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→External and Internal Contradictions and Obvious Errors
[[image:Mortalitysweden.jpg|thumb|400px|Mortality in Sweden between 1964 and 1996]]
[[image:Mortalitysweden.jpg|thumb|400px|Mortality in Sweden between 1964 and 1996]]
[[image:ALLsweden.jpg|ALL in Sweden Acta Oncol 2003;42|300px|thumb]]
[[image:ALLsweden.jpg|ALL in Sweden Acta Oncol 2003;42|300px|thumb]]
[[image:Hodgkinsweden.jpg|Hogkin in Sweden Acta Oncol 2003;42|300px|thumb]]
[[image:Hodgkinsweden.jpg|Hodgkin in Sweden Acta Oncol 2003;42|300px|thumb]]
[[image:Smokecancer.jpg|300px|thumb]]
[[image:Smokecancer.jpg|300px|thumb]]
[[image:Yoshihiro.jpg|300px|thumb]]
[[image:Yoshihiro.jpg|300px|thumb]]
Hamer made many different public statements about his doctrines being in conflict with each other and being in a clear contrast and conflict to the actual knowledge in scientific medicine.
Many of Hamer's different public statements regarding his doctrines are in conflict with each other and in a clear contrast and conflict to the actual knowledge in scientific medicine.
*'''Cancer:''' Hamer states that he was able to cure cancer patients in 98% of all cases but is unable to present a single cured patient. At the same time, it is well known (see his trials, the ''Aribert-Decker-List''<ref>http://www.ariplex.com/ama/ama_ham2.htm</ref> and [[Victims of New Medicine]] / [[Testimonies of former associates of Hamer]]) that many cancer patients following his method died. Some of his statements seem to indicate that the therapeutic principle in new medicine is the so far unknown induction of a ''spontaneous remission'' of cancer after a psychotherapeutical intervention by the patient himself, and assisted by a GNM therapist. The probability of any spontaneous remission is however known to be very low and occurs only in about 1:50,000 to 1:140,000 of all cancer cases. These remissions are not only very rare, but at the same time no cure is known today to induce them. Every spontaneous remission is also subject to possible relapses and patients must wait at least five (or more) years until they know that recovery seems to be definitive. At least two different groups of experts are performing research on spontaneous remissions in Germany (one for instance in Nuremberg). At the same time, Hamer declared many times, and still continues to repeat, that ''scientific medicine'' offered only about a 2% survival chance for a cancer patient.<ref>[...] So aber gibt es nur schlechte Verlierer in der dummen und falschen Schulmedizin. Von der strafrechtlichen Seite wollen wir noch gar nicht einmal sprechen., d.h. von der Frage, wer denn für den seit 18 Jahren geübten, vorsätzlichen wissenschaftlichen Massenmord oder Superholokaust an unseren Patienten verantwortlich ist. Denn beim Deutschen Krebsforschungszentrum Heidelberg kann sich doch jeder erkundigen: Bei der "Standesamtsstatistik" (d.h.: Wer lebt wirklich noch nach Chemo-Pseudotherapie ?) findet man, daß nach 5 Jahren 95% der Patienten tot sind, nach 7 Jahren 98%! Das heißt: Man hat alle Patienten regelrecht um ihr Leben betrogen, indem man die Erkenntnisse der neuen Medizin mit ihrer 95%igen (und mehr) Überlebenschance unterdrückt hat! Das war aber nicht ein paar vertrottelte Medizyn-Onkelchens oder saudumme Medienredakteure, xxxxx Richter oder Politiker, sondern das waren die finsteren Mächte der Logenonkelchen und Onkologenbrüderchen, die dieses schlimmste Verbrechen der Menschheitsgeschichte für den Wahn der Weltherrschaft begehen mußten [...] see: http://www.pilhar.com/Hamer/Korrespo/1999/19990415_Hamer_an_Freund_Gallmeier.htm (rif 107)</ref> Hamer sometimes refers to Ulrich Abel, a German expert who never made any statement like this. In reality, modern medicine (evidenced-based medicine and good clinical practice) today offers a survival rate of about 55% (all cases) in Germany<ref>Robert Koch Institut, Germany</ref>, and in other countries, like the USA or Australia, even over 60%<ref>http://annonc.oxfordjournals.org/cgi/reprint/14/suppl_5/v61.pdf (periodo 1990-94, pag. 58)</ref>. National Cancer Institute (USA) indicates a cancer survival of only 20% in 1920. And cancer incidence started to decrease about ten years ago in Germany.<ref>http://www.aerzteblatt.de/v4/archiv/bild.asp?id=12796 (source: http://www.ekr.med.uni-erlangen.de/GEKID/Doc/kid2006.pdf)</ref>
*'''Cancer:''' Hamer states that he was able to cure cancer patients in 98% of all cases but is unable to present a single cured patient. At the same time, it is well known (see his trials, the ''Aribert-Decker-List''<ref>http://www.ariplex.com/ama/ama_ham2.htm</ref> and [[Victims of New Medicine]] / [[Testimonies of former associates of Hamer]]) that many cancer patients following his method died. Some of his statements seem to indicate that the therapeutic principle in new medicine is the so far unknown induction of a ''spontaneous remission'' of cancer after a psychotherapeutical intervention by the patient himself, and assisted by a GNM therapist. The probability of any spontaneous remission, however, is known to be very low, occuring only in about 1:50,000 to 1:140,000 of all cancer cases. These remissions are not only very rare, but at the same time no cure is known today to induce them. Every spontaneous remission is also subject to possible relapses and patients must wait at least five (or more) years until they know that recovery seems to be definitive. At least two different groups of experts are performing research on spontaneous remissions in Germany (one for instance in Nuremberg). At the same time, Hamer declared many times, and still continues to repeat, that ''scientific medicine'' offered only about a 2% survival chance for a cancer patient.<ref>[...] So aber gibt es nur schlechte Verlierer in der dummen und falschen Schulmedizin. Von der strafrechtlichen Seite wollen wir noch gar nicht einmal sprechen., d.h. von der Frage, wer denn für den seit 18 Jahren geübten, vorsätzlichen wissenschaftlichen Massenmord oder Superholokaust an unseren Patienten verantwortlich ist. Denn beim Deutschen Krebsforschungszentrum Heidelberg kann sich doch jeder erkundigen: Bei der "Standesamtsstatistik" (d.h.: Wer lebt wirklich noch nach Chemo-Pseudotherapie ?) findet man, daß nach 5 Jahren 95% der Patienten tot sind, nach 7 Jahren 98%! Das heißt: Man hat alle Patienten regelrecht um ihr Leben betrogen, indem man die Erkenntnisse der neuen Medizin mit ihrer 95%igen (und mehr) Überlebenschance unterdrückt hat! Das war aber nicht ein paar vertrottelte Medizyn-Onkelchens oder saudumme Medienredakteure, xxxxx Richter oder Politiker, sondern das waren die finsteren Mächte der Logenonkelchen und Onkologenbrüderchen, die dieses schlimmste Verbrechen der Menschheitsgeschichte für den Wahn der Weltherrschaft begehen mußten [...] see: http://www.pilhar.com/Hamer/Korrespo/1999/19990415_Hamer_an_Freund_Gallmeier.htm (rif 107)</ref> Hamer sometimes refers to Ulrich Abel, a German expert who never made any statement like this. In reality, modern medicine (evidenced-based medicine and good clinical practice) today offers a survival rate of about 55% (all cases) in Germany<ref>Robert Koch Institut, Germany</ref>, and in other countries, like the USA or Australia, even over 60%<ref>http://annonc.oxfordjournals.org/cgi/reprint/14/suppl_5/v61.pdf (periodo 1990-94, pag. 58)</ref>. National Cancer Institute (USA) indicates a cancer survival of only 20% in 1920. And cancer incidence started to decrease about ten years ago in Germany.<ref>http://www.aerzteblatt.de/v4/archiv/bild.asp?id=12796 (source: http://www.ekr.med.uni-erlangen.de/GEKID/Doc/kid2006.pdf)</ref>
*Another '''big error:''' Hamer claims that ''1,500 German non-Jewish cancer patients'' were ''killed'' every day by scientific medicine and this can be seen or heard in a video interview dated 2006<ref>http://www.lnc-2010.de/html/neues_deutschland.html</ref> and he continues to assert this claim on different web pages in open letters.<ref>http://www.pilhar.com/Hamer/Korrespo/2007/20070205_Hamer_an_HR3.htm</ref> These data, however, contradict published German cancer statistics of 2002: 420,000 people were newly diagnosed with cancer in that year in Germany, and at the same time 210,000 died because of cancer in 2002. 210000/365=575, Hamer's numbers cannot be correct and 1,500 x 365 = 547,500. This means the number of dead patients would exceed the number of newly diagnozed patients by 120,000. This is of course impossible.
*Another '''big error:''' Hamer claims that ''1,500 German non-Jewish cancer patients'' were ''killed'' every day by scientific medicine and this can be seen or heard in a video interview dated 2006<ref>http://www.lnc-2010.de/html/neues_deutschland.html</ref> and he continues to assert this claim on different web pages in open letters.<ref>http://www.pilhar.com/Hamer/Korrespo/2007/20070205_Hamer_an_HR3.htm</ref> These data, however, contradict published German cancer statistics of 2002: 420,000 people were newly diagnosed with cancer in that year in Germany, and at the same time 210,000 died because of cancer in 2002. 210000/365=575, Hamer's numbers cannot be correct and 1,500 x 365 = 547,500. This means the number of dead patients would exceed the number of newly diagnosed patients by 120,000. This is of course impossible.
*'''Chemotherapy and cancer''': According to the inventor Hamer, chemotherapy in cancer treatment would have a fatal effect on every patient and caused to death of many people in the past. However, chemotherapy is mostly used as a coadjuvant therapy combined with surgery or a radiation therapy. Some (not all) cancers are sensitive to particular drugs used. Cancer of this type are for instance Acute lymphoblastic leukemia in children, Hodgkin-disease or testicular cancer.<ref>Brandt L, A systematic overview of chemotherapy effects in Hodgkin's disease, Acta oncol 2001;40(2-3):185-97, A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This synthesis of the literature on chemotherapy for Hodgkin's disease (HD) is based on 113 scientific reports including four meta-analyses, 44 randomised studies, 18 prospective studies and 40 retrospective studies. These studies involve 69,196 patients. The conclusions reached can be summarised into the following points: Chemotherapy is of utmost importance for the cure of HD. At early stages, extended field radiotherapy cures most patients. For the majority of patients with relapses after radiotherapy, chemotherapy is curative and the total proportion of cured early stage patients is 75-90%. Chemotherapy in addition to extended field radiotherapy reduces recurrences but does not improve long-term survival. In early stage HD with a large mediastinal mass and/or systemic symptoms, combined treatment with chemotherapy and radiotherapy is recommended. It is likely that chemotherapy will in future play a greater role in the treatment of early stage patients, too, in order to reduce later consequences from extended field radiotherapy. However, this conclusion remains to be better documented in literature. At advanced stages, chemotherapy or a combination of chemotherapy and limited field radiotherapy are effective treatment options and, using the regimens available 10-20 years ago, 40-50% of the patients are cured. Based upon more favourable short-term (three to eight years) results of more recently developed regimens, it can be expected that today a higher proportion of the patients will become long-term survivors. Several chemotherapy regimens containing four to eight drugs are effective in HD. The best regimen considering both antitumour activity and acute and later side-effects is not known. The choice of regimen is probably best done after considering various pre-treatment factors such as the number of poor prognostic signs, concomitant diseases, and individual preferences. The results of chemotherapy are more favourable in young than in elderly patients. The development of less toxic but still effective treatment programmes is therefore particularly important for the elderly. High dose chemotherapy with stem cell support is presently often used in patients who are chemotherapy induction failures, who relapse after a short initial remission or after a longer initial remission and treated initially with seven or eight drugs, or who have had multiple relapses. However, this use is based on data from uncontrolled or small controlled studies, not being fully convincing with respect to effect on survival. Persistent side-effects of treatment are common among long-term survivors, although most patients apparently have a normal life. The relative contributions of chemotherapy and radiotherapy to the persistent effects are not well documented.</ref>. Overall (additional = contribution for chemotherapy for cancer survival is estimated to be between 5-10%.
*'''Chemotherapy and cancer''': According to Hamer, chemotherapy in cancer treatment would have a fatal effect on every patient and caused the death of many people in the past. However, chemotherapy is mostly used as a coadjuvant therapy combined with surgery or a radiation therapy. Some (not all) cancers are sensitive to particular drugs used. Cancer of this type for instance is Acute Lymphoblastic Leukemia in children, Hodgkin-disease or testicular cancer.<ref>Brandt L, A systematic overview of chemotherapy effects in Hodgkin's disease, Acta oncol 2001;40(2-3):185-97, A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This synthesis of the literature on chemotherapy for Hodgkin's disease (HD) is based on 113 scientific reports including four meta-analyses, 44 randomised studies, 18 prospective studies and 40 retrospective studies. These studies involve 69,196 patients. The conclusions reached can be summarised into the following points: Chemotherapy is of utmost importance for the cure of HD. At early stages, extended field radiotherapy cures most patients. For the majority of patients with relapses after radiotherapy, chemotherapy is curative and the total proportion of cured early stage patients is 75-90%. Chemotherapy in addition to extended field radiotherapy reduces recurrences but does not improve long-term survival. In early stage HD with a large mediastinal mass and/or systemic symptoms, combined treatment with chemotherapy and radiotherapy is recommended. It is likely that chemotherapy will in future play a greater role in the treatment of early stage patients, too, in order to reduce later consequences from extended field radiotherapy. However, this conclusion remains to be better documented in literature. At advanced stages, chemotherapy or a combination of chemotherapy and limited field radiotherapy are effective treatment options and, using the regimens available 10-20 years ago, 40-50% of the patients are cured. Based upon more favourable short-term (three to eight years) results of more recently developed regimens, it can be expected that today a higher proportion of the patients will become long-term survivors. Several chemotherapy regimens containing four to eight drugs are effective in HD. The best regimen considering both antitumour activity and acute and later side-effects is not known. The choice of regimen is probably best done after considering various pre-treatment factors such as the number of poor prognostic signs, concomitant diseases, and individual preferences. The results of chemotherapy are more favourable in young than in elderly patients. The development of less toxic but still effective treatment programmes is therefore particularly important for the elderly. High dose chemotherapy with stem cell support is presently often used in patients who are chemotherapy induction failures, who relapse after a short initial remission or after a longer initial remission and treated initially with seven or eight drugs, or who have had multiple relapses. However, this use is based on data from uncontrolled or small controlled studies, not being fully convincing with respect to effect on survival. Persistent side-effects of treatment are common among long-term survivors, although most patients apparently have a normal life. The relative contributions of chemotherapy and radiotherapy to the persistent effects are not well documented.</ref>. Overall (additional = contribution for chemotherapy for cancer survival is estimated at between 5-10%.
*'''Tumors in transplanted organs:''' Tumors may also come up in transplanted organs, they were already present in these organs before transplantation (too small to be detected), but it is also known that a tumor can build up after transplantation. After a transplantation, no nerve links this organ to the brain, and therefore the GNM theory of cancer origin fails.<ref>Schwarz A, Renal cell carcinoma in transplant recipients with acquired cystic kidney disease, Clin J Am Soc Nephrol. 2007 Jul;2(4):750-6. Epub 2007 Apr 25 [...] CONCLUSIONS: Renal cell carcinoma occurs often after renal transplantation [...]</ref><ref>Aguilera Tubet C, Multifocal renal cell carcinoma on renal allograft, Actas Urol Esp. 2007 May;31(5):553-5 [...] We report a case of multifocal renal cell carcinoma diagnosed in a kidney grafted 17 years before [...]</ref><ref>Besarani D Urological malignancy after renal transplantation, BJU Int. 2007 Sep;100(3):502-5</ref><ref>Roithmaier S, Incidence of malignancies in heart and/or lung transplant recipients: a single-institution experience, J Heart Lung Transplant. 2007 Aug;26(8):845-9</ref><ref>Ondrus D The incidence of tumours in renal transplant recipients with long-term immunosuppressive therapy, Int Urol Nephrol. 1999;31(4):417-22</ref><ref>Birkeland SA Risk for tumor and other disease transmission by transplantation: a population-based study of unrecognized malignancies and other diseases in organ donors, Transplantation. 2002 Nov 27;74(10):1409-13</ref><ref>Buell JF Donor transmitted malignancies, Ann Transplant. 2004;9(1):53-6</ref>
*'''Tumors in transplanted organs:''' Tumors may also come up in transplanted organs, they were already present in these organs before transplantation (too small to be detected), but it is also known that a tumor can build up after transplantation. After a transplantation, no nerve links this organ to the brain, and therefore the GNM theory of cancer origin fails.<ref>Schwarz A, Renal cell carcinoma in transplant recipients with acquired cystic kidney disease, Clin J Am Soc Nephrol. 2007 Jul;2(4):750-6. Epub 2007 Apr 25 [...] CONCLUSIONS: Renal cell carcinoma occurs often after renal transplantation [...]</ref><ref>Aguilera Tubet C, Multifocal renal cell carcinoma on renal allograft, Actas Urol Esp. 2007 May;31(5):553-5 [...] We report a case of multifocal renal cell carcinoma diagnosed in a kidney grafted 17 years before [...]</ref><ref>Besarani D Urological malignancy after renal transplantation, BJU Int. 2007 Sep;100(3):502-5</ref><ref>Roithmaier S, Incidence of malignancies in heart and/or lung transplant recipients: a single-institution experience, J Heart Lung Transplant. 2007 Aug;26(8):845-9</ref><ref>Ondrus D The incidence of tumours in renal transplant recipients with long-term immunosuppressive therapy, Int Urol Nephrol. 1999;31(4):417-22</ref><ref>Birkeland SA Risk for tumor and other disease transmission by transplantation: a population-based study of unrecognized malignancies and other diseases in organ donors, Transplantation. 2002 Nov 27;74(10):1409-13</ref><ref>Buell JF Donor transmitted malignancies, Ann Transplant. 2004;9(1):53-6</ref>
*'''Inherited cancer:''' In some cancer types it is known for sure that these are inherited and therefore transmitted genetically. One example is familial adenomatous polyposis<ref>http://en.wikipedia.org/wiki/Familial_adenomatous_polyposis</ref> or Xeroderma pigmentosum<ref>http://en.wikipedia.org/wiki/Xeroderma_pigmentosum</ref>. Other cases are Louis-Bar syndrome, Gardner syndrome, Turcot syndrome and familiar form of retinoblastoma. In these cases a ''biological conflict'' as an origin can be excluded.
*'''Inherited cancer:''' In some cancer types it is known for sure that these are inherited and therefore transmitted genetically. One example is familial adenomatous polyposis<ref>http://en.wikipedia.org/wiki/Familial_adenomatous_polyposis</ref> or Xeroderma pigmentosum<ref>http://en.wikipedia.org/wiki/Xeroderma_pigmentosum</ref>. Other cases are Louis-Bar syndrome, Gardner syndrome, Turcot syndrome and familiar form of retinoblastoma. In these cases a ''biological conflict'' as an origin can be excluded.
*'''Cancer caused by virus:''' About 15% of all cancer are caused by viruses (oncovirus), the presence of a viral infection increases incidence. This is the case in high-risk HPV, Burkitt lymphoma and HIV.
*'''Cancer caused by virus:''' About 15% of all cancer are caused by viruses (oncovirus), the presence of a viral infection increases incidence. This is the case in high-risk HPV, Burkitt lymphoma and HIV.
*'''No chemical carcinogens in new medicine:''' The Hamer doctrine allows no chemical carcinogens to exist, they have simply no effect on tumor formation and smoking does not cause cancer, for instance. Cancer may occur because people were ''in panic'' after hearing that carcinogenes like asbestos were harmful.
*'''No chemical carcinogens in new medicine:''' The Hamer doctrine allows no chemical carcinogens to exist, they have simply no effect on tumour formation and smoking does not cause cancer, for instance. Cancer may occur because people were ''in panic'' after hearing that carcinogens like asbestos were harmful.
*'''No metastasis in GNM:''' According to the same doctrine metastases does not exist and allegedly was never proved by scientific medicine. Tumors appearing after a first tumor were due to the panic of the patient who, suffering, was producing new tumors. Also, isolate tumor cells would not be detectable in blood, especially not in arterial blood.<ref>http://www.neue-medizin.de/html/3__naturgesetz.html</ref> Many scientific articles tell us the opposite. Since 1869 (more than 130 years ago), it is known that tumors emit single cancer cells or groups of them into the blood, and every day a tumor may emit millions of cells even if only a minority may survive (perhaps 0,01%) and be the source of a distant metastasis<ref>Wong LS, Detection of circulating tumour cells and nodal metastasis by reverse transcriptase-polymerase chain reaction technique, Br J surg 2005 Vol 84 (6) 834, In the search for occult metastases in lymph nodes or circulating tumour cells, a reverse transcriptase-polymerase chain reaction (RT-PCR) assay was developed to detect tumour-specific splice variants of the transcript of the CD44 gene. The assay was highly sensitive and could detect ten tumour cell per 10(5) leucocytes. METHODS: RNA was purified from peripheral blood (n = 24) and regional lymph nodes (n = 14) from patients with colorectal cancer. Complementary DNA was made and amplified using primers specific for the CD44 gene. Southern blotting with exon-specific probes was used to enhance the sensitivity. RESULTS: Tumour cells were detected in peripheral blood samples in four patients and lymph nodes in nine, in one of whom conventional histology had not detected tumour cells. CONCLUSION: This technique may be useful in the early diagnosis of primary or metastatic tumours, in assessing prognosis and in detecting residual disease after treatment.</ref><ref>Sadahiro S, Detection of Carcinoembryonic Antigen Messenger RNA-Expressing Cells in Peripheral Blood 7 Days After Curative Surgery is a Novel Prognostic Factor in Colorectal Cancer, Ann Surg Oncol 2007 jan 3, BACKGROUND: The significance of detection of circulating cancer cells in blood during surgery in patients with colorectal cancer (CRC) remains controversial. Experimental study revealed that the cancer cells injected from the vein disappeared completely until 7 days. The aim of this study was to clarify that the detection of circulating cancer cells in blood taken later than 7 days after curative surgery may be a prognostic factor. METHODS: Two hundred consecutive patients with CRC who underwent potentially curative surgery were the subjects. Peripheral blood was collected between 7 and 10 days after resection. Cancer cells were detected using reverse transcriptase-polymerase chain reaction targeting carcinoembryonic antigen (CEA) messenger RNA (mRNA). The median follow-up period was 52 months (range: 34-69 months). RESULTS: The overall positive incidence of CEA mRNA was 22%. Detection of CEA mRNA was not significantly related to conventional clinicopathological findings. Recurrence has been confirmed in 55 patients (28%). The recurrence rate was significantly higher in patients with rectal cancer, deep penetration, lymph node metastasis, preoperative chemoradiotherapy and positive CEA mRNA. The CEA mRNA positive patients showed significantly poorer disease free survival (DFS) and overall survival (OS) than the negative patients (DFS, P=0.007; OS, P=0.04). Multivariate analysis revealed that the positive expression of CEA mRNA (P < 0.01) as well as the tumor location and TNM stage classification was identified as the significant risk factors for recurrence. CONCLUSIONS: Detection of CEA mRNA expressing cells in peripheral blood 7 days after curative surgery is a novel independent factor predicting recurrence in patients with CRC.</ref><ref>Castells A, Detection of colonic cells in peripheral blood of colorectal cancer patients by means of reverse transcriptase and polymerase chain reaction, Br J Cancer, 1998 78(10) 1368, Circulating tumour cells play a central role in the metastatic process, but little is known about the relationship between this cellular subpopulation and the development of secondary disease. This study was aimed at assessing the presence of colonic cells in peripheral blood of patients with colorectal cancer in different evolutionary stages, by means of reverse transcriptase polymerase chain reaction (RT-PCR) targeted to carcinoembryonic antigen (CEA) mRNA. In vitro sensitivity was established in a recovery experiment by preparing serial colorectal cancer cell dilutions. Thereafter, 95 colorectal cancer patients and a control group including healthy subjects (n = 11), patients with other gastrointestinal neoplasms (n = 11) or inflammatory bowel disease (n = 9) were analysed. Specific cDNA primers for CEA transcripts were used to apply RT-PCR to peripheral blood samples. Tumour cells were detected down to five cells per 10 ml blood, thus indicating a sensitivity limit of approximately one tumour cell per 10(7) white blood cells. CEA mRNA expression was detected in 39 out of 95 colorectal cancer patients (41.1%), there being a significant correlation with the presence of distant metastases at inclusion. None of the healthy volunteers and only 1 of 11 patients (9.1%) with other gastrointestinal neoplasms had detectable CEA mRNA in peripheral blood. By contrast, CEA mRNA was detected in five of the nine patients (55.6%) with inflammatory bowel disease. These results confirm that it is feasible to amplify CEA mRNA in the peripheral blood, its presence being almost certainly derived from circulating malignant cells in colorectal cancer patients. However, CEA mRNA detectable in blood of patients with inflammatory bowel disease suggests the presence of circulating non-neoplastic colonic epithelial cells.</ref><ref>Nakamori S, Genetic detection of colorectal cancer cells in circulation and lymph nodes, Dis Colon Rectum 1997 40(10 sup) S29-36, PURPOSE: This study was undertaken to investigate the clinical implications of detection of genetic alterations in blood and lymph nodes in colorectal cancer patients. METHODS: The reverse transcriptase polymerase chain reaction product of the cytokeratin gene in blood was examined as a cancer cell-specific expression in 35 colorectal cancer patients. The K-ras or p53 gene mutations in the lymph nodes histopathologically negative for metastasis were studied by the mutant-allele-specific amplification method in 26 colorectal cancer patients. RESULTS: The reverse transcriptase polymerase chain reaction assay was able to detect a cytokeratin reverse transcriptase polymerase chain reaction product at a concentration from a single to ten colon cancer cells per 10(6) normal peripheral blood mononuclear cells. Cytokeratin reverse transcriptase polymerase chain reaction products were detected in nine patients' blood samples, although none of the samples were cytologically detectable. The blood's cytokeratin positivity correlated with the invasive mode of the tumor (P < 0.05) and the presence of distant metastasis (P < 0.01). Two (50 percent) of four patients whose blood was positive for cytokeratin had recurrences. Of 17 patients with the K-ras or p53 gene mutation in primary tumors, 9 (53 percent) had the corresponding mutations in lymph nodes. Mutation positivity in lymph nodes correlated with the presence of lymphatic invasion of the primary tumor (P < 0.05). All patients with mutation-negative lymph nodes remained disease-free for more than two years after surgery. CONCLUSION: Detection of cytokeratin reverse transcriptase polymerase chain reaction products in the blood and K-ras or p53 gene mutations in the lymph nodes histologically negative for metastasis may be applicable for clinical use, despite some limitations, and may serve as a useful clinical factor for stratifying patients who are at high or low risk for recurrence after surgery.</ref><ref>Iinuma H, Detection of tumor cells in blood using CD45 magnetic cell separation followed by nested mutant allele-specific amplification of p53 and K-ras genes in patients with colorectal cancer, Int J Cancer 2000 89(4) 337,
*'''No metastasis in GNM:''' According to the same doctrine metastases do not exist and allegedly were never proved by scientific medicine. Tumours appearing after a first tumour were due to the panic of the patient who, suffering, was producing new tumours. Also, isolate tumor cells would not be detectable in blood, especially not in arterial blood.<ref>http://www.neue-medizin.de/html/3__naturgesetz.html</ref> Many scientific articles tell us the opposite. Since 1869 (more than 130 years ago), it is known that tumors emit single cancer cells or groups of them into the blood, and every day a tumor may emit millions of cells even if only a minority may survive (perhaps 0,01%) and be the source of a distant metastasis<ref>Wong LS, Detection of circulating tumour cells and nodal metastasis by reverse transcriptase-polymerase chain reaction technique, Br J surg 2005 Vol 84 (6) 834, In the search for occult metastases in lymph nodes or circulating tumour cells, a reverse transcriptase-polymerase chain reaction (RT-PCR) assay was developed to detect tumour-specific splice variants of the transcript of the CD44 gene. The assay was highly sensitive and could detect ten tumour cell per 10(5) leucocytes. METHODS: RNA was purified from peripheral blood (n = 24) and regional lymph nodes (n = 14) from patients with colorectal cancer. Complementary DNA was made and amplified using primers specific for the CD44 gene. Southern blotting with exon-specific probes was used to enhance the sensitivity. RESULTS: Tumour cells were detected in peripheral blood samples in four patients and lymph nodes in nine, in one of whom conventional histology had not detected tumour cells. CONCLUSION: This technique may be useful in the early diagnosis of primary or metastatic tumours, in assessing prognosis and in detecting residual disease after treatment.</ref><ref>Sadahiro S, Detection of Carcinoembryonic Antigen Messenger RNA-Expressing Cells in Peripheral Blood 7 Days After Curative Surgery is a Novel Prognostic Factor in Colorectal Cancer, Ann Surg Oncol 2007 jan 3, BACKGROUND: The significance of detection of circulating cancer cells in blood during surgery in patients with colorectal cancer (CRC) remains controversial. Experimental study revealed that the cancer cells injected from the vein disappeared completely until 7 days. The aim of this study was to clarify that the detection of circulating cancer cells in blood taken later than 7 days after curative surgery may be a prognostic factor. METHODS: Two hundred consecutive patients with CRC who underwent potentially curative surgery were the subjects. Peripheral blood was collected between 7 and 10 days after resection. Cancer cells were detected using reverse transcriptase-polymerase chain reaction targeting carcinoembryonic antigen (CEA) messenger RNA (mRNA). The median follow-up period was 52 months (range: 34-69 months). RESULTS: The overall positive incidence of CEA mRNA was 22%. Detection of CEA mRNA was not significantly related to conventional clinicopathological findings. Recurrence has been confirmed in 55 patients (28%). The recurrence rate was significantly higher in patients with rectal cancer, deep penetration, lymph node metastasis, preoperative chemoradiotherapy and positive CEA mRNA. The CEA mRNA positive patients showed significantly poorer disease free survival (DFS) and overall survival (OS) than the negative patients (DFS, P=0.007; OS, P=0.04). Multivariate analysis revealed that the positive expression of CEA mRNA (P < 0.01) as well as the tumor location and TNM stage classification was identified as the significant risk factors for recurrence. CONCLUSIONS: Detection of CEA mRNA expressing cells in peripheral blood 7 days after curative surgery is a novel independent factor predicting recurrence in patients with CRC.</ref><ref>Castells A, Detection of colonic cells in peripheral blood of colorectal cancer patients by means of reverse transcriptase and polymerase chain reaction, Br J Cancer, 1998 78(10) 1368, Circulating tumour cells play a central role in the metastatic process, but little is known about the relationship between this cellular subpopulation and the development of secondary disease. This study was aimed at assessing the presence of colonic cells in peripheral blood of patients with colorectal cancer in different evolutionary stages, by means of reverse transcriptase polymerase chain reaction (RT-PCR) targeted to carcinoembryonic antigen (CEA) mRNA. In vitro sensitivity was established in a recovery experiment by preparing serial colorectal cancer cell dilutions. Thereafter, 95 colorectal cancer patients and a control group including healthy subjects (n = 11), patients with other gastrointestinal neoplasms (n = 11) or inflammatory bowel disease (n = 9) were analysed. Specific cDNA primers for CEA transcripts were used to apply RT-PCR to peripheral blood samples. Tumour cells were detected down to five cells per 10 ml blood, thus indicating a sensitivity limit of approximately one tumour cell per 10(7) white blood cells. CEA mRNA expression was detected in 39 out of 95 colorectal cancer patients (41.1%), there being a significant correlation with the presence of distant metastases at inclusion. None of the healthy volunteers and only 1 of 11 patients (9.1%) with other gastrointestinal neoplasms had detectable CEA mRNA in peripheral blood. By contrast, CEA mRNA was detected in five of the nine patients (55.6%) with inflammatory bowel disease. These results confirm that it is feasible to amplify CEA mRNA in the peripheral blood, its presence being almost certainly derived from circulating malignant cells in colorectal cancer patients. However, CEA mRNA detectable in blood of patients with inflammatory bowel disease suggests the presence of circulating non-neoplastic colonic epithelial cells.</ref><ref>Nakamori S, Genetic detection of colorectal cancer cells in circulation and lymph nodes, Dis Colon Rectum 1997 40(10 sup) S29-36, PURPOSE: This study was undertaken to investigate the clinical implications of detection of genetic alterations in blood and lymph nodes in colorectal cancer patients. METHODS: The reverse transcriptase polymerase chain reaction product of the cytokeratin gene in blood was examined as a cancer cell-specific expression in 35 colorectal cancer patients. The K-ras or p53 gene mutations in the lymph nodes histopathologically negative for metastasis were studied by the mutant-allele-specific amplification method in 26 colorectal cancer patients. RESULTS: The reverse transcriptase polymerase chain reaction assay was able to detect a cytokeratin reverse transcriptase polymerase chain reaction product at a concentration from a single to ten colon cancer cells per 10(6) normal peripheral blood mononuclear cells. Cytokeratin reverse transcriptase polymerase chain reaction products were detected in nine patients' blood samples, although none of the samples were cytologically detectable. The blood's cytokeratin positivity correlated with the invasive mode of the tumor (P < 0.05) and the presence of distant metastasis (P < 0.01). Two (50 percent) of four patients whose blood was positive for cytokeratin had recurrences. Of 17 patients with the K-ras or p53 gene mutation in primary tumors, 9 (53 percent) had the corresponding mutations in lymph nodes. Mutation positivity in lymph nodes correlated with the presence of lymphatic invasion of the primary tumor (P < 0.05). All patients with mutation-negative lymph nodes remained disease-free for more than two years after surgery. CONCLUSION: Detection of cytokeratin reverse transcriptase polymerase chain reaction products in the blood and K-ras or p53 gene mutations in the lymph nodes histologically negative for metastasis may be applicable for clinical use, despite some limitations, and may serve as a useful clinical factor for stratifying patients who are at high or low risk for recurrence after surgery.</ref><ref>Iinuma H, Detection of tumor cells in blood using CD45 magnetic cell separation followed by nested mutant allele-specific amplification of p53 and K-ras genes in patients with colorectal cancer, Int J Cancer 2000 89(4) 337,
A new method for detecting circulating tumor cells that is based on magnetic-activated cell separation (MACS) and nested mutant allele-specific amplification (nested MASA) was evaluated in patients with colorectal cancer using the p53 and K-ras genes as genetic markers. By negative selection with anti-CD45 monoclonal antibody-conjugated supermagnetic microbeads, the proportion of tumor cells was enriched 9-fold. By the combination of MACS and nested MASA, 10 tumor cells in 10(7) normal peripheral blood mononuclear cells could be detected without false-positives. Using this method, we examined blood taken from the tumor drainage veins of 23 patients with colorectal cancer. Eighty-seven percent (20/23) of primary tumor tissues showed p53 and/or K-ras gene mutations. Forty-five percent (9/20) of patients with p53 and/or K-ras mutations in the primary tumor showed the same mutated genes in the blood samples. There was a significant association between the presence of p53 and K-ras gene mutation in the blood and tumor size, depth of invasion, and venous invasion. Blood gene mutation was detected in 80% (4/5) of samples from patients with synchronous liver metastases. Sixty percent (3/5) of patients with mutant genes in the blood developed asynchronous liver metastases after surgery. The overall survival of patients with p53 and/or K-ras gene mutation-positive findings in blood was significantly shorter than that of patients testing negative on Kaplan-Meier analysis. Our results suggest that the method may be useful for reliable detection of tumor cells circulating in the blood and may help to identify patients at high risk for relapse. Copyright 2000 Wiley-Liss, Inc.</ref><ref>Wang JY, Molecular detection of APC, K- ras, and p53 mutations in the serum of colorectal cancer patients as circulating biomarkers, World J Surg 2004 28(7) 721, Early detection of tumor DNA in serum/plasma prior to the development of recurrence or metastases could help improve the outcome of patients with colorectal cancer (CRC) after tumor resection. Recent advances in the detection of tumor DNA in the serum/plasma has opened up numerous new areas for investigation and new possibilities for molecular diagnosis. APC and K- ras mutations are considered to be early-stage developments of CRCs, whereas p53 mutations are thought to be relatively late events in the tumorigenesis of CRCs. The aim of this study was to search for the presence of genetic mutations in the DNA extracted from the serum of CRC patients and healthy subjects. We simultaneously evaluate the significance of APC, K- ras, and p53 gene mutations in cancer tissues and their paired serum samples of 104 CRC patients by polymerase chain reaction-single strand conformation polymorphism analysis (PCR-SSCP) followed by direct sequencing. Additionally, analysis was carried out to detect the serum carcinoembryonic antigen (CEA) levels in CRC patients. Overall, we found at least one of the gene mutations in tumor tissues from 75% (78/104) of the CRC patients. Comparison of the three molecular markers showed that the detection rates in the serum were 30.4%, 34.0%, and 34.2% for APC, K- ras, and p53 genes, respectively. Of these patients, 46.2% (36/78) were identified as having positive serum results, whereas all healthy controls remained negative. The overall positive tumor DNA detection rates in the serum were 0% (0/7) for Dukes' A classification, 22.4% (11/49) for Dukes' B, 48.7% (19/39) for Dukes' C, and 66.7% (6/9) for Dukes' D. The detection rate increased as the tumor stage progressed ( p = 0.012). Concurrently, a significant difference was observed between lymph node metastases and positive serum tumor DNA detection ( p < 0.001). A significantly higher postoperative metastasis/recurrence rate in patients harboring gene mutations with serum tumor DNA than those without serum tumor DNA was also demonstrated ( p < 0.001). However, no significant correlation between the postoperative metastasis/recurrence and serum CEA levels was observed ( p = 0.247). These data suggest that the identification of circulating tumor DNA using the molecular detection of APC, K- ras, and p53 gene mutations is a potential tool for early detection of postoperative recurrence/metastases. Moreover, these genes may be potential molecular markers of poor clinical outcome in CRC patients.</ref><ref>Wang JY, Molecular detection of circulating tumor cells in the peripheral blood of patients with colorectal cancer using RT-PCR: significance of the prediction of postoperative metastasis, World J Surg 2006 june 30(6) 1007,
A new method for detecting circulating tumor cells that is based on magnetic-activated cell separation (MACS) and nested mutant allele-specific amplification (nested MASA) was evaluated in patients with colorectal cancer using the p53 and K-ras genes as genetic markers. By negative selection with anti-CD45 monoclonal antibody-conjugated supermagnetic microbeads, the proportion of tumor cells was enriched 9-fold. By the combination of MACS and nested MASA, 10 tumor cells in 10(7) normal peripheral blood mononuclear cells could be detected without false-positives. Using this method, we examined blood taken from the tumor drainage veins of 23 patients with colorectal cancer. Eighty-seven percent (20/23) of primary tumor tissues showed p53 and/or K-ras gene mutations. Forty-five percent (9/20) of patients with p53 and/or K-ras mutations in the primary tumor showed the same mutated genes in the blood samples. There was a significant association between the presence of p53 and K-ras gene mutation in the blood and tumor size, depth of invasion, and venous invasion. Blood gene mutation was detected in 80% (4/5) of samples from patients with synchronous liver metastases. Sixty percent (3/5) of patients with mutant genes in the blood developed asynchronous liver metastases after surgery. The overall survival of patients with p53 and/or K-ras gene mutation-positive findings in blood was significantly shorter than that of patients testing negative on Kaplan-Meier analysis. Our results suggest that the method may be useful for reliable detection of tumor cells circulating in the blood and may help to identify patients at high risk for relapse. Copyright 2000 Wiley-Liss, Inc.</ref><ref>Wang JY, Molecular detection of APC, K- ras, and p53 mutations in the serum of colorectal cancer patients as circulating biomarkers, World J Surg 2004 28(7) 721, Early detection of tumor DNA in serum/plasma prior to the development of recurrence or metastases could help improve the outcome of patients with colorectal cancer (CRC) after tumor resection. Recent advances in the detection of tumor DNA in the serum/plasma has opened up numerous new areas for investigation and new possibilities for molecular diagnosis. APC and K- ras mutations are considered to be early-stage developments of CRCs, whereas p53 mutations are thought to be relatively late events in the tumorigenesis of CRCs. The aim of this study was to search for the presence of genetic mutations in the DNA extracted from the serum of CRC patients and healthy subjects. We simultaneously evaluate the significance of APC, K- ras, and p53 gene mutations in cancer tissues and their paired serum samples of 104 CRC patients by polymerase chain reaction-single strand conformation polymorphism analysis (PCR-SSCP) followed by direct sequencing. Additionally, analysis was carried out to detect the serum carcinoembryonic antigen (CEA) levels in CRC patients. Overall, we found at least one of the gene mutations in tumor tissues from 75% (78/104) of the CRC patients. Comparison of the three molecular markers showed that the detection rates in the serum were 30.4%, 34.0%, and 34.2% for APC, K- ras, and p53 genes, respectively. Of these patients, 46.2% (36/78) were identified as having positive serum results, whereas all healthy controls remained negative. The overall positive tumor DNA detection rates in the serum were 0% (0/7) for Dukes' A classification, 22.4% (11/49) for Dukes' B, 48.7% (19/39) for Dukes' C, and 66.7% (6/9) for Dukes' D. The detection rate increased as the tumor stage progressed ( p = 0.012). Concurrently, a significant difference was observed between lymph node metastases and positive serum tumor DNA detection ( p < 0.001). A significantly higher postoperative metastasis/recurrence rate in patients harboring gene mutations with serum tumor DNA than those without serum tumor DNA was also demonstrated ( p < 0.001). However, no significant correlation between the postoperative metastasis/recurrence and serum CEA levels was observed ( p = 0.247). These data suggest that the identification of circulating tumor DNA using the molecular detection of APC, K- ras, and p53 gene mutations is a potential tool for early detection of postoperative recurrence/metastases. Moreover, these genes may be potential molecular markers of poor clinical outcome in CRC patients.</ref><ref>Wang JY, Molecular detection of circulating tumor cells in the peripheral blood of patients with colorectal cancer using RT-PCR: significance of the prediction of postoperative metastasis, World J Surg 2006 june 30(6) 1007,
BACKGROUND: Approximately 20%-45% of colorectal cancer (CRC) patients ultimately develop local recurrence or metastasis following curative surgical resection. The latter is caused by tumor cells shed from the primary carcinoma prior to or during operation, currently undetected by standard clinical staging. Fortunately, the presence of tumor cells in peripheral blood can be detected by molecular methods and is being regarded increasingly as a clinically relevant prognostic factor. MATERIALS AND METHODS: To detect the presence of circulating tumor cells and evaluate their relationship to postoperative metastatic relapse, we simultaneously examined human telomerase reverse transcriptase (hTERT), cytokeratin-19 (CK-19), cytokeratin-20 (CK-20), and carcinoembryonic antigen (CEA) mRNA (messenger RNA) in the peripheral blood of 72 CRC patients and 30 healthy individuals. Using a reverse-transcriptase polymerase chain reaction (RT-PCR), these tumor-related mRNAs were amplified; in addition, analyses were carried out for their correlation with patients' clinicopathologic features, as well as the occurrence of postoperative metastasis. RESULTS: In RT-PCR analysis of the peripheral blood, 69.4% (50 out of 72), 66.7% (48 out of 72), 52.8% (38 out of 72), and 72.2% (52 out of 72) of CRC patients were positive for hTERT, CK-19, CK-20, and CEA mRNA respectively. All 30 healthy individuals were negative for hTERT and CEA mRNA expression, while 2 were positive for either CK-19 mRNA or CK-20 mRNA expression. The detection of CEA mRNA was significantly correlated with depth of tumor invasion (P=0.012), vessel invasion (P=0.035), TNM stage (P<0.0001), and postoperative metastasis (P<0.0001), while positive hTERT mRNA was correlated with TNM stage (P=0.037) and CK-19 was correlated with depth of tumor invasion (P=0.039) and postoperative metastasis (P=0.017). In addition, multivariate logistic regression showed that only CEA mRNA was an independent and significant predictor of postoperative metastasis (P=0.006). Our findings suggest that CEA mRNA may be a more reliable marker than hTERT, CK-19, and CK-20 for the detection of circulating cancer cells in the peripheral blood of CRC patients. CONCLUSIONS: Using RT-PCR for the detection of CEA mRNA is feasible and may be a promising tool for early detection of micrometastatic circulating tumor cells in CRC patients. CRC patients expressing positive CEA mRNA in peripheral blood have a significantly higher risk of postoperative metastasis. Nevertheless, confirmation of CEA mRNA as a prognostic predictive factor requires the continuation of patient follow-up.</ref><ref>Guadagni F, Detection of blood-borne cells in colorectal cancer patients by nested reverse transcription-polymerase chain reaction for carcinoembryonic antigen messenger RNA: longitudinal analyses and demonstration of its potential importance as an adjunct to multiple serum markers, Cancer res 2001 15 61(6) 2523, The use of reverse transcription-PCR (RT-PCR) to analyze cells in the blood of cancer patients for the detection of mRNA expressed in tumor cells has implications for both the prognosis and the monitoring of cancer patients for the efficacy of established or experimental therapies. Carcinoembryonic antigen (CEA) is expressed on approximately 95% of colorectal, gastric, and pancreatic tumors, and on the majority of breast, non-small cell lung, and head and neck carcinomas. CEA shed in serum is useful as a marker in only approximately 50% of colorectal cancer patients and rarely is shed by some other carcinoma types. RT-PCR has been used previously to detect CEA mRNA in cells in the blood and lymph nodes of cancer patients. Under the assay conditions validated in the studies reported here, 34 of 51 (67%) patients with different stages of colorectal cancer had blood cells that were positive by RT-PCR for CEA mRNA, whereas none of 18 patients with colonic polyps were positive; 2 of 60 apparently healthy individuals (who were age and sex matched with the carcinoma patients and were part of a colon cancer screening program as controls) were marginally positive. The results of CEA PCR in the blood of the carcinoma patients and the other groups showed strong statistical correlation with the disease (P2 < 0.0001). Analyses were carried out to detect both serum CEA protein levels and CEA mRNA in blood cells of colorectal carcinoma patients by RT-PCR. For all stages of disease, 18 of 51 patients (35%) were positive for serum CEA, whereas 35 of 51 (69%) were positive by RT-PCR. More importantly, only 5 of 23 (20%) of stage B and C colorectal cancer patients were positive for serum CEA, whereas 16 of 23 (70%) were positive by RT-PCR. The use of two other serum markers (CA19.9 and CA72-4) for colorectal cancer in combination with serum CEA scored two additional patients as positive; both were positive by RT-PCR for CEA mRNA. Pilot long-term longitudinal studies conducted before and after surgery identified some patients with CEA mRNA in blood cells that were negative for all serum markers, who eventually developed clinical metastatic disease. The studies reported here are the first to correlate RT-PCR results for CEA mRNA in blood cells with one or more serum markers for patients with different stages of colorectal cancer, and are the first long-term longitudinal studies to use RT-PCR to detect CEA mRNA in blood cells of cancer patients. Larger cohorts will be required in future studies to define the impact, if any, of this technology on prognosis and/or disease monitoring.</ref><ref>Guller U, Disseminated single tumor cells as detected by real-time quantitative polymerase chain reaction represent a prognostic factor in patients undergoing surgery for colorectal cancer, Ann Surg 2002 dec 236(6) 768, OBJECTIVE: To evaluate the clinical relevance of real-time quantitative polymerase chain reaction (qPCR) detection of CEA and CK20 transcripts, as potentially related to tumor cell dissemination, in blood and peritoneal lavage from patients undergoing surgery for colorectal cancer. SUMMARY BACKGROUND DATA: Dissemination of single colorectal cancer cells in the peritoneal cavity, as well as in tumor drainage and peripheral blood vessels, might play a role in the metastasis process, thus affecting the clinical course. However, this phenomenon needs further elucidation. METHODS: In a prospective study the authors evaluated the potential of qPCR in the detection of CEA and/or CK20 transcripts in the peritoneal lavage fluid and in the peripheral and mesenteric venous blood of 39 patients undergoing curative resection for colorectal cancer. Peritoneal lavage and peripheral blood was sampled before and after tumor resection; mesenteric venous blood was sampled from the major tumor-draining vein immediately before clamping. After RNA extraction and reverse transcription, qPCR was performed using specific cDNA primers and probes for CEA and CK20. The dichotomous results from the qPCR were used as a predictor along with other covariates in Cox proportional hazard regression models of long-term outcome (disease-free survival and overall survival). RESULTS: Of 39 patients, 11 were positive. The median follow-up at analysis was 31 months for all patients. The dichotomous qPCR covariate was significant, with P =.001 and.0035 for disease-free survival and overall survival, respectively, in the proportional hazard regression models with only qPCR. In seven patients, disseminated colorectal cancer cells were found in the peritoneal lavage fluid but not in blood specimens; five of these patients (71%) had recurrence. CONCLUSIONS: These data suggest that detection of mRNA coding for CEA and/or CK20 using qPCR has potential clinical utility as a prognostic marker and should be evaluated in larger clinical studies. Identification of patients at high risk for metastatic disease after curative resection of colorectal cancer might be improved by analyzing peritoneal lavage specimens in addition to blood samples. This is based on the observation that in more than half of qPCR-positive patients, disseminated colorectal cancer cells were detected in peritoneal lavage specimens but not in blood samples, and that 71% of them had recurrence.</ref><ref>Elshimali YI, The clinical significance of circulating tumor cells in the peripheral blood, Diagn Mol Pathol 2006 15(4) 187, Tumors launch malignant cells into the circulation continuously. In early stages, the immune surveillance system eliminates these cells from the circulation, but at later times they may persist longer and be detected. The first recorded evidence of the presence of circulating tumor cells in the peripheral blood of cancer patients was documented in 1869. Now, modern molecular biologic and cell sorting techniques make their detection and characterization more practicable. This review will consider the methods currently available for their detection and characterization, and the clinical implications of their presence in various malignant conditions.</ref><ref>Mejean A, Detection of circulating prostate derived cells in patients with prostate adenocarcinoma is an independent risk factor for tumor recurrence, J Urol 2000 june 163 (6) 2022, PURPOSE: To determine whether the presence of prostate-derived cells in the peripheral blood circulation is a marker of prostate cancer and to define the clinical impact of the test. MATERIALS AND METHODS: We tested the peripheral blood of 99 patients with prostate adenocarcinoma (PAC), 79 of them undergoing radical prostatectomy, and 92 controls (31 healthy volunteers, 50 patients with adenoma and 11 with prostatitis) using a highly controlled procedure including reverse-transcriptase polymerase chain reaction (RT-PCR) targeted to prostate-specific antigen (PSA) mRNA. Patients were followed for 26 +/- 12 (range: 4 to 49) months. Forty tumor tissues were analyzed by immunohistochemistry for expression of p53 and E-cadherin antigens. RESULTS: Thirty three (33%) patients with PAC and 2 (2%) controls scored positive (p <0.0001) for the test. Detection of circulating prostatic cells was associated with development of metastases (p <0. 001), with relapse (p <0.001) and with a serum PSA level at diagnosis higher than 15 ng./ml. (p = 0.009). The rate of development of metastases according to time was significantly higher in patients who scored positive for the test (p <0.04). In a multivariate analysis, only the RT-PCR test was an independent risk factor associated with relapse (RR: 6.7). Finally, E-cadherin expression was significantly lower in the tumor tissues of positive patients as compared with those who scored negative for the test (p <0.01). CONCLUSIONS: This RT-PCR procedure, performed at diagnosis and with appropriate controls, is a clinically useful assay in evaluating the risk of tumor recurrence after radical prostatectomy in patients with PAC.</ref><ref>Massimo Cristofanilli,Circulating Tumor Cells, Disease Progression, and Survival in Metastatic Breast Cancer, NEJM Vol 351 august 2004, http://content.nejm.org/cgi/content/abstract/351/8/78</ref>. Often the PCT-technique is used known from the genetic fingerprints. A newer work (december 2007) by Mehmet Toner about an automat registering single cancer cells: <ref>*http://www.istitutoncologicoveneto.it/it/rassegna/2012/201207-02.pdf (nature medicine No 20 december 2007</ref>. Hamer instead believes that there were no studies showing these cancer cells in arterial blood, but this is false and irrelevant because the presence of isolated cancer cells in venous blood of the controlateral side of the tumors can't be explained either. Some articles (out of many) showing cancer cells in arterial blood are: <ref>Yoshihiro Hayata M.D, Significance of Carcinoma Cells in the Blood Relative to Surgery of Pulmonary Carcinoma, Chest 1964;46:51-60.)
BACKGROUND: Approximately 20%-45% of colorectal cancer (CRC) patients ultimately develop local recurrence or metastasis following curative surgical resection. The latter is caused by tumor cells shed from the primary carcinoma prior to or during operation, currently undetected by standard clinical staging. Fortunately, the presence of tumor cells in peripheral blood can be detected by molecular methods and is being regarded increasingly as a clinically relevant prognostic factor. MATERIALS AND METHODS: To detect the presence of circulating tumor cells and evaluate their relationship to postoperative metastatic relapse, we simultaneously examined human telomerase reverse transcriptase (hTERT), cytokeratin-19 (CK-19), cytokeratin-20 (CK-20), and carcinoembryonic antigen (CEA) mRNA (messenger RNA) in the peripheral blood of 72 CRC patients and 30 healthy individuals. Using a reverse-transcriptase polymerase chain reaction (RT-PCR), these tumor-related mRNAs were amplified; in addition, analyses were carried out for their correlation with patients' clinicopathologic features, as well as the occurrence of postoperative metastasis. RESULTS: In RT-PCR analysis of the peripheral blood, 69.4% (50 out of 72), 66.7% (48 out of 72), 52.8% (38 out of 72), and 72.2% (52 out of 72) of CRC patients were positive for hTERT, CK-19, CK-20, and CEA mRNA respectively. All 30 healthy individuals were negative for hTERT and CEA mRNA expression, while 2 were positive for either CK-19 mRNA or CK-20 mRNA expression. The detection of CEA mRNA was significantly correlated with depth of tumor invasion (P=0.012), vessel invasion (P=0.035), TNM stage (P<0.0001), and postoperative metastasis (P<0.0001), while positive hTERT mRNA was correlated with TNM stage (P=0.037) and CK-19 was correlated with depth of tumor invasion (P=0.039) and postoperative metastasis (P=0.017). In addition, multivariate logistic regression showed that only CEA mRNA was an independent and significant predictor of postoperative metastasis (P=0.006). Our findings suggest that CEA mRNA may be a more reliable marker than hTERT, CK-19, and CK-20 for the detection of circulating cancer cells in the peripheral blood of CRC patients. CONCLUSIONS: Using RT-PCR for the detection of CEA mRNA is feasible and may be a promising tool for early detection of micrometastatic circulating tumor cells in CRC patients. CRC patients expressing positive CEA mRNA in peripheral blood have a significantly higher risk of postoperative metastasis. Nevertheless, confirmation of CEA mRNA as a prognostic predictive factor requires the continuation of patient follow-up.</ref><ref>Guadagni F, Detection of blood-borne cells in colorectal cancer patients by nested reverse transcription-polymerase chain reaction for carcinoembryonic antigen messenger RNA: longitudinal analyses and demonstration of its potential importance as an adjunct to multiple serum markers, Cancer res 2001 15 61(6) 2523, The use of reverse transcription-PCR (RT-PCR) to analyze cells in the blood of cancer patients for the detection of mRNA expressed in tumor cells has implications for both the prognosis and the monitoring of cancer patients for the efficacy of established or experimental therapies. Carcinoembryonic antigen (CEA) is expressed on approximately 95% of colorectal, gastric, and pancreatic tumors, and on the majority of breast, non-small cell lung, and head and neck carcinomas. CEA shed in serum is useful as a marker in only approximately 50% of colorectal cancer patients and rarely is shed by some other carcinoma types. RT-PCR has been used previously to detect CEA mRNA in cells in the blood and lymph nodes of cancer patients. Under the assay conditions validated in the studies reported here, 34 of 51 (67%) patients with different stages of colorectal cancer had blood cells that were positive by RT-PCR for CEA mRNA, whereas none of 18 patients with colonic polyps were positive; 2 of 60 apparently healthy individuals (who were age and sex matched with the carcinoma patients and were part of a colon cancer screening program as controls) were marginally positive. The results of CEA PCR in the blood of the carcinoma patients and the other groups showed strong statistical correlation with the disease (P2 < 0.0001). Analyses were carried out to detect both serum CEA protein levels and CEA mRNA in blood cells of colorectal carcinoma patients by RT-PCR. For all stages of disease, 18 of 51 patients (35%) were positive for serum CEA, whereas 35 of 51 (69%) were positive by RT-PCR. More importantly, only 5 of 23 (20%) of stage B and C colorectal cancer patients were positive for serum CEA, whereas 16 of 23 (70%) were positive by RT-PCR. The use of two other serum markers (CA19.9 and CA72-4) for colorectal cancer in combination with serum CEA scored two additional patients as positive; both were positive by RT-PCR for CEA mRNA. Pilot long-term longitudinal studies conducted before and after surgery identified some patients with CEA mRNA in blood cells that were negative for all serum markers, who eventually developed clinical metastatic disease. The studies reported here are the first to correlate RT-PCR results for CEA mRNA in blood cells with one or more serum markers for patients with different stages of colorectal cancer, and are the first long-term longitudinal studies to use RT-PCR to detect CEA mRNA in blood cells of cancer patients. Larger cohorts will be required in future studies to define the impact, if any, of this technology on prognosis and/or disease monitoring.</ref><ref>Guller U, Disseminated single tumor cells as detected by real-time quantitative polymerase chain reaction represent a prognostic factor in patients undergoing surgery for colorectal cancer, Ann Surg 2002 dec 236(6) 768, OBJECTIVE: To evaluate the clinical relevance of real-time quantitative polymerase chain reaction (qPCR) detection of CEA and CK20 transcripts, as potentially related to tumor cell dissemination, in blood and peritoneal lavage from patients undergoing surgery for colorectal cancer. SUMMARY BACKGROUND DATA: Dissemination of single colorectal cancer cells in the peritoneal cavity, as well as in tumor drainage and peripheral blood vessels, might play a role in the metastasis process, thus affecting the clinical course. However, this phenomenon needs further elucidation. METHODS: In a prospective study the authors evaluated the potential of qPCR in the detection of CEA and/or CK20 transcripts in the peritoneal lavage fluid and in the peripheral and mesenteric venous blood of 39 patients undergoing curative resection for colorectal cancer. Peritoneal lavage and peripheral blood was sampled before and after tumor resection; mesenteric venous blood was sampled from the major tumor-draining vein immediately before clamping. After RNA extraction and reverse transcription, qPCR was performed using specific cDNA primers and probes for CEA and CK20. The dichotomous results from the qPCR were used as a predictor along with other covariates in Cox proportional hazard regression models of long-term outcome (disease-free survival and overall survival). RESULTS: Of 39 patients, 11 were positive. The median follow-up at analysis was 31 months for all patients. The dichotomous qPCR covariate was significant, with P =.001 and.0035 for disease-free survival and overall survival, respectively, in the proportional hazard regression models with only qPCR. In seven patients, disseminated colorectal cancer cells were found in the peritoneal lavage fluid but not in blood specimens; five of these patients (71%) had recurrence. CONCLUSIONS: These data suggest that detection of mRNA coding for CEA and/or CK20 using qPCR has potential clinical utility as a prognostic marker and should be evaluated in larger clinical studies. Identification of patients at high risk for metastatic disease after curative resection of colorectal cancer might be improved by analyzing peritoneal lavage specimens in addition to blood samples. This is based on the observation that in more than half of qPCR-positive patients, disseminated colorectal cancer cells were detected in peritoneal lavage specimens but not in blood samples, and that 71% of them had recurrence.</ref><ref>Elshimali YI, The clinical significance of circulating tumor cells in the peripheral blood, Diagn Mol Pathol 2006 15(4) 187, Tumors launch malignant cells into the circulation continuously. In early stages, the immune surveillance system eliminates these cells from the circulation, but at later times they may persist longer and be detected. The first recorded evidence of the presence of circulating tumor cells in the peripheral blood of cancer patients was documented in 1869. Now, modern molecular biologic and cell sorting techniques make their detection and characterization more practicable. This review will consider the methods currently available for their detection and characterization, and the clinical implications of their presence in various malignant conditions.</ref><ref>Mejean A, Detection of circulating prostate derived cells in patients with prostate adenocarcinoma is an independent risk factor for tumor recurrence, J Urol 2000 june 163 (6) 2022, PURPOSE: To determine whether the presence of prostate-derived cells in the peripheral blood circulation is a marker of prostate cancer and to define the clinical impact of the test. MATERIALS AND METHODS: We tested the peripheral blood of 99 patients with prostate adenocarcinoma (PAC), 79 of them undergoing radical prostatectomy, and 92 controls (31 healthy volunteers, 50 patients with adenoma and 11 with prostatitis) using a highly controlled procedure including reverse-transcriptase polymerase chain reaction (RT-PCR) targeted to prostate-specific antigen (PSA) mRNA. Patients were followed for 26 +/- 12 (range: 4 to 49) months. Forty tumor tissues were analyzed by immunohistochemistry for expression of p53 and E-cadherin antigens. RESULTS: Thirty three (33%) patients with PAC and 2 (2%) controls scored positive (p <0.0001) for the test. Detection of circulating prostatic cells was associated with development of metastases (p <0. 001), with relapse (p <0.001) and with a serum PSA level at diagnosis higher than 15 ng./ml. (p = 0.009). The rate of development of metastases according to time was significantly higher in patients who scored positive for the test (p <0.04). In a multivariate analysis, only the RT-PCR test was an independent risk factor associated with relapse (RR: 6.7). Finally, E-cadherin expression was significantly lower in the tumor tissues of positive patients as compared with those who scored negative for the test (p <0.01). CONCLUSIONS: This RT-PCR procedure, performed at diagnosis and with appropriate controls, is a clinically useful assay in evaluating the risk of tumor recurrence after radical prostatectomy in patients with PAC.</ref><ref>Massimo Cristofanilli,Circulating Tumor Cells, Disease Progression, and Survival in Metastatic Breast Cancer, NEJM Vol 351 august 2004, http://content.nejm.org/cgi/content/abstract/351/8/78</ref>. Often the PCT-technique is used known from the genetic fingerprints. A newer work (december 2007) by Mehmet Toner about an automat registering single cancer cells: <ref>*http://www.istitutoncologicoveneto.it/it/rassegna/2012/201207-02.pdf (nature medicine No 20 december 2007</ref>. Hamer instead believes that there were no studies showing these cancer cells in arterial blood, but this is false and irrelevant because the presence of isolated cancer cells in venous blood of the controlateral side of the tumors can't be explained either. Some articles (out of many) showing cancer cells in arterial blood are: <ref>Yoshihiro Hayata M.D, Significance of Carcinoma Cells in the Blood Relative to Surgery of Pulmonary Carcinoma, Chest 1964;46:51-60.)