15. Mutations in CCBE1 on chromosome 18 have been reported in some cases of lymphatic dysplasia, but not in LCS.
Consanguineous parents of Mexican ancestry had a child with LCS who did not exhibit extended homozygosity in the LCS1 region. A subsequent pregnancy was electively terminated due to fetal hydrops. We performed whole-genome single nucleotide polymorphism genotyping to identify regions of homozygosity in these siblings, and sequenced promising candidate genes.
Both siblings harbored a homozygous mutation in CCBE1, c.398 T>C, predicted to result in the missense change p.L133P. Regions containing known ‘cholestasis genes’ did not demonstrate homozygosity in the LCS patient.
Mutations in CCBE1 may yield a phenotype not only of lymphatic dysplasia, but also of LCS or fetal hydrops; however, the possibility that the sibling with LCS also carries a homozygous mutation in an unidentified gene influencing cholestasis cannot be excluded.
Background and Aim. Neonatal hemochromatosis (NH) is characterised by severe liver injury and extrahepatic siderosis sparing the reticuloendothelial system. Its aetiology is obscure, although it has been proposed as an alloimmune disease, resulting from immunological reaction to self-antigens (alloantigens) which the body recognizes as foreign. We studied an infant with NH and his mother whose sera contained antimitochondrial antibody (AMA), the hallmark of primary biliary cirrhosis (PBC). Material and Methods. To investigate the origin of AMA in the infant, we studied isotype distributions in serum from the mother and infant. Serum samples were obtained at diagnosis of NH, after liver transplantation (LT; age 1 month), and over the ensuing 17 months. Results. At NH diagnosis, infant and maternal serum contained AMA of the IgG isotype, predominantly of the G3 and G1 subclasses. AMA strongly reacted against the pyruvate dehydrogenase complex E2 subunit (PDC-E2), the major PBC-specific AMA autoantigen. Anti-PDC-E2 responses in both infant and mother declined over time, being present 2 months after LT (mother and child) and absent 10 months later (mother) and 17 months later (child). Conclusion. The association of maternally transferred IgG1 and IgG3 subclass AMA with the appearance of liver damage in an infant with NH may suggest a causal link between antibody and liver damage.
Stapes footplate surgery is complex and delicate. This surgery is carried out in the middle ear to improve hearing. High accuracy is required to avoid critical tissues and structures near the surgical worksite. By suppressing the surgeon’s tremor during the operation, accuracy can be improved. In this paper, a fully handheld active micromanipulator known as Micron is evaluated for its feasibility for this delicate operation. An ergonomic handle, a custom tip, and a brace attachment were designed for stapes footplate surgery and tested in a fenestration task through a fixed speculum. Accuracy was measured during simulated surgery in two different scenarios: Micron off (unaided) and Micron on (aided), both with image guidance. Preliminary results show that Micron significantly reduces the mean position error and the mean duration of time spent in specified dangerous zones.
The diagnosis-specific Graded Prognostic Assessment (GPA) was published to clarify prognosis for patients with brain metastases. This study refines the existing Breast-GPA by analyzing a larger cohort and tumor subtype.
A multi-institutional retrospective database of 400 breast cancer patients treated for newly-diagnosed brain metastases was generated. Prognostic factors significant for survival were analyzed by multivariate Cox regression (MCR) and recursive partitioning analysis (RPA). Factors were weighted by the magnitude of their regression coefficients to define the GPA index.
Significant prognostic factors by MCR and RPA were Karnofsky Performance Status (KPS), HER2, ER/PR status, and the interaction between ER/PR and HER2. RPA showed age was significant for patients with KPS 60–80. The median survival time (MST) overall was 13.8 months, and for GPA scores of 0–1.0, 1.5–2.0, 2.5–3.0 and 3.5–4.0 was 3.4 (n=23), 7.7 (n=104), 15.1 (n=140) and 25.3 (n=133) months, respectively (p < 0.0001). Among HER2-negative patients, being ER/PR-positive improved MST from 6.4 to 9.7 months whereas in HER2-positive patients, being ER/PR-positive improved MST from 17.9 to 20.7 months. The log-rank statistic (predictive power) was 110 for the Breast-GPA versus 55 for tumor subtype.
The Breast-GPA documents wide variation in prognosis and shows clear separation between subgroups of patients with breast cancer and brain metastases. This tool will aid clinical decision-making and stratification of clinical trials. These data confirm the effect of tumor subtype on survival and show the Breast-GPA offers significantly more predictive power than the tumor subtype alone.
breast cancer; brain metastases; prognosis; radiation therapy; stereotactic radiosurgery; estrogen; progesterone; HER2; outcomes
Our group has previously published the Graded Prognostic Assessment (GPA), a prognostic index for patients with brain metastases. Updates have been published with refinements to create diagnosis-specific Graded Prognostic Assessment indices. The purpose of this report is to present the updated diagnosis-specific GPA indices in a single, unified, user-friendly report to allow ease of access and use by treating physicians.
A multi-institutional retrospective (1985 to 2007) database of 3,940 patients with newly diagnosed brain metastases underwent univariate and multivariate analyses of prognostic factors associated with outcomes by primary site and treatment. Significant prognostic factors were used to define the diagnosis-specific GPA prognostic indices. A GPA of 4.0 correlates with the best prognosis, whereas a GPA of 0.0 corresponds with the worst prognosis.
Significant prognostic factors varied by diagnosis. For lung cancer, prognostic factors were Karnofsky performance score, age, presence of extracranial metastases, and number of brain metastases, confirming the original Lung-GPA. For melanoma and renal cell cancer, prognostic factors were Karnofsky performance score and the number of brain metastases. For breast cancer, prognostic factors were tumor subtype, Karnofsky performance score, and age. For GI cancer, the only prognostic factor was the Karnofsky performance score. The median survival times by GPA score and diagnosis were determined.
Prognostic factors for patients with brain metastases vary by diagnosis, and for each diagnosis, a robust separation into different GPA scores was discerned, implying considerable heterogeneity in outcome, even within a single tumor type. In summary, these indices and related worksheet provide an accurate and facile diagnosis-specific tool to estimate survival, potentially select appropriate treatment, and stratify clinical trials for patients with brain metastases.
External beam radiotherapy (EBRT) has become the preferred options for non-surgical treatment of prostate cancer and cervix cancer. In order to deliver higher doses to cancerous regions within these pelvic structures (i.e. prostate or cervix) while maintaining or lowering the doses to surrounding non-cancerous regions, it is critical to account for setup variation, organ motion, anatomical changes due to treatment and intra-fraction motion. In previous work, manual segmentation of the soft tissues is performed and then images are registered based on the manual segmentation. In this paper, we present an integrated automatic approach to multiple organ segmentation and nonrigid constrained registration, which can achieve these two aims simultaneously. The segmentation and registration steps are both formulated using a Bayesian framework, and they constrain each other using an iterative conditional model strategy. We also propose a new strategy to assess cumulative actual dose for this novel integrated algorithm, in order to both determine whether the intended treatment is being delivered and, potentially, whether or not a plan should be adjusted for future treatment fractions. Quantitative results show that the automatic segmentation produced results that have an accuracy comparable to manual segmentation, while the registration part significantly outperforms both rigid and non-rigid registration. Clinical application and evaluation of dose delivery show the superiority of proposed method to the procedure currently used in clinical practice, i.e. manual segmentation followed by rigid registration.
Image segmentation; Non-rigid registration; Image guided radiotherapy; Prostate cancer; Cervical cancer; Dose delivery
Cholate-CoA ligase (CCL) and bile acid-CoA: amino acid N-acyltransferase (BAAT) sequentially mediate bile-acid amidation. Defects can cause intrahepatic cholestasis. Distinction has required gene sequencing. We assessed potential clinical utility of immunostaining of liver for CCL and BAAT. Using commercially available antibodies against BAAT and CCL, we immunostained liver from an infant with jaundice, deficiency of amidated bile acids, and transcription-terminating mutation in BAAT. CCL was normally expressed. BAAT expression was not detected. Immunostaining may facilitate diagnosis in bile-acid amidation defects.
Amidation; Bile acid-CoA; Amino acid N-acyltransferase; Cholate-CoA ligase; Cholestasis; Conjugation; Electrospray ionisation-mass spectroscopy; Immunohistochemistry; Liver; Neonatal hepatitis; SLC27A5; Transmission electron microscopy
Melanoma patients with brain metastases are typically excluded from clinical trials due to historically dismal survival (<4 months) and concerns about blood brain barrier drug penetration. The pleural cavity is another location with potential decreased drug penetrance, yet malignant effusion patients are not excluded. Here we discuss whether new technologies for local control of brain metastases have altered survival patterns. We also report our findings from a retrospective chart review of 251 metastatic melanoma patients diagnosed after 2005, and evaluate our findings in the context of eligibility for clinical trials with novel agents. We found that median survival of malignant effusion patients was significantly shorter than brain metastasis patients (two versus eight months, p < 0.0001). Only one pleural effusion patient lived >9 months, whereas 41 (39.4%) brain metastasis patients survived beyond this time. We conclude that with the advent of effective means for providing local control for brain metastases, survival of these patients has improved, and they often succumb to extra-cranial disease. Exclusion of melanoma brain metastasis patients from clinical research programs is no longer justified and alternative investigational approaches, possibly combining local and systemic therapies, are urgently needed for these individuals.
melanoma; brain metastases; prognosis; clinical trial design
Trichohepatoenteric syndrome (THES) is an autosomal recessive disorder characterised by life-threatening diarrhoea in infancy, immunodeficiency, liver disease, trichorrhexis nodosa, facial dysmorphism, hypopigmentation and cardiac defects. We attempted to characterise the phenotype and elucidate the molecular basis of THES.
Twelve patients with classical THES from 11 families had detailed phenotyping. Autozygosity mapping was undertaken in 8 patients from consanguineous families using 250k single nucleotide polymorphism (SNP) arrays and linked regions evaluated using microsatellite markers. Linkage was confirmed to one region from which candidate genes were analysed. The effect of mutations on protein production and/or localisation in hepatocytes and intestinal epithelial cells from affected patients was characterised by immunohistochemistry.
Previously unrecognised platelet abnormalities (reduced platelet α-granules, unusual stimulated alpha granule content release, abnormal lipid inclusions, abnormal platelet canalicular system and reduced number of microtubules) were identified. The THES locus was mapped to 5q14.3 – 5q21.2. Sequencing of candidate genes demonstrated mutations in TTC37, which encodes the uncharacterised tetratricopeptide repeat protein, thespin. Bioinformatic analysis suggested thespin to be involved in protein-protein interactions or chaperone. Preliminary studies of enterocyte brush-border ion transporter proteins (NHE2, NHE3, Aquaporin 7, Na/I symporter and H / K ATPase) showed reduced expression or mislocalisation in all THES patients with different profiles for each. In contrast the basolateral localisation of Na/K ATPase was not altered.
THES is caused by mutations in TTC37. TTC37 mutations have a multisystem effect which may be due to abnormal stability and / or intracellular localisation of TTC37 target proteins.
phenotypic diarrhoea of infancy; platelet alpha granules; ion transporter proteins; thespin
Introduction. Gamma Knife radiosurgery (GK-SRS) is commonly used to treat cerebral metastases. Although additional intracranial metastases are often found on the day of GK-SRS, the significance of finding them is unknown. Methods. A retrospective review of 133 patients undergoing GK-SRS for cerebral metastases was performed. The change in number of metastases detected between initial referral magnetic resonance imaging (MRI) and subsequent treatment MRI was quantified. Multivariate and Kaplan-Meier analyses were employed to examine the significance of identifying additional lesions. Results. Additional lesions were identified in 41% of patients. An increasing number of metastases on referral MRI (P = 0.001) and the presence of progressive systemic disease (P = 0.003) were predictive of identifying additional metastases. Median survival was 6.9 months for patients with additional metastases, compared to 12.1 months for patients without additional metastases (hazard ratio 1.56, P = 0.021). Conclusions. Identifying additional metastases on the day of GK-SRS may add important prognostic information.
Background & Aims
Progressive familial intrahepatic cholestasis (PFIC) with normal serum levels of gamma-glutamyltranspeptidase can result from mutations in ATP8B1 (encoding familial intrahepatic cholestasis 1 [FIC1]) or ABCB11 (encoding bile salt export pump [BSEP]). We evaluated clinical and laboratory features of disease in patients diagnosed with PFIC, who carried mutations in ATP8B1 (FIC1 deficiency) or ABCB11 (BSEP deficiency). Our goal was to identify features that distinguish presentation and course of these 2 disorders, thus facilitating diagnosis and elucidating the differing consequences of ATP8B1 and ABCB11 mutations.
A retrospective multi-center study was conducted, using questionnaires and chart review. Available clinical and biochemical data from 145 PFIC patients with mutations in either ATP8B1 (61 “FIC1 patients”) or ABCB11 (84 “BSEP patients”) were evaluated.
At presentation, serum aminotransferase and bile salt levels were higher in BSEP patients; serum alkaline phosphatase values were higher, and serum albumin values were lower, in FIC1 patients. Elevated white blood cell counts, and giant or multinucleate cells at liver biopsy, were more common in BSEP patients. BSEP patients more often had gallstones and portal hypertension. Diarrhea, pancreatic disease, rickets, pneumonia, abnormal sweat tests, hearing impairment, and poor growth were more common in FIC1 patients. Among BSEP patients, the course of disease was less rapidly progressive in patients bearing the D482G mutation.
Severe forms of FIC1 and BSEP deficiency differed. BSEP patients manifested more severe hepatobiliary disease, while FIC1 patients showed greater evidence of extrahepatic disease.
cholestasis; genetics; transport protein; pediatrics; P-type ATPase; ATP binding cassette protein; ATP8B1; FIC1; ABCB11; BSEP
A constrained non-rigid registration (CNRR) algorithm for use in prostate image-guided adaptive radiotherapy is presented in a coherent mathematical framework. The registration algorithm is based on a global rigid transformation combined with a series of local injective non-rigid multi-resolution cubic B-spline Free Form Deformation (FFD) transformations. The control points of the FFD are used to non-rigidly constrain the transformation to the prostate, rectum, and bladder. As well, the control points are used to rigidly constrain the transformation to the estimated position of the pelvis, left femur, and right femur. The algorithm was tested with both 3D conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) dose plan data sets. The 3DCRT dose plan set consisted of 10 fan-beam CT (FBCT) treatment-day images acquired from four different patients. The IMRT dose plan set consisted of 32 cone-beam CT (CBCT) treatment-day images acquired from 4 different patients. The CNRR was tested with different combinations of anatomical constraints and each test significantly outperformed both rigid and non-rigid registration at aligning constrained bones and critical organs. The CNRR results were used to adapt the dose plans to account for patient positioning errors as well as inter-day bone motion and intrinsic organ deformation. Each adapted dose plan improved performance by lowering radiation distribution to the rectum and bladder while increasing or maintaining radiation distribution to the prostate.
Non-rigid image registration; B-spline free form deformation; Rigid registration; Image-guided radiotherapy; Adaptive prostate radiotherapy
The GGA family of monomeric clathrin adaptors are known to bind to cargo molecules via short C-terminal peptide motifs conforming to the sequence DXXLL (X= any amino acid), while the heterotetrameric adaptors AP-1 and AP-2 utilize a similar but discrete sorting motif of the sequence [D,E]XXXL[L,I]. While it has been established that a single cargo molecule may contain either or both types of these acidic cluster-dileucine (AC-LL) sorting signals, there are no examples of cargo with overlapping GGA and AP-1/AP-2 binding motifs. Here we report that the cytosolic tail of LRP9 contains a bifunctional GGA and AP-1/AP-2 binding motif at its carboxy terminus (EDEPLL). We further demonstrate that the internal EDEVLL sequence of LRP9 also binds to GGAs in addition to AP-2. Either AC-LL motif of LRP9 is functional in endocytosis. These findings represent the first study characterizing the trafficking of LRP9 and also have implications for the identification of additional GGA cargo molecules.
GGAs; AP-1; AP-2; dileucine motif; endocytosis; LRP9
One hundred and five drug-dependent women in outpatient perinatal addiction treatment were classified by cluster analysis of the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) profiles into high and low psychopathology (HP and LP) groups that differed on three validation measures. The HP group (n = 29, 27.6%) had elevations on MMPI-2 Scales F, 2, 4, 6, 7, and 8, while the LP group (n = 76, 72.4%) generated a normal range profile with elevations on Scales F and 4. Psychological outcomes differed by group. HP participants showed reduced alcohol, family, and psychiatric severity, and reduced depressive symptoms, while LP subjects showed reduced drug, self-debasing, and acting-out problems. Data suggest the need for lower intensity services for the majority of the perinatal drug dependent population with LP.
Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome is a multi-system autosomal recessive disorder caused by germline mutations in VPS33B. The detection of germline VPS33B mutations removes the need for diagnostic organ biopsies (these carry a >50% risk of life-threatening haemorrhage due to platelet dysfunction); however, VPS33B mutations are not detectable in ∼25% of patients. In order further to define the molecular basis of ARC we performed mutation analysis and mRNA and protein studies in patients with a clinical diagnosis of ARC. Here we report novel mutations in VPS33B in patients from Eastern Europe and South East Asia. One of the mutations was present in 7 unrelated Korean patients. Reduced expression of VPS33B and cellular phenotype was detected in fibroblasts from patients clinically diagnosed with ARC with and without known VPS33B mutations. One mutation-negative patient was found to have normal mRNA and protein levels. This patient's clinical condition improved and he is alive at the age of 2.5 years. Thus we show that all patients with a classical clinical course of ARC had decreased expression of VPS33B whereas normal VPS33B expression was associated with good prognosis despite initial diagnosis of ARC.
arthrogryposis; renal tubular dysfunction; neonatal cholestasis; ARC; vesicular trafficking defect
This paper tracks organ (prostate, rectum, bladder) overlap in a constrained non-rigid registration (NRR) algorithm to register computed tomographic (CT) images used in external beam prostate radiotherapy. The local motion of the organs is described by a hierarchical multi-resolution FFD based on cubic B-splines. Registration is achieved by minimizing a cost function which is a combination of three functions representing the overlap of the critical organs, image similarity and smoothness of the transformation. The constrained NRR algorithm generated better registration results when compared to an unconstrained NRR algorithm.
Free-Form Deformation; Image Registration; Radiotherapy
In many radiotherapy clinics, geometric uncertainties in the delivery of 3D conformal radiation therapy and intensity modulated radiation therapy of the prostate are reduced by aligning the patient's bony anatomy in the planning 3D CT to corresponding bony anatomy in 2D portal images acquired before every treatment fraction. In this paper, we seek to determine if there is a frequency band within the portal images and the digitally reconstructed radiographs (DRRs) of the planning CT in which bony anatomy predominates over non-bony anatomy such that portal images and DRRs can be suitably filtered to achieve high registration accuracy in an automated 2D-3D single portal intensity-based registration framework. Two similarity measures, mutual information and the Pearson correlation coefficient were tested on carefully collected gold-standard data consisting of a kilovoltage cone-beam CT (CBCT) and megavoltage portal images in the anterior-posterior (AP) view of an anthropomorphic phantom acquired under clinical conditions at known poses, and on patient data. It was found that filtering the portal images and DRRs during the registration considerably improved registration performance. Without filtering, the registration did not always converge while with filtering it always converged to an accurate solution. For the pose-determination experiments conducted on the anthropomorphic phantom with the correlation coefficient, the mean (and standard deviation) of the absolute errors in recovering each of the six transformation parameters were θx:0.18(0.19)°, θy:0.04(0.04)°, θz:0.04(0.02)°, tx:0.14(0.15) mm, ty:0.09(0.05) mm, and tz: 0.49(0.40) mm. The mutual information-based registration with filtered images also resulted in similarly small errors. For the patient data, visual inspection of the superimposed registered images showed that they were correctly aligned in all instances. The results presented in this paper suggest that robust and accurate registration can be achieved with intensity-based methods by focusing on rigid bony structures in the images while diminishing the influence of artifacts with similar frequencies as soft tissue.
2D-3D image registration; spectral analysis; prostate radiotherapy; cone beam CT; setup verification; portal image
The objective of this study was to develop a fully automated two-dimensional (2D)–three-dimensional (3D) registration framework to quantify setup deviations in prostate radiation therapy from cone beam CT (CBCT) data and a single AP radiograph. A kilovoltage CBCT image and kilovoltage AP radiograph of an anthropomorphic phantom of the pelvis were acquired at 14 accurately known positions. The shifts in the phantom position were subsequently estimated by registering digitally reconstructed radiographs (DRRs) from the 3D CBCT scan to the AP radiographs through the correlation of enhanced linear image features mainly representing bony ridges. Linear features were enhanced by filtering the images with “sticks,” short line segments which are varied in orientation to achieve the maximum projection value at every pixel in the image. The mean (and standard deviations) of the absolute errors in estimating translations along the three orthogonal axes in millimeters were 0.134 (0.096) AP(out-of-plane), 0.021 (0.023) ML and 0.020 (0.020) SI. The corresponding errors for rotations in degrees were 0.011 (0.009) AP, 0.029 (0.016) ML (out-of-plane), and 0.030 (0.028) SI (out-of-plane). Preliminary results with megavoltage patient data have also been reported. The results suggest that it may be possible to enhance anatomic features that are common to DRRs from a CBCT image and a single AP radiography of the pelvis for use in a completely automated and accurate 2D-3D registration framework for setup verification in prostate radiotherapy. This technique is theoretically applicable to other rigid bony structures such as the cranial vault or skull base and piecewise rigid structures such as the spine.
image registration; prostate radiotherapy; cone beam CT; sticks; setup verification; portal; radiograph
This paper presents a novel free-form deformation registration algorithm with non-rigid constraints to capture the transformation between the planning day and treatment day CT images used for external beam radiotherapy for prostate cancer. The algorithm is constrained to the predetermined motion of a segmented organ, which is described by an injective free-form deformation (FFD) based on B-splines. The end goal is for the injective transformation to be used to update the radiotherapy plan to take into account bone and soft tissue deformation. The results of the algorithm have been compared to those achieved using rigid and fully non-rigid registration. The results clearly indicate that the constrained non-rigid registration algorithm presented in this paper performed much better at capturing the motion of the constrained organ, the bladder in this case, than the rigid or fully non-rigid registration algorithms.
Image Registration; Biomedical Image Processing; Prostate Radiotherapy
To develop an accurate, fast, and robust algorithm for registering portal and computed tomographic (CT) images for radiotherapy using a combination of sparse and dense field data that complement each other.
Methods and Materials
Gradient Feature Weighted Minimax (GFW Minimax) method was developed to register multiple portal images to three-dimensional CT images. Its performance was compared with that of three others: Minimax, Mutual Information, and Gilhuijs' method. Phantom and prostate cancer patient images were used. Effects of registration errors on tumor control probability (TCP) and normal tissue complication probability (NTCP) were investigated as a relative measure.
Registration of four portals to CTs resulted in 30% lower error when compared with registration with two portals. Computation time increased by nearly 50%. GFW Minimax performed the best, followed by Gilhuijs' method, the Minimax method, and Mutual Information.
Using four portals instead of two lowered the registration error. Reduced fields of view images with full feature sets gave similar results in shorter times as full fields of view images. In clinical situations where soft tissue targets are of importance, GFW Minimax algorithm was significantly more accurate and robust. With registration errors lower than 1 mm, margins may be scaled down to 4 mm without adversely affecting TCP and NTCP.
Multimodality image registration; Prostate radiotherapy; Patient positioning; Tumor control probability; NTCP