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Image analysis of androgen receptor immunostaining in prostate cancer accurately predicts response to hormonal therapy.

PURPOSE: Immunostaining for androgen receptor in prostate tumor specimens has revealed that the majority of primary and advanced stage cancers are positive for this regulatory transcription factor. Consequently, its use as a marker for tumor behavior and therapeutic response has been discounted. However, past reports have noted significant heterogeneity of androgen receptor immunostaining between prostate tumor cells in contrast to staining homogeneity in normal epithelium, which indicates that variability in androgen receptor content may exist within certain tumor specimens. To analyze this phenomenon more thoroughly and to determine whether this variability possesses clinical correlates, androgen receptor immunostaining profiles within androgen receptor positive prostate tumor specimens were categorized using an image analysis based system. MATERIALS AND METHODS: Tumor specimens were obtained before hormone therapy from 44 patients with advanced stage prostate cancer and 4 with early stage disease who later had progression. Response to antiandrogen therapy and survival was monitored. Paraffin embedded tumor sections were processed for immunocytochemistry and stained for androgen receptor. A Quantimet image analysis system was used to analyze nuclear immunostaining for androgen receptor and Receptogram patterns were established for each specimen based on univariate distributions of nuclear receptor content and concentration. RESULTS: Data revealed that 17 of 18 responders to hormone therapy possessed type 1 (15) or type 3 (2) Receptograms, which are characterized by a unimodal peak or multimodal peaks within a narrow concentration range. Of the 17 cases that stabilized following therapy 16 had type 3 Receptograms and 1 was characterized as type 1. In contrast, all 13 patients in whom endocrine treatment failed had either type 2 or 4 Receptograms, which are characterized by a highly skewed or bimodal androgen receptor distribution. Positive and negative predictive values for this assay were 100 and 93%, respectively. In addition, the type 1/3 Receptogram patterns were correlated with longer mean survival. CONCLUSIONS: Image analysis of prostate cancer androgen receptor immunostaining with a pattern oriented approach for response is capable of accurately predicting response to hormone therapy in patients with advanced stage disease. Application of this analytic scheme may assist the clinician with therapeutic management of advanced prostate cancer.

Adenocarcinoma↗

Weaning from mechanical ventilation: a retrospective analysis leading to a multimodal perspective.

Practitioners' decision for mechanical aid discontinuation is a challenging task that involves a complete knowledge of a great number of clinical parameters, as well as its evolution in time. Recently, an increasing interest on respiratory pattern variability as an extubation readiness indicator has appeared. Reliable assessment of this variability involves a set of signal processing and pattern recognition techniques. This paper presents a suitability analysis of different methods used for breathing pattern complexity assessment. The contribution of this analysis is threefold: 1) to serve as a review of the state of the art on the so-called weaning problem from a signal processing point of view; 2) to provide insight into the applied processing techniques and how they fit into the problem; 3) to propose additional methods and further processing in order to improve breathing pattern regularity assessment and weaning readiness decision. Results on experimental data show that sample entropy outperforms other complexity assessment methods and that multidimensional classification does improve weaning prediction. However, the obtained performance may be objectionable for real clinical practice, a fact that paves the way for a multimodal signal processing framework, including additional high-quality signals and more reliable statistical methods.

Algorithms↗

Multimodal cerebral monitoring and decompressive surgery for the treatment of severe bacterial meningitis with increased intracranial pressure.

Bacterial meningitis is still associated with a high mortality, mainly because of cerebral herniation as a result of increased intracranial pressure. Published data stress the necessity of an early diagnosis and immediate start of antibiotic therapy. Nevertheless, there are only few reports in which therapeutic strategy was based on the monitoring and the reduction of intracranial pressure (ICP). We report one case of bacterial meningitis caused by Neisseria meningitidis with an initial ICP value of 60 mmHg, which was treated by large hemicraniectomy and ventriculostomy, leading to a favorable neurological long-term result. The surgical decision was accelerated by an accurate ICP evaluation based on cerebral monitoring [transcranial Doppler ultrasonography (TCD) and intracranial ICP-device]. In selected patients with bacterial meningitis and clinical and radiological evidence of elevated ICP, cerebral monitoring and aggressive reduction of ICP may be crucial to improve survival and neurological outcome. When maximal medical ICP treatment fails to reduce severe intracranial hypertension, decompressive craniectomy should be rapidly proposed.

Adult↗

Robotic multimodality stereotactic brain tissue identification: work in progress.

Real-time identification of tissue would improve procedures such as stereotactic brain biopsy (SBX), functional and implantation neurosurgery, and brain tumor excision. To standard SBX equipment has been added: (1) computer-controlled stepper motors to drive the biopsy needle/probe precisely; (2) multiple microprobes to track tissue density, detect blood vessels and changes in blood flow, and distinguish the various tissues being penetrated; (3) neural net learning programs to allow real-time comparisons of current data with a normative data bank; (4) three-dimensional graphic displays to follow the probe as it traverses brain tissue. The probe can differentiate substances such as pig brain, differing consistencies of the 'brain-like' foodstuff tofu, and gels made to simulate brain, as well as detect blood vessels imbedded in these substances. Multimodality probes should improve the safety, efficacy, and diagnostic accuracy of SBX and other neurosurgical procedures.

Animals↗

Multimodal anatomic, functional, and metabolic brain imaging for tumor resection.

OBJECTIVE: Improvement of neurosurgical techniques with a more detailed description of brain tumors and their functional environment. METHODS: We performed: (1) anatomical magnetic resonance imaging (MRI) for reference, (2) functional sequences dedicated to the adjacent cortical structures (sensorimotor, visual, language paradigms), and (3) thallium 201 cerebral tomoscintigraphy to visualize active tumor invasion. Data were transferred to a workstation for automatic registration. RESULTS: All data were combined into one synthetic image showing the foci of high proliferative activity, which have to be completely resected, and the peritumoral functional structures, which have to be spared in order to minimize postoperative sequelae. This trimodal image is entered into a surgical neuronavigation computer for preoperative planning in order to outline tumoral target and functional risk areas. All this information is displayed in the operative microscope (Zeiss MKM) optically linked to MR images. This multimodality technique diminishes operative time by reducing electrocorticography and improves the operative short-term outcome. CONCLUSION: Multimodal imaging is useful for optimization of neurosurgical tumor resection.

Adult↗

A grand challenge for research: multimodal, multilevel and multiscale systems in medicine and biology.

Computational modelling, nano-bioscience and information technology in biology and medicine will play a major role in the interdisciplinary attempts to elucidate structures and functions of living systems. Developing tools capable to integrate the new advances and make benefit of them is crucial: accumulation of data and knowledge base with only storage and retrieval capabilities will have a poor impact if they are not made "active" or "operational". This is where models will play a central role in offering, not only sound ways for representation or simulation, but also the appropriate frames to put the players in the right place, with intra- and inter-level coupling and multisource handling. This paper advocated that sequential observations of multiple and complex mechanisms will be of limited interest to understand the inter-relations that are occurring at the same time, and therefore, that designing multimodal, multilevel and multiscale experiments, matched with these models, are of major importance.

Animals↗

CBA--an atlas-based software tool used to facilitate the interpretation of neuroimaging data.

CBA, a software tool used to improve quantification and evaluation of neuroimaging data has been developed. It uses a detailed 3-dimensional brain atlas that can be adapted to fit the brain of an individual patient represented by a series of displayed images. Anatomical information from the atlas can then be introduced into the images. If the patient has been imaged in different modalities, adaptation of the atlas to the different images will provide the transformation that brings the images into registration. CBA can thus be used as a tool for fusing multimodality information from the same patient. Furthermore, by applying the inverse atlas transformation, images from a patient can be transformed to conform to the anatomy of the atlas brain. This anatomical standardization, where the atlas brain itself serves as the anatomy standard, brings data from different individuals into a compatible form providing possibilities to perform individual-group and group-by-group comparisons between patients and normal controls.

Animals↗

Psychiatric disorders in children with speech and langauge retardation. Factors associated with development.

One hundred children (mean age, 5 to 6 years) who were seen consecutively at a suburban speech and hearing clinic were systematically evaluated for speech and language disorders and psychiatric disorders. Fifty-three were found to have a psychiatric illness. The three groups were compared with the psychiatrically well group to ascertain factors associated with the presence of a psychiatric disorder. Significantly differentiating the ill group were more academic and classroom behavior problems and the presence of both speech and language problems. The two groups were not significantly different in intellectual retardation, hearing impairment, medical factors, nonlanguage development disorders, and a variety of family and demographic factors. Common in both groups were psychiatric illness in parents and first-degree relatives. The data indicate that children with speech and langauge disorders are highly at risk for the development of significant psychiatric problems, which suggests the need for proper screening and multimodal treatment planning.

Adolescent↗

High-intensity intravenous cyclophosphamide and cisplatin, interim surgical debulking, and intraperitoneal cisplatin in advanced ovarian carcinoma: a pilot trial with ten-year follow-up.

PURPOSE: This trial was undertaken to study the effect of intensified intravenous cyclophosphamide/cisplatin and interim surgical debulking, followed by intraperitoneal cisplatin on surgically defined complete remission rate and survival in advanced ovarian cancer. PATIENTS AND METHODS: Forty patients with stage IIB through IV ovarian cancer were entered and 36 were evaluable for response and survival and approximately 10 years. Following a first laparotomy for diagnosis and debulking, the patients received two cycles, spaced 28 days apart, of intravenous cisplatin 30-40 mg/m2/day with hypertonic saline for 4 to 5 days and cyclophosphamide 200 mg/m2/day for 5 days. A second laparotomy was done to further debulk remaining cancer and to place an intraperitoneal catheter. Four cycles of intraperitoneal cisplatin at 50 or 100 mg/m2 were administered 21 days apart and followed by a third laparotomy to define response and plan any further therapy. RESULTS: The surgically confirmed complete response rate was 47% and median survival is 68.3 months for this group. Ten of the 17 patients (58.8%) relapsed following complete response at a median of 19.5 months (range, 5-98). Both aggressive chemotherapy and surgery seemed to play a role in inducing this high complete response rate. Traditional prognostic factors, including stage and diameter of largest residual disease, had little apparent effect on likelihood of complete response or survival, whereas tumor grade had a more significant effect on survival. Nadir fever was experienced by 33% of patients but peripheral neuropathy was dose limiting. CONCLUSION: In the context of recent data failing to support any clinical benefit to modest increases in dose escalations of cisplatin or carboplatin, in this trial the high complete response rate suggests that the multimodality approach (i.e., interval surgical debulking and intraperitoneal cisplatin) is worthy of further study. The high relapse rate among complete responders and the unacceptable neurotoxicity also suggest that modifications could improve the results. The use of newer agents and further intensification (substituting carboplatin for cisplatin and the use of paclitaxel) with stem cell support are two examples.

Antineoplastic Combined Chemotherapy Protocols↗

Minimal residual disease in gastric cancer.

In curatively resected gastric cancer, the incidence of distant relapse is as high as 30%. Although the most important factor contributing to the local control of the tumor is the microscopic tumor-free margin of the surgical resection, the occurrence of distant metastases is in many cases due to preoperative or perioperative tumor cell dissemination. In addition to the established TNM staging system, disseminated tumor cells may serve as independent prognostic factors influencing patient outcome after curative surgery. Basically, in gastric cancer three compartments have been identified in which single tumor cells may be shed: lymph nodes, peritoneal cavity, and bone marrow. Assessment of resected regional lymph nodes with monoclonal antibodies directed against cytokeratin antigens leads to an upstaging in comparison with conventional histology. Nodal micrometastases detected by immunohistochemistry result in an upstaging of up to 36% of patients. However, their prognostic significance remains controversial. Local dissemination of tumor cells in the peritoneal cavity determines the outcome in advanced gastric cancer and diffuse-type carcinoma. Patients with negative peritoneal washings seem to have a more favorable prognosis. Moreover, with the use of these diagnostic tools, patient subpopulations may be identified which profit from intraperitoneal therapy regimens. Diffuse hematogenous tumor cell dissemination into the bone marrow has been shown to be a prognostic factor in several studies. In our own population of 180 gastric cancer patients, bone marrow cells were screened immunohistochemically with a monoclonal antibody directed against cytokeratin 18 (CK18). In 95 patients (53%), CK2-posititve cells were detected. In a multivariate analysis, the independence of the presence of three or more disseminated tumor cells per 10(6) mononuclear cells was proven to be a prognostic factor in patients with intestinal-type tumors, pT1/2 status, and pN0 status. In conclusion, the TNM status only partially reflects the actual extent of systemic disease in patients with resected gastric cancer. The assessment of minimal residual disease is valuable in estimating the prognosis in many patients. In the future, staging systems will have to not only include TNM data but also provide specific information on biological properties of residual cancer cells in order to establish more exact prognostic estimates and provide patients with an individually tailored multimodal treatment.

Bone Marrow Neoplasms↗

From multimodality digital imaging to multimedia patient record.

The constant improvement in computer power and performance nowadays offers convenient and efficient means of manipulating images, graphics, and movies on off-the-shelf workstations. With this improvement the trend toward integration of multimodality clinical documents from patient records comes naturally. Images and graphs are certainly the most important part of the complementary information that must accompany the text and numerical data. It is, however, possible to include sounds and voice messages together with all the other modalities. In medicine that could certainly help conveying hart murmur or sounds, but could also offer a convenient way of including vocal messages and comments. These new possibilities will certainly change the way physicians use workstations for direct communication. The computer industry will soon offer means of interactive communication between remote users through computer workstations. That alone will open a completely new era in cooperative computing and remote consultation scenarios in medicine. More than the technology itself, a complete change in behavior and work habits can be expected in the medical community.

Computer Communication Networks↗

P300 recordings during event-related fMRI: a feasibility study.

Analysis of combined event-related potentials (ERP) and functional magnetic resonance imaging (fMRI) can provide a high temporal and high spatial resolution to study functional cerebral processes. However, EEG data recorded inside an MR scanner is heavily distorted by artifacts. It is important in cognitive studies to ensure that recorded data reflect the same brain activity, and this is achieved through interleaved electroencephalographic (EEG) and fMRI measurements. Here, we demonstrate the feasibility of recording P300 ERPs during fMRI using a three-stimulus visual oddball task and involving a small number of trials for each stimulus. Ten EEG channels were acquired interleaved with fMRI images in five healthy subjects. The stimuli, including rare targets "X," frequent repetitive distractors "O," and rare distractors referred to as novels, were randomly presented every 2 +/- 1 s. The post hoc filter presented here was designed and applied to EEG data to remove the cardiac pulse artifact. Interleaved EEG/fMRI acquisition evidenced two P300 ERPs evoked at Fz, Cz, and Pz by targets and novels. Novel-related ERPs were of higher amplitude than their target-related counterparts. The fMRI maps acquired concurrently showed stronger BOLD response for target condition. We have shown that interleaved acquisition allows to obtain reliable P300 data and fMRI results, likely to shed light on the anatomical location of brain regions involved in cognitive ERPs relevant to many disorders affecting CNS functions. These noninvasive multimodal neuroimaging techniques can be used to explore and better understand processes underlying the functional brain organization.

Adolescent↗

Locoregional recurrence after mastectomy: incidence and outcomes.

BACKGROUND: Locoregional recurrences (LRR) after mastectomy may be ominous events, but incidence and outcomes data are limited by heterogeneous study populations and the time period studied. We sought to evaluate the rate of LRR at a single institution in the era of multimodality therapy, identify predictors for isolated LRR, and examine treatment strategies and outcomes of postmastectomy patients with isolated LRR. STUDY DESIGN: In a prospective database, we identified 1,057 patients who underwent mastectomy for invasive cancer at Memorial Sloan-Kettering Cancer Center from 1995 to 1999. Predictive factors for isolated LRR were determined by univariate and multivariate analyses. Treatments and outcomes of patients with isolated LRR were reviewed. All patients with at least 2 years of followup were included. Median followup was 6 years. RESULTS: Overall, LRR developed in 93 of 1,057 (8.8%) patients. Thirty-four (3.2%) had synchronous distant metastases. Distant recurrences developed in thirty-one (2.9%) during the followup period (median followup, 6 years). Twenty-eight patients with LRR (2.6%) remained free of distant disease during the study period. Multivariate analysis showed age less than 35 years, lymphovascular invasion, and multicentricity as major predictors for isolated LRR. In the 28 patients with isolated LRR, 24 had recurrence in the chest wall, 2 in the axilla, and 2 in more than 1 local site. Seventy-eight percent (22 of 28) of patients were rendered disease free with surgery (15 of 22), radiotherapy (13 of 22), chemotherapy (6 of 22), or hormones (9 of 22). CONCLUSIONS: Despite widespread use of adjuvant therapies during the study period, we found an LRR rate after mastectomy of 9%. But for patients presenting with LRR without evidence of distant disease, aggressive multimodality therapy is warranted because many of these patients can be rendered disease free.

Adult↗

Locally linear discriminant analysis for multimodally distributed classes for face recognition with a single model image.

We present a novel method of nonlinear discriminant analysis involving a set of locally linear transformations called "Locally Linear Discriminant Analysis (LLDA)." The underlying idea is that global nonlinear data structures are locally linear and local structures can be linearly aligned. Input vectors are projected into each local feature space by linear transformations found to yield locally linearly transformed classes that maximize the between-class covariance while minimizing the within-class covariance. In face recognition, linear discriminant analysis (LDA) has been widely adopted owing to its efficiency, but it does not capture nonlinear manifolds of faces which exhibit pose variations. Conventional nonlinear classification methods based on kernels such as generalized discriminant analysis (GDA) and support vector machine (SVM) have been developed to overcome the shortcomings of the linear method, but they have the drawback of high computational cost of classification and overfitting. Our method is for multiclass nonlinear discrimination and it is computationally highly efficient as compared to GDA. The method does not suffer from overfitting by virtue of the linear base structure of the solution. A novel gradient-based learning algorithm is proposed for finding the optimal set of local linear bases. The optimization does not exhibit a local-maxima problem. The transformation functions facilitate robust face recognition in a low-dimensional subspace, under pose variations, using a single model image. The classification results are given for both synthetic and real face data.

Algorithms↗

[Basic concept in computer assisted surgery].

OBJECTIVE: To investigate application of medical digital imaging systems and computer technologies in orthopedics. METHODS: The main computer-assisted surgery systems comprise the four following subcategories. RESULTS: (1) A collection and recording process for digital data on each patient, including preoperative images (CT scans, MRI, standard X-rays), intraoperative visualization (fluoroscopy, ultrasound), and intraoperative position and orientation of surgical instruments or bone sections (using 3D localises). Data merging based on the matching of preoperative imaging (CT scans, MRI, standard X-rays) and intraoperative visualization (anatomical landmarks, or bone surfaces digitized intraoperatively via 3D localiser; intraoperative ultrasound images processed for delineation of bone contours). (2) In cases where only intraoperative images are used for computer-assisted surgical navigation, the calibration of the intraoperative imaging system replaces the merged data system, which is then no longer necessary. (3) A system that provides aid in decision-making, so that the surgical approach is planned on basis of multimodal information: the interactive positioning of surgical instruments or bone sections transmitted via pre- or intraoperative images, display of elements to guide surgical navigation (direction, axis, orientation, length and diameter of a surgical instrument, impingement, etc. ). And (4) A system that monitors the surgical procedure, thereby ensuring that the optimal strategy defined at the preoperative stage is taken into account. CONCLUSION: It is possible that computer-assisted orthopedic surgery systems will enable surgeons to better assess the accuracy and reliability of the various operative techniques, an indispensable stage in the optimization of surgery.

Humans↗

Multimodal protocol for awake craniotomy in language cortex tumour surgery.

BACKGROUND: Intra-operative neurophysiological language mapping has become an established procedure in patients operated on for tumours in the area of the language cortex. Awake cranial surgery has specific risks and patients are exposed to an increased physical and mental stress. The aim of the study was to establish an algorithm that enables tailoring the neurosurgical and anaesthetic techniques to the individual patient. METHOD: A total of 25 patients underwent awake craniotomy for intra-operative language mapping between 1999 and 2004. Following craniotomy under analgesia and sedation without rigid pin fixation of the head, cortical language mapping was performed in the fully co-operative patient. The results of functional magnetic resonance imaging and of cortical language mapping were incorporated into the 3D dataset for neuronavigation. Depending on the functional data and the individual operative risk tumour resection then proceeded either under conscious sedation with the option of subcortical language monitoring or under general anaesthesia. FINDINGS: After cortical language mapping patients are assigned to one of four groups: BACC (Berlin awake craniotomy criteria) I-IV. BACC I (9 patients): adequate functional data+operative risk not increased-->tumour resection in the awake patient; BACC II (4 patients): limited functional data+operative risk not increased-->tumour resection in the awake patient with the option of language monitoring as needed; BACC III (9 patients): adequate functional data+increased operative risk-->tumour resection under general anaesthesia using functional navigation; BACC IV (3 patients): limited functional data+increased operative risk-->tumour resection in the awake patient with the option of language monitoring as needed. We observed less adverse events in group BACC III. No permanent deterioration of language function occurred in this series. CONCLUSIONS: The multimodal protocol for awake craniotomy provides for tumour resection under general anaesthesia in selected patients using functional neuronavigation. Our experience with the algorithm suggests that it is a useful tool for preserving function in patients undergoing surgery of the language cortex while reducing the operative risk on an individual basis.

Adult↗

A critical review of behavioural treatments for chronic benign pain other than headache.

Studies of the effectiveness of operant, relaxation, cognitive, and multimodal behavioural approaches to the treatment of chronic benign pain other than headache were evaluated. In general, the quality of the studies was poor, and most investigations lacked appropriate and adequate control conditions, outcome measures, and/or follow-ups. While outcome reports for all four behavioural treatments have been mainly positive, few data were found which conclusively demonstrate that any of the approaches are effective or that they are the treatment of choice. The data do, however, imply that behavioural approaches may help patients lead more normal and productive lives. Specifically, the literature suggests that: (1) the operant method leads to increased activity levels and decreased pain and drug intake, (2) the relaxation approach results in decreased EMG levels and some pain reductions, (3) the cognitive techniques are speculative at this time, and (4) the multimodal method regularly produces a variety of improvements, but the diversity of the treatments makes general statements about utility impossible. It is concluded that behavioural treatments for pain are warranted in the clinic and that research dealing with effectiveness and subsequently with component analyses of treatments is badly needed.

Back Pain↗

Multimodal similarity and categorization of novel, three-dimensional objects.

Similarity has been proposed as a fundamental principle underlying mental object representations and capable of supporting cognitive-level tasks such as categorization. However, much of the research has considered connections between similarity and categorization for tasks performed using a single perceptual modality. Considering similarity and categorization within a multimodal context opens up a number of important questions: Are the similarities between objects the same when they are perceived using different modalities or using more than one modality at a time? Is similarity still able to explain categorization performance when objects are experienced multimodally? In this study, we addressed these questions by having subjects explore novel, 3D objects which varied parametrically in shape and texture using vision alone, touch alone, or touch and vision together. Subjects then performed a pair-wise similarity rating task and a free sorting categorization task. Multidimensional scaling (MDS) analysis of similarity data revealed that a single underlying perceptual map whose dimensions corresponded to shape and texture could explain visual, haptic, and bimodal similarity ratings. However, the relative dimension weights varied according to modality: shape dominated texture when objects were seen, whereas shape and texture were roughly equally important in the haptic and bimodal conditions. Some evidence was found for a multimodal connection between similarity and categorization: the probability of category membership increased with similarity while the probability of a category boundary being placed between two stimuli decreased with similarity. In addition, dimension weights varied according to modality in the same way for both tasks. The study also demonstrates the usefulness of 3D printing technology and MDS techniques in the study of visuohaptic object processing.

Concept Formation↗