Testing Your Tumor written and compiled by doctordee | Search LMS site |

How Cancer Starts, and Dedifferentiation Chemosensitivity Testing Some Chemotherapy Drugs to Test Some Labs Testing Chemosensitivity Tumor Drug Resistance Prognostic Markers Predictive Markers Hormonal Markers Ckit {CD117} Testing Other Targeted Drug Test Markers International LMS Tissue Bank Immunohistochemical Tests Gene Expression Profiling Proteomic Studies More Information References
How Cancer Starts, and Dedifferentiation
Carcinogenesis, Accumulation of More Mutations, and De-Differentiation How Cancer Starts [Carcinogenesis] Mutations occur to the genes of cells by exposure to 'ionizing' radiation [like the sun's rays, radioactivity, Xrays], or chemical mutagens [like benzene and its derivatives] or viruses [which can introduce foreign DNA into the cell's DNA] or autoantibodies to DNA [created if a person has an autoimmune disease.] The usual mutation is one that causes a gene NOT to work. This means that the enzyme/protein that the gene produces [the gene product] does NOT work. For cancer to happen, a single cell needs to accumulate five or six different mutations. The usual probability of this happening is very very small. So what makes it happen? In every healthy normal cell, during reproduction there is a safety mechanism that checks that the DNA is intact and has no errors. The p53 gene is part of this safety mechanism. If the DNA is damaged, and cannot be repaired, then the p53 gene sets off a series of reactions that leads to apoptosis---the cell self-destructs. The p53 gene is called "the guardian of the genome" because it does not allow faulty DNA to exist, or to be passed on in the cell line. The "guardian of the genome" will cause a cascade of reactions that lead to apoptosis in cells whose DNA is damaged and cannot be repaired. What happens if the "the guardian of the genome" has a mutation? If the Guardian Gene Doesn't Work So a key mutation in the development of cancer would be damage to this p53 gene, or damage somewhere in its cascade of reactions. If the p53 cascade of reactions does not occur, then faulty DNA CAN is passed on from the mother to the daughter cell. Furthermore, the cell line with faulty p53 can now start collecting mutations. If the "caretaker gene" doesn't work, it allows defective-DNA daughter cells in the next generation. The defective daughter cells then accumulate their own additional mutations, which are ALSO passed to THEIR daughters. Who also accumulate some additional mutations. Which are ALSO passed to THEIR daughters. And so on... Eventually, besides not being able to police its own DNA, there will be mutations involving reproduction and growth, invasiveness, and coherence to other cells. When you have a cell that cannot destroy faulty DNA, which has ungovernable growth, which invades neighboring tissue, and which can separate itself from other tissue and journey via lymph or bloodstream to grow in a new place, you have an invasive, metastasizing cancer. So 'loss of function' mutations in these "caretaker genes" lead to an accumulation of mutations in the cell, and these mutations are carried through to subsequent cell generations. These cells are genetically unstable, as more and more mutations accumulate, and ARE PASSED ON to the next generation of cells. Inexorably, and inevitably, eventually, a cancerous cell will occur. Accumulation of More Mutations In the cells with defective p53, as more mutations occur, they are passed on to the daughter cells, and the daughter cells pass the mutations on to their daughters, along with further new mutations which have occurred. The results of these actions means that the tumor made up of these cells is not homogeneous...it is not composed of the same cancer cell repeated again and again. It actually is composed of many different branches of cell lines, with an increasing numbers of mutations. There will different mutations from one batch of cancer cells to another. It is this variation in the cell lines, in their mutations, that can make it difficult to interpret and apply chemosensitivity/resistance testing. The tumor may be sensitive to a chemotherapy agent in one of its cell lines, but resistant in another. Or one metastasis can be sensitive, and another resistant. Dedifferentiation Differentiation is the process by which the original fertilized egg, and its descendants, change from being identical to each other to being different...e.g. hair follicle cells and muscle cells and nerve cells and blood cells.... and so on. Differentiation refers to the process by which the cells become different from each other as they become more sophisticated, specialized types of cells. As the cancer cells in the tumor accumulate more and more mutations, the specialized nature of the original cell is lost. For instance, if it originally had an estrogen receptor on its cell membrane, often that receptor is lost. The cell with more and more mutations loses its abilities because of those mutations, and becomes less specialized and more primitive. And as more and more damage accumulates, the cell becomes more and more primitive, aberrant, and bizarre. This process is called dedifferentiation. It occurs in all cancers, it is inevitable, and it is a function of time, as it takes time to accumulate the mutations. It will usually occur more quickly in tumors with high reproductive rates, and can be hastened by chemotherapy or radiation. It may result in tumors that suddenly grow uncontrollably - even while being treated with chemotherapy AND radiation.
Chemosensitivity Testing
Chemosensitivity or Extreme Drug Resistance requires live tissue cells for testing. We have been doing throat cultures and pus cultures for decades. Finding out what will kill the bugs and what won't has been the ''standard of care'' in infectious disease for yonks. Why can't we grate some fresh cancer tumor, grow tissue cultures of the tumor, and then sprinkle different chemotherapy agents over the cultures...to see what kills the growing cells, and what doesn't? We CAN do this. There are different methods including, among others, the human tumor colony-forming assay (HTCA), the succinate dehydrogenase inhibition (SDI) test, the fluorescent cytoprint assay, the adenosine triphosphate assay (ATP assay), Differential Staining and Cytotoxicity (DiSC) Assays, and the MTT assay. It is a bit more complicated than making cookies, but the live tissue cultures of the cancer can be used to do the following:
Determine what chemotherapy drugs work well on the cultures. Because of LMS tumor cell heterogeneity, development of resistance, and generally poorly effective chemotherapy agents, this may not be of as much use as one would wish. Determine what chemotherapy drugs are useless for this tumor. Check out new cancer drugs on the tumor, to see if it works for that kind of tumor? Check a test's predictions against what actually happened when the tumor owners were given the chemotherapy agents. [Seeing how good the test is]. Suggest prognosis for patients, depending upon whether their tumor is chemosensitive or chemoresistant.
Discussion of Factors Affecting Chemosensitivity/Resistance Testing of LMS tumors There are two terms you will need to know. In vitro [in VEE troe] means ''in glass'', which means in the laboratory test tubes; in this case how chemo agents act upon the cultures of the tumor cells. In vivo [in VEE voe] means ''in the living''. It means how the chemo agent performs ''clinically''; how it reacts upon the tumor when in the patient's body. Ex vivo means in vitro. Chemosensitivity Testing: How a chemotherapy agent performs in test tubes may be very different from the performance inside a body. Because there are many factors which happen in tumors and bodies which are not applicable to studying in a tissue culture:
whether enough tumor cells will grow [evaluability] in the test tube, excluding nonmalignant components [stromal and vascular and necrotic, usually present in tumor specimens] from the test tube, preserving cell-to-cell interactions present in the original tumor in the test tube, the drug's ability to get into the tumor in the body, structural factors related to the tumor in the body, variations of the micro-environment in and around the tumor in the body, whether the drug acts on hypoxic tissue [ parts of the tumor that don't get enough blood supply to be well oxygenated], metabolism of the drug to its active metabolite within the body
Likewise, anti-angiogenesis drugs, which work by preventing new blood vessel formation in order to stall tumor growth, cannot be tested by tissue culture. So the chemosensitivity tests cannot always predict that the tumor will respond to the chemotherapy drug. The current prediction accuracy is about 60% to 69%... meaning that approximately 2/3 of the tumors designated as ''sensitive'' to a chemotherapy drug will respond to that drug. BUT the response could be a partial response or stable disease, not necessarily a complete remission. AND it does not indicate how long the response will last. LMS tumors are not homogeneous, like jello, they are heterogeneous like beef stew. They are not made up of identical cancer cells throughout, but have groups of cells with differing mutations. Often in leiomyosarcoma, clones or colonies of cells resistant to the chemotherapy agent occur, and the tumor then becomes composed of these cells during treatment [because the sensitive cells are being killed off], and resistant to the chemotherapy agent. Or the testing might have been done on one metastasis, but when the chemotherapy is carried out, one or more of the other remaining metastases might not be sensitive to this chemo agent. The metastases may have come from different cells in the original tumor, and may have different chemosensitivities. So a short-time clinical usefulness of sensitivity tests has been reported, but whether this will be useful in LMS longterm survival is much less likely because of the development of resistance and the lack of really effective agents to choose from. However, the elimination of some chemotherapy agents because of the likelihood that they will be ineffective, is useful. And if a tumor shows marked chemoresistance to most or all chemotherapy agents, other methods than chemotherapy, like ablative, antiangiogenesis or vaccine or immunological methods would probably be worth exploring. Tumor cell heterogeneity poses significant problems in the clinical use of chemosensitivity assays. Tumors are not homogeneous cells of one cell line. They are heterogeneous [all the cells are not the same]. See the section on "de-differentiation". The question arises as to whether a single biopsy specimen is representative of a patient's disease. In one study, evidence of tumor heterogeneity was sought by comparing chemosensitivity responses between: 1) different portions of a single tumor, 2) a primary and a metastatic biopsy taken from a patient on the same day, and 3) different metastases from a patient taken on the same day. The results demonstrated the presence of considerably different responses to chemotherapy among different tumors from the same patient, and even within the same tumor. The reported discrepancies of in vitro and in vivo sensitivity may be due to such heterogeneity among tumors. Extreme Drug Resistance Testing: But if a drug can't stop tissue culture growth in a test tube, with all the best conditions for it to work... then it is a good bet that the drug will not stop the tumor growth in a live body. The accuracy of prediction of drug ineffectiveness is reportedly 91% to 97%... meaning that over 90% of the drugs that are designated as useless for the tumor, will indeed be useless. Since there is a lifetime limit on the amount of radiation and chemotherapy that one can have*, avoidance of useless chemotherapy agents is worthwhile. The elimination of ineffective drugs is an issue of crucial importance because the side effects of chemotherapy agents are severe. [*The development of life-threatening myelodysplasia syndromes, and subsequent cancers of the blood or bone marrow, is a well known effect of multiple chemotherapy treatments.] Where there are cases of tumors that are very sensitive to chemotherapy agents, the use of chemosensitivity testing can indeed lengthen lifespan, and even predict/contribute to longterm remission. But where effective agents are not available, and only short term partial responses the rule rather than the exception, the major benefit from chemosensitivity testing of the standard chemotherapy agents will be avoidance of the useless ones. With LMS, none of the chemotherapy agents is very effective against the cancer, some or the entire tumor becomes resistant, and then response is variable. So there is no marked increase in survival when chemosensitivity testing is used late in the course of the disease. In vitro chemosensitivity/extreme resistance testing may prevent the administration of ineffective chemotherapy. It might also be useful in investigational work with new drugs, to see whether they might be effective against LMS. Whether it will make a difference in long term survival when used early, in chemotherapy-naive patients, is not known. To optimize the patient's chance of survival and to justify related toxicities, the chemo regimen should be individualized and based on the patient's extreme drug resistance profiles, to avoid treatment with ineffective drugs and their associated toxic side effects. In several cancers, there is noted benefit in using the testing to help decide chemotherapy regimens. The major limitation in the treatment of leiomyosarcoma is the lack of availability of effective agents for treatment. In order to have this testing done, live tumor cells must be obtained through surgery or laparoscopic biopsy. At least one to two grams of fresh biopsy tissue is needed to perform the tests, and placed in a special kit [obtained in advance from the lab.] A gram of tissue is a cube of approximately one cm [3/8 inch] on a side. Needle or core biopsies will not provide enough tissue. Laparoscopic biopsies and initial or follow up surgery is an excellent time to obtain a specimen for testing, even when chemotherapy is not planned, as tumor tissue may not be available later on when the information may be needed. The surgeon and/or the pathologist prepare the specimen and arrange for it to be sent. The tests should never be used as a reason to deny giving chemotherapy. If there is a proven effective therapy that has not yet been tried, it would perhaps be unwise to let assay results determine that this therapy should not be used. However, if a person is not able to undergo aggressive regimens, the tests can help to choose less toxic drugs that might be effective. If resistance occurs to a chemotherapy agent, the tests can help to identify a different agent that MIGHT work. If clinical trials are under consideration, these tests can identify the specific clinical trial in which the odds for success are the greatest. The tests reveal, but cannot alter, an individual tumor's resistance to drugs. Not every patient will respond to an assay-favored drug, and there is no guarantee that a drug will be found that shows activity against the cancer cells of a particular patient. I cannot emphasize enough how the number of toxic treatments is limited because of cumulative bone marrow effects, how the LMS is radio and chemo resistant. You need to get the best chance you can.
Some Chemotherapy Drugs to Test
Most of the chemosensitivity/chemoresistance testing companies have a list of chemotherapy agents that they test sarcomas for. ADD THE FOLLOWING TO THEIR LIST if it is possible. This is not an exhaustive list, but a place to start from. Gemcitabine Navelbine Temozolomide and/or Dacarbazine Gemcitabine & Taxotere Navelbine & Taxotere, Doxorubicin [Adriamycin] Ifosfamide Taxotere Alpha Interferon Vinblastine Etoposide ET-743 Cisplatin An argument can be made for cost/benefit analysis if your insurance company does not routinely pay for it. Omitting the use of a drug that the tumor is highly resistant to offsets the cost of the chemo testing. Even inexpensive drugs require chemo cycles with drugs and other fees and scans to see if they are working.
Some Labs Testing Chemosensitivity
Laboratories That Test for Chemosensitivity or Extreme Drug Resistance READ FIRST written by doctordee Live Tissue Testing Here is a list of laboratories that reportedly test chemo agents on live tissue. They may or may not do other tissue tests. They require one to two grams of tissue in each carrying container. A gram of water is one cubic centimeter. A cube approximately 3/8 " on a side. This cannot be gotten by needle biopsy, not even core needle biopsy. This particular test requires special carrier medium and FedEx Express refrigerated shipping to the laboratory. You must contact the laboratory ahead of time to arrange to receive the shipping material as well as determining the testing you want done. Paraffin Block Tissue Testing Paraffin block tumor is the resected tumor, which was embalmed and then set in a wax block, which can be shaved [microtome slices] to provide microscope slides for tests on dead tissue. The paraffin or wax block of the tumor is the one that is stored at the original laboratory where your tumor went for diagnosis after surgery. Some of this tumor can be easily forwarded to other laboratories or sarcoma pathologists or sarcoma oncologists for tests and further investigation. This list is not exhaustive, and no recommendation is made toward use of any specific laboratory. Check with your health insurance as to which tests they will pay for. Note: Rational Therapeutics will do testing for drug combinations, like gemcitabine + taxotere, as well as single agents. This is a useful addition. Where is it done? compiled by Jack 1. Rational Therapeutics, INC Rational Therapeutics Website Tel: 562-989-6455 Fax: 562-989-8160 750 East 29th St.Long Beach CA 90806 E-mail: Client.Services@RationalTherapeutics.com Dr. Nagourney is the director. He will test combinations of chemotherapy agents and will also test some novel ones like trisenox [arsenic trioxide] 2. Weisenthal Cancer Group 15140 Transistor Lane Huntington Beach CA 92649 Tel 714-894-0011 The group does not have a website for patients to contact about its clinical services, but information about these clinical services is available by phone ( after 9 AM Pacific Time) in the United States. 3. Oncotech , INC Oncotech Website (800) 662-6832 (24Hr) (800) 576-6326 Oncotech, Incorporated 1791 Kaiser Avenue Irvine, California 92614 Contact them for all the details on how to go about sending fresh tissue from a tumor for most of the tests . Some of the tests may be able to be done on pathology paraffin blocks. 4. Impath,INC Impath Website New York, NY 10019 Los Angeles, CA 90066 Phoenix, AZ 85034 Client Services: (800) 447-5816 5. Precision Therapeutics, Inc. Precision Therapeutics Website Email: Info@ptilabs.com Precision Therapeutics, Inc. 2516 Jane Street Pittsburgh, PA 15203 Phone 866.243.6639 Fax 866.243.2424 6. Carl von Hess Hospital Germany Carl Von Hess Hospital Website For questions and information call the number: (0049) 9732-900156 fax-number: (0049) 9732-900159 U.Reith, Secretary Dr.Müller 7. Bath Cancer Research Unit England Bath Cancer Research Unit Website Wolfson Centre, Royal United Hospital, Bath, BA1 3NG, England Department of Postgraduate Medicine, University of Bath Tel: +44 (0) 1225 824 124 Fax: +44 (0) 1225 824 114 Email: bcr@bath.ac.uk 8. Human Tumor Cloning Laboratory Laboratory Director: Mary Guzman e-mail: "mguzman@azcc.arizona.edu" Laboratory Technician: Robert B. Isett e-mail: "bisett@azcc.arizona.edu" Telephone: (520) 626-7871 Arizona Cancer Center 1515 N. Campbell Ave. Rm. 3916 Tucson AZ 85724 9. NuOncology Labs,INC NuOncology Labs Website Medical Laboratory 8032 El Rio Houston, TX 77054 Telephone: 713.747.6003 Toll Free: 888.274.4657 Facsimile:713.747.0799
Tumor Drug Resistance
For testing for tumor drug resistance and resistance reversal, live tumor cells are required. Significant advances over the past 10 to 15 years in chemotherapy of some tumors such as testicular cancer and some leukemias indicates that, in spite of the undesirable side effects, chemotherapy has the potential to effect cure in the majority of patients with certain types of cancer. Multiple drug resistance [MDR], inherent or acquired, is one important limiting factor in extending this success to most solid tumors. By classifying individual tumors according to their specific resistance mechanisms it may be possible to define the multidrug resistance problem properly. And it may be possible to reverse such resistance. Results from clinical trials using cyclosporin A or verapamil are encouraging, but these agents are far from ideal, and reverse resistance in only a subset of resistant tumors. Those tumors can be tested for possibilities of resistance reversal with cyclosporin A or verapamil. Proper definition of the other mechanisms of MDR, and how to antagonize them, is an urgent research priority.
Prognostic Markers
Tests for prognostic markers are usually done on the tumor preserved in the paraffin block. p53 Protein Test done on paraffin block tumor. The prognostic marker p53 protein (Cell cycle and TSP-1 Regulator) can provide insight into tumor behavior. It is well known that mutated p53 binds abnormally, thus leading to dysregulation of the cell cycle. p53 gene is a tumor-suppressor gene that regulates cell cycle progression and cellular proliferation. Accumulation of [mutated and ineffectual] p53 protein in tumor cell nuclei is associated with increased tumor progression and decreased survival in many tumor types [and is often present in LMS]. Overexpression of p53 protein might be an indication for p53 gene replacement therapy. One or both of two tests could be done: One could test for the p53 GENE, or the p53 GENE PRODUCT [which is the same thing as the p53 PROTEIN]. The FISH method, using DNA probes, is probably more reliable, especially in inexperienced hands, than the immunochemistry method. The test for the p53 gene would tell you what percentage of the tested tumor cells had the p53 gene missing. In testing for p53 protein, the results would indicate whether the protein was OVEREXPRESSED or not. Missing or mutated p53 genes, or overexpressed p53 proteins...are poorer prognostic signs, but might be indications for p53 gene replacement therapy. DNA Ploidy and Cell Cycle Analysis Prognostic markers such as DNA Ploidy, and S-phase fraction analysis [cell cycle analysis] correlate significantly with disease recurrence and overall survival. High S-phase fraction and aneuploidy indicate aggressive disease and are associated with shorter survival. DNA ploidy and proliferative index are independent indicators of prognosis. Patients with aneuploid tumors, having high S-phase fractions may have inferior disease-free survival compared with patients whose tumors are diploid and have low S-phase fractions.
Predictive Markers
Testing for predictive markers is usually done on the paraffin block tumor. Information obtained from predictive markers give an indication of how effective clinically indicated chemotherapy agents might be in treating the patient's tumor cells. This is different from sensitivity/resistance testing. MDR-1 (P170 Glycoprotein) Multidrug Resistance For example, MDR-1 (P170 Glycoprotein) acts as an efflux pump to rid the cell of toxins and alien metabolic products. Expression of increased levels of MDR-1 by tumor cells is associated with resistance to natural product chemotherapy agents such as Taxol, Doxorubicin, and Etoposide. Detection of MDR-1 can play a critical role in the selection of a treatment regimen.
Hormonal Markers
Tests done for hormone receptors are usually done on paraffin block tumor. Tests for Estrogen and Progestogen Receptors could be done if the tumor is Uterine or female genital [vulval, vaginal, ovarian] LMS. Androgen Receptors if the tumor is male genital LMS. If the tumor cells have sex hormone receptor sites, giving the sex hormone might very well stimulate tumor growth. Presence of these sites also makes possible the use of Anti-Hormone treatment which might control tumor growth. Anti-Hormone treatment, or "Hormonal Manipulation" is generally less toxic than standard LMS chemotherapy. Even LMS tumors that are NOT uterine can have estrogen or progestogen cell receptors, and might be sensitive to prevention of stimulation by these hormones. Progestogen and estrogen receptor tests are also tests done with 'stains'; they are 'dye' tests. Often tests done on tumors have a 20% cut-off point, so they are read as negative, even if 19% of the cells respond positively. So sometimes even if the test is read as negative you might have benefit from hormone directed therapy. You might ask your friendly pathologist to review the original test slides and see if there is ANY staining? Or if it is possible, have a PCR or probe type test done on the tumor for estrogen and progestogen receptors. See also About Uterine LMS and Hormones.
Ckit {CD117} Testing
Ckit or CD117, should be done if tumor's primary site was abdominal. This test is done on the paraffin block tumor. If the tumor is Ckit positive, it might respond to Gleevec [Glivec, STI-571], the molecular targeted drug. If it is a gastrointestinal tumor, and is CKit positive, you may have been misdiagnosed as LMS, and really have a GIST [gastrointestinal stromal tumor]. In that case, you should contact the Life Raft Group online, the patient advocacy and educational group for people with GIST. GISTs are notoriously resistant to most chemotherapy, but are often very sensitive to Gleevec, and there is another drug, SU 11248, which has also shown good effect in GIST. Some LMS tumors are also positive for ckit. Most of these do not respond to Gleevec, however some have. It is postulated that what is going on in these LMS tumors is that PDGFr, and not CKit, is the marker that indicates Gleevec sensitivity. However, at this time there is no commercial test available for testing tumors for PDGFr. So use of Gleevec in LMS with or without ckit positivity is a hit or miss chance. However, one study showed that 8 out of 9 LMS tumors tested was positive for PDGF. But of the 8 Ckit positive nonGIST LMS patients in the Gleevec clinical trial, none of them responded to Gleevec. this section was updated October 2003 doctordee
Other Targeted Drug Test Markers
Other Drug Test Markers [PDGF, EGFr, VEGF and more] PDGFr Gleevec will have an effect on controlling tumor growth if the tumor reproduction is driven by the tyrosine kinase responsible for the Ckit protein marker on the cell membrane. Gleevec is also reportedly effective in PDGFr [platelet derived growth factor] positive cells. However this test is not available commercially at this time. Palman C, Bowen_Pope DF, Brooks JJ. Platelet derived growth factor receptor (beta subunit) immunoreactivity in soft tissue tumors. Lab Invest 1992 Jan;66(1):108_15 Department of Pathology and Laboratory Medicine, North Shore University Hospital, Manhasset, New York. "Using a well characterized monoclonal antibody (PR7212) to the beta subunit of the platelet derived growth factor receptor (PDGF_R(beta) and the avidin biotin peroxidase method on frozen sections, we analysed PDGF_R(beta) expression .... PDGF_R(beta) reactivity was observed in normal salivary gland, normal cutaneous and visceral fibroblasts, muscularis mucosa of bowel, and endothelial cells; ... Interestingly, hepatocytes and lymph node histiocytes were also positive. Positive tumors included malignant fibrous histiocytoma (6/6), benign and malignant smooth muscle tumors (5/6 leiomyoma, 8/9 leiomyosarcoma), liposarcoma (4/4), synovial sarcoma (6/7), angiosarcoma (2/2), and sarcoma NOS (2/2). Fibromatosis cases were also positive (2/2). In many tumors, the reactive fibroblasts and vascular components were also reactive. The characteristic pattern of reactivity in fibroblastic lesions highlighted thin cytoplasmic extensions or strands not visible in normal hematoxylin and eosin stained sections. Expression of PDGF_R(beta) was not necessarily correlated with the presence of PDGF. We conclude that PDGF_R (beta) expression can be identified in a wide variety of mesenchymal lesions and postulate that its presence may be important in the mechanism of growth of these tumors." Fetch PMID: 1309926 EGF Iressa, Avastin, and similar drugs have targeted EGF molecules in the cells. VEGF VEGF is another marker whose activity is targeted by developing drugs, especially antiangiogenesis drugs like Avastin. Others Development of other drugs whose effectiveness can be predetermined by a cell membrane marker that can be tested for on the paraffin block tumor slide is assured.
International LMS Tissue Bank
An International Leiomyosarcoma Tissue Bank When Willie Sutton, a notorious bank robber, was asked why he robbed banks, he replied, "That's where the money is." If LMS tissue blocks, tissue cultures and frozen tissue are easily available in large numbers to medical researchers, more research will be done on LMS. There will be enough samples of different tumors to validate their research on LMS. If there is an International Leiomyosarcoma Tissue Bank, then all manner of LMS research becomes possible. The International LMS Tissue Bank would store LMS tumor tissue leiomyoma tissue normal uterine smooth muscle tissue normal smooth muscle tissue This is important, because some research is aimed at the differences between normal tissue and the tumors associated with that tissue. The Tissue Bank could provide LMS cell lines-- for research on new chemotherapy agents and regimes by means of chemoresistance testing for research on which enzyme systems drive LMS to grow and reproduce for research on chemical monkey wrenches to throw at those enzyme systems. The Tissue Bank could provide LMS tissue blocks in paraffin wax, for research on markers and gene products, to see if a new targeted molecular drug might have a spin-off for LMS treatment as well. The Tissue Bank could provide flash frozen LMS tissue, for gene expression profiling, and for proteomic studies. Currently, tests done on LMS tissue are done on small numbers, because there is no major collection. LMS tissue is hard to get, it is a rare cancer. If LMS tissue is stored in one bank, there can be hundreds of tumors represented there. Researchers can easily request a batch, or a microarray, and test the LMS tumors for markers or enzymes or whatever their interest is. It would make LMS tissue easily available in large numbers to people doing original research. It makes it more likely that an original researcher would think of LMS and actually see if the current research is applicable to LMS, simply because the tissue IS available. Usually, Tissue Bank rules do not allow results of research tests done on the tissue be given to the donor. The reason for this is that research results are not always clear in their implications, and cannot have the same quality controls that path labs have for routine well established tests. The uncertainties of measurement and meaning allow for considerable confusion and possible liabilities. An International Leiomyosarcoma Data Base Would you like to walk into your oncologist's office after your LMS diagnosis, and have him tell you: "We have done the genetic and proteomic profiling on your LMS tumor, and these are the drugs that will work for you." Flash frozen or fresh tumor tissue can be genetically profiled. This means that all of the many variations of mutations that LMS has, would be tabulated. And each tumor's response to treatment with specific drugs can be correlated with the mutations it has, since the Data Base would have the genetic profiles of many tumors as well as the clinical course and response to drugs. With GIST tumors, we know now that certain mutations mean that Gleevec will work very well on those tumors, but others indicate poorer response. It would be useful to have this information for LMS for drug resistance and sensitivity. [1] An International Leiomyosarcoma Patient Registry For more valid survival statistics. For better Data Base collection. 1. Friedrich, MJ. Genomics and Proteomics May Help Clinicians Individualize Cancer Treatment. JAMA 287:22
Immunohistochemical Tests
Immuno- Immuno-histo-chemical tests use antibodies [that's the immuno part] that will react with a particular cell protein [like Actin, for instance]. These antibodies have been "tagged" in some way, so that they can be recognized...like with dyes that appear dark under the microscope. So a thin slice of the wax block containing the tumor is incubated with the antibody-tagged-with-dye, and after a period of time, the tumor slice is washed off and looked at under the microscope. Where the cell part [like Actin] exists, it will be combined with the antibody carrying the dye. The dye will show up under the microscope. Then the tumor is positive for the presence of that protein. If it doesn't show up, the tumor is negative for the protein. -histo- Tests for Actin, Desmin, and quite a few other cell proteins are what are called immunohistochemical tests. Because many tumors can resemble each other under the microscope, these tests differentiate between LMS, other sarcomas, and other tumors which are not sarcomas but resemble them. These tests tell us that you have LMS and not rhabdomyosarcoma or another type of tumor. They are TUMOR IDENTIFYING tests. This is histology [looking at the identifying features of cells.] That is why the -histo- is part of the name of these test. -chemical And it is chemical histology, because it is the identifying of different tissues by different molecules, rather than cell structure and appearance. Immunohistochemical Immunohistochemical tests will have been done on your primary tumor, to identify its tissue type, e.g. leiomyosarcoma. We are NOT discussing these kinds of tests further here, but rather discuss tests oriented toward giving treatment choices and/or prognosis.
Gene Expression Profiling
It is currently possible to analyze the entire genetic code of the tumor cells. Because there are different mutations in different LMS tumors, it might be possible to genetically profile your LMS tumor and compare it with other tumors. There would be a history attached to those other tumors, of which drugs and treatments worked. This would replace random choice treatment decisions with information on what did work for this particular set of LMS genes on other people in the past. [1] {For example, in GIST patients it is known that response to Gleevec is better with some mutations than with others. Genetic profiling can identify those GIST patients who are cKit positive, but who will not respond well to Gleevec, as well as identifying those who will have a marked therapeutic response.} Gene expression profiles could possibly predict which patients would fail therapy, who would remain disease free and who would relapse. Gene expression profiling may also yield information that would prove useful in identifying targets for new therapeutic agents. Profiling might also indicate which patients were more likely to develop serious late effects from treatment. [1]
Proteomic Studies
Proteomics is the cataloging and analyzing of the many proteins [enzymes] in the body and discovering how they function in tissues. Getting a better understanding of what goes wrong in the protein networks in cancer cells may allow understanding of where therapeutic efforts should be aimed. [2] [e.g. Creating an environment which enhances apoptosis in cancer cells would be a useful addition to chemotherapy.] [Apoptosis is cell suicide of abnormal or badly damaged cells.] One could treat live cancer tissue [either in cell culture or in a person] with a chemotherapy agent, checking the tumor before and after treatment to see the protein profile of the cells. If there were a change in proteins that would favor tumor cell death, one would know that the agent might be effective. If there were no such change, then perhaps one would stop that treatment and try another. The combination of Gene Expression Profiling and Proteomics [analysis of protein interactions within the cell] would make it possible for researchers to literally construct a molecule that would effectively treat a cancer.[2] The NIH is currently involved in research with these technologies. 1. Friedrich, MJ. Genomics and Proteomics May Help Clinicians Individualize Cancer Treatment. JAMA 287:22 2. JAMA. 2001;286:2211-2214
More Information
Searches For more information, or the complete PubMed search, click here: Latest Pubmed Search on chemosensitivity testing and cancer Latest Pubmed Search on chemosensitivity testing and leiomyosarcoma Latest Pubmed Search on hormones and leiomyosarcoma Latest Pubmed Search on hormones and uterine sarcoma Once you have access to PubMed, you can amend or initiate any further search you want, Using a capitalized AND between the search words.
References
Selected Illustrative Medical Journal Abstracts THESE HAVE BEEN EDITED because of copyright, but the complete abstract can be called up by the link. The complete article can be gotten at a medical library, or paid for online, or by writing to the authors for reprints. Int J Gynecol Pathol 1999 Jan;18(1):20-8 Expression of steroid receptors, Ki-67, and p53 in uterine leiomyosarcomas. Zhai YL, Kobayashi Y, Mori A, Orii A, Nikaido T, Konishi I, Fujii S. Department of Obstetrics and Gynecology, Shinshu Univ. School of Medicine,Matsumoto, Japan. "The expression of estrogen receptor (ER), progesterone receptor (PR), tumor suppressor oncogene p53, and Ki-67 was compared in uterine smooth muscle tumors, including leiomyosarcoma (LMS), tumor of uncertain malignant potential (UMP), cellular leiomyoma (CL), bizarre leiomyoma (BL), and usual leiomyoma (UL). ER and PR were expressed in all ULs. PR was expressed in UL irrespective of the phase of the menstrual cycle; this staining was also observed in CL, UMP, and BL, although BL showed variable staining for ER. Compared to these tumors, the expression of both ER and PR was markedly reduced in LMS. The results of ER and PR transcripts by reverse transcription-polymerase chain reaction were compatible with those of immunohistochemistry. The number of Ki-67 positive cells in LMS was significantly higher than in UMP, BL, CL, and UL. p53 immunoreactivity was seen in 10 of 14 LMSs, and missense mutation in the p53 gene was found in 4 of 10 LMSs. These results suggest that abnormal expression of ovarian steroid receptors, p53, and Ki-67 is frequently associated with LMS of the uterus." Fetch PMID: 9891238 Mod Pathol 1999 Nov;12(11):1001-9 Comparative immunohistochemical and molecular analysis of uterine and extrauterine leiomyosarcomas. Rao UN, Finkelstein SD, Jones MW. Department of Pathology, University of Pittsburgh Medical Center, Presbyterian University Hospital, Pennsylvania 15213-2582, USA. "Histologic criteria defining malignancy in smooth muscle tumors are currently site specific. This study was undertaken to determine whether, in leiomyosarcomas (LMS) occurring in different anatomic locations, there were differences in patterns of expression of molecules that have been demonstrated to be associated with biologically aggressive behavior in malignant neoplasms, and also to determine their diagnostic utility. Formalin-fixed paraffin-embedded tissue blocks were selected from 16 extrauterine leiomyosarcomas (EULMS), 14 cases of uterine leiomyosarcomas (ULMS) and from five cases each of uterine and extrauterine leiomyomas (LM). Utilizing immunohistochemical (ABC) techniques with antigen retrieval, we assessed serial sections of each tumor for immunoreactivity with Glut1, CD44s, bcl2, cyclin D1, and estrogen receptor. Molecular genotyping for detecting k-ras-2 point mutation, p53 gene loss, and mdm2 gene amplification was performed on microdissected tumor samples from the same histologic sections. All of the uterine and extrauterine LM were diffusely positive for CD44s, bcl2, and cyclin D1, and uniformly negative for Glut1. In contrast, 50% of the ULMS and 25% of EULMS were Glut l positive. Moreover, Glut1 positivity closely correlated with aggressive biologic behavior reflected by distant metastatic spread. Eighty-percent of LM and 70% of the ULMS were estrogen receptor positive, whereas only one retroperitoneal tumor had focal weak positivity. Over 80% of the extrauterine and 50% of the uterine sarcomas showed absence of CD44s immunoreactivity. Percentage of cyclin D1 immunoreactivity was independent of tumor grade and inversely proportional to the percent of bcl2 positivity. An LMS of the male breast contained k-ras-2 exon 1 point mutation (codon 12 aspartate substitution of glycine). P53 allelic imbalance was present in 29% of ULMS and 57% EULMS. Mdm2 amplification was present in three of six EULMS but not in ULMS. In addition to clinical staging, Glut1 positivity together with patterns of immunoreactivity of CD44 and bcl2 may be helpful in identifying aggressive smooth muscle tumors of the uterus and some EULMS. The presence of estrogen receptor staining may be helpful in identifying uterine versus nonuterine LMS. Although sample numbers are too small for definite conclusions, this study suggests that there are differences in glucose transport, expression of adhesion molecules, and estrogen receptors in ULMS and EULMS, which in part may be due to the estrogen dependency of the ULMS. P53 mutations and mdm2 amplifications appear to be more frequent in EULMS." Publication Types: Clinical trial Randomized controlled trial Fetch PMID: 10574596 Eur J Gynaecol Oncol 1999;20(5-6):379-82 Hormone replacement therapy after uterine leiomyosarcoma treatment. Case reports. Ursic-Vrscaj M. Institute of Oncology, Ljubljana, Slovenia. "Uterine sarcomas are extremely rare uterine malignancies; with a review of the literature we could not find any data dealing with exogenous oestrogens or combined hormone replacement therapy (HRT) after leiomyosarcoma treatment. We report two cases of patients with leiomyosarcoma of the uterine corpus. Both patients were without pelvic irradiation or exogenous oestrogen treatment before the diagnosis. Leiomyoma of the uterus was found during surgery in both cases. Both patients were receiving HRT with non-conjugated oestrogens, after an intensive non-hormonal treatment had failed. No recurrence was established after surgical treatment in the patient with 12 mitoses per 10 high power fields (HPF). The patient is still on HRT (61 months). The other patient with a leiomyosarcoma with very high mitotic activity (40 mitoses per 10 HPF) received cytostatic and irradiation therapy after surgery because of locally widespread disease. Ten months after the diagnosis and 3 months after beginning HRT, recurrence was observed. The patient thereupon stopped HRT. After two additional operations, the patient is alive and without evidence of disease. We presume that the present case reports observations might suggest that HRT did not appear to have a pronounced adverse effect on the leiomyosarcoma outcome in our patients. Nevertheless, until more collected data determine that HRT is safe, caution is needed." Fetch PMID: 10609499 Pathol Res Pract 1996 Mar;192(3):215-23 Immunohistological detection of estrogen and progesterone receptors in multiple and well differentiated leiomyomatous lung tumors in women with uterine leiomyomas (so-called benign metastasizing leiomyomas). A report on 5 cases. Jautzke G, Muller-Ruchholtz E, Thalmann U. Institut fur Pathologie, Universitatsklinikum Rudolf Virchow, Berlin, Germany. "Seventy-four cases of so-called "benign metastasizing uterine leiomyomata" are reported in the literature. In these cases, well differentiated, leiomyomatous lung tumors developed, usually after a period of several years. Histologically, these tumors appear to be benign. We report on five more such cases in which we investigated the contents of estrogen and progesterone receptors in the pulmonary tumors by immunohistological procedures. All the lung tumors exhibited a high content of progesterone receptors, and in 4 out of the 5 cases a high estrogen receptor content was also found. Modern immunohistological techniques permit the investigation of routinely fixed tissue blocks, and it is thus recommended that the contents of these hormone receptors should be determined in well differentiated, leiomyomatous lung tumors from women. This would both provide information on the pathogenesis of these tumors and establish a basis for possible later institution of hormone treatment. It is likely that the majority of these lung tumors are in fact metastases of extremely well differentiated leiomyosarcomas of the uterus. The possibility that lung tumors of this type may constitute a small group that develop in situ as hormone-sensitive proliferations cannot, however, be fully excluded." Fetch PMID: 8739468 Cancer 1996 Feb 15;77(4):717-24 Exogenous sex hormone use, correlates of endogenous hormone levels, and the incidence of histologic types of sarcoma of the uterus. Schwartz SM, Weiss NS, Daling JR, Gammon MD, Liff JM, Watt J, Lynch CF, Newcomb PA, Armstrong BK, Thompson WD. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center,Seattle,Washington, " We analyzed data from a population-based, multi-center, case-control study to determine whether the occurrence of histologic types of uterine sarcoma is related to exogenous hormone use and/or to two correlates of endogenous estrogens: excess weight and cigarette smoking. ... One hundred sixty-seven women with newly-diagnosed uterine sarcoma (56 leiomyosarcoma...) were interviewed by telephone regarding possible risk factors ... For comparison, 208 women identified at random from the general population of the study areas were interviewed as controls. ..Use of oral contraceptives was positively associated with the risk of leiomyosarcoma (odds ratios [OR] = 1.7, 95% confidence interval [CI] = 0.7, 4.1), primarily among women who last used these medications 15 or more years prior to diagnosis. .... Women in the highest quantile of body mass index (> or = 27.5 kg/m2) one year prior to diagnosis were at increased risk of each type of uterine sarcoma (leiomyosarcoma, OR = 2.5, 95% CI = 1.1, 5.7...). Women who had ever smoked cigarettes were at reduced risk of leiomyosarcoma (OR = 0.6, 95% CI = 0.3, 1.1) .. but the relationship was not more pronounced among heavy smokers; .. CONCLUSIONS: Several of these findings parallel those from studies of endometrial carcinoma and may indicate a role for unopposed estrogen in the etiology of histologic types of uterine sarcoma." Fetch PMID: 8616764 Surg Today 1996;26(2):138-41 The effectiveness of medroxyprogesterone in the treatment of multiple metastasizing leiomyosarcomas: report of a case. Uchida T, Nakakawaji K, Sakamoto J, Kojima H, Murakami H, Kato J, Yasue M. Department of Surgery, Aichi Prefectural Hospital, Kakemachi, Okazaki, Japan. "A 51-year-old woman was admitted to our hospital for further investigation of chest X-ray films which showed multiple shadows that had been growing slowly over 2 years. ... The lesions were suspected of being metastasizing leiomyoma due to her past history of uterine leiomyoma. Just 1 week before undergoing scheduled open lung biopsy, the lung lesions increased remarkably in size and number. A thoracotomy was performed and six of the numerous nodules were removed. The resected specimens were pathologically diagnosed as metastasizing leiomyosarcoma that was positive for the progesterone and estrogen receptors. Thus, 1 month postoperatively, a course of medroxyprogesterone (MPA), 600 mg daily, was commenced. The residual lesions in her chest started to diminish, shortly afterward. She has remained well on this MPA regimen for 45 months. The prognosis of patients with metastasizing leiomyosarcoma is poor because of its low sensitivity to chemotherapy; however, some types of leiomyosarcoma are hormone-sensitive. It is therefore important to examine the hormone receptors of excised tumors from patients suspected of having metastasizing leiomyoma or leiomyosarcoma." Fetch PMID: 8919287 Anticancer Res 2000 Jul-Aug;20(4):2389-92 Cumulative results of chemosensitivity tests for antitumor agents in Japan. Japan Research Society for Appropriate Cancer Chemotherapy. Do TK, Kubota T, Ura HT, Yamaue H, Akiyama S, Maehara Y, Tanigawa N, Kitajima M, Takagi H. Tokai Central Hospital, Japan. " The correlation of in vitro and in vivo results revealed 215 true positive (S/S), 246 false positive (S/R), 45 false negative (R/S) and 595 true negative (R/R) cases, resulting in rates of 47% for true positives and 93% for true negatives, with a 74% accuracy. We concluded that chemosensitivity testing is widely applied in this country and has a high accurate predictive value for advanced carcinomas." Fetch PMID: 10953301 Cancer 2000 Jul 15;89(2):288-96 Thymidylate synthase quantitation and in vitro chemosensitivity testing predicts responses and survival of patients with isolated nonresectable liver tumors receiving hepatic arterial infusion chemotherapy. Link KH, Kornmann M, Butzer U, Leder G, Sunelaitis E, Pillasch J, Salonga D, Danenberg KD, Danenberg PV, Beger HG.Department of General Surgery, University of Ulm, Ulm, Germany. [This study was done on 24 patients with unresectable liver tumors receiving hepatic arterial infusion. HTCA chemosensitivity testing and Thymidylate synthase [TS] testing was done on the tumor cells. Seventy-seven percent of the "Sensitive" patients had a complete or partial response. Nine percent of the "Resistant" patients had a response. Median survival time was 32 months for the "Sensitive" as against 17 months for the "Resistant" patients (P=0.003)] [edited. Ed.] "These results suggest that the clinical outcomes of patients receiving HAI therapy may be predictable with TS quantitation and HTCA. It is possible, therefore, that this combination may be used in the future to select patients with liver tumors who will benefit from HAI before the start of regional chemotherapy." Copyright 2000 American Cancer Society. Publication Types: Clinical trial Fetch PMID: 10918158 Anticancer Drugs 2000 Apr;11(4):269-73 Intra-arterial mitoxantrone and paclitaxel in a patient with Stewart-Treves syndrome: selection of chemotherapy by an ex vivo ATP-based chemosensitivity assay. Breidenbach M, Rein D, Schmidt T, Heindel W, Kolhagen H, Mallmann P, Kurbacher CM. Department of Gynecology and Obstetrics, University of Cologne, Germany. Martina.Breidenbach@medizin.uni-koeln.de "Facing the poor track record of both irradiation and chemotherapy in this highly malignant lymphangiosarcoma, ... limb conserving-therapy using three courses of intra-arterial mitoxantrone (MX) and paclitaxel (PTX) was attempted.This novel chemotherapy protocol was selected by pretherapeutic ex vivo ATP-based chemosensitivity testing of autologous tumor tissue. The patient experienced complete response, which was subsequent histologically confirmed by compartment resection. When developing recurrent STS outside of the perfused area 6 months after primary therapy, the patient was retested and reinduced with three other courses of intraarterial MX/PTX which again produced durable complete remission. This case demonstrates the benefit of individualized therapy in this prognostically desperate disease allowing both limb conservation and maintained quality of life." Fetch PMID: 10898542 Gan To Kagaku Ryoho 2000 Mar;27(3):423-7 [Efficacy of docetaxel for recurrent breast cancer: evaluation based on chemosensitivity test and clinical response].[Article in Japanese] Sakurai T, Tanino H, Oura S, Suzuma T, Yamamiti N, Yoshimasu T, Sakurai T, Naito Y. First Dept. of Surgery, Wakayama Medical College. "We investigated the chemosensitivity of anticancer agents against primary (230 patients, 268 tumors) and recurrent breast cancer (40 patients, 51 tumors) using histoculture drug response assays (HDRA) of surgical specimens. ... ... The clinical response ... Of the ten patients with recurrent breast cancer, eight were pretreated with anthracycline, and seven showed a partial response. These results indicate that docetaxel is effective against recurrent breast cancer, even anthracycline-resistant breast cancer. " [And that chemosensitivity/EDR testing can pre-test possible chemotherapy agents for cancer types as well as for individual patients. Ed.] Publication Types: Clinical trial Fetch PMID: 10740636 Swiss Surg 2000;6(3):137-41 [Neoadjuvant therapy in breast carcinoma]. [Article in German] Baumann S, Kochli OR. Abteilung fur Gynakologie und Gynakologische Onkologie, Universitatsfrauenklinik Basel. sbaumann@uhbs.ch .. "The assessment of predictive factors like S-phase, Ki67, ploidy, c-erb-B2, in-vitro-chemosensitivity-testing results and others could help to differentiate patients who will have a benefit from chemotherapy." Review, tutorial Fetch PMID: 10894015 Eur J Cancer 2000 Mar;36(4):489-95 p53-regulated GML gene expression in non-small cell lung cancer. a promising relationship to cisplatin chemosensitivity. Higashiyama M, Miyoshi Y, Kodama K, Yokouchi H, Takami K, Nishijima M, Nakayama T, Kobayashi H, Minamigawa K, Nakamura Y. Department of Thoracic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Nakamichi 1-3-3, Higashirariku, Osaka, Japan. "The GML gene (glycosylphosphatidylinositol-anchored molecule-like protein gene) is a novel gene specifically induced by wild-type p53, which may participate in cell cycle control or the cell apoptotic pathway. Recent experiments suggest that the expression of this novel gene in cancer cells is closely associated with sensitivity to certain anticancer drugs. To elucidate the role of the gene expression in cisplatin (CDDP) chemosensitivity of non-small cell lung cancer (NSCLC), 30 surgically resected materials were examined by reverse transcriptase-polymerase chain reaction (RT-PCR). GML gene expression was detected in 9 (30%) samples. Its incidence was significantly higher in immunohistochemically p53-negative (P=0.040) or wild-type p53 tissues (P=0.041). On in vitro chemosensitivity testing using 29 primary tissues, six samples with GML gene expression showed good sensitivity to CDDP. In particular, in tissues with immunohistochemically p53-negative accumulation, those with GML gene expression showed significantly better in vitro sensitivity to CDDP (P=0.012). Clinically a good response to CDDP-based chemo(thermo)therapy for NSCLC patients with tumour residue or recurrence, was observed only in those with p53-negative accumulation and GML gene expression, in agreement with in vitro results. Thus, although the number of tested samples was small, GML gene expression is commonly detected in immunohistochemically p53-negative NSCLCs in close association with good sensitivity to CDDP. GML gene expression analysis may serve as a predictor of CDDP-based chemotherapy for patients with NSCLC." Fetch PMID: 10717525 Anticancer Res 1999 Nov-Dec;19(6B):5155-8 Chemosensitivity testing of primary tumor cells from gastric cancer patients with liver metastasis can identify effective antitumor drugs. Kurihara N, Kubota T, Furukawa T, Watanabe M, Otani Y, Kumai K, Kitajima M. Department of Surgery, School of Medicine, Keio University, Tokyo, Japan. "The liver metastasis of gastric carcinoma is resistant to conventionally available treatment. .... The resected primary gastric cancer specimen was used for chemosensitivity assay .... The mean survival period was assessed according to the histology of the primary lesion, the grade of liver metastasis and, the presence of peritoneal dissemination. ... Nine patients were treated with drugs that were effective in the chemosensitivity assay, and their responses included two complete responses and two partial responses; these patients showed a significantly prolonged survival period compared with patients treated with drugs that were not effective in the assay. The chemosensitivity assay is useful for evaluating the effectiveness of antitumor agents against liver metastasis of gastric cancer." Clinical trial Fetch PMID: 10697526 J Orthop Res 1999 Nov;17(6):935-40 Multidrug resistance-1 and p-glycoprotein in human chondrosarcoma cell lines: expression correlates with decreased intracellular doxorubicin and in vitro chemoresistance. Wyman JJ, Hornstein AM, Meitner PA, Mak S, Verdier P, Block JA, Pan J, Terek RM. Department of Orthopaedics, Brown University and Rhode Island Hospital, Providence, USA. "We report on two chondrosarcoma cell lines ... Multidrug resistance-1 expression was assayed ... Immunostaining for the multidrug resistance-1 product...was performed ... Chemosensitivity was assayed ... [and]. Cytotoxicity was assessed ... ... Chemosensitivity testing showed that the FS cell line was significantly more resistant to doxorubicin than was the AQ cell line at all doses tested. Our results show that multidrug resistance-1 expression in a human chondrosarcoma cell line results in resistance to doxorubicin in vitro." Fetch PMID: 10632461 Hepatogastroenterology 1999 May;46 Suppl 1:1287-92 Tumor specific CTL therapy for advanced cancer and development for cancer vaccine. Tsunoda T, Tanimura H, Yamaue H, Tanaka H, Matsuda K. Second Department of Surgery, Wakayama Medical School, Japan. tsuntsun@wakayama-med.ac.jp "Advanced gastrointestinal (GI) cancer is a virulent disease with a poor prognosis despite multidisciplinary treatment. The present study was designed to clarify the clinical effects of tumor specific cytotoxic T Lymphocyte (CTL) therapy as multidisciplinary treatment for patients with advanced cancer. ... The ... cancer patients had distant metastases derived from gastric cancer, colon cancer and bilio-pancreatic cancer. The patients had received the chemotherapy according to the results of chemosensitivity test and adoptive immunotherapy by various kinds of the activated killer cells. ..." Publication Types: Clinical trial Fetch PMID: 10429976 Melanoma Res 1999 Apr;9(2):125-32 Treosulfan is an effective alkylating cytostatic for malignant melanoma in vitro and in vivo. Neuber K, tom Dieck A, Blodorn-Schlicht N, Itschert G, Karnbach C. Department of Dermatology, University Hospital Eppendorf, Hamburg, Germany. "The therapy of metastatic malignant melanoma is limited by poor responses and short overall survival. Thus it remains an important issue to identify and test potential new drugs in this disease. This study was performed to examine the effects of the bifunctional alkylating cytostatic treosulfan in vitro. Using an in vitro ... tumour chemosensitivity assay ... five highly chemoresistant melanoma cell lines and melanoma cells freshly isolated from metastases surgically resected from [10 patients'] stage IV melanoma ... were incubated with treosulfan. Three cell lines and eight of the 10 tested tumour cells isolated from melanoma metasteses showed tumour growth inhibition >50% after incubation with treosulfan. Therefore, 14 patients with rapidly progressing stage IV malignant melanoma who had been pretreated with at least one standard chemotherapy regimen received treosulfan. In this population of patients with highly refractory advanced melanoma, one complete remission (7.1%), two partial remissions (14.3%) and three cases of stable disease (21.4%) were observed. ... Therefore, we conclude that treosulfan was well tolerated in this small series of patients and seems to be a promising alkylating cytostatic for the treatment of metastatic melanoma." Publication Types: Clinical trial Fetch PMID: 10380934 Anticancer Res 1998 May-Jun;18(3B):1973-8 Further evidence for the value of the chemosensitivity test in deciding appropriate chemotherapy for advanced gastric cancer. Fujita K, Kubota T, Matsuzaki SW, Otani Y, Watanabe M, Teramoto T, Kumai K, Kitajima M. Department of Surgery, School of Medicine, Keio University, Tokyo, Japan. " The chemosensitivity test using the MTT endpoint is useful in predicting chemosensitivity. ... One hundred twenty-eight patients with advanced gastric cancer were enrolled in the study, [in] which mitomycin C (MMC), doxorubicin (DXR), 5-fluorouracil (5-FU), and cisplatin (DDP) were used. ... The corresponding efficacy rates were 12.5% for MMC, 6.3% for DXR, 5.4% for 5-FU and 13.4% for DDP. The overall predictive accuracy was 78% in the patients with measurable lesions. Among the patients without measurable lesions, 21 were treated with a curative operation, and 33 with a non-curative operation. In those patients undergoing curative surgery, the "adapted" group detected by MTT assay survived longer than "non-adapted" cases (p < 0.05). CONCLUSIONS: The present study provides further evidence that the chemosensitivity test may be useful for evaluating appropriate chemotherapy for advanced gastric cancer." Publication Types: Clinical trial Multicenter study Fetch PMID: 9677452 Clin Cancer Res 1996 Sep;2(9):1469-74 Regional chemotherapy directed by individual chemosensitivity testing in vitro: a prospective decision-aiding trial. Link KH, Kornmann M, Leder GH, Butzer U, Pillasch J, Staib L, Gansauge F, Beger HG. Department of General Surgery, University of Ulm, Steinhovelstrasse 9, 89075 Ulm, Germany. "A prospective decision-aiding trial was performed to select drugs for regional chemotherapy of various liver tumors (n = 36) by individual drug testing. The drugs were chosen for hepatic artery infusion according to the individual chemosensitivity of tumor biopsies in the human tumor colony-forming assay (HTCA). In vitro HTCA sensitivity correlated with complete response (CR) + partial response (PR) + no change (NC) 93% of the time and with CR + PR 55% of the time. The test sensitivity was 90%, and the specificity was 67% for CR + PR + NC versus progressive disease (PD), whereas the sensitivity and specificity were 89% and 28%, respectively, for CR + PR versus NC + PD. The overall predictive accuracy of the test was 86% for CR + PR + NC versus PD and 58% for CR + PR versus NC + PD. Overall, 83% of this heterogenous patient group with various tumors achieved CR + PR + NC and a 50% clinical response (CR + PR). In vitro-sensitive patients showed a significantly lower intrahepatic progression rate (7% PD) than in vitro-resistant patients (57%; P < 0.05). These results indicate that the HTCA could identify active drugs for individualized hepatic artery infusion, and patients may profit from the use of in vitro-sensitive drugs." Publication Types: Clinical trial Fetch PMID: 9816322 Gan To Kagaku Ryoho 1996 Apr;23(5):587-93 [Successful treatment of clear cell adenocarcinoma of the ovary (OCCA) with a combination of CPT-11 and mitomycin C]. [Article in Japanese] Shimizu Y, Umezawa S, Hasumi K. Dept. of Gynecology, Cancer Institute Hospital, Japan. "Among advanced ovarian cancer, OCCA has worse prognosis compared with serous cystadenocarcinoma because of its poor sensitivity to CDDP-based chemotherapy (CTX). Indeed, there has ever been no one patient with pure OCCA showing an appreciable response to CTX. OCCA has recently been increasing in prevalence and has occupied approximately 20-25% of all ovarian cancer. Thus, there is an urgent need to find effective regimens. Based on the results of chemosensitivity tests previously performed both in vitro and in vivo, we designed a combination of ... Six responders showed a significantly longer survival compared with 4 non-responders ...Thus, the present protocol is the first to demonstrate a significant activity for pure OCCA." Publication Types: Clinical trial Fetch PMID: 8678517 Anticancer Res 1994 May-Jun;14(3B):1371-5 In vitro chemosensitivity test of malignant gliomas: clinical relevance of test results independent of adjuvant chemotherapy. Tonn JC, Schachenmayr W, Kraemer HP. Department of Neurosurgery, University of Wurzburg, Germany. "...However, in 33 patients treated with either ACNU or BCNU, a prospective correlative trial clearly demonstrates a predictive value of the CFA [a chemosensitivity/EDR test] in adjuvant chemotherapy of gliomas." Publication Types: Clinical trial Randomized controlled trial Fetch PMID: 8067708 Semin Surg Oncol 1994 Mar-Apr;10(2):140-4 Clinical value of SDI test for predicting effect of postoperative chemotherapy for patients with gastric cancer. Baba H, Takeuchi H, Inutsuka S, Yamamoto M, Endo K, Ohno S, Maehara Y, Sugimachi K. Cancer Center, Faculty of Medicine, Kyushu University, Fukuoka, Japan. "...Survival rates for patients with a positive chemosensitivity to MMC and postoperatively prescribed more than 20 mg of MMC were significantly better than those without sensitivity to MMC, even when treated with MMC, although no statistical differences existed in clinicopathologic factors between the two groups. We conclude that the SDI test for human gastric cancer is a rapid, reliable, and useful assay to determine the compatibility between the results of assay and the clinical effects of corresponding chemotherapy. We propose that the regimen of postoperative adjuvant chemotherapy be tailored according to results of the SDI test, using tissues resected from individual patients." Publication Types: Clinical trial Fetch PMID: 8052784 Cancer 1993 Feb 1;71(3):661-6 Preoperative in vitro chemosensitivity test of esophageal cancer with endoscopic specimens. Kondo K, Okuma T, Yoshioka M, Torigoe Y, Miyauchi Y, Katsuki T. Department of First Surgery, Kumamoto University Medical School, Japan. "... the authors tested in vitro chemosensitivity before surgery with endoscopic biopsy specimens from 23 patients with intrathoracic esophageal cancer. ... The authors tested eight anticancer agents using the dye exclusion method, and all 23 patients received chemotherapy with the most sensitive three drugs according to the results of the chemosensitivity test. .... Ten patients (43.5%) had a tumor reduction of more than 50% on radiologic studies, and 4 patients (17.4%) had a good histologic effect. CONCLUSIONS. The chemosensitivity test is useful in selecting preoperative chemotherapeutic agents for patients with esophageal cancer." Publication Types: Clinical trial Fetch PMID: 8431844 Anticancer Drugs 1991 Apr;2(2):139-43 Dipyridamole combination chemotherapy can be used safely in treating gastric cancer patients. Sakaguchi Y, Maehara Y, Emi Y, Kusumoto T, Kohnoe S, Sugimachi K. Cancer Center of Kyushu University Hospital, Fukuoka, Japan. "The feasibility of a combined chemotherapy using dipyridamole (DP) with adriamycin (ADM) and 5-fluorouracil (5-FU) was investigated. First, the chemosensitivity of gastric cancer tissues was determined by the succinate dehydrogenase inhibition test, which showed sensitivity to ADM and 5-FU is increased by DP. Next, a clinical trial of combined therapy of DP, ADM and 5-FU, as a post-operative adjuvant chemotherapy for gastric cancer patients, was performed. ... DP did not appear to alter the toxicity of ADM and 5-FU, and no severe adverse effect was noted for this combination therapy. .... This combination chemotherapy appears to be safe and may be useful clinically in treating cancer. Fetch PMID: 1958858 Gan To Kagaku Ryoho 1990 Oct;17(10):2025-30 [MTT assay using fresh surgical specimens with reference to the transfer system and reproducibility in "test center" method]. [Article in Japanese] Kubota T, Suto A, Ishibiki K, Abe O, Yamada Y, Asanuma F, Kawamura E, Yamada T, Suzuki Y, Suzuki T. Dept. of Surgery, Keio University. "A chemosensitivity test (MTT assay) was conducted using 59 fresh surgical specimens ... in order to assess the specimen transfer system and the reproducibility of the assay results obtained .... Although the optical density yielded by the tumor cells in a number of 5 x 10(4)/well and the number of evaluable cases were significantly reduced through the transfer, the chemosensitivity pattern of the specimen was identical before and after the transfer. Fifty seven of 59 cases were evaluable and the concordant rate of the assay results between the two institutes was 80.6% (108/134) among each case-drug combination. Since the transfer system of the specimen was established and the reproducibility of the assay results in two institutes was confirmed, the "test center" method of the MTT assay appears to be possible by collecting the surgical specimens from the affiliated hospitals." Publication Types: Clinical trial Multicenter study Fetch PMID: 2221925 Behring Inst Mitt 1984 May;(74):273-84 Use of tritiated nucleotide incorporation for prediction of sensitivity of tumors to cytostatic agents. Volm M. "Development of a means for prediction of sensitivity or resistance of tumors is of paramount importance for future patient specific tumor therapy. A simple, easily performed short-term in vitro test is described whose basic feature is measurement of changes in incorporation of radioactive nucleic acid precursors into tumor cells after addition of cytostatic agents. In order to determine whether acquired resistance is detectable by means of this in vitro short-term test, resistant animal tumor cell lines were developed to different cytostatic agents. This developed resistance was detectable in the in vitro test system. It was observed that the short-term test could demonstrate cross-resistance, and also development and reversibility of resistance to cytostatics. Further, it is possible to assess the role of proliferative activity of tumors. In a clinical study patients with inoperable ovarian and lung carcinomas (n = 49) were treated by chemotherapy and the results of the treatment compared with the results of the in vitro tests. Tumors which show only a weak response in the in vitro test, also failed to respond to chemotherapy in the clinic. In a cooperative study - conducted by nine different hospitals - results of the short-term test in vitro were compared with results of drug therapy in 151 patients. Of these, 76 were judged resistant and 75 sensitive in the in vitro test. Of these 76 resistant tumors, 56 were clinically progressive (73%), 2 (2%) were in remission and 19 (25%) showed no change. Whilst in the 75 sensitive tumors 18 (24%) progressed clinically, 40 (53%) were in clinical remission and 17 (23%) were unchanged. Therefore if only the definite progression or remission evaluations are compared with the in vitro results 55 of the 57 tumors which were resistant in the test were clinically progressive (96%) and 40 of 58 tumors which were sensitive in the test showed clinical remission (69%). There is also good agreement between the in vitro test results and survival time. Patients whose tumors were resistant in the test generally died sooner than those whose tumors were sensitive. In the studies described - as in other investigations - chemoresistance is shown to be more successfully predicted than chemosensitivity." Publication Types: Clinical trial Fetch PMID: 6383325 last updated October 2003

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