RATIONALE FOR OUR APPROACHES TO NON-TOXIC REVERSAL OF CANCERS, PROFOUND IMMUNE SUPPRESSION, AND OTHER SYNDROMES: TRACK RECORD OF MAINSTREAM RATIONALIST APPROACHES TO CANCER
Early detection of cancer as many statistics can show, has had a significant impact on general morbidity and probably survival. Advanced cancers that become established may constitute a different disease than operable cases, and therefore our focus over the years has been more acutely focused on those cancers deemed terminal syndromes. However, it is generally acknowledged in the cancer community that directed and often-aggressive chemo-therapies, radiation therapies, or immune therapies constitute assaults on the cancer patient. Not only do these “rational,” target-directed approaches not increase life expectancy in most cancer patients, they cause significant harm in the form of bone marrow suppression, immune dysfunction, epithelial cell destruction, nervous system stress or destruction, loss of salivation and taste in head and neck radiotherapy, burns of the skin, massive infections, and gastrointestinal collapse, castration, cachexia, and consequent mal-absorption of food, and other side-effects leading to morbidity and death. According to a recent New England Journal of Medicine meta-analysis of Phase 1 Oncology Trials (where toxicity is typically assessed) between 1991 and 2002:
“In a survey of 460 Phase I trials of standard toxic cancer chemotherapy agents given to slightly less than 12,000 patients, the partial and complete response rates were reported to have changed from 4-5% to 10% during 1991-2002, with 3% showing a complete response, and 7% showing a partial response.”
3% complete response does not mean a 3% “cure” rate, but simply, the rate of complete tumor regression, as measured by the best current methods of tumor detection during the period studied. Although the meta-analysis claimed that as many as 44.7% of patients showed some “benefit” from their therapy, and that there was a 0.5% death rate attributable to Phase I dose escalation itself, suggesting minimal overall toxicity, the “benefits” they measured were not defined and included surrogate endpoints. The data they present also must be qualified because a host of different cancer types were assessed, in which blood-borne cancers that are now more responsive than ever before to targeted therapies, heavily weighted their analysis toward the positive value of the 3% complete response rate they reported. The overall success rate of complete response is not encouraging, not to mention the fact that a cure rate is not even considered, or discussed, or mentioned. When discussion of “cure” does occur, it is typically about the successes, as shown recently by a new target, the abl receptor, targeted by Gleevec (imatnib mesylate). However it should be borne in mind that this drug combats a “free-swimming” blood-borne population of tumor cells, instead of solid tumors, and many issues regarding abl inhibitors have been raised.
A survey of oncology reviews about the toxicity and lack of efficacy of current Phase I, II, and III trials for specific cancers treated with traditional chemotherapeutic agents, radiation, and targeted immunotherapy can be obtained on a daily basis at the website of the peer-review institute at: email@example.com.
These clinical trial assessments show much lower response rates with solid tumors from trails aimed at specific types of cancer. For example, The European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, The World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593, in a trial of 832 melanoma patients, reported that:
“The results of this study show that regional infusion of chemotherapy to the limb in proximity to a melanoma lesion in the attempt to reduce the risk of future tumor recurrences is associated with significant adverse events, and no benefits. Eight hundred thirty-two patients were enrolled in the study; 412 underwent surgery consisting of resection of the melanoma lesion, and 420 underwent surgery followed by isolated limb perfusion with the anticancer drug melphalan plus mild hyperthermia. Progression of disease and overall survival did not differ between the two groups. Toxicity (including two limb amputations) occurred significantly more often in patients who underwent chemotherapy compared to those who did not. These data do not support the use of adjuvant chemotherapy in the management of patients with early cancer.”
In a different kind of prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b, it was reported recently that: “This was a randomized study to determine whether the addition of immunotherapy to chemotherapy results in better tumor control in patients with advanced melanoma. One hundred-two patients were enrolled; 52 patients received chemotherapy only, and 50 patients received chemotherapy plus immunotherapy (interferon alpha and interleukin-2). Although tumor responses were observed more frequently in the chemo-immunotherapy group (44% vs. 27%), this group also experienced higher treatment-related toxicity and showed a trend of decreased survival. Both regimens produced tumor responses that were only partial and short lasting.”
These outcomes, although bleak for the cancer patient, are as problematic for the cancer survivor. An Institute of Medicine report was just released calling for a paradigm shift regarding how cancer patients are managed over the long term, and asking for ways to reduce the toxicity and often morbid long-term side effects of conventional chemotherapies and radiation. (Institute of Medicine Report: Cancer Survivorship: Improving Care and Quality of Life, November 7, 2005; http://www.iom.edu/report.asp?id=30869).
“Some 10 million Americans are now cancer survivors. Large numbers are living longer than ever because of remarkable advances in early detection and treatment. But many survivors receive less than optimal follow-up, and improvements in care are necessary, the Institute of Medicine, part of the National Academies of Science, advised in a major report released Monday, November 7, 2005”.
As presented in the Chicago Tribune:
“The negative consequences of cancer and its treatments are substantial and under-appreciated,” said Dr. Sheldon Greenfield, panel chairman and director of the center for health policy research at the University of California, Irvine. “Many [patients] suffer permanent and disabling symptoms that impair normal functioning … [but] there is much that can be done to avoid, ameliorate or arrest these late effects.”
“The Institute of Medicine study, which focuses on adult cancer survivors, highlights a profound shift in thinking about this once-deadly disease. Until recently, researchers and clinicians had one goal: saving more lives. With improved survival rates, however, cancer increasingly is being viewed as a chronic illness like diabetes or hypertension, presenting a new set of challenges.”
“Some are medical. The very toxic therapies that assault tumors and help save lives put patients at risk of new problems down the road, including second cancers, heart disease, sexual dysfunction, cognitive impairment, infertility, and chronic inflammation, research shows. For any given patient, experts note, the risk of long-term complications depends on the type and location of the cancer, the nature and duration of treatment and other factors.”
“For instance, women with breast cancer who receive chest radiation therapy are at risk of developing lung cancer later, according to research cited in the report. Chemotherapy using agents known as anthracyclines increases the odds of contracting leukemia. And tamoxifen, a commonly used therapy for women with estrogen receptor-positive tumors, increases the risk of stroke, blood clots, and endometrial cancer.”
Nevertheless, a survey of the FDA’s list of approved drugs entering mainstream cancer chemotherapy clearly reveals a tendency to repeat the failures of the past. The FDA granted marketing applications to 71 oncology applications between January 1, 1990, and November 1, 2002 (see list following references). New additions to the FDA lists include cytotoxic drugs, monoclonal antibodies that have no efficacy and significant toxicity, immune-modulating drugs that oxidize cells and cause severe morbidity, and, a plethora of accessory drugs to boost erythrocyte production or T-cell production, anti-diarrhea medications, or medications to correct the myriad of complications due to the current toxic regimens the patient experiences.
It is truly surprising that despite these kinds of results from studies that directly target tumors (and these examples are representative of hundreds of similar trials not discussed here), new ideas or strategies that could potentially combat cancer more effectively and less toxically, are seldom given a chance, or are suppressed. When new approaches or treatments are permitted a phase I trial, it is only after a targeted drugging, radiation, or targeted immuno-therapy regimen has failed numerous times, and after the patient is considered “terminal.” In this context, how can new rational approaches be scientifically tested? How can new rational therapies begin to accrue toxicity and efficacy (or non-efficacy data) after a patient’s immune system has been assaulted numerous times, and when the disease has advanced to the point where death is imminent?
A survey of oncology reviews about various trials (only melanoma because melanoma and breast cancer are our principal areas) yield the same information, day in, and decade out: toxicity and objective failure of 20 clinical trials using current cancer establishment drugs used in human cancer chemotherapy are presented in support of this sad statement:
1) The role of adjuvant therapy in melanoma management. This article underlines that two decade of research in melanoma treatment failed to demonstrate a relapse-free and overall survival advantage in patients with stage II and stage III melanoma treated with adjuvant chemotherapy or levamisole, compared to those treated with surgery only. One trial that studied the efficacy of interferon-gamma was interrupted after patients in the treatment group demonstrated higher mortality rates that the control group.
2) Cutaneous malignant melanoma in Scotland: incidence, survival, and mortality, 1979-94 [The Scottish Melanoma Group. MacKie RM, et al. BMJ 1997 Nov 1;315(7116):1117-21]: The results of this study show that overall mortality rates in patients with melanoma decreased by 12% from 1984 to 1990, and this decrease seems attributable to earlier detection and other unknown factors, but not to treatment. The study was conducted on 6288 patients who had been diagnosed with melanoma between 1979 and 1990. During this time frame, the incidence of melanoma approximately doubled in both men and women (from 3.5 to 7.8 new cases for 100,000 men per year, and from 6.8 to 12.3 new cases for 100,000 women per year). Mortality rates remained steady from 1979 to 1984, then decreased by 10% in men and by 6% in women during 1985-1987, due to an increased detection of early stage cancers, and again decreased slightly from 1987 to 1990. The reasons for this latter decline in mortality rates is unknown, but it is not attributed to treatment, since the only change in treatment modalities that occurred during this time was the introduction of a more conservative surgical approach to tumor removal.
3) Interferon alfa-2a and interleukin-2 with or without cisplatin in metastatic melanoma: a randomized trial of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group. Keilholz U; et al. J Clin Oncol, 15(7):2579-88 1997 Jul. The results of this study show that chemotherapy treatment with cisplatin does not prolong survival in patients with metastatic melanoma. The study was conducted on 138 patients with advanced melanoma who were divided in two groups: one group received interferon and interleukin-2 plus cisplatin, and the other received interferon and interleukin only. No differences in survival were detected between the two groups.
4) Adjuvant treatment in stage I and II malignant melanoma: a randomized trial between chemoimmunotherapy and immunotherapy. Castel T; et al. Dermatologica, 183(1):25-30 1991. The results of this study show that chemotherapy does not prolong survival in patients with early stage melanoma. Eighty-two patients were randomized to receive immunotherapy (with the bacillus Calmette-Gu´erin) only, or immunotherapy and chemotherapy. No differences in survival were observed between the two groups.
5) Recombinant interleukin-2-based treatments for advanced melanoma: the experience of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group.Keilholz U; Stoter G; Punt CJ; Scheibenbogen C; Lejeune F; Eggermont AM Cancer J. Sci Am, 3 Suppl 1():S22-8 1997 Dec. This article presents current evidence on the role of chemotherapy in the management of patients with advanced melanoma. Single-agent or combination chemotherapy in patients with stage IV melanoma has shown to produce high rates of tumor responses (tumor shrinkage), but no improvement in overall survival. It has not yet been determined whether the toxicity of these regimens outweighs their potential (and yet to be proven) benefits.
6) Phase II trial of topotecan in malignant melanoma. Kraut EH; Walker MJ; Staubus A; Gochnour D; Balcerzak SP. Cancer Invest, 15(4):318-20 1997. This study assessed the effects of the anticancer drug topotecan in patients with advanced melanoma. Sixteen patients were enrolled in the trial. No tumor responses were observed. Severe toxicity occurred in 70% of patients.
7) Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. Rosenberg SA, et al. J Clin Oncol, 17(3):968-75 1999 Mar. This was a randomized study to determine whether the addition of immunotherapy to chemotherapy results in better tumor control in patients with advanced melanoma. One hundred-two patients were enrolled; 52 patients received chemotherapy only, and 50 patients received chemotherapy plus immunotherapy (interferon alpha and interleukin-2). Although tumor responses were observed more frequently in the chemo-immunotherapy group (44% vs. 27%), this group also experienced higher treatment-related toxicity and showed a trend of decreased survival. Both regimens produced tumor responses that were only partial and short lasting.
8) Randomized phase II trial of BCDT [carmustine (BCNU), cisplatin, dacarbazine (DTIC) and tamoxifen] with or without interferon alpha (IFN-alpha) and interleukin (IL-2) in patients with metastatic melanoma. Johnston SR; et al. Br J Cancer, 77(8):1280-6 1998 Apr. The results of this randomized trial show that the addition of interleukin 2 and interferon 2 alpha to chemotherapy in patients with advanced melanoma does not result in prolonged relapse-free and overall survival, and is associated with a twofold increased rate of toxic reactions.
9) Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma National Cancer Institute of Canada Clinical Trials Group. Rusthoven JJ; et al. J Clin Oncol, 14(7):2083-90 1996 Jul. The results of this double-blind placebo-controlled, randomized trial show that the addition of tamoxifen to chemotherapy does not improve rate of tumor response in patients with advanced melanoma.
10) Phase II trial of interleukin 1 alpha and indomethacin in treatment of metastatic melanoma. Janik JE; et al. J Natl Cancer Inst, 88(1):44-9 1996 Jan 3. The results of this study show that combination treatment with interleukin 1 alpha and indomethacin in patients with melanoma is associated with minimal tumor response (10%) and significant adverse effects.
11) Phase II trial of recombinant human interleukin-4 in patients with disseminated malignant melanoma: a Southwest Oncology Group study. Whitehead RP; et al. J Immunother, 21(6):440-6 1998 Nov. The results of this study show that interleukin 4 is not effective in the management of patients with advanced melanoma. Thirty-four patients were enrolled in the study. Tumor response was observed in only one patient (3%). Average survival was 6 months. Adverse effects included liver toxicity, nausea and vomiting, diarrhea, headache, fatigue, muscular and joint pains, edema, fever and chills.
12) Eastern cooperative group trial of interferon gamma in metastatic melanoma: an innovative study design. Schiller JH; Pugh M; Kirkwood JM; Karp D; Larson M; Borden E. Clin Cancer Res, 2(1):29-36 1996 Jan. The results of this study show that treatment with interferon gamma is ineffective in the management of patients with metastatic melanoma. Ninety-eight patients were enrolled in the study. Tumor responses were observed in 5% of patients and were of short duration. Toxicity included liver toxicity, fever and chills.
13) Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma. A randomised phase III trial. Jungnelius U; et al. Eur J Cancer, 34(9):1368-74 1998 Aug. The results of this study show that the addition of cisplatin to a chemotherapy regimen consisting of dacarbazine and vindesine does not result in improved survival and adds significant toxicity in patients with advanced melanoma.
14) Phase II clinical trial of recombinant alpha 2b interferon and 13 cis retinoic acid in patients with metastatic melanoma. Rosenthal MA; Oratz R. Am J Clin Oncol, 21(4):352-4 1998 Aug. The results of this study show that treatment with interferon alpha and retinoic acid does not improve survival and causes significant toxicity in patients with metastatic melanoma. Thirteen patients were enrolled in the study. Tumor shrinkage was observed in one case. All patients experienced substantial fatigue, muscle pains, loss of appetite, and inflammation of the oral lining. Severe toxicity required 50% dose reduction in 7 patients, and interruption of treatment in another one.
15) Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma An Eastern Cooperative Oncology Group study. Falkson CI; Ibrahim J; Kirkwood JM; Coates AS; Atkins MB; Blum RH. J Clin Oncol, 16(5):1743-51 1998 May. The results of this study show that tamoxifen and interferon are ineffective in the treatment of patients with advanced melanoma. Two hundred fifty-eight patients were randomized to receive the anticancer drug dacarbazine in one of the following four regimens: dacarbazine only, dacarbazine plus tamoxifen, dacarbazine plus interferon, or dacarbazine plus both tamoxifen and interferon. No differences in survival were observed between the four groups, but patients receiving interferon experienced significantly more toxicity.
16) Interferon-alpha and chemohormonal therapy for patients with advanced melanoma:Final results of a phase I-II study of the Cancer Biotherapy Research Group and the Mid-Atlantic Oncology Program. Stark JJ; et al. Cancer, 82(9):1677-81 1998 May 1. The results of this study show that the addition of interferon alpha to combination chemotherapy in patients with advanced melanoma does not improve survival and is associated with severe toxicity.
17) A phase II study of carboplatin, cisplatin, interferon-alpha, and tamoxifen for patients with metastatic melanoma. Gause BL; et al. Cancer Invest, 16(6):374-80 1998. The results of this study show that combination treatment consisting of cisplatin, carboplatin, tamoxifen, and interferon-alpha in patients with advanced melanoma is associated with an 18% tumor response and with unacceptable toxicity.
18) The role of interleukin-2 in the management of stage IV melanoma The EORTC melanoma cooperative group program. Keilholz U, Eggermont AM. Cancer J Sci Am 2000 Feb;6 Suppl 1:S99-103. This study reviewed the results of 27 trials conducted on 631 patients with advanced stage melanoma receiving combination treatment with interleukin (IL)-containing regimens. Administration of chemotherapy was not associated with improved outcome. The effects of IL2 on survival are still being evaluated in a trial that is currently under way.
19) Combined treatment with dacarbazine, cisplatin, fotemustine and tamoxifen in metastatic malignant melanoma. Richard MA, et al. Melanoma Res, 8(2):170-4 1998 Apr. The results of this trial, conducted on 20 patients with advanced stage melanoma, show that treatment with a combination chemotherapy regimen consisting of dacarbazine, cisplatin, fotemustine, and tamoxifen does not improve survival and causes significant toxicity, and is therefore not recommended in the management of this disease.
20) Phase II study of combined levamisole with recombinant interleukin-2 in patients with advanced malignant melanoma. Creagan ET, et al. Am J Clin Oncol, 20(5):490-2 1997 Oct. This study presents the results of a trial conducted on 19 patients with advanced melanoma enrolled to receive an experimental protocol consisting of levamisole and interleukin-2. No tumor responses were observed. Severe toxicity was observed in 5 patients. The authors conclude that this regimen should not be further tested on patients with malignant melanoma.
It is truly surprising, in fact, that upon these kinds of results, our modern cancer establishment has launched an all out campaign against any new ideas or strategies that could potentially combat cancer more effectively. The massive drugging campaigns currently permitted, and increasingly funded, are vigorously defended at all costs.
Most of the new additions to the FDA lists for the past several years include similar cytotoxic drugs as presented in the limited trials shown above, monoclonal antibodies that have no efficacy and significant toxicity, and of course, a plethora of accessory drugs to boost erythrocyte production or T-cell production, anti-diarrhea medications, or medications to correct the myriad of complications due to the current toxic regimens while the patient is waiting to die.
PROMOTING NON-TOXIC TESTING AND REVERSION OF CANCER, AIDS, AND VACCINE INJURIES THAT INDUCE CANCERS
A general unifying theme to all of our research programs has been to determine how non-living biological extracellular matrix (ECM) scaffolds have a multitude of purposes in Nature, and have a fundamental importance in all living processes including cancer, profound immune suppression as in lymph node fibrosis and AIDS, and in the production of microbial biofilms.
Perhaps our most noted contribution constitutes the new field of vasculogenic mimicry (VM). The phenomenon of VM emerged from studies of melanoma that we were the first to explore, and then in the context of the therapeutic reversal of melanoma and breast cancer that followed, using applications of non-toxic natural ECM molecules, their subfragments, or antibodies against them such as anti-fibronectin and laminin, that are critical in tissue building and tissue maintenance embryos, adults, tumors, AIDS, cirrhosis, and microbial biofilms.
There currently are over 100 cancer research and clinical trial-studying groups throughout the world now employing the finding, testing methods, and therapeutic strategies that employ vasculogenic mimicry based on our “mechanogenomic-directed”discoveries of global chromatin organizational control and phenotypic control of tissue formation via the ECM, and tumor reversion studies (please see The National Library of Medicine on line here: http://www.ncbi.nlm.nih.go/pubmed?term=vasculogenic%20mimicry).
The ECM is not only like a glue on the outside of cells that cements them together: it provides perhaps the most important information signals for cell growth, cell differentiation, and genome organization and gene expression. These extracellular matrices determine how normal cells, cancer cells, microbial biofilms, or viruses behave, and we have shown that only two matrix molecules, laminin and fibronectin, are required to completely and consistently change the organization and expression of genes and tissue structure reversibly between cancer-like and normal tissue growth and structure in the context of melanoma and breast cancer.
A hundred years of research on embryonic development and cancers further suggests that cancer should be approached as a syndrome that is correctable, or reversible. Several years ago, armed with this hypothesis, we demonstrated in the laboratory that through non-toxic control of the levels and distribution of extracellular matrix molecules that normally up or down regulate tissue growth during all tissue development, it was possible to generate normal breast gland milk ducts from malignant breast cancer tumor cells. In effect, these experiments demonstrated the possibility of regenerating normal tissue from cancer cells. The same approach applied to several other types of cancer (melanoma and lung cancer tissue), and theoretically, could be applied to other debilitating or fatal syndromes attributed to viral, bacterial, fungal, mycoplasmal, or other disease-associated entities.
Basic research has shown there appears to be an incompletely understood balance and distribution of the normal tissue-building and homeostatic molecules, laminin and fibronectin, that controls both normal and tumor tissue growth and development, microbial biofilm formation and resistance, how a virus behaves, and how these matrix-determined phenomena can be exploited toward goals such as cancer reversion or immune reconstitution.
This idea has been greatly augmented only recently by population studies that studied when and where tumors arise in our pet cats and dogs. For instance, recent consensus statements from The American Veterinary Medical Association, The Feline Sarcoma Society, Purdue University’s Veterinary School in Indiana, and other veterinary associations in Australia, and in England, have claimed that tumors may arise at or nearby vaccination sites in our pets with a variety of vaccines. This information, together with our reversal studies suggest that it is likely that a variety of routinely administered preventative vaccinations of our pets apparently can cause a profound local disturbance of these two important tissue- regulating molecules, laminin and fibronectin, followed by a systemic immunological attack on these two molecules and several other molecules, such as collagen, cardiolipin, and even DNA. Some estimates of data developed by such agencies as the Feline Sarcoma Society, in collaboration with Purdue University have estimated that 160,000/tumors occur in cats at their vaccination sites in cats and cancer is reported as being the single largest inducer of illness and death in dogs over two years old, and anti-bodies against these and several other ECM components are found in the blood of these vaccine-cancer-induced pets. Dogs may pertain even more to the human situation with respect to tumor formation at vaccine sites, or tumor formation nearby them in lymph nodes, than that cat data. For melanoma in dogs alone (and in other vaccinated animals such as horses), there are 31 pages of National Library of Medicine-listed studies that can be found here (http://www.ncbi.nlm.nih.gov/pubmed?term=melanoma%2C%20dogs). Please also see a round-table panel discussion regarding how leading veterinarians have surmised the true incidence of vaccine-associated sarcomas in cats (http://www.avma.org/journals/javma/articles_public/vafstf_050601.asp).
The following kinds of statements, for instance, have been advanced:
The American Veterinary Medical Association (AVMA) Vaccine-Associated Feline Sarcoma Task Force initiated several studies to find out why 160,000 cats each year in the USA develop terminal cancer at their vaccine injection sites. (1. Please also see “Notes” at the end of this page for more conservative estimations and also for more information about vaccine-induced tumors as being an untapped resource for cancer reversal) The fact that cats can get vaccine-induced cancer has been acknowledged by veterinary bodies around the world, and even the British Government acknowledged it through its Working Group charged with the task of looking into canine and feline vaccines (2) following pressure from Canine Health Concern.
A team at Purdue University School of Veterinary Medicine conducted several studies (3,4) to determine if vaccines can cause changes in the immune system of dogs that might lead to life-threatening immune-mediated diseases. The vaccinated, but not the non-vaccinated, dogs in the Purdue studies developed autoantibodies to many of their own biochemicals, including fibronectin, laminin, DNA, albumin, cytochrome C, cardiolipin and collagen.This means that the vaccinated dogs — ”but not the non-vaccinated dogs”— were attacking their own fibronectin, which is involved in tissue repair, cell multiplication and growth, and differentiation between tissues and organs in a living organism.
There is ample evidence also to conclude that other disturbed matrix syndromes such as arthritis, asthma, neurological disorders especially those involving demyelination such as MS, various autism spectrum disorders, and many others are the result of vaccinations in both the animal and human context, as was detailed in the 2008 Nobel speech of Harold Zur Hausen. During this televised talk (the URL is given in the section of this website devoted to vasculogenic mimicry), Zur Hausen showed as yet unpublished human and cattle data of vaccine-induced tumors at the sites of injection.
Our recent research and the research of other groups also have provided experiments that show that the presence and relative concentration balance of these two fundamental tissue-forming molecules also controls drug and radiation resistance and stem cell behaviors.
Similarly, because it has now been demonstrated that one of these ECM molecules can control growth and and at high concentrations, the lysis (killing) of drug-resistant microbial biofilms, because they are perhaps Nature’s most fundamental growing tissues too, as they are comprised of impenetrable associations of microbes and the matrix they secrete to constitute the world’s first and most primitive tissues. As a result of these observations, an entirely new class of bacteria or fungi-static or lytic molecules are being developed derived from ECM molecules that are non-toxic, yet are at least as effective in preliminary studies at stopping biofilm formation, as is penicillin, gentimycin, or fungizone. These matrix proteins exert their anti-microbial action without the toxicity or a need for limited recommended periods of usage of antibiotics or anti-fungals, as they do not suppress respiration or mitochondria. Thus, this and other evidence suggests that at this point, the antibodies made against these molecules following vaccination need to be prospectively monitored carefully and systematically, in populations of vaccinated and non-vaccinated pets and people that do or do not develop cancers following vaccination. These molecules also may constitute the earliest detection method for cancer, through a simple blood test, and is worth developing if only because as shown in the surveys above, early detection remains the only advance that significantly has improved cancer patient survival.
The gene revolution has essentially come and gone-leaving us with very little to show for such awesome support, continuing investment, and initial promise. Its failure to achieve its promised goals has been the result of tacit assumptions about Nature that proved to have been incomplete.
A new revolution in the biological sciences is currently taking shape along with the discovery of epigenetic forces that control the genes, and “apogenetic forces” and materials that originate from the extracellular matrix. At the basis of this revolution, is a new appreciation of how Nature operates according to what can best be described as “efficient causes,” and is best modeled through such concepts of tensegrity and other new sciences. It is hoped that the above information emphasizes the urgency to tolerate and support new approaches to the diseases currently diagnosed as cancer, which may be best regarded as a disease of tissue growth at the wrong place and time in the already developed organism. As such, it is not a degenerative disease (especially in its earlier stages or indeed late into its metastatic spread). Instead, urgent and in earnest discussions and experiments need to take place in large-bodied animal models whose tumors originated from “self” (not foreign grafted tumor cells from other sources that are immunologically different from self), and which possess a functional immune system at the onset of their cancer, unlike animal models that are genetically or pharmacologically repressed so they won’t reject foreign grafts. In this context, non-toxic treatments should be tested that ultimately can reverse, or in another sense, “regenerate” normal tissue from tumor tissue.
Even if vaccine-induced cancers in companion animals, livestock, and humans is of a more aggressive nature than naturally induced tumors, it still will someday become a necessary step to demonstrate, as did Pasteur, a therapeutic effect in the background containing an initially-intact immune system, and cancer cells that develop from “self” as opposed to those experimental models created in rodent or other small-bodied mammalian models, into which foreign tumor cells, genetically-weakened or pharmacologically-weakened immune systems are in place, as once advocated by a Late dear colleague of mine, who was director of Madison, Wisconsin’s Veterinary Clinics and Medical student training, Dr.Greg MacEwen:
Spontaneous tumors in dogs and cats: Models for the study of cancer biology and treatment. E. Gregory MacEwen
“Spontaneous tumors in dogs and cats are appropriate and valid model tumor systems available for testing cancer therapeutic agents or studying cancer biology. The pet population is a vastly underutilized resource of animals available for study. Dogs and cats develop spontaneous tumors with histopathologic and biologic behavior similar to tumors that occur in humans. The tumors with potential relevance for human cancer biology include osteosarcoma, mammary carcinoma, oral melanoma, oral squamous cell carcinoma, nasal tumors, lung carcinoma, soft tissue sarcomas, and malignant non-Hodgkin’s lymphoma.”
“Canine osteosarcoma is a malignant aggressive bone tumor with a 90% matastasis rate after surgical amputation. Its predictable metastatic rate and pattern and its relative resistance to chemotherapy make this tumor particularly attractive for studying anti-metastasis approaches. Canine and feline malignant mammary tumors are fairly common in middle-aged animals and have a metastatic pattern similar to that in women; that is, primarily to regional lymph nodes and lungs. Chemotherapy has been minimally effective, and these tumors may be better models for testing biological response modifiers.”
Oral tumors, especially melanomas, are the most common canine malignant tumor in the oral cavity. Metastasis is frequent, and the response to chemotherapy and radiation has been disappointing. This tumor can be treated with anti-metastatic approaches or biological response modifiers. Squamous cell carcinomas, especially in the gum, are excellent models for radiation therapy studies.
“Nasal carcinomas are commonly treated with radiation therapy. They tend to metastasize slowly, but have a high local recurrence rate. This tumor is suitable for studying radiation therapy approaches.”
“Primary lung tumors and soft tissue sarcomas are excellent models for studying combined modality therapy such as surgery with chemotherapy or biological response modifiers.”
“Finally, non-Hodgkin’s lymphoma is a common neoplastic process seen in the dog. These tumors respond to combination chemotherapy and have great potential as a model for newer chemotherapeutic agents and biological response modifiers.”
In the context of epistemology, efficient versus final causal thinking needs to be more widely implemented in seeking mechanistic explanations in biology, because even in physics, the cause of gravity is still among the most active and out of reach areas in research. For example, hypothetical constructs such as “gravitons,” or “gravity nets” have been proposed to describe how quantum gravity may be caused, but these particles or nets have yet to be discovered, or even vaguely implicated as existing as real entities in an experiment. In the contexts of biology and medicine, it isn’t only evoking semantics or political incorrectness to loudly protest when cancer (or “AIDS”) are said to be caused by a single entity.
Current conceptual frameworks regarding the initiation, promotion, and progression of cancer are typically more complex than are causal associations first appreciated by young children who associate the sound of a rattle with the shaking of the rattle itself. In fact, simple genetic determinism in the context of cancer was replaced with a growing body of work that dates back at least as far as the 1800’s, when Galliotti and Boveri and others first described aneuploidy in connection with human cancer. Or when in E.B. Wilson’s famous book, “The Cell In Development and Inheritance,” the observations of Roemer were reviewed concerning cellular direct division. Or when Coley also in the 1800’s discovered how in some cases, bacterial skin infections and bacterial endotoxins induced high fever and subsequent complete “immune” rejection of cancer in some of his terminally ill cancer patients. From the records of his patients kept by his daughter, Helen Coley Nauts, who founded the Cancer Research Institute associated with Sloan Kettering in New York in 1953, just under 1,000 cases of treating cancer with the bacterial vaccine Coley developed can be found. In these well-documented cases, many of the patients were followed, and almost half of them lived to old age or died from a cause other than cancer. Presumably, all of Coley’s documented responses to his treatment occurred in what were terminal or near terminal cancer patients, whose tumors harbored all kinds of mutations and aneuploidy, yet were reversed via a kind of “immune modulation” that is still poorly understood, and difficult to repeat in practice, probably due to antibiotic usage among patients who acquire fevers during their terminal days?
One hypothesis that has attempted to explain how a tumor might be rejected by the cancer patient through sudden recognition of the tumor cells as non-self may involve a phenomenon known as “the danger hypothesis” (see The Danger Model in Its Historical Context-P. Matzinger, Scandanavian Journal of Immunology Vol.61, 2003). Tumor rejection may work by alerting the organism that something is amiss within the body. The science stimulated by Coley’s observations and development of his toxins is still alive and promising, and has evolved into modern cancer immunotherapy, which is just one example of many types of treatment strategies that have been shown to be promising yet have nothing whatsoever to do with genetic determinism.
It can also be cogently argued that “the oncogene” theory was thrown out after the accidental inoculation in 1963 of 100 million Americans with early poliovirus vaccines that were contaminated with simian virus 40 without apparent increases in cancer resulting (Carrol-Pankhurst et al. British Journal of Cancer, 85 (9), 1205-1207, 2001). Yet the able insights and work of Michele Carbone and his colleagues, at the University of Hawaii and elsewhere suggest that brain cancers, mesothelioma, and the tissue tropisms of the SV-40 agent have a mechanistic basis in the molecules transferred into cells, and which can “transform” them differentially:
Tissue Tropism of SV40 Transformation of Human Cells: Role of the Viral Regulatory Region and of Cellular Oncogenes. Zhang L, Qi F, Gaudino G, Straianese O, Yang H, Morris P, Pass HI, Nerurkar VR, Bocchetta M, Carbone M. Genes Cancer, Oct;1(10):1008-20, 2010. Source University of Hawai’i Cancer Center, Honolulu, HI, USA).
Carbone and his colleagues, for instance, have shown with convincing scientific epidemiological rigor, and contrary to the 35 year study of Pankhurst et al. mentioned above, that followed more than 1000 infants injected with the SV-40 agent, that indeed there is reason to believe that the polio vaccines, laced with the SV-40 agent, injected into millions, has caused cancer, in addition to other environmental toxins such as erionite found in high abundance in Turkey, where cancer occurs at extremely high frequency. Carbone’s hypothesis, in addition, is supported by veterinarians and the American Veterinary Medical Association in the context of inducing cancers at or near injection sites.
The nature of cancer is still unknown and may not be due to genetic mistakes. In contrast to immune modulation of cancer, genetic associations with cancer in human populations, have to date only been linked to an identifiable genetic event in 1% or perhaps 5% of human cancers, leaving 95% of them, and perhaps all of them, unexplainable in the simple terms of genetic determinism. TPA, the tumor- promoting compound, promotes cancer without inducing genetic changes. Moving the rattle causes sound, the infant learns. Genes cause cancer we are told. Those genes can be isolated we are instructed. Those genes can be put into cells with viral promoters, and “transform” cells by disturbing the cells’ chromatin and cytoskeleton and adhesion receptor distribution and expression during the transfection procedure, and perhaps because of other toxic effects that happen in a Petri dish. Cause and effect. In other words, our ignorance of the complexity of disease in general, and cancer and “AIDS” in particular constitute valid reasons for each generation of scientists to ask fundamental questions, even about the cause of gravity, or the “cause and development of cancer or “AIDS,” which are still unknown.
Common sense, on the other hand, teaches us (as we do our medical students), that cancer, autoimmune syndromes, or immune defects aren’t contagious illnesses. If as viruses, cancer, autoimmune, or immunosuppression-associated viruses were transmissible (contagious), and spread from person to person to cause illnesses, then unlike influenza, rabies, and other viral illnesses, why can physicians and family members have direct and intimate exposure to cancer patients (or AIDS patients) as much as they like even on their death beds, and yet the treating physician or family member need not worry at all about the patient passing on to them a horrible virus that will infect them and generate that same type of cancer, autoimmune syndrome, or immune-deficiency?
In real human cancer syndromes that involve invasive and/or metastatic cellular processes, and which lead to the predictable interruption of normal organ system function and eventual death, the progression of events thought to occur in many cases of cancer cannot be said to be caused by or reduced to the effects of a single gene or virus anymore than the development of a tumor can be attributed specifically to radiation, carcinogens, excessive cellular oxidation damage to genetic material or proteins or lipids, immune deficiency, centrosome deregulation, DNA repair mechanism deregulation, aneuploidy (as Duesberg and others have suggested in the recent literature, and as drawings from 100 years ago of Galeotti’s and Boveri’s comparisons of cancer cell and normal cell chromosomes illustrated through documenting the gross differences in chromatin structure and chromosome numbers in human tissue harboring a tumor), changes in mitochondrial membrane permeability, changes in the composition or organization of the cell cytoskeleton, the cell membrane, or the cell cortex, the development of sub-populations of cells within tumors that stimulate or repress other populations of cells within the tumors, a breakdown or reorganization of the extracellular matrix, tumor angiogenesis, vasculogenic mimicry, advancing age, hot soup, and potentially because of a trillion other factors. In terms of the statistical associations with agents or phenomena that are associated with cancer, we warn medical students to be aware of the following scenario in working up a differential diagnosis, or before advancing a new hypothesis regarding an association between cause X, and a disease syndrome Y.
In New York City, during the summer, the sidewalks get hot from the sun and crack more frequently than they do in the winter. Also during the summer there is a higher rate of infant mortality. Therefore, cracking sidewalks cause a higher infant mortality rate in New York during the summertime.
In fact, it would not be too extreme to advocate that the concept of causality should be abolished from modern scientific thinking altogether (as it was in physics after Heisenberg), and replaced by a mechanistic systems approach in the basic sciences, and an empirical, case-based, differential diagnosis-like model, in medicine. This revolution in science and medicine, is in fact occurring. For example, in biology, muscle biologists, neurobiologists, as well as vascular physicians and neurologists in the medical field are now describing how the heart works and how heart attacks result, and how epilepsy kindles in the brain, according to new principles borrowed from chaos theory and systems biology. The evidence that these new approaches can predict biological processes better than older conceptual models based on causality is demonstrated by the nature of the chaos theory-based stimulation circuitry built into modern pace makers. Cell biologists are now describing the complex motions and behaviors of cells according to new conceptual frameworks such as tensional integrity, which seeks to advance a physical description of the cytoarchitectural coordination of cell movements as complex as cell motility or even mitosis (see Donald Ingber, “The Architecture of Life.” Scientific American, January, pp48-57, 1998, or Maniotis, A., Chen, C., Ingber, D. Demonstration of mechanical interconnections between integrins, cytoskeletal filaments, and nuclear scaffolds that stabilize nuclear structure. Proc. Nat. Acad. Sci . Vol. 94 pp.849-854, 1997). At the same time, a pharmacogenomic approach for cancer, in which the complex genetic profiles of individual patients that involve thousands of genes acting in concert, is being developed in the arena of cancer therapeutics, and the end result of this thinking aims at designing a particular cancer therapeutic regimen for each individual cancer patient. Although pharmacogenomics may be short sighted because the focus is genetically based, at least pharmacogenomic approaches are implementing the realization that hundreds of genes and gene products fluctuate not only among different cancer patients who may harbor the same type of diagnosed cancer, but fluctuate within cancer cells within a single tumor (Maniotis A., Folberg R., Hess A., Seftor E., Gardner L., Pe’er J., Trent J., Meltzer P., Hendrix M. Vascular channel formation by human uveal melanoma cells in vivo and in vitro: Vasculogenic mimicry. Amer. J. Path. Vol. I55, No 3, pps. 739-752, September, 1999; Maniotis AJ, Valyi-Nagy K, Karavitis J, Moses J, Boddipali V, Wang Y, Nuñez R, Setty S, Arbieva Z, Bissell MJ, and Folberg R: Chromatin organization measured by Alu I restriction enzyme changes with malignancy and is regulated by the extracellular matrix and the cytoskeleton. Am J Pathol 166: No. 4 April 2005).
1. Illmensee K, Mintz B. Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts. Proc Natl Acad Sci U S A 1976;73:549-553.
2. Kulesa PM, Kasemeier-Kulesa JC, Teddy JM, et al. Reprogramming metastatic melanoma cells to assume a neural crest cell-like phenotype in an embryonic microenvironment. Proc Natl Acad Sci U S A 2006;103:3752-3757.
3.Folkman J, Moscona A. Role of cell shape in growth control. Nature. Jun 1;273(5661):345-9, 1978.
4. Strohman, R.C., Bayne, E., Spector,D., Obinata,T., Micou-Eastwood, J., Maniotis A. Myogenesis and histogenesis of skeletal muscle on flexible membranes. In Vitro Cell Dev. Biology, Vol 26: pp. 201-208, 1990.
5. Maniotis, A., Chen, C., Ingber, D. Demonstration of mechanical interconnections between integrins, cytoskeletal filaments, and nuclear scaffolds that stabilize nuclear structure. Proc. Nat. Acad. Sci . Vol. 94 pp.849-854, 1997.
6. Maniotis A., Folberg R., Hess A., Seftor E., Gardner L., Pe’er J., Trent J., Meltzer P., Hendrix M. Vascular channel formation by human uveal melanoma cells in vivo and in vitro: Vasculogenic mimicry. Amer. J. Path. Vol. I55, No 3, pps. 739-752, September, 1999.
7. Bissell MJ, Radisky DC, Rizki A, Weaver VM, Petersen OW. The organizing principle: microenvironmental influences in the normal and malignant breast. Differentiation. 2002 Dec;70(9-10):537-46. Review.
8. Weaver VM, Petersen OW, Wang F, et al. Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J Cell Biol;137:231-245, 1997.
9. Maniotis AJ, Valyi-Nagy K, Karavitis J, Moses J, Boddipali V, Wang Y, Nuñez R, Setty S, Arbieva Z, Bissell MJ, and Folberg R: Chromatin organization measured by Alu I restriction enzyme changes with malignancy and is regulated by the extracellular matrix and the cytoskeleton. Am J Pathol 166: No. 4 April 2005.
10. Folberg R, Arbieva Z, Moses J, Hayee A, Sandal T, Kadkol S, Lin AY, Valyi-Nagy K, Setty S, Leach L, Chevez-Barrios P, Larsen P, Majumdar D, Pe’er J, Maniotis AJ.Tumor cell plasticity in uveal melanoma: microenvironment directed dampening of the invasive and metastatic genotype and phenotype accompanies the generation of vasculogenic mimicry patterns. Am J Pathol. Oct;169(4):1376-89, 2006.
11. Tone Sandal, Klara Valyi-Nagy, Robert Folberg, Mina Bissell, Virginia Spensor, Andrew Maniotis. Epigenetic reversion of breast carcinoma phenotype and DNA sequestration. American Journal Of Pathology, Vol. 170(5):1739-49. May, 2007.
12. Klara Valyi-Nagy, Robert Folberg, Tibor Valyi-Nagy, Andrew J. Maniotis. Susceptibility of Herpes simplex Virus Type I and II, The Role of Tumor Invasiveness, The Extracellular Matrix, and Chromatin Sequestration. In press, May, Experimental Eye Research, Vol. 84, 9991-10,000, 2007.
13. Jon Cohn. “It’s The Gut, Stupid.” 4 March Vol 307, p. 1395, 2005.
14. Pantaleo G, Graziosi C, Demarest JF, Butini L, et al. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 1993b;362(6418):355-8.
15. Yarkoni E., Rapp HJ. Influence of type of oil and surfactant concentration on the efficacy of emulsified Mycobacterium bovis cell walls to induce tumor regression in Guinea pigs. Infection and Immunity, Vol 28, No 3, June, 1980 p. 881-886.
16. Ghori A. Usselmann B., Odogwu S., Fraser I., Morris A. Colorectal Disease, April, vol. 2, no. 2, pp. 106-112, 2000.
17. Mangiacasale R, Pittoggi C, Sciamanna I, Careddu A, Mattei E, Lorenzini R, Travaglini L, Landriscina M, Barone C, Nervi C, Lavia P, Spadafora C. CNR, Institute of Molecular Biology and Pathology, Rome, Italy. Exposure of normal and transformed cells to nevirapine, a reverse transcriptase inhibitor, reduces cell growth and promotes differentiation. Oncogene. May 8;22(18):2750-61, 2003.
17. Adusumilli et al., Radiation therapy potentiates effective oncolytic viral therapy in the treatment of lung cancer. Ann Thorac Surg. 2005 Aug;80(2):409-16; discussion 416-7.
18. Stiles et al., Minimally invasive localization of oncolytic herpes simplex viral therapy of metastatic pleural cancer. Cancer Gene Ther. 2005 Jul 22;
19. Liu et al., Intracarotid delivery of oncolytic HSV vector G47Delta to metastatic breast cancer in the brain. Gene Ther. 2005 Apr;12(8):647-54).
20. Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. Rosenberg SA, et al. J Clin Oncol, 17(3):968-75 1999 Mar.
REFERENCES REGARDING VACCINE-INDUCED CANCERS:
2. Veterinary Products Committee (VPC) Working Group on Feline and Canine Vaccination, DEFRA, May 2001.
3.. “Effects of Vaccination on the Endocrine and Immune Systems of Dogs, Phase II”, Purdue University, November 1,1999, at http://www.homestead.com/vonhapsburg/haywardstudyonvaccines.html.
It is estimated that 22 million cats were vaccinated during 1991.5 However, because many cats received multiple vaccines, the number of vaccines administered to cats that year was much higher than 22 million. In addition, there has been a proliferation of new vaccines for cats in the marketplace since the late 1980s, including vaccines for FeLV, feline infectious peritonitis virus, Bordetella bronchiseptica, Giardia spp, and dermatophytes. The need to prevent infectious diseases should now be balanced against the risk of VAFS and other adverse advents. Vaccination should be viewed as a medical, rather than a routine, procedure. However, the profession lacks sufficient data to accurately assess the relative risk of administering a particular vaccine or antigen to an individual cat.
Incidence of VAFS—The true incidence of vaccine-associated sarcomas in cats is unknown. Sarcomas develop at vaccination sites at rates ranging from 1 case/10,000 cats to 10 cases/10,000 cats and develop primarily after administration of rabies virus and FeLV vaccines.3,4,16 These estimates are based on retrospective epidemiologic studies and surveys of biopsy specimens submitted to diagnostic laboratories and, in conjunction with current estimates of the US cat population and the number of annual visits to veterinarians, suggest that between 2,200 and 22,000 cats will develop vaccine-associated sarcomas each year.
In a retrospective study4 of 345 cats with vaccine-associated sarcomas, the risk that a cat would develop a sarcoma after administration of a single vaccine in the cervical-interscapular region (a site not recommended by the VAFSTF or AAFP guidelines) was 50% higher than the risk that a cat not receiving any vaccines at this site would. In the same study, the risk for a cat given 2 vaccines at the same site was approximately 127% higher, and the risk for a cat given 3 or 4 vaccines was 175% higher than the risk for a cat not receiving vaccines at that site. Time to tumor development in cats following vaccination was as short as 3 months and as long as 3 years or longer.4
Pathologic abnormalities—Vaccine-associated sarcomas in cats are most often fibrosarcomas, but many other types of sarcomas have also been reported.6,12,14 These sarcomas in cats are usually characterized by marked nuclear and cellular pleomorphism, high mitotic activity, and large central zones of necrosis, features consistent with an aggressive biological behavior. Often a peripheral inflammatory infiltrate consisting of lymphocytes and macrophages is seen. Macrophages in these sarcomas often contain a bluish-gray foreign material identified by electron probe x-ray microanalysis to be aluminum and oxygen. Aluminum hydroxide is 1 of several adjuvants used in currently available feline vaccines. Similar inflammatory responses and foreign material have been described for inflammatory vaccination-site reactions in cats, dogs, and humans.3,24
Vaccine-associated sarcomas consist of cells that are morphologically and immunohistochemically compatible with fibroblasts and myofibroblasts. The precise pathogenesis of vaccine-associated sarcomas is unknown but may involve stimulation of these cells by highly immunogenic and persistent adjuvants or other vaccine components resulting in inflammation that alone or in association with unidentified carcinogens or oncogenes leads to neoplastic transformation and tumor development. Transition zones from inflammatory granuloma to sarcoma have been identified and strongly suggest that the inflammatory response to vaccination is antecedent to sarcoma development in cats.25 Inflammation is known to precede development of other types of cancers in cats and other species.26
REFERENCES CITED IN “NOTES.”: Full reference list can be obtained at: http://www.avma.org/vafstf/vafstf01.asp
3. Hendrick MJ, Goldschmidt MH, Shofer FS, et al. Postvaccinal sarcomas in the cat: epidemiology and electron probe microanalytical identification of aluminum. Cancer Res 1992;52:5391–5394.
4. Kass PH, Barnes WG Jr, Spangler WL, et al. Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats. J Am Vet Med Assoc 1993;201:396–405.
5. Esplin DG, McGill LD, Meininger AC, et al. Postvaccination sarcomas in cats. J Am Vet Med Assoc 1993;202:1245–1247.
6. Hendrick MJ, Brooks JJ. Postvaccinal sarcomas in the cat: histology and immunohistochemistry. Vet Pathol 1994;31:126–129.
7. Hendrick MJ, Schofer FS, Goldschmidt MH, et al. Comparison of fibrosarcomas that developed at vaccination sites and at nonvaccination sites in cats: 239 cases (1991–1992). J Am Vet Med Assoc 1994;205:1425–1429.
16. Coyne MJ, Reeves NCP, Rosen DK. Estimated prevalence of injection-site sarcomas in cats during 1992. J Am Vet Med Assoc 1997;210:249–251.
26. Morrison WB. Environmental causes of naturally occurring cancers in dogs and cats. In: Morrison WB, ed. Cancer in dogs and cats: medical and surgical management. Philadelphia: The Williams & Wilkins Co, 1998;31–41.
Also, for an round table discussion transcript by veterinary vaccine experts discussing how estimates of true vaccine-caused sarcomas have been obtained , and also, the the VAFSTF report ( Morrison WB, Starr RM. Vaccine-associated feline sarcomas. J Am Vet Med Assoc 2001;218:697–702) see:
Here is part of that discussion:
In 1985, we made a big change in the way cats are vaccinated in this country. We went from the use of a modified-live rabies virus vaccine to an adjuvanted killed virus vaccine. In the same year, an aluminum adjuvanted FeLV vaccine was introduced. Both of those events correspond temporally to the emergence of vaccine-associated sarcomas in the late 1980s.
I think it’s important to note that the requirement to use killed rabies virus vaccines was thrust on the veterinary community as well as the vaccine manufacturers because of concern that the modified-live virus vaccines could potentially cause rabies in immunosuppressed animals.22-24 Also, a new or novel adjuvant was not introduced during that same time. The same types of adjuvants had been used for a long time in veterinary medicine, and until just a few years ago, they were the only types allowed for use in vaccines for humans.
Results of epidemiologic studies8,25 performed in the 1990s indicated an incidence rate of approximately 1 to 3 sarcomas/10,000 vaccinated cats, but some claim that results of later studies suggest a lower incidence rate. Is there a discrepancy?
Some studies measure incidence, and some measure prevalence; they’re not the same thing. Simplistically speaking, incidence refers to the occurrence of new disease over a period of time. It can be measured as a cumulative proportion, or it can be measured per unit time at risk (ie, a rate). Prevalence is a reflection of the cross-sectional presence of disease in a population at a particular point in time and is, simplistically speaking, a function of the incidence rate and the duration of the disease. The early estimates were very rough approximates. Initially, when the problem was first recognized, we weren’t even sure exactly what we were looking at or whether it was even a real problem. It was difficult to try to establish the incidence of something that we didn’t even know existed.
There are many challenges in trying to accurately measure the incidence, even in a prospective cohort study like our Web-based survey.26 One of the single biggest problems was that the pathologists used in these studies were unable to definitively determine that a sarcoma was caused by a vaccine. It’s important that the results of that study are not misinterpreted. We did not say that we had finally determined the incidence of vaccine-associated sarcomas. Rather, the major thrust of the study was what the incidence of vaccine-associated sarcoma is not; it is not a common tumor among vaccinated cats. The results did not appear to be compatible with an incidence of more than approximately one in 5,000 cats. I don’t know how many of these tumors remain undiagnosed, and that is a big impediment when performing incidence studies. But to come back to the question about discrepancies, I don’t think we can compare results of various studies because the studies were performed differently.
Are there any other comments on incidence studies?
I think we know enough about the biology and pathology of the sarcoma to make educated guesses about which sarcomas are associated with injection sites. I think, as in any epidemiologic study, there would be confirmed cases and suspect but unconfirmed cases. Then, the incidence rate of each could be measured, and I suspect that the true incidence would be somewhere between the two. I think such an incidence study is possible. It would take tremendous resources and collaborations to conduct, but I think the challenges to doing it are not that different from those presented by other diseases that have a clinical definition but no firm diagnostic criteria. But I agree with Dr. Kass that the estimates are going to vary because the studies are extremely different. Whatever the incidence rate is, it’s going to be low.
DR. LINK WELBORN:
But from a practitioner’s standpoint, I think there is an incredible need to inform clients of the risk of their cat developing a sarcoma. Although I recognize the limitations associated with determining an incidence rate, I think we need to be able to give clients an educated guess.
There are two ways of looking at this. First, if the risk is one in 5,000 as opposed to one in 10,000 cats, would it really make a difference to the owner? How precise of an estimate is necessary for a client to make an educated decision? Second, I think what means more to the client is the relative risk; that is, if we give this vaccine, then the risk that their cat will develop a vaccine-associated sarcoma is three to four times greater than if we give another vaccine. Results of studies by Kass et al8,9 clearly indicate that there is an increased risk of sarcoma formation after administration of rabies virus and FeLV vaccines in cats. However, that still doesn’t tell the veterinarian or the owner just how likely it is that a particular vaccine will cause a problem.
I think we have to be careful because there may well be a great deal of difference among vaccines. All rabies virus vaccines are not necessarily the same, nor are all FeLV vaccines.
It may be sufficient for practitioners to inform clients that there may be a potential problem but that the problem is rare. They don’t have to say that the risk is one in 10,000 or one in 1,000 cats; only that it’s a rare event and that if the client decides not to vaccinate their cat, then here is the potential outcome. In other words, inform clients of the risk of an adverse reaction associated with vaccination, compared with the risk of not vaccinating.
As we have noted, one of the problems confronting epidemiologic studies is the difficulty in determining whether a particular sarcoma was indeed caused by a vaccine. Are there any histopathologic criteria that can clearly distinguish vaccine-associated sarcomas from those that develop from other causes?
Strictly speaking, no. When I’m looking at a sarcoma, there are no criteria that indicate to me that it was caused by a vaccine. Having said that, histologically, the sarcomas look different from other sarcomas. One study27 compared the histopathologic findings in vaccination site and nonvaccination site sarcomas; results indicate that differences were detected. Sarcomas at the vaccination site were associated with more inflammation, necrosis, and cellular pleomorphism and increased mitotic activity and extracellular matrix. Visually, the most interesting characteristic is how much sclerosis and matrix there are in the sarcoma, and in the matrix, there are really bizarre, markedly pleomorphic tumor cells with high mitotic indices. In fact, I can pick up a slide, know that the sarcoma is from a cat, look at it, and 99.9% of the time I’m correct in saying it is a sarcoma from a vaccination site.
The criteria used to identify most of these sarcomas are very good. The sarcomas are just different from the typical fibrosarcomas in cats. The cells have large irregular nuclei, they are frequently pleomorphic, and the mitotic index is high. Commonly, there is a central area of necrosis containing fluid. The sarcoma will frequently have aggregates of lymphoid tissue around it and irregular aggregates of macrophages. If those macrophages have foamy cytoplasm containing bluish-gray granular material (not that the material necessarily caused the sarcoma), then this essentially locks in the diagnosis. Not all of the criteria are detected in all sarcomas. The question becomes, does a less aggressive neoplastic process related to these sarcomas exist that would make them more difficult to identify?
We have noticed all kinds of differentiation. We have seen fibrosarcomas, malignant histiocytomas, osteosarcomas, and mixed-cell differentiation. Occasionally, we’ve seen hemangiosarcomas, rhabdomyosarcomas, chondrosarcomas, myofibrosarcomas, liposarcomas, and lymphosarcomas associated with this neoplastic process.
A sarcoma induced by an injection of any substance may not necessarily first appear at the site of injection because antigen-processing cells can migrate away, and sarcomas can develop at some distance away from the original injection site. If there were histologic criteria that would invariably describe injection-induced sarcomas, regardless of whether they initially appeared at an injection site, you could interpret the published data entirely differently in terms of incidence.
When I make a diagnosis, I call the sarcoma what it is: a fibrosarcoma, rhabdomyosarcoma, or whatever. Then, in my comment, I will indicate that these features are most consistent with a vaccine-associated sarcoma.
If the same slide was sent to different pathologists, how much agreement would there be?
At least 70% or 80%, maybe even 90%.
I agree. In a previous study,27 we gave slides to different pathologists and there was good general agreement as to whether they were the type of sarcomas seen at vaccination sites or the type of sarcoma they had seen for years in sites that were not associated with vaccination sites.
Practitioners who might not think twice about a tumor developing at a vaccination site would read an article about vaccine-associated sarcomas and then report it or indicate that it was a tumor from a vaccination site. So, to overcome potential bias in that study,27 we examined feline sarcomas that developed during a 20- or 30-year period and classified them as appearing either at a vaccination site or at a nonvaccination site on the basis of what was provided in the history. Then, we examined the ratio of vaccination site sarcomas to nonvaccination site sarcomas with time. The ratio changed dramatically from perhaps 10% or 20% of all sarcomas developing at vaccination sites in the early 1980s to the opposite, 80% to 90% developing at vaccination sites, in the 1990s. So, something happened at vaccination sites to change that ratio. As others have pointed out, we have to try to understand what changed, but in my experience, it has been very difficult to determine. Specifics about vaccine formulations and manufacturing processes are proprietary information. So, industry and veterinary scientists will have to work together to find the answer.
Are there any other factors that make epidemiologic studies difficult?
Retrospective studies are easy to conduct because they rely on preexisting cases of sarcomas and do not require waiting long periods for sarcomas to develop. The major drawback to retrospective studies, however, is that the incidence rate cannot be determined, and accurate vaccination histories are difficult to obtain. We have performed 20 or 30 studies in which we try to retrieve vaccination history from owners, such as which vaccines were given, when, and at what site, and it’s tremendously difficult. There’s so much inaccuracy, and veterinary records are often no better.
Prospective or cohort studies are preferable to retrospective studies because they yield incidence rates of sarcomas associated with different types of vaccines, but they generally require large sample sizes and many years to perform. However, it is now possible to overcome these obstacles by use of the millions of cats vaccinated at large corporate practices with electronic records. But even then, there are problems. For example, a corporate practice may use products from only one vaccine manufacturer, making it impossible to answer the question, “does this brand of rabies virus vaccine cause more reactions than that brand?” And results of those studies are easy to misinterpret if someone says, “Aha! See, that vaccine causes three reactions/10,000 cats, so let’s use some other vaccine,” when, in fact, we have no information on the other vaccine.
Obviously, the longer you look, the more difficult the study will be and the greater the number of external confounders (eg, other products given in the same injection site). Incidence studies may also need to be supplemented with owner questionnaires, measurement of vaccination site masses, or follow-up histopathologic examination. A single incidence study would probably cost as much as all other VAFSTF-funded studies combined. I’m confident with enough resources it can be done, but I’m not sure it’s worth the effort.
I worry, too, that as time goes on we may be getting skewed samples of cats because veterinarians may become less inclined to submit biopsy specimens from masses for diagnosis, fearing that they may be opening themselves to litigation. I agree with Dr. Glickman that the only realistic way to perform incidence studies is to use an enormous database from a large corporate practice. However, there would be a problem of representativeness because corporate practices tend to practice medicine in a fairly unified way, including fealty to a small number of vaccine brands.
Just for fun, I decided to perform some sample size calculations with the assumption that the incidence of vaccine-associated sarcomas in cats was one in 10,000, and I wanted to determine whether a particular vaccine doubled the risk. What sample size would be needed if I were going to perform a prospective study? I don’t have the answer yet because it’s so computationally difficult. The sample size was at 1.9 million cats and still going on my computer when I last looked. If complete information is contained in an electronic database, that would be great. Otherwise, I would have to go back and collect information on 2 million cats and that could involve contacting and obtaining accurate data from perhaps millions of owners. I agree, though, that prospective studies are superior to retrospective studies for measuring incidence. This is not the case, however, for studying incidence risk factors.
I second Dr. Glickman’s comments about the difficulty of getting accurate vaccination histories; owners don’t remember everything, veterinarians often don’t keep detailed records, and owners sometimes take their cats to more than one veterinarian for care. Performing a prospective cohort study like our Web-based survey26 seems simple enough; here is how many cats were vaccinated, and here is how many sarcomas were diagnosed, but that doesn’t necessarily translate into incidence because some cats may have been vaccinated prior to the start of the study; the diagnosis in some cats may have been determined elsewhere; the diagnosis in some cats may have been determined at hospitals that were contributing information, but the cats were not vaccinated there, and so on. It’s much more complicated than just counting the number of cats vaccinated and the number of sarcomas diagnosed at a particular hospital.
References from the above round table discussion:
AVMA Web site. Vaccine-Associated Feline Sarcoma Task Force. Available at: www.avma.org/vafstf. Accessed Apr 18, 2005.
- AVMA Web site. Vaccine-Associated Feline Sarcoma Task Force. Vaccines and sarcomas: a concern for cat owners. Available at: www.avma.org/vafstf/ownbroch.asp. Accessed Apr 18, 2005.
- AVMA Web site. Vaccine-Associated Feline Sarcoma Task Force. VAFSTF selected bibliographic references. Available at: www.avma.org/vafstf/bibrefs.asp. Accessed Apr 18, 2005.
- Hendrick MJ, Bergman PJ, Couto CG, et al. Vaccine-associated feline sarcoma symposium. J Am Vet Med Assoc 1998;213:1422–1430.
- McEntee MC. Treatment decision making for cats with vaccine-associated sarcomas, Part 1 and II. In: Convention notes of the 138th Annual Convention of the American Veterinary Medical Association. Schaumburg, Ill: American Veterinary Medical Association, 2001;447–448.
- Borjesson D, Madewell BR, McEntee MC, et al. Feline vaccine-associated fibrosarcomas. Vet Cancer Soc Newsl 1999;23:1–11.
- Morrison WB, Starr RM. Vaccine-associated feline sarcomas. J Am Vet Med Assoc 2001;218:697–702.
- Kass PH, Barnes WG, Spangler WL, et al. Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats. J Am Vet Med Assoc 1993;203:396–405.
- Kass PH, Spangler WL, Hendrick MJ, et al. Multicenter case-control study of risk factors associated with development of vaccine-associated sarcomas in cats. J Am Vet Med Assoc 2003;223:1283–1292.
- Hendrick MJ, Goldschmidt MH, Shofer FS, et al. Postvaccinal sarcomas in the cat: epidemiology and electron probe microanalytical identification of aluminum. Cancer Res 1992;52:5391–5394.
- Hill AB. The environment and disease: association or causation, in Proceedings. Royal Soc Med 1965;58:295–300.
- Esplin DG, Mcgill LD, Meininger AC, et al. Postvaccination sarcomas in cats. J Am Vet Med Assoc 1993;202:1245–1247.
- Esplin DG. Widespread metastastisis of a fibrosarcoma associated with a vaccination site in a cat. Feline Pract 1995;23(1):13–16.
- Esplin DG. Metastasizing liposarcoma associated with a vaccination site in a cat. Feline Pract 1996;24(5):20–23.
- Lester S, Clemett T, Burt A. Vaccine site-associated sarcomas in cats: clinical experience and laboratory review (1982–1993). J Am Anim Hosp Assoc 1996;32:91–95.
- Rudmann DG, Van Alstine WG, Doddy F, et al. Pulmonary and mediastinal metastases of a vaccination-site sarcoma in a cat. Vet Pathol 1996;33:466–469.
- Sandler I, Teeger M, Best S. Metastatic vaccine associated fibrosarcoma in a 10-year-old cat. Can Vet J 1997;38:374.
- Munday JS, Stedman NL, Richey LJ. Histology and immunohistochemistry of seven ferret vaccination-site fibrosarcomas. Vet Pathol 2003;40:288–293.
- Vascellari M, Melchiotti E, Bozza MA, et al. Fibrosarcomas at presumed sites of injection in dogs: characteristics and comparison with non-vaccination site fibrosarcomas and feline post-vaccinal fibrosarcomas. J Vet Med A Physiol Pathol Clin Med 2003;50:286–291.
- Esplin DG, Mcgill LD. Fibrosarcoma at the site of lufenuron injection in a cat. Vet Cancer Soc Newsl 1999;23:8–9.
- Martins-Green M, Boudreau N, Bissell MJ. Inflammation is responsible for the development of wound-induced tumors in chickens infected with Rous sarcoma virus. Cancer Res 1994;54:4334–4341.
- Erlewein DL. Post-vaccinal rabies in a cat. Feline Pract 1981;11(2):16–21.
- Esh JB, Cunningham JG, Wiktor TJ. Vaccine-induced rabies in four cats. J Am Vet Med Assoc 1982;180:1336–1339.
- Bellinger DA, Chang J, Bunn TO, et al. Rabies induced in a cat by high-egg-passage Flury strain vaccine. J Am Vet Med Assoc 1983;183:997–998.
- Coyne MJ, Reeves NCP, Rosen DK. Estimated prevalence of injection-site sarcomas in cats during 1992. J Am Vet Med Assoc 1997;210:249–251.
- Gobar GM, Kass PH. World Wide Web-based survey of vaccination practices, postvaccinal reactions, and vaccine site-associated sarcomas in cats. J Am Vet Med Assoc 2002;220:1477–1482.
- Doddy FD, Glickman LT, Glickman NW, et al. Feline fibrosarcomas at vaccination sites and non-vaccination sites. J Comp Pathol 1996;114:165–174.
- Richards JR, Rodan I, Elston T, et al. 2000 Report of the American Association of Feline Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vaccines. Available at: http://www.aafponline.org/pdf/guidelines_vaccine.pdf. Accessed Apr 18, 2005.
- Zeiss CJ, Johnson EM, Dubielzig RR. Feline intraocular tumors may arise from transformation of lens epithelium. Vet Pathol 2003;40:355–362.
- Carew JS, Schmidt JA, Humphrey SA, et al. Growth factor expression and vaccine-associated sarcoma tumorigenicity, in Proceedings. 19th Annu Vet Cancer Soc Conf 1999;11–13.
- Katayama R, Huelsmeyer MK, Marr AK, et al. Imatinib mesylate inhibits platelet-derived growth factor activity and increases chemosensitivity in feline vaccine-associated sarcoma. Cancer Chemother Pharmacol 2004;54:25–33.
- Massague J. The TGF-beta family of growth and differentiation factors. Cell 1987;49:437–438.
- Silingardi P, Klein JL, Mesnil M, et al. Growth suppression of transformed BALB/c 3T3 cells by transforming growth factor beta 1 occurs only in the presence of their normal counterparts. Carcinogenesis 1994;15:1181–1185.
- Turner FC. Sarcomas at sites of subcutaneously implanted Bakelite disks in rats. J Natl Cancer Inst 1941;2:81–83.
- Brand KG, Johnson KH, Buoen LC. Foreign body tumorigenesis. CRC Crit Rev Toxicol 1976;4:353–394.
- Sinibaldi K, Rosen H, Liu S, et al. Tumors associated with metallic implants in animals. Clin Orthop Relat Res 1976;118:257-266.
- Macy DW. The potential role and mechanisms of FeLV vaccine-induced neoplasms. Semin Vet Med Surg (Small Anim) 1995;10:234–237.
- Macy DW. Vaccine adjuvants. Semin Vet Med Surg (Small Anim) 1997;12:206–211.
- Macy DW, Chretin J. Local postvaccinal reactions of a recombinant rabies vaccine. Vet Forum 1999;16:44–49.
- Jelínek F. Postinflammatory sarcoma in cats. Exp Toxicol Pathol 2003;55:167–172.
- Nieto A, Sánchez A, Martínez E, et al. Immunohistochemical expression of p53, fibroblast growth factor-β, and transforming growth factor-α in feline vaccine-associated sarcomas. Vet Pathol 2003;40:651–658.
- Burton G, Mason KV. Do postvaccinal sarcomas occur in Australian cats? Aust Vet J 1997;75:102–106.
- Hershey AE, Sorenmo KU, Hendrick MJ, et al. Prognosis for presumed feline vaccine-associated sarcoma after excision: 61 cases (1986–1996). J Am Vet Med Assoc 2000;216:58–61.
- Carroll EE, Dubielzig RR, Schultz RD. Cats differ from mink and ferrets in their response to commercial vaccines: a histologic comparison of early vaccine reactions. Vet Pathol 2002;39:216–227.
- Hennings H, Devor D, Wenk ML, et al. Comparison of two-stage epidermal carcinogenesis initiated by 7,12-dimethybenz(a)-anthracene or N-methyl-N’-nitro-N-nitrosoguanidine in newborn and adult SENCAR and BALB/c mice: effects of tumor promoters and steriodal anti-inflammatory agents on skin of newborn mice in vivo and in vitro. Cancer Res 1981;41:773–779.
- Shacter E, Weitzman SA. Chronic inflammation and cancer. Oncology (Huntingt) 2002;16:217–226, 229; discussion 230–232.
- AVMA Web site. Vaccine-Associated Feline Sarcoma Task Force. Vaccine-Associated Feline Sarcoma Task Force guidelines: diagnosis and management of suspected sarcomas. Available at: www.avma.org/vafstf/tfguidelines99.asp. Accessed Apr 12, 2005.
- Davidson EB, Gregory CR, Kass PH. Surgical excision of soft tissue fibrosarcomas in cats. Vet Surg 1997;26:265–269.
- Kuntz CA. Sarcoma surgery technique debated [lett]. Veterinary Practice News 2001;13(11):5.
- Hendrick MJ, Shofer FS, Goldschmidt MH, et al. Comparison of fibrosarcomas that developed at vaccination sites and at nonvaccination sites in cats: 239 cases (1991–1992). J Am Vet Med Assoc 1994;205:1425–1429.
- Barber LG, Sorenmo KU, Cronin KL, et al. Combined doxorubicin and cyclophosphamide chemotherapy for nonresectable feline fibrosarcoma. J Am Anim Hosp Assoc 2000;36:416–421.
- Jeglum KA, deGuzman E, Young KM. Chemotherapy of advanced mammary adenocarcinoma in 14 cats. J Am Vet Med Assoc 1985;187:157–160.
- Poirier VJ, Thamm DH, Kurzman ID, et al. Liposome-encapsulated doxorubicin (Doxil) and doxorubicin in the treatment of vaccine-associated sarcoma in cats. J Vet Intern Med 2002;16:726–731.
- Cronin K, Page RL, Spodnick G, et al. Radiation therapy and surgery for fibrosarcoma in 33 cats. Vet Radiol Ultrasound 1998;39:51–56.
- Kobayashi T, Hauck ML, Dodge R, et al. Preoperative radiotherapy for vaccine associated sarcoma in 92 cats. Vet Radiol Ultrasound 2002;43:473–479.
- Bregazzi VS, LaRue SM, McNiel E, et al. Treatment with a combination of doxorubicin, surgery, and radiation versus surgery and radiation alone for cats with vaccine-associated sarcomas: 25 cases (1995–2000). J Am Vet Med Assoc 2001;218:547–550.
- Cohen M, Wright JC, Brawner WR, et al. Use of surgery and electron beam irradiation, with or without chemotherapy, for treatment of vaccine-associated sarcomas in cats: 78 cases (1996–2000). J Am Vet Med Assoc 2001;219:1582–1589.
- Bailey DB, Rassnick KM, Erb HN, et al. Effect of glomerular filtration rate on clearance and myelotoxicity of carboplatin in cats with tumors. Am J Vet Res 2004;65:1502–1507.
- Williams LE, Banerji N, Klausner JS, et al. Establishment of two vaccine-associated feline sarcoma cell lines and determination of in vitro chemosensitivity to doxorubicin and mitoxantrone. Am J Vet Res 2001;62:1354–1357.
- Banerji N, Li X, Klausner JS, et al. Evaluation of in vitro chemosensitivity of vaccine-associated feline sarcoma cell lines to vincristine and paclitaxel. Am J Vet Res 2002;63:728–732.
- Matteucci ML, Anyarambhatla G, Rosner G, et al. Hyperthermia increases accumulation of technetium-99m-labeled liposomes in feline sarcomas. Clin Cancer Res 2000;6:3748–3755.
- Ray-Coquard I, Ranchere-Vince D, Thiesse P, et al. Evaluation of core needle biopsy as a substitute to open biopsy in the diagnosis of soft-tissue masses. Eur J Cancer 2003;39:2021–2025.
- McLeod DA, Thrall DE. The combination of surgery and radiation in the treatment of cancer: a review. Vet Surg 1989;18:1–6.
- O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomized trial. Lancet 2002;359:2235–2241.
- Zagars GK, Ballo MT, Pisters PWT, et al. Preoperative versus postoperative radiation therapy for soft tissue sarcoma: a retrospective comparative evaluation of disease outcome. Int J Radiat Oncol Biol Phys 2003;56:482–488.
- Roko JL, Hardy WD. Feline leukemia virus and other retroviruses. In: Sherding R, ed. The cat: diseases and clinical management. New York: Churchill-Livingston, 1994;263–432.