Abstract:
A system for automatic segmentation of tumor tissue, useful for motion correction during radiotherapy using real-time imaging, identifies multiple regions based on the values of data and then identifies the tumors within the regions based on a priori knowledge about tumor size and/or location. The regions may be refined with robust and fast morphological operations, providing segmentation at speeds commensurate with the motion to be corrected.

Description:
BACKGROUND OF THE INVENTION 
       [0001]    The present invention relates to tumor segmentation in medical imaging with applications in radiation therapy, surgery and chemotherapy, and, in particular, to a method and apparatus for real-time tracking of tumor location for improved radiation therapy. 
         [0002]    External beam radiation therapy treats tumor tissues by directing a beam of high-energy radiation into the patient and through the tumor, exploiting increased sensitivity of rapidly dividing tumor cells to radiation damage. Radiation, and radiotherapy, as used herein, will generally be understood to include high-energy electromagnetic radiation, as well as particles such as protons. 
         [0003]    The success of external beam radiation therapy is strongly linked to the delivered dose, the latter which is constrained by the need to protect tissue and organs near the tumor. Damage to healthy tissue can be reduced by directing the radiation beam along a number of different axes that all intersect at the tumor while reducing dose to the tissue outside of the intersection. In addition, precise collimation of the radiation beam, for example by computer-controlled shutters, can provide sharp dose gradients at the tumor boundary. 
         [0004]    Sophisticated external beam radiation therapies rely on a computerized treatment plan that may be prepared, for example, from images obtained on a CT or MRI machine prior to the radiation treatment. In formulating the plan, the tumor and surrounding healthy tissue are “segmented” into defined volumes and each of the volumes is assigned to a minimum dose (for tumors) or maximum dose (for healthy tissue). The process of segmenting tumor volume can be time-consuming, requiring a healthcare professional to draw boundary lines on multiple image “slices” that together describe a volume of tissue to be treated. Semiautomatic procedures for segmentation are available in which the healthcare professional identifies a “seed” in each volume and the volume is automatically contoured by identifying tissue surrounding the seed that is similar to the seed tissue. 
         [0005]    During the radiation treatment, ability to precisely control the dose to the tumor is significantly limited by uncertainties in the position and size of the tumor. “Fractionation”, which breaks the radiation therapy into multiple sessions on different days, each delivering a fraction of the total desired dose, may be used to increase the susceptibility of the tumor cells and allow healthy cells to repair between fractions, but can reduce the accuracy of dose placement because of tumor position changes between fractionation sessions. Further, the tumor size may change over time (regression) as a result of the treatment itself. 
         [0006]    Even during a particular treatment session, uncertainty in the tumor position can result from periodic organ movements such as those of the heart and lungs or aperiodic motion such as bladder filling. 
         [0007]    The problems of tumor motion can be addressed to some extent by monitoring periodic motion (for example with an ECG or respiration sensor) and providing the radiation plan developed for a contour which envelops the tumor motion in all the 10 different phases. Using this approach, a typical radiation plan for lung cancer may include approximately 100 images for each plan. The process of segmenting the tumor in each of these images is extremely time-consuming and prone to error. 
         [0008]    A new generation of radiation therapy equipment such as the Renaissance system of ViewRay, Inc. of Cleveland, Ohio provides real-time MR imaging of the patient during the radiation therapy, for example, providing images every quarter second during a 30 seconds to 5 min. radiation therapy session. Ideally, these images could be used to monitor the changing location and position of the tumor during a treatment session. Manual and semiautomatic segmentation is much too slow to exploit this ability. Unfortunately, automatic segmentation techniques such as thresholding, region growing, clustering, and neural networks, have failed to achieve sufficiently accurate or rapid segmentation for real-time tumor segmentation. 
       SUMMARY OF THE INVENTION 
       [0009]    The present invention provides an extremely fast automatic segmentation technique for use with radiation therapy or other applications, and providing real-time medical imaging. The segmentation technique works by dividing the data into multiple regions based on data value similarity. Selected regions are then identified as tumors using an area filtering exploiting rough a priori knowledge about the tumor size optionally augmented by tumor location. Rapid morphological operators are used to generate the multiple regions at speeds allowing real-time tumor motion and deformation correction. 
         [0010]    Specifically then, one embodiment of the present invention provides a radiation therapy machine having a radiation delivery system controllable to direct a radiation beam preferentially to a located tumor region during a radiation treatment session and an imaging system operable to image a region of interest holding a tumor at multiple times during the radiation treatment session. An electronic computer receives electronic data representing tissue of the patient and segregates the data according to data values and spatial positions of the data into multiple regions. At least one region is identified as a tumor according to a predetermined tumor characteristic, and then this location is output to the radiation delivery system to change the radiation beam according to that location. 
         [0011]    It is thus a feature of at least one embodiment of the invention to provide a segmentation approach that permits real-time correction of the radiation beam during a treatment session. Segregating data according to data values may be performed in a one-pass rapid calculation making the tumor segmentation a simple selection among these regions. 
         [0012]    The predetermined tumor characteristic used to select among the regions may be tumor size. 
         [0013]    It is thus a feature of at least one embodiment of the invention to identify a simple a priori rule for selecting among the regions. The inventors have recognized that tumor size (when combined with tissue data values) tends to be a robust identifier. 
         [0014]    The tumor size may be a single value or a value range. 
         [0015]    It is thus a feature of at least one embodiment of the invention to provide a flexible method of identifying tumor size based on either precise measurements or a known range. In real time radiation therapy, for example, there is a need to measure tumor size in real-time to identify changes in tumor volume. In this case, a typical range of tumor size is taken as the input and not the single value of tumor size. 
         [0016]    The tumor may be further identified according to a predetermined tumor characteristic of a tumor location. 
         [0017]    It is thus a feature of at least one embodiment of the invention to select among identified regions using known location information. 
         [0018]    The tumor location may be locations received by the electronic computer or tumor location proximate to a predetermined organ. 
         [0019]    It is thus a feature of at least one embodiment of the invention to accept a variety of types of location data including those implicit in the organ being treated. 
         [0020]    The step of segregating the data according to data values and spatial positions may divide the data into at least two classifications defined by a predetermined range of data values for a tumor. 
         [0021]    It is thus a feature of at least one embodiment of the invention to focus the segmentation process on information about the tumor to provide greatest accuracy in the tumor segmentation. 
         [0022]    The data within the predetermined range of data values for a tumor may be subject to morphological processing to eliminate overlap with data outside the predetermined range of data values for a tumor to provide a region related to the tumor and nonoverlapping with other regions. 
         [0023]    It is thus a feature of at least one embodiment of the invention to provide isolated regions using extremely fast morphological processing. 
         [0024]    The morphological processing performs morphological erosion to eliminate overlap. 
         [0025]    It is thus a feature of at least one embodiment of the invention to provide a robust and rapid method for refining the identified regions. 
         [0026]    The morphological erosion may be followed by a comparable morphological dilation. 
         [0027]    It is thus a feature of at least one embodiment of the invention to provide volume neutral processing to preserve accurate demarcation of the tumor volume. 
         [0028]    The radiation therapy machine may output location information which may be either a spatial boundary (including shape and boundary) of the region identified as a tumor or a center point of the region identified as a tumor. 
         [0029]    It is thus a feature of at least one embodiment of the invention to provide a flexible output format for different radiation beam correction systems. 
         [0030]    The imaging system may be either an MRI machine or data from a CT machine. 
         [0031]    It is thus a feature of at least one embodiment of the invention to provide a system suitable for imaging modalities providing data that may be used to demarcate different tissue types. 
         [0032]    These particular objects and advantages may apply to only some embodiments falling within the claims and thus do not define the scope of the invention. 
     
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         [0033]      FIG. 1  is a simplified block diagram of a combination radiation therapy and imaging system having a computer system suitable for executing a stored program implementing the present invention; 
           [0034]      FIG. 2  is a flowchart of the principal steps of one embodiment of the present invention; and 
           [0035]      FIG. 3  is a flow diagram depicting the operations of the steps of  FIG. 2  by means of simplified two-dimensional images. 
       
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
     Hardware 
       [0036]    Referring now to  FIG. 1 , a combination imaging radiotherapy machine  10  may provide, for example, an MRI magnet assembly  12  having two toroidal magnet elements  14   a  and  14   b  spaced along an axis  16  and having aligned bores  18  sized to admit a patient  20  supported on a patient table  22 . The magnet elements  14   a  and  14   b  may hold a superconducting BO electromagnet and one or more gradient and RF coils as is understood in the art of magnetic resonance imaging. The gradient and RF coils may communicate with an MRI subsystem  23  providing power amplifiers and the like as is also understood in the art. 
         [0037]    A radiation therapy gantry  24  may be positioned between the magnet elements  14   a  and  14   b , and may hold one or more radiation delivery systems  26  positioned to rotate about the axis  16  and direct radiation beams  29  toward the patient  20  when the patient  20  is positioned within the MRI magnet assembly  12 . Each radiation delivery system  26  may include an electronically controllable collimator  28 , for example a multi-leaf collimator controlling an outline of the radiation beam  29  and/or the intensity of different portions of the radiation beam “beamlets”. The radiation delivery systems  26  may be accurately positioned in rotation under the guidance of gantry motors and feedback control of position sensors (not shown). The collimators  28  and the gantry motors and position sensors may communicate with a gantry radiation therapy subsystem  30  providing the necessary driving and control electronics to control the multi-leaf collimators  28  and position the gantry  24 . 
         [0038]    The MRI subsystem  23  and radiation therapy subsystem  30  may in turn be controlled by a system computer  32  having one or more processors  34  communicating with a memory  36 . The memory  36  may include radiation therapy control program  38  providing software control of the position of the gantry  24  and the multi-leaf collimators  28  via the gantry radiation therapy subsystem  30  according to techniques well known in the art. This control may follow a stored radiation treatment plan  40  defining intensities of elements of the beamlets of beams  29  at various angles about the axis  16  for treatment of the specific tumor of the patient  20 . 
         [0039]    The memory  36  may also hold an imaging program  42  which may provide software control of the RF excitation and gradient coil excitation of the MRI magnet assembly  12 . The imaging program  42  may further include reconstruction algorithms to generate multiple images  44  defining a volume of the patient  20  receiving radiation treatment, these images reconstructed from received NMR signals obtained from the RF coils. Finally, the memory  36  may hold a segmentation program  46  of the present invention together with data files  48  used by that segmentation program. 
         [0040]    The computer  32  may further communicate with a user terminal  50  providing, for example, a graphic display for outputting images and other data and a keyboard or the like for inputting information to any of the programs from an operator. 
         [0041]    In an alternative embodiment, the MRI system may be replaced with an x-ray CT system or a megavoltage imaging system using the radiation from the radiation delivery systems  26  and an appropriate portal-imaging device to provide the necessary images. Equipment of this type is well known in the art. 
       Program Operation 
       [0042]    Referring now to  FIG. 2 , the segmentation program  46  may coordinate the radiation therapy control program  38  and imaging program  42  to provide substantially real time correction of the radiation treatment plan  40  based on images  44  obtained from the imaging program  42 . 
         [0043]    At a first optional process block  52 , the segmentation program  46  may receive an input radiation treatment plan  40  that will be used by the radiation therapy control program  38 . This radiation treatment plan  40  may provide for a quantitative volume of the tumor, or a range of volumes containing the volume of the tumor and optionally a location of the tumor. The location of the tumor may be a coordinate, for example, with respect to a fiducial point on the patient  20 , or a more general indication of tumor proximity to an identifiable organ such as a left or right lung. 
         [0044]    After receipt of this data, the radiation therapy control program  38  may initiate a first phase of the radiation treatment plan  40  (separately received by the radiation therapy control program  38 ) per process block  54  and may further initiate the patient imaging program  42  per process block  56  to collect images of the patient in the vicinity of the tumor. With each execution of process block  54 , a portion or phase of the radiation may be delivered that is less than the entire dose intended for the session. With each execution of process block  56 , one or more of a set of images  44  defining the volume around the tumor may be obtained. 
         [0045]    When an MRI machine is used, the present invention is not limited to a particular imaging sequence but may, for example, use highly constrained back projection (HYPR), for example, as taught by Mistretta Calif., “Under Sampled Radial MR Acquisition and Highly Constrained Back Projection (HYPR) Reconstruction: Potential Medical Imaging Applications in the Post-Nyquist Era, J. Magen. Reson. Imaging 2009; 29:501-516 hereby incorporated by reference. This imaging sequence provides for a rapid image commensurate with the real-time processes of the present invention. 
         [0046]    After completion of one execution of process blocks  54  and  56 , the program  46  may use the images  44  collected by the patient imaging program  42  to update the tumor location as indicated by process block  58 . Updating of the tumor location will be generally understood to be one or more of updating a tumor center location, tumor dimension, or map of a periphery of the tumor. 
         [0047]    At succeeding process block  60 , the information from the updated tumor location is used to correct the treatment plan  40  to adjust the size of the radiation beam and its location to match the new tumor position. This correction process may, in theory, recalculate the radiation plan based on the new tumor location taking into account the dose that has already been delivered. Alternatively, and for higher-speed, the correction process may directly adjust the sinograms used to drive the multi-leaf collimators  28 , for example, as taught by U.S. Pat. Nos. 6,385,286 entitled: “Delivery Modification System for Radiotherapy” and 5,673,300 entitled: “Method of Registering a Radiation Treatment Plan to a Patient” both assigned to the assignee of the present invention and hereby incorporated by reference. 
         [0048]    At decision block  62 , if the session is not complete, the program loops back to execute process block  54 ,  56 ,  58  and  60  again until the full radiation treatment session is complete. At that time, at decision block  62 , the program proceeds to process block  64  to update the dose statistics showing cumulative dose to the patient mapped, for example, to the original treatment plan images. This mapping may be performed as taught, for example, in U.S. patent Ser. No. 13/173,481, filed Jun. 30, 2011, and entitled: “Reduction of Transitivity Errors in Radiotherapy Image Registration” assigned to the assignee of the present invention and hereby incorporated by reference. 
         [0049]    Referring still to  FIG. 2 , the above described process of updating the tumor location per process block  58  may begin, as indicated by process block  66 , by collecting the data of the images  44  describing the three-dimensional area around the tumor as obtained during execution of process block  56 . The images  44  will generally include multiple image “slices” each comprised of multiple data values related to volume elements (voxels) in the patient  20 . Each data value is associated with a spatial coordinate in three dimensions, and may represent, for example, proton density or other MRI type values including measures of spin relaxation. The data may be collected from untreated tissue or from contrast agents such as hyperpolarized helium. 
         [0050]    Referring now also to  FIG. 3 , for the purpose of explanation, one slice of image data  68   a  is depicted being part of a set of slices of the finding volume. Each slice of image data  68  may, for example, be 128×128 voxels and the full set of data may comprise 128 slices displaced along the axis  16  defining a volume of interest. It will be understood that the operations described with respect to an individual slice will be applied to the multiple slices which define a volume of tissue and that the operations will be performed in three dimensions not simply within a given slice 
         [0051]    The received image data  68   a  will generally include a cross-sectional image of the patient  20  and of the patient support table  22  as well as additional environmental structures around the patient  20 . As shown in  FIG. 2 , the next step in processing, as represented by process block  70 , is the generation of a binary body mask defining portions of these image data  68   a  describing the body of the patient  20 . Generally, this binary body mask  68   c  (shown in  FIG. 3 ) will have a value of one for all data related to the patient  20  and a value of zero for all data not related to the patient  20 . This binary body mask  68   c  will be used to eliminate data in the images  44  unrelated to the body. 
         [0052]    Formation of the binary body mask  68   c  includes a first step, indicated by process block  72 , of filtering image data  68   a  according to a range of values preselected to predominantly include tissue of the patient  20  and to exclude structure such as the table  22  to produce filtered body data  68   b . These range values may be empirically derived and stored in a table or the like or may be developed from a pre-scan of the patient by the imaging system of  FIG. 1  or from a treatment planning image input at process block  52 . In the event that the treatment-planning image is a different modality than that of the combination imaging radiotherapy machine  10 , conversion factors may be employed to generate this range. For different modalities such as CT (x-ray attenuation) and MR (proton density) where there may not be one-to-one mapping between data values of the acquired data, a-priori information from scans of the same modality performed on other patients may be used to obtain a generic range. 
         [0053]    This resulting filtered body data  68   b  (shown in  FIG. 3 ) will include some table structure  74  caused by overlap between value ranges of table structure and body structure inevitable in most imaging modalities. 
         [0054]    At succeeding process block  76  (shown in  FIG. 2 ), any background voxels that cannot be reached from the edges of the filtered body data  68   b  are converted to foreground voxels (data values of zero). Connectivity may be established based on an eight-connected neighborhood described, for example, in Soille P., Morphological Image Analysis: Principles and Applications, Berlin; N.Y.: Springer 2003 hereby incorporated by reference. After this step, a mathematical morphology operation of “opening” is applied to the filtered body data  68   b . This process produces the binary body mask  68   c  eliminating the table structure. 
         [0055]    The opening operation is understood to be sequential mathematical operations of dilation and erosion using the same structuring element for both operations and that remove small objects from the “foreground” (in this case being the desired mask of the body) and place them in the “background” (being the non-body portion of the mask). The operation of erosion can be understood as a trimming away of a certain number of voxels around the outer periphery of all foreground objects in an image. In this process, it will be understood that thin foreground objects, such as the table structure  74 , will be erased whereas thicker objects, such as the body, will simply have their dimensions reduced. 
         [0056]    The succeeding operation of dilation can be understood to be the opposite of erosion and to involve adding a certain number of voxels around the outer periphery of all foreground objects in an image. In this process, the thicker foreground objects will be approximately restored but the thinner foreground objects previously fully eroded during the erosion operation will not be restored. 
         [0057]    The number of voxels used in erosion is set to be same as the number of voxels used in dilation so that the resulting foreground objects retain, substantially, their original dimensions. 
         [0058]    Referring still to  FIGS. 2 and 3 , after generation of the binary body mask  68   c , a binary organ mask  68   f  (in this case for lungs) will be generated per process block  78 . The particular organ with which the tumor is associated (and the characterization of this mask) may be input by the user as part of process block  52  described above. In this process of generating the binary organ mask  68   f , the image data  68   a  is again filtered as indicated by process block  80  but not for a range that encompasses the entire body (as which produces filtered body data  68   b ), but using a value range specific to the particular organ such as the lung to produce filtered lung data  68   d . These ranges of values for this filtration may again be empirically derived and stored in internal tables or may be obtained from inputs by the user as described above with respect to the binary body mask  68   c.    
         [0059]    As before with the case with filtered body data  68   b , this filtering process will not perfectly identify only the tissue of the lung but will include other non-lung voxels within this image range. In the case of the lung, these other voxels will largely be outside of the body in the air about the patient  20 . Accordingly, at process block  82 , the body mask  68   c  may be applied to the filtered lung data  68   d  (in a logical AND-ing operation) to eliminate voxel data outside of the body producing masked lung data  68   e . At this time, those background voxels that are not connected to the edges of the image (as described above) are converted to foreground voxels. The masked lung data  68   e  will have voids representing voxels that did not fit within the range of the filter range despite their location within the lungs. These voxels are eliminated by a morphometric “close” operation per process block  84  similar to the morphometric open operation but reversing the order of the erosion/dilation to be first dilation and then erosion. The effect is to eliminate small background areas included within foreground areas as opposed to the elimination of small foreground areas within background areas as provided with the open operation. The result of this close operation is to produce a binary organ mask  68   f  for the lung having a value of one for voxels within the lung and a value of zero for voxels outside of the lung. In this case the dilation may have a larger voxel number than the erosion so as to include a small margin of tissue around the organ of interest. 
         [0060]    Alternatively, the binary organ mask  68   f  may be replaced with a mask in the general known vicinity of the tumor, for example, a sphere about that location (represented as a circle in a given slice). 
         [0061]    Referring still to  FIGS. 2 and 3 , after generation of the binary organ mask  68   f  per process block  78 , a set of disjoint regions will be developed per process block  86 . This process again takes the raw image data  68   a  and applies the binary organ mask  68   f  to that data to provide tumor region data  68   g  isolating tissue related to the organ (e.g. lungs) and a small margin of tissue around the organ per process block  88 . 
         [0062]    The tumor region data  68   g  is then filtered per process block  90  to identify data values associated with tumor tissue (as opposed to lung tissue) to provide potential tumor data  68   h , in this case encompassing a tissue margin around the lungs (lung margin region  92 ), the heart region  94  and two tumor regions  95  all which have data values within this range because of the similarities of the tissue types and the inclusive breadth of the selected range. Again the range values identifying tumor tissue may be empirically determined and stored in a table, derived from the initial planning image, or input by the user after a prescan using the imaging system of  FIG. 1 . In this example, the tumors  95  are partially embedded in the wall of the lung forming a continuous region therewith. 
         [0063]    The potential tumor data  68   h  is then eroded per process block  98  to produce disjoint region data  68   i  which resolves each of the different tissues described above (lung, heart, tumor) in the potential tumor data  68   h  as isolated regions. The amount of erosion may be determined empirically for a population of individuals and then an average value used. 
         [0064]    Each of the separate regions  92 ,  94 , and  95  in the disjoint region data  68   i  is then enumerated and the volume occupied by each enumerated region determined by a simple addition of the voxels contiguous with each region. The volumes of each region may be identified, for example, using a union-find algorithm, for example, as described by Sedgewick R., Algorithms in C, Reading Mass.: Addison-Wesley 1998 hereby incorporated by reference. 
         [0065]    The enumerated regions  92 ,  94 , and  95  may then be analyzed by process block  100  to identify the tumor region  95 . This analysis process first identifies only those regions having volumes most closely matching the known volume of the tumor (either input at process block  52  or obtained from a stored table of tumor types sizes). This identification may be supplemented with location data if known. All other regions are then erased. 
         [0066]    This process produces tumor region data  68   j  providing the data only for tumor region  95 . At subsequent process block  104 , the erosion of process block  98  is reversed through a dilation to restore the tumors to their approximate original size as indicated by tumor image data  68   k.    
         [0067]    The volume and center point of these volume-restored tumors  95 ′ are then output as indicated by process block  106  where they will be used to correct the treatment plan as has been previously described. Generally the treatment plan will be modified so that the radiation beams maximize the dose to the tumor in its new position. Generally, the tumor location information output at process block  106  may be expressed in a variety of ways including: tumor volume, tumor centroid location or shape or volume of the tumor. This information can be measured in a sequential fashion at different times to provide information about changes in tumor location, volume and shape in real-time, which could be used by radiation therapy planning system to optimize treatment delivery. 
         [0068]    The present invention has obtained computational time for auto segmenting a volume of 128×128×128 voxels in 2 seconds, adequate for real-time correction of the treatment plan to accommodate tumor motion. This high-speed segmentation eliminates the need to separately calculate treatment phases and allows the system to work with both periodic and nonperiodic motion. 
         [0069]    It should be understood that the present invention is not limited to radiotherapy but may be used in a variety of different applications where tumor size, shape or location need to be monitored or identified, including, for example, in monitoring a patient for surgery or in assessing chemotherapy doses and rates or the effectiveness of chemotherapy treatment. 
         [0070]    Certain terminology is used herein for purposes of reference only, and thus is not intended to be limiting. For example, terms such as “upper”, “lower”, “above”, and “below” refer to directions in the drawings to which reference is made. Terms such as “front”, “back”, “rear”, “bottom” and “side”, describe the orientation of portions of the component within a consistent but arbitrary frame of reference which is made clear by reference to the text and the associated drawings describing the component under discussion. Such terminology may include the words specifically mentioned above, derivatives thereof, and words of similar import. Similarly, the terms “first”, “second” and other such numerical terms referring to structures do not imply a sequence or order unless clearly indicated by the context. 
         [0071]    When introducing elements or features of the present disclosure and the exemplary embodiments, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of such elements or features. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements or features other than those specifically noted. It is further to be understood that the method steps, processes, and operations described herein are not to be construed as necessarily requiring their performance in the particular order discussed or illustrated, unless specifically identified as an order of performance. It is also to be understood that additional or alternative steps may be employed. 
         [0072]    References to “a computer” and “a processor” or “the microprocessor” can be understood to include one or more microprocessors that can communicate in a stand-alone and/or a distributed environment(s), and can thus be configured to communicate via wired or wireless communications with other processors, where such one or more processor can be configured to operate on one or more processor-controlled devices that can be similar or different devices. Furthermore, references to memory, unless otherwise specified, can include one or more processor-readable and accessible memory elements and/or components that can be internal to the processor-controlled device, external to the processor-controlled device, and can be accessed via a wired or wireless network. 
         [0073]    It is specifically intended that the present invention not be limited to the embodiments and illustrations contained herein and the claims should be understood to include modified forms of those embodiments including portions of the embodiments and combinations of elements of different embodiments as come within the scope of the following claims. All of the publications described herein, including patents and non-patent publications, are hereby incorporated herein by reference in their entireties.