News Column

Patent Application Titled "Treatment Planning Based on Polypeptide Radiotoxicity Serum Markers" Published Online

May 15, 2014

By a News Reporter-Staff News Editor at Politics & Government Week -- According to news reporting originating from Washington, D.C., by VerticalNews journalists, a patent application by the inventors Bitter, Katrin (Aachen, DE); Ribbing, Carolina (Aachen, DE), filed on June 29, 2012, was made available online on May 1, 2014.

The assignee for this patent application is Koninklijke Philips N.v.

Reporters obtained the following quote from the background information supplied by the inventors: "Generally, events occurring in the body are molecularly mediated, mostly by proteins. Ongoing physiological or pathological events are represented by the relative cellular abundance of tens of thousands of different proteins along with their chemically modified and cleaved forms. Every cell gives an account of its physiological state in the molecular products it contains and releases. Within molecular diagnostics (MDx), some of the cellular products from this diagnostic information mine are used as disease markers or as pathological fingerprints. The outcome of such tests may be important input for any decision support tool that combines diagnosis and disease prognosis.

"Mass spectrometry (MS) is a method for determining molecular mass, involving sample ionization and transfer to the gas phase. By acceleration in an electric field and separation in vacuum, the molecular ions are separated according to their mass-to-charge ratio. During the last decades, MS has proven to be a viable technique for accurate and sensitive analysis of biological species like proteins and peptides. With the introduction of soft ionization techniques, it became possible to transfer these non-volatile, large, and thermally labile molecules into the gas phase without dissociating them.

"In matrix-assisted laser desorption ionization (MALDI), the sample is co-crystallized with a UV absorbing aromatic compound which is added to the sample in large excess. Common UV absorbing matrices include a-cyano-4-hydroxy cinnamic acid (CHCA) and 3,5-dimethoxy-4-hydroxy cinnamic acid (sinapinic acid). A pulsed UV laser supplies the energy for ionization and desorption, and the matrix absorbs the UV energy and transfers it to the sample. Typically, a N.sub.2 laser with 337 nm wavelength (3.7 eV) and e.g., 4 ns pulses is used. As comparison, about 13-14 eV is required for one .about.12 kDa (Dalton) molecule to be desorbed and ionized. Using MALDI-MS, molecules with masses exceeding 105 Da can be ionized and analyzed without appreciable fragmentation.

"Prior to performing MALDI-MS, complex samples like molecular digests, cell lysates and blood serum have to be pre-fractionated in order to eliminate the suppression of molecular desorption/ionization often observed with complex mixtures (ion suppression), to avoid too heterogeneous sample compositions and to avoid detector overload. Common pre-fractionation methods include liquid chromatography, electrophoresis, isoelectric focusing, desalting, and removal of particles by centrifugation, as well as concentration and dilution. Often, 2D gel electrophoresis is performed; spots of interests are excised from the gel and dissolved for subsequent MALDI-MS analysis. Another common arrangement is liquid chromatography (LC) coupled directly to another type of mass spectrometer with electrospray ionization (ESI-MS), corresponding to a low-resolution mass separation (LC) in series with a high-resolution mass separation (MS).

"MALDI was further refined by introduction of a combination with chromatographic sample pre-fractionation in surface-enhanced affinity capture (SEAC), later surface enhanced laser desorption ionization (SELDI), and by covalent binding of matrix to the sample holding plate in an approach called surface-enhanced neat desorption (SEND). In SELDI, the sample is brought into contact with a chromatographic surface which binds a subgroup of the sample molecules. For sample preparation, individual chromatographic chips are accommodated in a special holder (a bio-processor) to achieve a standard microtiter plate format. Unbound molecules are removed by buffer washing, and a MALDI-MS measurement is performed directly off the chromatographic surface. Matrix is either added as a last step before MS measurement, or is already covalently bound to the chip surface. Only little or no fragmentation is observed.

"As an example, when using a hydrophobic surface in SELDI, the subgroup of hydrophobic molecules will be fished out of a complex sample. For biomarker discovery, protein expression profiling, and diagnostic purposes, this is useful for investigation or diagnosis of diseases which lead to a change in the expression of hydrophobic peptides. SELDI advantages include that the sample is concentrated directly on a chromatographic surface in a relatively short process with high throughput potential. The chromatographic MS targets can be automatically loaded with a sample, prepared, and analyzed in the MS. Therefore, the method is interesting for diagnostic applications. The SELDI-TOF mass spectrometers have a simple design and are installed in many clinics and clinical chemistry departments of hospitals.

"From blood serum, diagnostic mass spectrometric proteomic patterns showing e.g. early cancer or host response to radiation can be obtained. The literature has indicated that such a diagnostic peptide pattern has enabled early diagnosis of ovarial cancer. The approach of a spectral pattern as a diagnostic discriminator represented a new diagnostic paradigm. For the first time, the pattern itself was the discriminator, independent of the identity of the proteins or peptides. The underlying thesis was that pathological changes within an organ are reflected in proteomic patterns in serum. This is plausible because, generally speaking, and as stated in the opening paragraph, every event occurring in our bodies is molecularly mediated, mostly by proteins.

"Tumors are often treated with radiotherapy. In radiotherapy, a radiation dose high enough to kill tumor cells is delivered to the tumor, while trying to spare healthy tissue surrounding the tumor and extra sensitive tissue like epithelial linings, rectum, bowel, urethra, bladder and certain nerve bundles. In external beam radiotherapy, there are always portions of healthy tissue that are exposed to and damaged by radiation. In addition, some patients react with severe side-effects, which have a severe influence on the patient's quality of life. By way of non-limiting example, acute and late toxicity of the bowel and the urinary tract are impeding side-effects in radiotherapy of prostate cancer. With this cancer, radiotherapy planning targets the prostate cancer while minimizing dose to the very closely situated bowel and bladder. The frequent and serious side-effects of prostate cancer radiotherapy especially affect the bladder and the bowel. For example, the side-effects include incontinence, bleeding, pain, etc. Other side-effects include impotence. Other cancers in this bodily region treated using radiotherapy include, but are not limited to, bladder, kidney, bowel, rectum, endometrial, cervix, ovarial or vaginal cancer. With all of these, there may be severe side-effects that may influence the patient's quality of life.

"To measure health related quality of life among men with prostate cancer, the Expanded Prostate cancer Index Composite (EPIC) was developed. EPIC consists of a questionnaire that is manually filled out by patients at several time points before, during and after radiotherapy. It assesses the disease-specific aspects of prostate cancer and its therapies and comprises the four summary domains: urinary, bowel, sexual and hormonal. Generally, higher EPIC scores are indicative of a better health-related quality of life. EPIC is a valuable tool for standardized assessment of radiotherapy side-effects and how these effects are perceived by the individual patients. However, EPIC can only report subjectively experienced effects. Furthermore, as with all patient-reported questionnaires, EPIC provides no reliable objective measure of side-effects. Because of at least these drawbacks, EPIC is not well suited to assist in individualization of treatment planning."

In addition to obtaining background information on this patent application, VerticalNews editors also obtained the inventors' summary information for this patent application: "Aspects of the present application address the above-referenced matters, and others.

"In one aspect, a method includes at least one of creating or adapting a treatment plan for a patient based on a set of serum polypeptides of the patient that are indicative of a radiotoxicity of the patient at least one of before or after at least one of a plurality of radiotherapy treatments of the treatment plan, wherein the radiotoxicity is induced by radiation exposure from the radiotherapy treatment.

"In another aspect, a system includes a treatment planning device (108) that facilitates at least one of creating or adapting a treatment plan for a patient based amounts or concentrations of a set of serum polypeptides of the patient that indicate a high risk of or an early radiotoxicity of the patient to radiation from radiotherapy.

"In another aspect, computer readable storage medium is encoded with computer readable instructions, which, when executed by a processor of a computing system, causes the system to: receive information about a polypeptide of a patient that indicates a radiotoxicity of the patient to radiotherapy treatment and create or adapt a treatment plan for the patient based on the received information, wherein the information includes at least a mass of the polypeptide and an intensity peak of the polypeptide.

"Still further aspects of the present invention will be appreciated to those of ordinary skill in the art upon reading and understanding the following detailed description.


"The invention may take form in various components and arrangements of components, and in various steps and arrangements of steps. The drawings are only for purposes of illustrating the preferred embodiments and are not to be construed as limiting the invention.

"FIG. 1 schematically illustrates an example system including a therapy treatment planning device.

"FIGS. 2-11 shows information about several polypeptide radiotoxicity serum markers.

"FIG. 12 illustrates an example method for treatment planning."

For more information, see this patent application: Bitter, Katrin; Ribbing, Carolina. Treatment Planning Based on Polypeptide Radiotoxicity Serum Markers. Filed June 29, 2012 and posted May 1, 2014. Patent URL:

Keywords for this news article include: Oncology, Peptides, Proteins, Proteomics, Amino Acids, Radiotherapy, Prostate Cancer, Quality of Life, Prostatic Neoplasms, Koninklijke Philips N.v..

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Source: Politics & Government Week

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