“A neoplasm should never be incised for diagnostic purposes, for one cannot tell at what split moment the cancer cells may be disseminated and the patient doomed. Aspirating the neoplasm to draw out the cells by suction. This, too, is a very  questionable procedure, for what of the cancer cells that may be present below the puncture point and around the needle that have been set free?”
Fitzgerald Report, United States Congressional Record, Interstate Commerce Commission


Biopsies as a metastatic mechanism

Biopsies and surgery disseminate cancer cells. Survival of cancer patients is jeopardized by first violating a cancerous tumor’s integrity. Surgically removing a malignant tumor creates adverse conditions that enhance the growth of pre-existent metastatic tumors and diminishes the body’s immunological system to deal with these abnormal cells. Nobody would expect the air to remain in a balloon once a pin has violated its integrity. Why would we expect malignant cells to remain in the primary tumor once its integrity has been violated? We we will demonstrate that spillage of the tumor cells from a biopsy or surgery violated tumor is exactly what does happen.

An inflated balloon, half filled with water, is pricked with a hypodermic needle

Recently, physicians have been pondering the quandary of dissemination of cancer by human intervention and have devised studies to determine whether our fears are justified. With the discovery of Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) technology, it has been determined that biopsies and surgery do dislodge cells from a tumor and precipitate their dissemination with resultant implantation of metastatic tumors elsewhere throughout the body.

For years, my patients told me that surgery disseminated cancer, and they would give me an example of one of their friends or relatives, who was doing fine until surgery was performed, and then, in a couple of months, was dead. When I was an intern, I used to quiet my patients’ anxiety by telling them that this was not an accurate appraisal, and that the only way to cure cancer was with early diagnosis and surgery like what I was taught in medical school. I was very fortunate though to have been mentored after med school by a few exceptional Doctors who convinced me to re-evaluate diagnosis and treatment processes from beginning to end. Understand that during medical school, there is no open dialogue where we as students can question current medical practices, no matter how illogical and barbaric they are.

In questions of science, the authority of a thousand is not worth the humble reasoning of a single individual.

Galileo Galilei (1564-1642)
Physicist and astronomer

Does putting a needle into a malignant tumor cause these highly unpredictable cells to spread through the severed blood and lymphatic vessels to distant sites in the body? When we grab the tumor with tissue forceps, are we extruding cancer cells into the bloody fluid of the operative field and subsequently into the surrounding healthy tissue, allowing these cells to implant and grow as a metastatic lesion? When we cut into a tumor inadvertently, because its cancerous crab-like tentacles have spread beyond the surgical field, are we precipitating metastasis?


The literature search was initially conducted by inserting the initials “RT-PCR” (Reverse Transcriptase-Polymerase Chain Reaction) into a Medline search engine. The initial search process generated 72,227 matches. This was refined by the use of various combinations of “dissemination,” “cancer cells,” “metastasis,” “breast or prostate cancer,” and “biopsies.” Secondary references were obtained from these original articles and were utilized to retrieve additional research papers. In order to focus on the subject, articles were selected as having pertinent material. Articles were included for analysis if they met the following criteria: 1) they discussed metastasis of cancer, 2) the diagnosis of cancer, or 3) they connected or denied an association of biopsy, surgery or radiation with the dissemination of cancer cells. Additional criteria were 4) the abstract was in the English language, and 5) they were published in a peer-reviewed journal.


Physicians from around the world, in medical institutions with distinguished reputations, have contributed thousands of articles relating directly and indirectly to this subject. I have arranged the material according to the following protocol: malignant cells following needle tracts into adjacent tissue; systemic dissemination of cancer cells with needle biopsy; dissemination with incisional biopsy; and then a comparison of the several modalities of performing biopsies and their relative risk for dissemination. I then looked at the propensity for surgery to disseminate cancer cells, including mechanical, biochemical and hormonal means. I have not chosen a particular cancer to study because the evidence is that almost all, if not all, disseminate when their integrity is violated.

Evidence that biopsy needles can dislocate malignant cells

There is a substantial quantity of literature reporting that malignant cells can follow the biopsying needle and become implanted in the tissue through which the needle passed. It has been reported in biopsy of the lung,[1][2] core-needle biopsy of the breast,[3][4][5][6]  other needling of breast lesions,[7][8]  along the track of a stereotactic cannula during treatment of a metastatic malignancy to the brain from a solitary, primary lung cancer,[9]  after a biopsy of a glioblastoma in the right basal ganglia,[10]  and from an anaplastic astrocytoma.[11] Other examples include papillary thyroid carcinoma,[12]  a pancreatic liver metastasis,[13]  and head and neck carcinomas.[14]
Dr. Thurfjell et al. reported that “Seeding or implantation was suspected as the cause of local recurrence in 7% of the invasive [breast] cancers,”[15] and following Image-Guided breast biopsy via Core Needle Biopsy (IGCNB) of a mucinous infiltrating ductal carcinoma.
Dr. Knight et al. reported that “Within the [needle] track were several nests of mucinous carcinoma cells” identified in the surgical excision specimen which included the needle track.[16]

Evidence of biopsy induced tumor spread

Dr. Sawabata et al. performed an interesting study in order to determine whether biopsies disseminated lung cancer. On 20 patients with positive chest X-Rays and positive bronchoscopic exams for cancer of the lung, they performed a lobectomy via an open thoracotomy. They washed the visceral pleural surface of the resected lung with 20 ml of heparinized saline and found 10% of specimens positive for malignant cells. They then performed a Fine Needle Aspiration Cytology (FNAC) “biopsy” of the suspected lesion through the pleura of the resected lung. They irrigated the visceral pleural surface again after the FNAC “biopsy” and reported that 60% of cases were positive for malignant cells. All the FNAC “biopsies” correlated specifically with the tumor type diagnosed at pathology and therefore, all FNAC needles penetrated the tumor on “biopsy.” The results of this study would imply that 10% of tumors were metastatic before “biopsy” and therefore this figure probably represents the biological or natural rate of metastasis for lung cancer. On the other hand, if 60% of the washings were positive for malignant cells after “biopsy,” it appears that physicians and surgeons are significantly responsible for the high rate of metastasis of lung cancer and the dismal statistics of 91.4% fatality with this disease. The weakness of this study is that it was not performed in vivo; nevertheless, dissemination of malignant cancer cells at a rate of 60% utilizing FNAC technique was demonstrated, resulting in spread of the malignant cells to the pleural space.[17]

It has become possible with RT-PCR to identify malignant epithelial cells in minute quantities in the blood stream and bone marrow that have metastasized as a result of biopsy and oncologic surgery. Some researchers have claimed that RT-PCR can detect one epithelial cell in the presence of 100,000,000 lymphoid cells.[17]  Whether or not these epithelial cells are cancer cells has been studied in both biopsy and surgical analysis of dissemination. The potential to find minute quantities of cancer cells in the bone marrow and blood has transformed our approach in analyzing the consequences of any procedure we might do, such as biopsy and definitive surgery. It has allowed us to determine whether or not these procedures are disseminating cancer cells into the blood stream and lymphatics, and ultimately to lymph nodes and bone marrow.

Dr. Straub et al. noted that 47 patients out of 87 (54%) patients who had proven carcinoma of the prostate were PSA mRNA positive before surgery, and thereby after biopsy, considering that under present-day standards, a biopsy is the sine qua non for determining that a patient has cancer.[18]  They also noted that 8% of the patients with benign hyperplasia were also PSA mRNA positive, indicating that benign cells can also be disseminated with biopsy.

Dr. Moreno et al. were able to demonstrate by RT-PCR PSA analysis, that 9.5% of transrectal ultrasound-guided prostate biopsies disseminated cells into the blood stream within 60 minutes of the procedure, and 100% of transurethral resections of the prostate [TURP] had a “highly intense positive signal.”[19]   The question was raised: what is the significance of these findings? From a later study by these physicians, we quote, “We conclude that the level of circulating tumor cells can be quantified in the circulation of patients with metastatic Carcinoma of the Prostate and that the change in circulating tumor cells correlates with disease progression.”[20]

Another study on the dissemination of cancer cells with biopsy was performed by Dr. Hara et al. who found that in 108 patients, of whom 46 had prostate cancer, 40 individuals (out of the 108) had RT-PCR detected PSA-mRNA in their peripheral blood after biopsy, suggesting an overall dissemination rate of 37.0%. The study did have 3 patients who had prostate cancer who had detectable PSA-mRNA before biopsy, a rate of 6.5% dissemination before human intervention. None of the benign cases had detectable PSA-mRNA before biopsy. Of those 46 individuals who had prostate cancer, 21 had PSA-mRNA identified in their peripheral blood only after biopsy, giving a dissemination rate in cancer cases of 45.7%. In addition, 16 of 62 cases of Benign Prostatic Hypertrophy (BPH) also had dissemination of their benign cells into the circulation (25.8%). None of the 3 patients who had PSA-mRNA detected in their peripheral blood before biopsy converted to negative after biopsy. From this study, with a 45.7% dissemination rate of cells from malignant prostate glands, it is suggested that “prostate biopsy might scatter prostate cells in the blood stream especially in cases with high sPSA and, thus, might contribute to tumour spreading in the cases of prostate cancer.”[21]

Many studies have been done utilizing the technique of RT-PCR, though several have been done unsuspecting that the biopsy itself might have already disseminated cancer cells before they began their investigation. In one study, Dr. Ellis et al. report, “Before prostatectomy, PSA-expressing epithelial cells were detected in 54% of [bone marrow] and 24% in [peripheral blood] samples.”[22]  The high percentage of cells in the bone marrow and peripheral blood before a prostatectomy was performed could have been due to the preceding biopsy, as they were only performing the study on known prostate cancer patients. The authors go on to state, “These disseminated PSA-expressing cells are [found in bone marrow and peripheral blood] … because of perturbations of the prostate such as Carcinoma of the prostate or biopsy.” Therefore, these authors were suspecting that the biopsy may have been a contributing factor in the dissemination of cancer.

Utilizing the technology of Cytokeratin 19 (CK19) RT-PCR, Dr. Kusukawa et al. attempted to determine whether biopsying a malignancy resulted in its distal metastasis. The study consisted of twenty patients with oral Squamous Cell Carcinoma and ten patients with benign oral lesions utilized as controls. Ten of the oral cancer patients were treated by first performing an incisional biopsy followed by radical excision of the lesion. The other ten had only radical excisional removal of the tumor. Two (20%) of the ten patients who had undergone incisional biopsy first were positive for CK19 transcripts in their peripheral blood (the specimens were drawn 15 minutes after the biopsy was performed). None of the ten individuals who had a radical excision alone had any CK19 transcripts in their blood. In addition, none was detected in the controls either.[23]  This would suggest that as much as 20% of metastases could occur because of an incisional biopsy and would not have occurred if the tumor were not violated before its excision.

Dissemination of breast cancer cells by biopsy was also studied. Dr. Hu et al. evaluated the effects of fine-needle aspiration (FNA) of breast tumors and whether inserting a needle into a malignant lesion can cause hematogenous dissemination of cancer cells. They utilized RT-PCR assay targeted against cytokeratin 19 (CK19), cytokeratin 20 (CK20) and the beta-subunit of human chorionic gonadotropin (beta-hCG) mRNAs. Their conclusion was, “FNA to breast tumor may cause hematogenous dissemination of breast cells.”[24]

Dr. Hansen et al. studied 663 patients with biopsy-proven breast cancer who underwent sentinel lymph node (SLN) dissection. They were divided into three groups according to the type of biopsy performed: 1) fine-needle aspiration (FNA), 2) large-gauge needle core, and 3) excisional. In multivariate analysis, considering patient age, tumor size and tumor grade, “the incidence of Sentinel Node metastases was higher in patients whose cancer was diagnosed by FNA (odds ratio, 1.531; 95% confidence interval, 0.973-2.406; P =.07, Wald test) or large-gauge needle core biopsy (odds ratio, 1.484; 95% confidence interval, 1.018-2.164; P =.04, Wald test) than by excision. Tumor size (P <.001) and grade (P =.06) also were significant prognostic factors.”[25]  They go on to say, “Manipulation of an intact tumor by FNA or large-gauge needle core biopsy is associated with an increase in the incidence of sentinel node metastases, perhaps due in part to the mechanical disruption of the tumor by the needle.” This study was consistent with the findings of the other studies using RT-PCR described above.

In another study, Dr. Chagpar et al. utilized 3,853 patients, of whom 32% had positive sentinel node biopsies for metastatic breast cancer. These patients were diagnosed by 1) FNA, 2) large-gauge needle core, 3) incisional, and 4) excisional biopsy. The rates of sentinel node positivity by univariate analysis for these biopsy types were: incisional 65%, FNA 45%, core-needle 32%, and excisional 29%. Incisional biopsy had over twice as many positive nodes as excisional biopsy yet, after subjecting his findings to multivariate analysis utilizing eight other variables, they were able to conclude, “Biopsy examination type does not independently influence the risk for nodal metastasis.”[26]  [See Discussion]

In a study by Dr. Crisan et al., “Cytokeratin 19 mRNA detection by … RT-PCR in preoperative and postoperative blood samples from 54 patients undergoing excisional biopsy for benign breast disease; 22 healthy volunteers represented the control group. No cytokeratin RT-PCR positivity was found in the control or preoperative samples. Cytokeratin RT-PCR positivity was found in 21 postoperative samples (39%). Conclusions: This finding shows that benign epithelial cells can be mobilized during breast surgery.”[27]  Only cells capable of producing substances such as Vascular Endothelial Growth Factor (VEGF), which stimulate angiogenesis and allow the displaced cells to grow beyond 2 to 3 mm in size, produce metastatic tumors from the malignant lesion. We will see, in the following study of biopsies and surgery of the liver that benign tumor cells as well as normal liver cells can be disseminated, but they do not produce metastases.

Utilizing RT-PCR-based assay targeted against alpha-fetoprotein (AFP) mRNA, 12 patients with and 16 patients without primary liver cancer were studied before, during and after liver resection. In addition, 2 patients with and 20 patients without primary liver cancer were tested before, 20 minutes after, and 24 hours after needle liver biopsy. Dr. Louha et al. found that “Six of 14 patients with and 0 of 36 patients without primary liver cancer scored positive before intervention (P <.001). Liver cell spreading was induced at different times after surgery and liver biopsy in 14 of 14 patients with, but also 23 of 36 without primary liver cancer (P <.05). We conclude that liver resection and needle liver biopsy induce release of cells from the liver, which are not necessarily liver tumor cells, into the peripheral blood circulation. This may be an important mechanism of liver cancer cell dissemination deserving further investigations.”[28]   This study demonstrates that even non-tumor cells of the liver can be disseminated by biopsy and surgery, but the rate of malignant liver cell dissemination was almost absolute.

A study where Dr. Stathopoulou et al. evaluated the significance of disseminated tumor cells in the bone marrow and peripheral blood, the authors noted that, “Detection rates for CK-19 mRNA-positive cells in the bone marrow/blood of patients with early or metastatic breast cancer were 63%/30% and 74%/52%, respectively. … In multivariate analysis, detection of peripheral-blood CK-19-positive cells was an independent prognostic factor for disease relapse and death.”[29]

It was also reported by Dr. Majima et al. that “Among the stage IV [gastric] cancer positive cases for CK [cytokeratin] showed significantly lower survival rates than those negative for CK.”[30]   Further reports of similar findings include a study before and after radiation therapy for prostate cancer.

Dr. Lilleby et al. concluded, “The presence of CK+ cells in 12 of 60 (20%) patients at the second Bone Marrow aspiration was significantly related to a shorter Progression-free Survival. … The presence of CK+ cells [in Bone Marrow] after local therapy defines a group of patients that have a high risk of developing distant metastases,”[31]   The figures for progression-free 5-year survival after therapy were: 78% if the CK+ cells were not identified and 55% if CK+ cells were identified. Therefore, the presence of CK19 transcripts in peripheral blood does not just indicate the presence of cells which cannot or will not produce a metastatic tumor, they actually indicate the potential for metastasis, and the prognosis is poor or diminished when CK19 transcripts are present.

Another study compared dissemination via the portal vein, peripheral blood and to bone marrow in cases of gastric and colon cancer. Dr. Zhang et al. utilized CK20 mRNA and found no positive expression in 6 non-cancer volunteers. “The positive rates of CK20 mRNA in bone marrow, portal vein were 87.2% (41/47) and 85.1% (40/47) in gastric cancer, and were 77.6% (45/58) and 74.1% (43/58) in colorectal cancer. The positive rates of CK20 mRNA in peripheral blood in gastric and colorectal cancer patients were 42.6% (20/47) and 44.8% (26/58) by one single test, and were 74.5% (35/47) and 69.0% (40/58) by two tests.”[32]   Though the authors were demonstrating that peripheral blood evaluation for micrometastasis of gastric and colorectal cancers was as sensitive and specific as portal vein and bone marrow, they also demonstrated in a one year follow-up that “The relapse rate within one year was higher in CK20 mRNA positive patients than the negative ones (P < 0.05).”

Evidence of Surgery Induced Tumor Spread

There is evidence that not just the biopsy but surgery itself disseminates cancer cells and precipitates metastasis. Dr. Demicheli et al. stated it succinctly, “The surgery-driven acceleration of metastasis development can provide a satisfactory explanation to some otherwise unanswered clinical findings, such as the different survival patterns between breast cancer patients undergoing surgery and patients never given treatment … and the paradoxical early mortality excess in the invited group for younger women recruited for mammographic screening studies.”[33]

According to Dr. Deshpande et al., “The increased breast cancer–specific mortality in younger women was not solely a result of advanced stage of disease at diagnosis, as evidenced by the considerably poorer outcomes in women younger than 40 years of age with early stages of disease. In addition, greater breast cancer mortality in younger women also has been observed after controlling for tumor stage… Younger women in our study were more likely than older women to have had mastectomies.”[34]   Would this imply that an incisional biopsy was performed before the mastectomy, whereas, in breast conserving surgery, a lumpectomy or excisional biopsy would be performed with no additional surgery thereafter.

Paradoxically, primary malignant tumors may secrete a substance known as angiogenesis inhibitor factor that prevents disseminated tumor cells from growing at their metastatic sites. It is as if the primary tumor were trying to protect the organism when a catastrophic event has occurred in its cellular reproductive mechanism. Cancerous tumors cannot grow beyond 2 to 3 mm in size unless an angiogenesis hormone is present to stimulate the production of blood vessels within the tumor to provide it with oxygen and nutrition.

Dr. Demicheli et al. reported that “In laboratory animals total … or partial … tumour removal may stimulate cell proliferation in macro-metastatic foci, due to an in serum detectable growth-stimulating factor. … For some experimental tumours producing angiogenesis inhibitor factors, primary tumour removal caused a switch of micrometastatic foci to the angiogenic phenotype, resulting in growth of metastases. … Surgery should be considered as a major perturbing factor for metastasis development,” [35]  and “Some metastatic processes are initiated at primary tumor removal.”[36]

Dr. Galán et al., performing similar research, concluded, “Seven percent of early breast cancer patients had circulating tumor cells before surgery [after biopsy?]. After surgery tumor cells were detected in 17% of patients. Surgery significantly increased the presence of occult breast cancer cells.”[37]   Can we conclude that more than twice the number of circulating tumor cells are released into the blood stream with definitive surgery as compared with biopsy? Other physicians have made similar conclusions.

Dr. Coffey et al. reported, “The process of tumour removal is associated with the inadvertent dissemination of viable neoplastic cells that in turn contribute to recurrent tumour growth.” They continued to point out that by grasping lymph nodes with forceps, arterial clips on tumors to control bleeding, the administration of local anesthesia, and intraoperative tumour manipulation in the process of its removal, all may promote metastatic embolization.[38]

Dr. Moreno et al. also pointed out that “Five of 14 (36%) patients tested positive for prostate epithelial cells in the operative field at one or more points during radical prostatectomy.”[39]

Dr. Yamaguchi et al. sought to demonstrate the clinical value of RT-PCR recognition of mRNA coding for carcinoembryonic antigen (CEA) and CK20 in colorectal cancer. Utilizing blood from peripheral and mesenteric veins before and after surgery and before resection, respectively, they were able to evaluate a 450 day recurrence rate. They concluded, “The PCR-positive group had a significantly shorter overall survival than the PCR-negative group only with the mesenteric venous blood specimens.”[40]   In addition to this conclusion, they were able to state, “Of the eight peripheral blood specimens found to be PCR-positive, five showed a change of PCR from negative to positive during surgery, and liver metastases developed 11 months later in one of these five patients. … Molecular detection in the peripheral blood at surgery suggests that hematogenic tumor cell dissemination is a common and early event and that surgical manipulation enhances this release of tumor cells into the circulation.” This study suggests that surgery precipitates metastasis and that re-evaluation of surgery techniques may be in order. Was manipulation of the cancerous tumor before the mesenteric vein sample was obtained responsible for cells disseminating through this route? Other studies suggest that ligation of the venous drainage first, might prevent dissemination during definitive surgery.[49]

The presence of room air during open surgery and laparoscopy with air insufflation was also identified as an inducer of metastasis. Dr. Pidgeon et al. stated, “Endotoxin or lipopolysaccharide (LPS) is a cell wall constituent of Gram-negative bacteria that is present ubiquitously in the atmosphere … [and in] endogenous gut bacteria. … We identified increased metastatic tumour growth in mice which underwent laparotomy or air laparoscopy, where the peritoneum was insufflated with air, compared to controls which received anæsthetic only. … A metastatic burden similar to controls was observed in animals undergoing CO2 laparoscopy, where air is excluded. … Our study suggests that air contamination during the surgical procedure is one of the stimuli responsible for the enhanced tumour growth and angiogenesis observed following open surgery.”[41]

Significantly elevated levels of VEGF, the most potent angiogenic factor known, were also noted in open surgery and air laparoscopy. The same scientists report, “Endotoxin, introduced into the circulation during the surgical procedure, augments metastatic growth by increasing tumour cell proliferation, decreasing tumour cell apoptosis and increasing production of the angiogenic factor VEGF.” More and more evidence accumulates that open surgery and biopsy are not only ineffective in reducing cancer mortality; the procedures may actually increase the incidence of metastasis. As Dr. Pidgeon et al. summarized, “Surgical removal of a primary tumour is often followed by rapid growth of previously dormant metastases”.

The blood shed during oncologic surgery may in itself be a modality of metastasis. Dr. Hansen et al. report, “In 57 (93%) of 61 patients, tumor cells were detected in the blood shed during oncologic surgery. … Of special interest are any free tumor cells in the surgical field or the peritoneal cavity, since they may explain the high rate of local tumor recurrence in spite of careful surgical procedure, no-touch isolation technique, resection with a tumor-free margin, or a low extension of the primary tumor. … In our study, viability, proliferation capacity, invasiveness and tumorigenicity were demonstrated for these cells from the surgical field.”[42]

Other surgeons suggest that excisional surgery is therapy at a cost. The effects of surgical excision include 1) disinhibition of angiogenesis during the post-operative period; 2) tumour manipulation during surgery leads to dissemination of tumour cells; 3) tumour removal may alter biological properties of neoplastic cells and lead to increased cellular proliferation and reduced cell death; 4) circulating tumour cells disseminated during surgery may be more tumorigenic because of mutations arising from genetic instability; 5) occurrence of post-operative immunosuppression; 6) the window of opportunity created after surgery may facilitate their escape from immunity thereby permitting “minimal residual disease” expansion. Dr. Coffey et al. also note that “Wounds represent an environment that favours tumour growth.”[33]

Surgery itself, suppresses the body’s natural tumoricidal activity, suppressing natural killer cells and lymphokine activated killer cells found in the spleen, according to Dr. Da Costa et al.[43]   Therefore, we inhibit the body’s response to the malignancy by removing it, placing every physician in that unenviable position of being damned if we do, and damned if we don’t. Nevertheless, if we are to “cure” cancer, it might be necessary to consider a different approach than surgery. The question is: how can we do it without causing these adverse reactions to occur?


It has been noted by Dr. Paik et al. that implantation of malignant cells along the needle tract can “change potentially resectable localized lung cancer to respectable carcinoma.”[44]   Dr. J. Kusukawa, who demonstrated that oral Squamous-cell Carcinoma patients fared better without preliminary incisional biopsy, went on to suggest that “Incisional biopsy is likely to increase the risk of dislodging cancer cells into circulation … The major physical barriers to the migration of tumor cells during this process are connective tissue stroma and basement membranes.”[19] These, of course, are disrupted when the biopsy needle penetrates the malignant tumor much like a pinprick penetrating a balloon.

biopsy-hurtsNobody would expect the air to remain in a balloon once a pin has violated its integrity. Why should we expect malignant cells to remain in the primary tumor once its integrity is violated? The above studies have demonstrated that spillage of the tumor cells from a biopsy or surgery violated tumor is exactly what indeed does happen.

There have been some investigations into what percentage of disseminated malignant cells will result in a metastatic tumor. Dr. Moreno et al. report, “Solid tumor animal experiments suggest that only 0.01% of circulating cancer cells eventually create a single metastatic deposit.”[17]  The significance of this number is determined by Progression-free five-year survival periods, and similar morbidity and mortality studies.

Prostatectomies without Preliminary Biopsy

If surgeons are disseminating the cancer in their effort to diagnose it, can we do curative surgery without a biopsy? For example, can we select the patients for prostatectomies with precision from laboratory analysis of their blood and without biopsies, such that our rate of removing normal prostates is at an acceptable level, particularly to the general public?

Utilizing free-PSA to obtain up to a 95% sensitivity for prostate cancer detection has been demonstrated.[45] The utilization of proenzyme (pro-PSA) and PSA-ACT (PSA found in serum, irreversibly bound to the protease inhibitor α1-antichymotrypsin) has been studied to further differentiate between cancer and BPH. Additionally, determining human kallikrein-2 levels may be helpful in identifying malignancy, and combining human kallikrein-2 (hK2), total PSA (tPSA) and free-PSA (fPSA) into an algorithm:

hK2 x tPSA / fPSA

at 55% sensitivity, the specificity at 90%,[46]  may also be helpful in pre-intervention diagnosis of carcinoma of the prostate. BPSA[47] is elevated in nodular Benign Prostatic Hypertrophy and can help discriminate between benignancy and malignancy. BPSA and iPSA are isoforms of free-PSA that occur principally in benign transition zone portions of the prostate. Complex PSA (cPSA) at 90 to 95% sensitivity was more specific for carcinoma of prostate than total PSA (tPSA).

In the European Randomized Study of Screening for Prostate Cancer (ERSPC), Dr. Raaijmakers et al. noted that, “Men with prostate cancer had a mean PSA velocity of 0.62 ng/ml/yr compared with 0.46 ng/ml/yr for men with a negative biopsy. … The mean PSA doubling time … was 5.1 years … for men with prostate cancer and 6.1 years … for men with negative biopsy. … For men without prostate cancer regardless of whether biopsy was performed or indicated … the mean PSA doubling time was 17.3 years.”[48]   Further use of PSA dynamics can increase the accuracy of diagnosing prostate cancer without resorting to a biopsy before definitive treatment.

Dr. Raaijmakers et al., in another study, noted that “15.7% of … men … in the PSA range 2.0 to 2.9 ng/ml had biopsy detectable prostate cancer … [19.8% in range of 3.0 to 3.9 ng/ml] … 90% with percent free-PSA below 10% indeed had unfavorable tumor characteristics and the percent with unfavorable tumor characteristics decreased at higher percent free-PSA ranges. … Half of the tumors with a PSA lower than 4.0 ng/ml had aggressive characteristics on radical prostatectomy specimens.”[49]

In a different study, looking at similar PSA ranges, Dr. Kobayashi et al. noted that “90% of the Cancer of the Prostate cases detected with a low PSA level was organ-confined and potentially curable disease.”[50]

Dr. Filella et al. noted that “When we use free-PSA and complexed PSA simultaneously, we should obtain a maximization of the differences between patients with prostate cancer and those with benign prostatic hypertrophy (BPH).”[51]

Dr. Catalona et al. added that “Serum percent pro-PSA was significantly increased for Gleason score 7 or greater vs. less that 7 … In the PSA range of 4 to 10 ng/ml percent pro-PSA had the highest cancer specificity … detecting 34 of 35 cancers with pathology Gleason score of 7 or greater and 29 of 31 extracapsular tumors.”[52]

In some cases, the results of PSA isoforms leave much to be desired. If the total PSA is between 4 and 10 ng/ml, and the free-PSA is less than 10%, the chance of finding cancer on a biopsy is 56% (specificity); if the free-PSA is less than 25%, 95% of the cancers will be detected (sensitivity).[53]

If we are avoiding biopsy and going directly to a prostatectomy, that translates to 44% of the patients operated on, limited to those whose free-PSA was less than 10%, would not have cancer; conversely, if we included those with a free-PSA up to 25%, only 5% of the patients not operated on would have cancer.

If, on the other hand, we add p53 antibodies to our diagnostic survey, we might increase the specificity significantly. The “p53 antibodies are found predominantly in human cancer patients with a specificity of 96%,” according to Dr. Soussi, “consistent results have been observed in breast, colon, oral, and gastric cancers, in which they have been associated with high-grade tumors and poor survival.” He goes on to say, “One of the disadvantages of this assay is its lack of sensitivity inasmuch as only 20-40% of patients with p53 mutations will develop p53 antibodies.”[54]

Dr. Suzuki et al. state, “All patients with prostate cancer had significantly higher total PSA, PSA density, PSA transition zone density and p53-Antibodies than patients with Benign Prostatic Disease. … The serum p53-Antibodies titer had the most useful validity in discriminating between prostate cancer and benign prostatic disease in the overall patient population and in patients with normal digital rectal examination … while p53-Antibodies titer cannot be used for patients harboring other malignancies.”[55]   Unfortunately, p53-Antibodies are ineffective in diagnosing testicular cancer, melanomas and hepatomas. Even so, p53-Antibodies are an additional method of confirmation that might be capable of confirming a diagnosis of prostate cancer without resorting to biopsy. It offers an opportunity of improving specificity when combined with studies that have a high sensitivity.

Mastectomy without Preliminary Biopsy

“Mammaglobin, known for its mammary tissue specificity, has been discussed as a promising diagnostic marker in breast cancer,” report Dr. Zehentner et al.[56]   Coupling this blood test with the routine mammograms and MRI mammograms may well define who has a malignancy and who does not, without first performing a biopsy of the suspected lesion.


Dr. Leygue et al. point out that “Using RT-PCR, it was possible to detect mammaglobin in 13 out of 13 sections from axillary lymph nodes shown by histo-pathological examination of adjacent paraffin sections to contain metastatic cells and in none of the seven nodes that were negative … Mammaglobin has recently been identified as a breast-specific gene over expressed by approximately 23 per cent of primary breast tumours. … Mammaglobin was detected at a higher frequency in primary tumours that were node-positive … (90%) than in primary tumours that were node-negative … (60%).”[57]   Utilizing mammaglobin along with an MRI of the breast might give us a high enough specificity to proceed with treatment without the intervention of an invasive biopsy.

Prevention of Metastasis at Surgery

Dr. Kurusu et al. demonstrated that “ligating the pulmonary vein before ligating the artery may lessen intraoperative hematogenous dissemination,”[58] in surgical excision of non-small cell lung cancers. They demonstrated that cutting off the route of exit of malignant cells before manipulating the tumor in the process of its excision, and before removing the vessel that feeds the tumor its nourishment, can reduce the number of metastatic cells disseminated during surgery.

In reference to dissemination of prostate cancer cells, Dr. Eschwège et al. stated, “Dissemination of malignant prostatic cells after radical prostatectomy could be partly due to prostate manipulation during dissection. We confirmed by assay of prostate-specific membrane antigen by reverse-transcription nested PCR that prostate manipulation seeded prostatic epithelial cells in the general circulation in 12 of 14 consecutive patients operated on for organ-confined prostate adenocarcinoma. … Antiandrogen therapy might reduce the hæmatogenous spread of prostatic cells during radical prostatectomy.”[59]  Dr. Oliver stated, “Use of neoadjuvant hormones before prostatectomy substantially reduced the postoperative prostate-specific membrane antigen reverse transcriptase PCR positivity.”[60] Therefore, should we give a drug such as bicalutamide for 10 to 14 days before we do a prostatectomy in order to reduce iatrogenic metastasis?

“Recent evidence suggests that early androgen deprivation therapy improves outcomes for men with nonmetastatic prostate cancer. Primary androgen deprivation therapy improves survival for men with locally advanced nonmetastatic prostate cancer,” was an observation by Dr. Smith et al.[61]

Dr. Baum et al. stated, “The removal of the primary tumour disinhibits angiogenesis and encourages epithelial proliferation with the surgical trauma encouraging the secretion of insulin-like growth factor, so in other words the act of surgery kick-starts metastasis. [62]

Progress in reduction of mortality in Cancer

Although in the past several decades we have become capable of diagnosing cancer much earlier, our mortality from cancer has remained largely unchanged in America and the rest of the world. It is as if all the medical advancements achieved in the past 50 years in cancer therapy were no more than “spinning the wheels” of our intellect without making any progress. On the other hand, although the mortality of two major cancers of the twentieth century (stomach and uterine cervix) has been significantly reduced; neither of these reductions was dependent upon early diagnosis of the malignancy nor upon a biopsy of the malignant tumor. The reduction un lung cancer diagnosis is directly correlated to less people smoking, not some fantastic madical diagnostic tool.


A moment’s insight is sometimes worth a life’s experience.

Oliver Wendell Holmes (1809-1894),
Physician and Author

It is suggested by these studies, that where there are peripheral-blood/bone marrow CK-19/20-positive cells, where PSA-mRNA, alpha-fetoprotein (AFP) mRNA, mRNA coding for carcinoembryonic antigen (CEA), or beta-human chorionic gonadotropin (beta-hCG) mRNA is identified by RT-PCR post-operatively, there is potential relapse and death. If these cells get into the blood stream by nature of the tumor, it is beyond surgical control. If these cells get into the blood stream because we as Doctors and Surgeons are the vector that transmits them to the blood, we, as a profession, should find another way to deal with malignant tumors other than putting needles into them, and find means of eliminating cancerous lesions without the dissemination of cells that occurs with surgery.

Controlling the mechanical means of dissemination of malignant cells requires a revolution in medical practice. We must begin to diagnose without destroying the stabilized milieu of our patients. We must treat considering that we can do as much harm as good in the process, and alter our treatment protocol to reflect the results of recent research that confirms that biopsy and surgery precipitate metastasis. I have listed numerous publications that have documented the existence of mechanical or physical dissemination of tumor cells: malignant cells embedding in the biopsy needle tract, tumor cells circulating in the blood stream following incisional and needle biopsy, significant dissemination of tumor cells with Transurethral Resection of the Prostate (TURP), and of course, dissemination of malignant cells with open surgery. If surgery is unavoidable, can’t we protect the patient with well planned preoperative and peroperative protocols which ensure that the circulating cells do not become metastatic foci with secondary tumor growth.

We must consider proceeding with oncologic surgery without first doing a biopsy, perhaps initiating immonotherapy before surgery is ever even considered. Perhaps surgery can be performed in a CO2 “tent” over the patient, with the surgeon passing his hands into the chamber through gloved portals, or by robotic mechanisms. Co-ordination of the schedule of the consultants should be empowered, such that the medical oncologist, radiation oncologist and the surgeon all see the patient before any procedure, including biopsy, is initiated, and the timing of treatment is immediate and intensive. Each must also accept their limitations without prejudice so that we can truly do what is in the best interest of the patient. The medical team should be on the court at the same time, like a basketball team and not as a golfer, each one hitting his ball at a time convenient to his own schedule. We must treat cancer at least as we treat severe infections: initiate well conceived therapy quickly and intensely, knowing that we may have only one chance to cure the patient.

Finding disseminated cancer cells in the peripheral blood and in bone marrow after biopsy and surgery, with significantly reduced survival rates, indicate that we must change our modus operandi for diagnosing and treating cancer. In the studies I have presented, physicians, surgeons and biological scientists around the world are questioning the techniques we have been following for the past century and are suggesting radically new approaches to diagnosing as well as treating malignancies.

Continuing on the same course as followed by our medical predecessors in the healing arts for the past hundred years without constant evaluation of good science isn’t good science at all. It is dogmatic, and very poor judgement.

It is this our opinion that the research already performed has presented adequate proof that biopsies and surgery disseminate cancer cells sufficiently to cause the demise of the patient.

If we proceed without condemnation of what we have done in the past, and utilizing innovative ideas and imaginative concepts of how to proceed in the future, we might appear to future generations as incompetent as were our predecessors in dealing with Puerperal Sepsis. Thomas Watson in London in 1842 and Oliver Wendell Holmes in Boston, in the following year, began writing and lecturing on the probability of physicians, nurses and midwives being the vectors of the contagious disease, childbirth fever or Puerperal Sepsis. Dr. Ignaz Semmelweis in Hungary also blamed the high mortality rate of delivering mothers to their professional caregivers, and for his efforts, he was dismissed from his post in the Vienna Lying-In Hospital, ostracized from the medical community, discredited and his ideas rejected. He died a broken man in a psychiatric hospital. The struggle to save women from the trained professionals, whom they sought for their medical and obstetrical care, was an uphill battle. He is now a national hero.



[1] Sinner WN, Zajicek J. Implantation metastasis after percutaneous transthoracic needle aspiration biopsy. Acta Radiologica: Diagnosis (Stockholm) 1 July 1976, 17(4): 473-80

[2]  Kim JH, Kim YT, Lim HK, Kim YH, Sung SW, Management for chest wall implantation of non-small cell lung cancer after fine-needle aspiration biopsy, European Journal of Cardio-thoracic Surgery 23 (2003) 828-832

[3]  Harter L, Curtis J, Ponto G, Malignant seeding of the needle track during stereotaxic core needle breast biopsy. Radiology (1992) 185: pp713-714. Abstract

[4]  Youngson B. Lieberman L, Rosen P, Displacement of carcinomatous epithelium in surgical breast specimens following stereotaxic core biopsy. Am J Surg Pathol ( 1995) 103: pp 598-602 Abstract

[5]  Hoorntje L. E., Schipper M. E., Kaya A., Tumor cell displacement after 14G breast biopsy, Eur J Surg Oncol (2004) 30: pp 520-525. Abstract

[6]  Diaz L. K., Wiley E. L., Venta L. A., Are malignant cells displaced by large-gauge needle core biopsy of the breast? AJR Am J Roentgenol (1999) 173: pp 1303-1313. Abstract

[7]  Youngson B, Cranor M, Rosen P, Epithelial displacement in surgical breast specimens following needling procedures. Am J Surg Pathol (1994) 18: pp 896-903. Abstract

[8]  Stolier A, Skinner J, Levine E. A., A prospective study of seeding of the skin after core biopsy of the breast. Am J Surg (2000) 180: pp 104-107. Abstract

[9]  Marx T, Rainov NG, Heidecke V, Burkert W. Secondary tumor formation after stereotactic biopsy for intracerebral metastatic disease. Surg Neurol -01 January 2001; 55(1): 41-5

[10]  Aichholzer M, Mazal PR, Haberler C, Dietrich W, Bertalanffy A, Roessler K, Ungersboeck K. Epidural Metastasis of a Glioblastoma after Stereotactic Biopsy: Case Report. Minim Invasive Neurosurg -01 Sep 2001, 44(3): 175-7

[11]  Kim JE, Kim CY, Kim DG, Jung HW. Implantation metastasis along the stereotactic biopsy tract in anaplastic astrocytoma: a case report. J Neurooncol -01 FEB 2003; 61(3): 215-8

[12]  Karwowski JK, Nowels KW, McDougall IR, Weigel RJ. Needle Track Seeding of Papillary Thyroid Carcinoma from Fine Needle Aspiration Biopsy. A Case Report. Acta Cytol -01 May-2002; 46(3): 591-5

[13] de Sio I, Castellano L, Calandra M, Del Vecchio-Blanco C; Subcutaneous needle-tract seeding after fine needle aspiration biopsy of pancreatic liver metastasis. Eur J Ultrasound -01-Jun-2002; 15(1-2): 65-8

[14] Shinohara S, Yamamoto E, Tanabe M, Maetani T, Kim T. Implantation metastasis of head and neck cancer after fine needle aspiration biopsy. Auris Nasus Larynx -01-NOV-2001; 28(4): 377-80

[15]  Thurfjell MG, Jansson T, Nordgren H, Bergh J, Lindgren A, Thurfjell E. Local Breast Cancer Recurrence Caused by Mammographically Guided Punctures. Acta Radiol, Vol. 41(5) Sept 2000.435-440

[16] Knight R, Horiuchi K, Parker SH, Ratzer ER, Fenoglio ME. Risk of Needle-track Seeding After Diagnostic Image-guided Core Needle Biopsy in Breast Cancer, JSLS -01-JUL-2002, 6(3): 207-9

[17] Sawabata N, Ohta M, Maeda H. Fine-Needle Aspiration Cytologic Technique for Lung Cancer Has a High Potential of Malignant Cell Spread Through the Tract. Chest, Vol. 118, No. 4 *October 2000, The American College of Chest Physicians.

[18]  Straub B, Müller M, Krause H, Schrader M, Goessl C, Heicappell R, Miller K. Detection of prostate-specific antigen RNA before and after radical retropubic prostatectomy and transurethral resection of the prostate using “Light-Cycler”-based quantitative real-time polymerase chain reaction. Urology -01-NOV-2001; 58(5): 815-20

[19] Moreno JG, O’Hara SM, Long JP, Veltri RW, Ning X, Alexander AA, Gomella LG. Transrectal ultrasound-guided biopsy causes hematogenous dissemination of prostate cells as determined by RT-PCR. Urology -01-APR-1997; 49(4): 515-20.

[20] Moreno JG, O’Hara SM, Gross S, Doyle G, Fritsche H, Gomella LG, Terstappen LW. Changes in circulating carcinoma cells in patients with metastatic prostate cancer correlate with disease status. Urology, 01-Sep-2001: 58(3): 386-92

[21] Hara N, Kasahara T, Kawasaki T, Bilim V, Tomita Y, Obara K, Takahashi K. Frequency of PSA-mRNA-bearing cells in the peripheral blood of patients after prostate biopsy. Br J Cancer – 17 AUG-2001: 85(4):557-62

[22] Ellis WJ, Pfitzenmaier J, Colli J, Arfman E, Lange PH, Vessella RL. Detection and isolation of prostate cancer cells from peripheral blood and bone marrow. Urology -01-Feb-2003; 61(2): 277-81

[23] Kusukawa J, Suefuji Y, Ryu F, Noguchi R, Iwamoto O, Kameyama T. Dissemination of cancer cells into circulation occurs by incisional biopsy of oral Squamous cell carcinoma. Journal of Oral Pathology and Medicine, 01 Aug 2000; 29(7): 303-7

[24] Hu XC, Chow LW; Fine needle aspiration may shed breast cells into peripheral blood as determined by RT-PCR. Oncology -01-SEP-2000; 59(3): 217-22

[25] Hansen NM, Ye X, Grube BJ, Giuliano AE, Manipulation of the primary breast tumor and the incidence of sentinel node metastases from invasive breast cancer. Archives of Surgery-01-JUN-2004; 139(6): 634-9; discussion 639-40

[26] Chagpar AB, Scoggins CR, Sahoo S, Martin RC II, Carlson DJ, Laidley AL, El-Eid SE, McGlothin TQ, Noyes RD, Ley PB, Tuttle TM, McMasters KM. Biopsy type does not influence sentinel lymph node status, American Journal of Surgery, Volume 190, Number 4, October 2005.

[27] Crisan D, Ruark DS, Decker DA, Drevon AM, Dicarlo RG, Detection of circulating epithelial cells after surgery for benign breast disease. Molecular Diagnosis: A Journal Devoted to the Understanding of Human Disease Through the Application of Molecular Biology -01-MAR-2000; 5(1); 33-08

[28] Louha M, Nicolet J, Zylberberg H, Sabile A, Vons C, Vona G, Poussin K, Tourmebize M, Capron F, Pol S, Franco D, Lacour B, Bréchot C, Paterlini-Bréchot P, Liver resection and needle liver biopsy cause hematogenous dissemination of liver cells. Hepatology- 01-MAR-1999; 29(3): 879-82

[29] Stathopoulou A, Vlachonikolis I, Mavroudis D, Perraki M, Kouroussis Ch, Apostolaki S, Malamos N, Kakolyris S, Kotsakis A, Xenidis N, Reppa D, Georgoulias V. Molecular detection of Cytokeratin-19-positive cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic significance. J Clin Oncol -15-AUG-2002; 20(16): 3404-12

[30] Majima T, Ichikura T, Takayama E, Chochi K, Mochizuki H. Detecting circulating cancer cells using reverse transcriptase-polymerase chain reaction for Cytokeratin mRNA in peripheral blood from patients with gastric cancer. Jpn J Clin Oncol -01-NOV-2000; 30(11): 499-503

[31] Lilleby W; Nesland JM; Fosså SD; Torlakovic G; Waehre H; Kvalheim G; The prognostic impact of cytokeratin-positive cells in bone marrow of patients with localized prostate cancer. International Journal of Cancer, 1-JAN-2003, 103(1): 91-6

[32] Zhang XW, Fan P, Yang HY, Yang L, Chen GY, [Significance of detecting disseminated tumor cells in peripheral blood of gastric and colorectal cancer patients.] Chung-Hua Chung Liu Tsa Chih [Chinese Journal of Oncology]-01-JAN-2003; 25(1): 66-9 Language Chinese, ABSTRACT (English)

[33] Demicheli R, Retsky MW. Comment on “The process of metastasisation for breast cancer: by J. Engel, R. Eckel, J, Kerr et al. Eur J Cancer -01-MAR-2004; 40(4); 619-20; author reply 621-3

[34] Jennifer L. Gnerlich, Anjali D. Deshpande, Donna B. Jeffe, Allison Sweet, Nick White, Julie A. Margenthaler, Elevated Breast Cancer Mortality in Women Younger than Age 40 Years Compared with Older Women Is Attributed to Poorer Survival in Early-Stage Disease, Journal of the American College of Surgeons – Volume 208, Issue 3 (March 2009)

[35] Demicheli R, Valagussa P, Bonadonna G. Does surgery modify growth kinetics of breast cancer micrometastases? Br J Cancer (2001) 85(4); 490-492, Cancer Research Campaign

[36] Demicheli R, Retsky MW, Swartzendruber DE, Bonadonna G. Proposal for a new model of breast cancer metastatic development. Annals of Oncology 8: 1075-1080, 1997.

[37] Galán M, Viñolas N, Colomer D, Soler G, Muñoz M, Longarón R, Ventura PJ, Gascón P, Estapé J. Detection of occult breast cancer cells by amplification of CK19 mRNA by reverse transcriptase-polymerase chain reaction: role of surgical manipulation. Anticancer Res -01-SEP-2002; 22(5): 2877-84

[38] Coffey JC, Wang JH, Smith MJF, Bouchier-Hayes D, Cotter TG, Redmond HP. Excisional surgery for cancer cure: therapy at a cost. The Lancet Oncology, Vol. 4, No. 12, December 2003

[39] Moreno JG, Shenot PJ, Shupp-Byrne D, Gomella LG. Analysis of tumor spillage during radical prostatectomy using RT-PCR of prostate specific antigen. Tech Urol -01-APR-1996: 2(1): 54-7

[40] Yamaguchi K, Takagi Y, Aoki S, Futamura M, Saji S, Significant detection of circulating cancer cells in the blood by reverse transcriptase-polymerase chain reaction during colorectal cancer resection. Annals of Surgery 01-JUL-2000; 232(1): 58-65 ABSTRACT

Good to there

[41] Pidgeon GP, Harmey JH, Kay E, Da Costa M, Redmond HP, Bouchier-Hayes DJ, The role of Endotoxin/lipopolysaccharide in surgically induced tumour growth in a murine model of metastatic disease. Br J Cancer -01-DEC-1999; 81(8): 1311-7

[42] Hansen E, Wolff N, Knuechel R, Ruschoff J, Hofstaedter F, Taeger K. Tumor Cells in Blood Shed From the Surgical Field. Arch Surg -01-APR-1995; 130(4): 387-93

[43] Da Costa ML; Redmond HP; Finnegan N; Flynn M; Bouchier-Hayes D. Laparotomy and laparoscopy differentially accelerate experimental flank tumour growth. Br J Surg, 01-Oct-1998: 85(10): 1439-42 Abstract

[44] Paik HC, Lee DY, Lee HK, Kim SJ, Lee KB. Chest Wall Implantation of Carcinoma after Fine Needle Aspiration Biopsy. Yonsei Medical Journal, Vol. 35, No. 3, 1994

[45] Partin AW; Catalona WJ; Southwick PC; et al. Analysis of percent free prostate-specific antigen (PSA) for prostate cancer detection; influence of total PSA, prostate volume, and age, Urology 1996, 48:55-61 ABSTRACT

[46] Haese A, Graefen M, Huland H, Lilja H, Prostate-specific Antigen and Related Isoforms in the Diagnosis and Management of Prostate Cancer, Current Urology Reports 2004, 5:231-240

[47] Canto EI, Singh H, Shariat SF, Lamb DJ, Mikolajczyk SD, Linton HJ, Rittenhouse HG, Kadmon D, Miles BJ, Slawin KM. Serum BPSA outperforms both total PSA and Free-PSA as a predictor of prostatic enlargement in men without prostate cancer. Urology -01-MAY-2004; 63(5): 905-10; discussion 910-1

[48] Raaijmakers R, Wildhagen MF, Ito K, Pàez A, de Vries SH, Roobol MJ, Schröder FH. Prostate-Specific Antigen change in the European Randomized Study of Screening for Prostate Cancer, section Rotterdam. Urology -01-FEB-2004; 63(2): 316-20

[49] Raaijmakers R, Blijenberg BG, Finlay JA, Rittenhouse HG, Wildhagen MF, Roobol MJ, Schröder FH. Prostate Cancer Detection in the Prostate Specific Antigen Range of 2.0 to 3.9 ng/ml: Value of percent Free Prostate Specific Antigen on Tumor Detection and Tumor Aggressiveness. Jour Urol Vol. 171, 2245-2250, June 2004

[50] Kobayashi T, Nishizawa K, Ogura K; Mitsumori K, Ide Y. Detection of Prostate Cancer in Men with Prostate-Specific Antigen levels of 2.0 to 4.0 ng/ml equivalent to that in men with 4.1 to 10.0 ng/ml in a Japanese population. Urology -01-APR-2004; 63(4): 727-31

[51] Filella X, Truan D, Alcover J, Quintó L, Molina R, Luque P, Coca F, Ballesta AM. Comparison of Several Combinations of Free, Complexed, and Total PSA in the Diagnosis of Prostate Cancer in Patients with Urologic Symptoms. Urology -01-JUN-2004; 63(6); 1100-3; Discussion 1103-4

[52] Catalona WJ, Bartsch G, Rittenhouse HG, Evans CL, Linton HJ, Horninger W, Klocker H, Mikolajczyk SD. Serum Pro-Prostate Specific Antigen preferentially detects aggressive prostate cancers in men with 2 to 4 ng/ml prostate specific antigen. Jour Urol, Vol. 171, 2239-2244, June 2004

[53] Han M; Gann PH; Catalona WJ. Prostate-specific antigen and screening for prostate cancer. Medical Clinics of North America, Vol. 88, No. 2, March 2004

[54] Soussi T, p53 Antibodies in the sera of patients with various types of cancer: a review. Cancer Res – 1-APR-2000; 60(7):1777-88 ABSTRACT

[55] Suzuki H, Akakura K, Igarashi T, Ueda T, Ito H, Watanabe M, Nomura F, Ochiai T, Shimada H. Clinical usefulness of serum anti-53 antibodies for prostate cancer detection: A comparative study with prostate specific antigen parameters. Jour Urol, Vol. 171, 182-186, January 2004

[56] Zehentner BK, Carter D. Mammaglobin: a candidate diagnostic marker for breast cancer. Clinical Biochemistry 37 (2004) 249-257

[57] Leygue E, Snell L, Dotzlaw H, Hole K, Troup S, Hiller-Hitchcock T, Murphy LC, Watson PH. Mammaglobin, a Potential Marker of Breast Cancer Nodal Metastasis. J Pathol 189; 28-33 (1999), John Wiley & Sons, Ltd.

[58] Kurusu Y, Yamashita J, Hayashi N, Mita S, Fujino N, Ogawa M. The Sequence of Vessel Ligation Affects Tumor Release into the Circulation. J Thoracic and Cardiovasc Surg -01-JUL-1998; 116(1): 107-13

[59] Eschwège P, Dumas F, Blanchet P, Le Maire V, Benoit G, Jardin A, Lacour B, Loric S. Hæmatogenous dissemination of prostatic epithelial cells during radical prostatectomy. Lancet -9-DEC-1995; 346(8989):30

[60] Oliver RTD. Does surgery disseminate or accelerate cancer? Letter to Editor, The Lancet, Vol. 346, Dec 9, 1995

[61] Smith MR, Finkelstein JS, McGovern FJ, Zietman AL, Fallon MA, Schoenfeld DA, Kantoff PW. Endocrine Care of Special Interest to the Practice of Endocrinology. Journal of Clinical Endocrinology and Metabolism, Vol. 87, No. 2, February 2002, The Endocrine Society.

[62] Baum M, Chaplain MAJ, Anderson ARA, Douek M, Vaidya JS. Does Breast Cancer Exist in a State of Chaos? Eur Jour Cancer, Vol. 35, No. 6, pp 886-891 (1999)