Malignant Melanoma Healed with Natural Therapies

How To Prevent Skin Cancer

How To Prevent Skin Cancer

Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.

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How I Survived Malignant Melanom

By The Time You've Finished Reading How I Survived Melanoma Skin Cancer Seven Survivors Tell Their Stories. You'll Feel Like A New Person, with A New, More Positive Outlook! You will learn: 1. How do I know if I have melanoma? What are the signs and symptoms? I wanted to know why the doctor was so concerned when she looked at that little mole on my forearm. What was it that looked so sinister? How worried should I be? Was the doctor over-reacting? 2. What tests will the doctor carry out to see if I have melanoma? Will they be able to tell me on the spot if there is a problem? Or will I have to wait for days, fretting about whats going on? 3. How curable is melanoma? If they do tell me its melanoma, what exactly does that mean? Is it a death sentence? Will they tell me You have 12 months to live. Get your life in order and prepare for the worst.? 4. What are the stages of the disease? The reading Id done said that there were different stages of melanoma. What are the symptoms of each stage? What are the survival rates of each stage? If I had a later stage melanoma, wouldnt I know about it? Wouldnt I actually feel like I was sick? 5. How quickly does the disease progress or spread? Should I have gone to the doctor sooner? Id noticed the mole changing over about 3 months. Was this delay critical? 6. How is melanoma normally treated? Would I have to go through chemotherapy and radiation treatment? If so, for how long? What are the odds of curing the disease using these treatments? How extensive is any surgery likely to be? How big will the scars be? 7. What are the common side effects of the treatments? Would I lose my hair? Would I become sterile? What else could I expect? 8. What alternative treatments are available? Id heard of people going on special macro-biotic diets. Id seen lots of herbal remedies on the internet. Which of these are proven and documented, and which ones are snake oil? Is it possible to combine alternative treatments with surgical other western treatments? How do I find a doctor that is open to using both alternative and western treatments? 9. What are the latest treatments being developed, and who is carrying out clinical trials of these new treatments?

How I Survived Malignant Melanom Summary


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Nail apparatus melanoma

In the authors' experience ungual melanoma is dermoscopically characterized by a brown background and the presence of irregular lines. These lines are different in colour from one another, and their thickness varies dramatically from one to another, as does the inter-band spacing. In some areas the bands abruptly stop and in other areas their parallelism is disrupted (Figures 12.2, 12.3). Micro-Hutchinson's sign is rare and we have observed this feature in melanoma only. However, it is known from previous clinical studies that pigmentation of the cuticle is not completely specific to melanoma. In more advanced cases the pigmentation of periungual tissue appears irregular on dermoscopy (Figure 12.1). Blood spots may be found in melanoma, therefore their presence should not mislead the clinician to a diagnosis of subungual haemorrhage.

Organspecific Modulation Of Il8 Expression In Melanoma Cells

Human melanoma is an excellent example of a hematogenous malignancy. Melanoma cells secrete a variety of angiogenic molecules, e.g., VEGF, bFGF, and IL-8, and are regulated by complex interactions with keratinocytes in the skin (82). Recent reports from this laboratory show that IL-8 is an important molecule in melanoma growth and progression. Constitutive expression of IL-8 directly correlated with the metastatic potential of the human melanoma cell lines tested. Further, IL-8 induced proliferation, migration, and invasion of endothelial cells, and, hence, neovascularization (83). Several organ-derived cytokines (produced by inflammatory cells) are known to induce expression of IL-8 in normal and transformed cells (83). Since IL-8 expression in melanocytes and melanoma cells can be induced by inflammatory signals, the question of whether specific organ microenvironments could influence the expression of IL-8 was analyzed. Melanoma cells were implanted into the subcutis, the spleen...

Melanoma in Xiphophorus Hybrids

Melanomas can result from matings between southern platyfish from different populations (Gordon, 1948 Kallman, 1975) or between Xiphophorus of different species (Figs 3.5 and 3.6). The most frequently studied Xiphophorus hybrids are inbred strains of southern platyfish X swordtail (F. Anders et al., 1984 Schwab, 1986 Vielkind et al, 1989 A. Anders et al, 1991b Morizot et al., 1991 Malitschek et al., 1995), but other Xiphophorus species have also been used. Similar melanomas sometimes occur in certain strains of purebred Xiphophorus spp. (Kazianis and Borowsky, 1995 Schartl et al., 1995). Melanomas in hybrids of Xiphophorus were reported in 1912-1913, and early studies on genetics of these hybrids were published in 1927-1928 (Schwab, 1986 F. Anders, 1991). A key feature of the Xiphophorus melanoma model is the macro-melanophore, a distinctive type of pigment cell. Macromelanophores are up to 500 mm in diameter compared with normal melanophores which are about 100 mm in diameter...

Susceptibility To Skin Cancer

Among the residents aged 60 or more years in the BFD-endemic area, the prevalence of skin cancer was 4.8 , 16.5 and 25.6 , respectively, for males whose drinking water had arsenic concentrations of 600 Mg l (Tseng et al., 1968). The corresponding figures for females were 0.9 , 6.2 and 11.0 , respectively. However, the status of undernourishment in the development of arsenic-induced skin cancer was not examined in this study. In a recent survey in the BFD-hyperendemic villages, the prevalence of skin cancer was found to increase with the duration of consuming sweet potato in a dose-response relationship (Hsueh et al., 1995). The multivariate-adjusted odds ratios were 5.5 and 8.5, respectively, for those who consumed sweet potato for 10-19 and 20 years compared with those that had a consumption duration of 20.0 mg l per year and a percentage of MMA 26.7 was around 24-fold, as compared with those that had a cumulative arsenic exposure of 14 mg l per year, a poor inorganic arsenic...

Nail apparatus melanoma has a poorprognosis with up to 50 of patients dying within 5 years of the diagnosis

Subungual melanoma has a poor prognosis. The reported 5-year survival rates range from 35 to 50 . Most patients present with advanced subungual melanoma however, even early diagnosis is not a guarantee of a good prognosis. Women have a better prognosis than men. Factors contributing to a poor prognosis are delay in diagnosis and, as a result of this, inadequate treatment. The tumour may be mistaken for a traumatic dystrophy, and valuable time may be lost before the diagnosis is made. Treatment depends on the stage of the disease. Levels I and II melanomas may be adequately treated by wide local excision, and repair of the defect with graft or flap. Amputation is usually advised for melanoma at levels more advanced than II. When the thumb has to be amputated, pollicization of a finger may provide a functional replacement. There would appear to be no relationship between the prognosis and the extent of the amputation, although metacarpo metatarsophalangeal amputation is considered to be...

Forms of skin cancer

There are three common forms of skin cancer caused by ultraviolet light basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. Whereas there seems to be a direct relationship with the amount of ultraviolet exposure and basal cell carcinoma and squamous cell carcinoma, the relationship with ultraviolet exposure and melanoma is more complex and it seems likely that intermittent exposure to ultraviolet light is the main factor (for example, exposure to sunlight on holidays). These different types of neoplastic change that occur in the skin are discussed in chapters 13 and 15.


Melanoma is an invasive malignant tumour of melanocytes. Most cases occur in white adults over the age of 30, with a predominance in women. The incidence of melanoma has doubled over the past 10 years in Australia (currently 40 100 000 population) and shown a similar increase in other countries. In Europe twice as many women as men develop melanoma about 12 100 000 women and 6 100 000 men. The highest incidence of melanoma occurs in countries with the most sunshine throughout the year. However, skin type and the regularity of exposure to sun are also important. The incidence is much greater in fair skinned people from higher latitudes who have concentrated exposure to sun during holidays than in those with darker complexions who have more regular exposure throughout the year. Severe sunburn may also predispose to melanoma. Since melanin protects the skin from ultraviolet light it is not surprising that melanoma occurs most commonly in fair skinned people who show little tanning on...

Types of melanoma

There are four main types of melanoma. Superficial spreading melanoma is the more common variety. It is common on the back in men and on the legs in women. As the name implies the melanoma cells spread superficially in the epidermis, becoming invasive after months or years. The margin and the surface are irregular, with pigmentation varying from brown to black. There may be surrounding inflammation and there is often clearing of the central portion. The invasive phase is associated with the appearance of nodules and increased pigmentation. The prognosis is correspondingly poor. Lentigo maligna melanoma occurs characteristically in areas exposed to sun in elderly people. Initially there is a slowly growing, irregular pigmented macule that is present for many years before a melanoma develops. Nodular melanoma presents as a dark nodule from the start without a preceding in situ epidermal phase. It is more common in men than women and is usually seen in people in their fifties and...

Skin Cancer

Skin cancer is induced by the ultraviolet rays of the sun. It occurs most often on the head and neck, where exposure to the sun is greatest. It is most common in fair-skinned people and the elderly, who have had the longest lifetime UV exposure (see insight 6.4). The ill-advised popularity of suntanning, however, has caused an alarming increase in skin cancer among younger people. Skin cancer is one of the most common cancers, but it is also one of the easiest to treat and has one of the highest survival rates when it is detected and treated early.

Nail melanoma

Melanoma of the nail apparatus most commonly derives from the matrix, much less frequently from the nail bed or hyponychium. Matrix melanoma usually causes longitudinal melanonychia (see Chapter 5). Whether atypical melanocytic hyperplasia is already subungual in situ melanoma is not entirely clear. Large, atypical melanocytes in all layers of the matrix and nail bed epithelium, pycnotic melanocytes in the nail plate mirroring the pagetoid spread in the epithelium, and mitoses, are seen as proof of a malignant melanoma. Sometimes nail clippings reveal single intraungual pycnotic melanoma cells which retain their protein S-100 positivity. Most subungual melanomas are of acrolentiginous type however, those in the nail bed tend instead to be nodular melanomas. Even long-standing melanomas are often still very superficial. Invasive melanomas have therefore usually a decade-long history.

Cancer Treatment and Research

Stack, M.S., Fishman, D.A. (eds) Ovarian Cancer. 2001. ISBN 0-7923-7530-0. Bashey, A., Ball, E.D. (eds) Non-Myeloablative Allogeneic Transplantation. 2002. ISBN 0-7923-7646-3. Leong, Stanley, P.L. (ed.) Atlas of Selective Sentinel Lymphadenectomy for Melanoma, Breast Cancer and Colon Cancer.

Peter C Albertsen MD MS

Adenocarcinoma of the prostate is the most common non-skin cancer among American men. The American Cancer Society estimates that 184,500 new cases of prostate cancer will be diagnosed in the United States in 1998 and that 39,200 men will die from the disease.1 The rate of new prostate cancer diagnoses has increased exponentially over the past three decades.2 During the 5 years preceding 1992, there has been an even more dramatic surge in prostate cancer incidence following the introduction of widespread testing for serum prostate-specific antigen (PSA).3 Since 1992, however, the annual incidence rate has declined by 11 and continues to decline.4

Tumor Specific Antigens

This category of tumor antigens, which represents non-mutated gene products that are not processed and presented on normal adult tissues, is predominantly comprised of members of the cancer testis (C T) family of genes (Table 2). The expression of C T gene products is limited in adult tissues to the normal testis, which lacks expression of HLA class I and class II molecules. The prototype for this family, MAGE-1, represents the first antigen to be identified as a target of human tumor reactive T cells, and was cloned by transfecting an autologous tumor cell line that appeared to have lost antigen expression with a cosmid library containing genomic DNA from antigen positive tumor cells (1). The cancer testis genes have been clustered into 10 families, 6 of which have been mapped to the X chromosome (3 8), and subsequent studies have lead to the identification of T cell epitopes expressed on multiple products derived from these gene families. The MAGE gene family includes 17 members,...

Terms Used for Neoplasms

The names used for fish neoplasms are similar to those used for mammalian neoplasms. Typically the name includes an indication of the tissue or cell type of origin and whether the disease is benign or malignant. Malignant neoplasia, commonly known as cancer, is usually indicated by the terms carcinoma or sarcoma. However, some types of neoplasms have names that vary from this pattern. Papillomas, for example, are named for the papillary appearance of the mass rather than for the cell type. Other exceptions are names used for neoplasms that are invariably malignant, such as lymphoma, melanoma and various 'blastomas' (such as nephroblastoma). There also have been changes over time in the names used for some types of neoplasms e.g. hepatocellular carcinoma was usually termed 'hepatoma' in older literature.

Distribution in Normal Tissues

Distributions of pO2 values in various normal human tissues have been described in detail (49-53). The normal tissues were subcutaneous tissues surrounding tumors for ear, nose, and throat (ENT), sarcoma, and melanoma patients, normal brain for gliomas, and vaginal mucosa for cervix tumors (49-55). As expected, there is a scattering of the individual pO2 values in normal tissues between 1 mmHg and values typical for arterial blood (80-100 mmHg). Whatever the normal tissue, median pO2 ranged from 15 to 70 mmHg. For example, in patients with head and neck tumors, median pO2was 52 mmHg in the Institut Gustave-Roussy (IGR) experience (mean 54 mmHg) (52) and mean pO2 was 57 mmHg at Stanford (55).

Distribution in Tumors

Melanoma In 20 patients, oxygen tension was measured the day before the surgical removal of a suspected metastatic lesion from a primarily treated melanoma (52). An histological confirmation of the malignant origin of the removed lesion was obtained in 18 cases. In 2 cases, the removed nodes were histologically noninvaded by the known melanoma. The median pO2 for normal tissues was 40.5 mmHg. For tumors, median pO2 was 11.6 mmHg, 17.1 mmHg in nodes, and 6.7 mmHg in skin metastases. Very low values (

Hla Class Ii Restricted Antigens

From HLA-DRpi*0401 positive melanoma patients with the peptide that appeared be most effective at stimulating T cells from immunized mice, NY-ESO-1 116-135, resulted in the generation of T cells that recognized HLA-DR4 positive tumor cells and target cells pulsed with the NY-ESO-1 protein.

Adaptation to Cancer

According to the American Cancer Society (ACS), cancer is an umbrella term for a group of diseases characterized by uncontrolled growth and spread of abnormal cells.'' Not counting some highly prevalent, rarely fatal forms of skin cancer, the most common cancers are (in order of prevalence) prostate, lung, colon rectal, and bladder (for men) and breast, colon rectal, lung, and uterus (for women). For both men and women, lung cancer causes the most deaths. Although it kills far fewer people than CVD, cancer is perceived as more dangerous, destructive, and deadly. In reality, the survival rate for cancer has been climbing steadily throughout this century. Taking a normal life expectancy into consideration, the ACS estimates that 50 of all people diagnosed with cancer will live at least 5 years. Nevertheless, cancer remains the second-leading cause of death and is associated with significant pain and disability. Another often-cited cancer intervention study...

Clinical Latency In Cancer Recurrence Following A Primary Tumor Treatment

Similar latency periods'' in cancer recurrence have been documented since the beginning of the twentieth century. Rupert A. Willis has summarized the time elapsing between the excision of a human malignant tumor and the appearance of a clinically recognizable recurrence'' for a variety of human cancers. For example, the latency period in breast cancer patients can be from 6 to 20 years cutaneous and ocular melanoma, 14 to 32 years kidney carcinoma,

Influence Of T Cell Tolerance On Tumor Antigen Recognition

Many of the T cell epitopes that have been identified from self antigens such as the MDAs bind to HLA class I gene products with relatively low affinities, and observations made in mouse as well as human studies indicating that the repertoire of T cells that is available for recognition of these antigens is at least partially influenced by tolerance mechanisms may be relevant to this finding. In one study, HLA-A2 transgenic mice that either expressed the normal mouse tyrosinase molecule or that failed to express this protein as a result of a radiation induced deletion of sequences that encoded this gene were immunized with the mouse analog of the tyr 369-377 peptide FMDGTMSQV (98). The results indicated that the precursor frequency of high affinity T cells reactive with the tyr 369-377 epitope was significantly reduced in normal mice relative the to knock-out mice. In a recent human study, an HLA-A24 restricted T cell epitope was identified from the OA1 melanocyte differentiation...

Malignancy In The Renal Transplant Patient

Cancer of the skin and lips Squamous cell carcinoma Basal cell carcinoma Malignant melanoma Malignant lymphoma Non-Hodgkin's lymphoma Reticulum cell sarcoma B-cell lymphoproliferative syndromes (Epstein-Barr virus) Kaposi's sarcoma Cutaneous form Visceral and cutaneous form Genitourinary cancer Carcinoma of the native kidney (acquired cystic kidney disease) Carcinoma of the transplanted kidney Renal cell carcinoma Malignant melanoma Carcinoma of the urinary bladder (cyclophosphamide associated) Uroepithelial tumors (associated with analgesic abuse) Gynecologic cancer Carcinoma of the cervix Ovarian cancer

Uva Uvb and Sunscreens

Some people distinguish between two forms of ultraviolet radiation and argue, fallaciously, that one is less harmful than the other. UVA has wavelengths ranging from 320 to 400 nm and UVB has wavelengths from 290 to 320 nm. (Visible light starts at about 400 nm, the deepest violet we can see.) UVA and UVB are sometimes called tanning rays and burning rays, respectively. Tanning salons often advertise that the UVA rays they use are safe, but public health authorities know better. UVA can burn as well as tan, and it inhibits the immune system, while both UVA and UVB are now thought to initiate skin cancer. As dermatologists say, there is no such thing as a healthy suntan. Whether or not sunscreens help to protect against skin cancer remains unproven. As the sale of sunscreen has risen in recent decades, so has the incidence of skin cancer. Indeed, recent studies have shown that people who use sunscreens have a higher incidence of basal cell carcinoma than people who do not, while data...

Conclusions 61 Prognosis

Contradictory results Retrospective studies on microvessel density in primary colorectal and malignant melanoma of the skin gave contradictory results on the prognostic significance of such a marker. Therefore, more homogeneous groups of patients need to be evaluated prior to drawing any definitive conclusions.

Cancer Vaccines That Elicit

In humans, extensive work has been done to define peptides associated with malignant melanoma such as MART-1 and gp100 (reviewed in 82 87), and clinical trials have been underway for the past several years. Clinical trials using a modified gp100 peptide administered together with IL-2 yielded promising results. Objective tumor regressions were obtained in 42 percent of HLA-A2-positive patients with advanced melanoma (88). IL-2 appeared to promote sequestration of responding CTL at the tumor site (89). In an unrelated trial a selected peptide from MART-1 was shown to induce significant CTL responses in melanoma patients, which correlated with a prolonged time to relapse (90). Vaccine trials with peptides representing other cancers including breast (91), cervical (92), and pancreatic (93), are underway, and have given broadly similar results where reported. As with the melanoma trials, these are all Phase I II studies, restricted to patients with advanced cancer who have failed...

Black spots in the skin

There has been a great increase in public awareness of melanoma, and any dark lesions of the skin are sometimes regarded with the same dread as Long John Silver's black spot in Treasure Island a sign of imminent demise. However, the vast majority of pigmented lesions are simply moles or harmless pigmented naevi. The most important thing is to know which moles can be safely ignored and which should be removed. Benign moles are described first, then malignant melanoma, followed by a discussion of the differences between these two.

Ist To Monitor T Cell Directed Vaccine Trials In Cancer Patients

Schrama et al. characterized the inoculation site of dendritic cell (DC) vaccination in patients with melanoma. They determined that antigen pulsed DC, but not unpulsed DC recruited and induced the local expansion of melanoma specific T cells at the inoculation site. They used MHC-multimers loaded with melanoma antigens MART, MAGE3, and gp100 and stained skin biopsies from vaccinated patients to demonstrate the specificity of the recruited and expanded T cells at the inoculation site. As discussed above, T cells specific for the tumor antigen survivin taken from melanoma and breast cancer tumors were shown to be cytolytic ex vivo (6). In contrast, recent studies of T cells specific for the MART tumor epitope showed that the tumor specific T cells had effector function in circulating blood but were functionally tolerant in tumor lesions (21). Findings such as these demonstrate that the functional status of T cells in blood does not always reflect the functional status in tissues and...

Modulation Of Angiogenesis By Host Lymphoid Cells

The regulation of physiologic angiogenesis by lymphoid cells is well established. Angiogenesis is influenced by cytokines released from mast cells, T-lymphocytes, and macrophages in the tumor microenvironment (88-95). Mast cells have been associated with disease progression in infantile cutaneous hemangiomas (96). In fact, the presence of elevated numbers of mast cells has been used to distinguish hemangiomas from vascular malformations (97). Lymphoid-mediated angiogenesis has been recognized in cutaneous melanoma. Increased vascularity at the vertical base of human melanoma is associated with poor prognosis (98). A local inflammatory reaction is often associated with invasive cutaneous melanoma. An intense inflammatory reaction is often associated with increased risk of metastasis, suggesting that inflammatory-associated angiogenesis may contribute to melanoma dissemination (99,100). This laboratory has shown an important role for host-infiltrating leukocytes and their products in...

Pigment Cell Neoplasms in Amazon Mollies

Occur in this gynogenetic species because descendants from a given female usually contain only maternal DNA. Embryogenesis of diploid eggs occurs after insemination by males of related species, but paternal DNA is not usually contributed to offspring. However, in rare matings paternal microchromosomes enter the egg, resulting in a new clone. Fish of the M-clone have macro-melanophores, the cell type giving rise to melanoma in the related genus Xiphophorus, but the oncogene involved in melanoma of Xiphophorus does not appear to be involved with the pigment cell tumours of Amazon mollies.

Lesions adjacent to the nail

Naevi may occur adjacent to the nail and a benign melanocytic naevus can produce a pigmented streak. Subungual melanoma may produce considerable pigmentation of the nail and often causes pigmentation of the cuticle, so called Hutchinson's sign. Sometimes subungual melanoma is amelanotic so there is no pigmentary changes and any rapidly growing soft tumour should raise suspicions of this condition.

Spontaneous tumor immunity

It has long been a matter of debate whether tumors are spontaneously immunogenic in patients. With the availability of sensitive methods, spontaneously occurring T cells directed against tumor associated antigens (TAA) can be detected in cancer patients. There is increasing evidence that CD8+ T cells directed against TAA spontaneously occur in various malignancies including melanoma, adenocarcinomas, and leukemias (reviewed in 13). Mechanisms leading to spontaneous induction of specific T cell responses are not well understood. Whether circulating TAA-specific T cells are able to kill tumor cells in vivo and how they influence the clinical course of disease has remained largely unclear. Further studies are necessary for a better understanding of the role of spontaneous T cell responses against TAA.

Tumor Invasion and Metastasis

The first studies with MMP inhibitors in cancer models examined their ability to block organ colonization or experimental metastasis. Marked inhibition of colonization was demonstrated for both TIMP-1 and the hydroxamate SC44463 (1 Searle) in mice inoculated with B16 murine melanoma cells (95,96). Similarly, TIMP-2 was shown to inhibit colonization by 4R transformed rat fibroblasts (97). These models only examine one discreet part of the the multistep process of tumour invasion and spread. More recently, MMP inhibitors have been tested in more complex and more clinically relevant cancer models.

Lymphadenectomy and Sentinel Lymph Node Mapping

Mapping of the sentinel lymph nodes is a technique that has proved successful in improving nodal staging in various malignancies, including melanoma and breast cancer. Identifying and assessing the initial node to which a tumor would spread could increase nodal staging accuracy. Some centers have begun applying sentinel lymph node mapping for colon cancer. With this technique, the colon tumor is typically injected with vital dye or fluorescein during surgery and the nodes are assessed minutes later. It can be performed either in vivo or ex vivo immediately following resection. The sentinel nodes are identified and analyzed separately, often using more complete histologic evaluation than what could be done for all the nodes in the specimen. Several studies have shown an increased sensitivity with this technique at detecting otherwise occult nodal involvement, which than may identify those at increased risk for recurrence (Bendavid et al, 2002 Paramo et al, 2002). The principal...

Induction of Immunity by Activated DCs

In an attempt to induce protective anti-tumor immunity, the melanoma antigen tyrosinase-related protein 2 (TRP2) was coupled to anti-DEC antibodies and injected into mice. Simultaneously, a DC-activating stimulus by injection of CpG was administered. After two consecutive injections of these anti-DEC-tumor antigen conjugates, mice were challenged for tumor growth by intravenous injection of the melanoma cell line B16. After two weeks, metastases in the lungs of the mice were counted. Our results clearly show that mice were protected from tumor growth after two immunizations with antibody-tumor antigen conjugates when injected together with an activating stimulus, i.e., CpG (38). This protection was lost when CpG was omitted from the immunization procedure, indicating that activation of the DC is mandatory for effective induction of an immune response.

Assay of Antisense Effects

Effects of a bcl2 bcl-xL bispecific AS-ODN on human MelJuso melanoma. (A) Morphological damage is induced only by antisense oligo plus lipofectin, with no comparable effect of the scrambled oligonucleotide plus lipofectin or the lipofectin vehicle. (B) A decrease in antiapoptotic bcl-xL and apoptosis-associated PARP fragmentation is induced only by antisense oligo plus lipofectin, with no comparable effect of the scrambled oligonucleotide plus lipofectin or the lipofectin vehicle. Similar results were obtained with human C8161 melanoma. Fig. 1. Effects of a bcl2 bcl-xL bispecific AS-ODN on human MelJuso melanoma. (A) Morphological damage is induced only by antisense oligo plus lipofectin, with no comparable effect of the scrambled oligonucleotide plus lipofectin or the lipofectin vehicle. (B) A decrease in antiapoptotic bcl-xL and apoptosis-associated PARP fragmentation is induced only by antisense oligo plus lipofectin, with no comparable effect of the scrambled...

Direct Assessment Of Tcell Responses Against Tumorassociated Antigens Utilizing A Qrtpcr Assay

An immunization monitoring assay that could detect CTL (cytotoxic T lymphocytes) reactivity directly from peripheral blood, rather than after prolonged in vitro proliferation, was developed in the context of a clinical trial in which melanoma patients were vaccinated with modified peptide derivatives from the gp100 tumor antigen (17). PBMC were obtained by leukapheresis from patients before and after two cycles of peptide vaccination. Initial optimization experiments were conducted by simply exposing bulk PBMC ex vivo to the immunizing and native peptides or melanoma tumor cells. No prior in vitro sensitization or culturing of the PBMC was performed, nor were exogenous cytokines added to the cells. Because of the low overall frequency of tumor reactive CTL in bulk PBMC after immunization, changes in cytokine release after peptide elicitation were typically below the sensitivity of standard antibody detection (ELISA) assays. Therefore, real-time qRT-PCR for cytokine gene expression was...

Role Of Organ Environment In Pathogenesis Of Metastasis

Clinical observations of cancer patients, and studies with experimental rodent tumors, have revealed that certain tumors produce metastasis to specific organs, independent of vascular anatomy, rate of blood flow, and number of tumor cells delivered to each organ. The distribution and fate of hematogenously disseminated, radiolabeled melanoma cells in experimental rodent systems amply demonstrate that tumor cells reach the microvas-culature of many organs (33-36). Extravasation into the organ parenchyma and proliferation of tumor cells occur in only some organs therefore, the mere presence of viable tumor cells in a particular organ does not always predict that the cells will proliferate to produce metastases (33,34,37). Experimental data supporting the seed and soil hypothesis were derived from studies on the preferential invasion and growth of B16 melanoma metastases in specific organs of syngeneic mice (39). The B16 melanoma cells injected intravenously produced lesions in the lungs...

Preoperative Investigations and Preparation for the Procedure

Family history ( 10 ), associated syndromes familial pancreatitis, Peutz-Jeghers syndrome, familial atypical multiple-mole melanoma (FAMMM) syndrome, hereditary nonpolyposis colon cancer (HNPCC) Jaundice, left supraclavicular adenopathy, ascites, nutritional status (weight loss), cardiovascular health, performance status (most important for assessment of operativel risk)

Problems during pregnancy

Malignancies may be affected by the different hormonal profile of pregnancy and its effects on the tissues this may make certain tumours more aggressive (e.g. breast cancer, melanoma). Some maternal malignancies may metastasise to the fetus or placenta (e.g. melanoma), although in general this is rare.

Antigenic changes on malignant cells

Abnormalities in TA expression as well as a variable degree of inter- and intra-lesional heterogeneity characterize many tumors. As a result, peptides may not be generated from TA or may be formed in very low amount and the corresponding HLA class I antigen-TA peptide complexes are not formed in spite of the expression of the relevant HLA class I allospecificity. The phenomenon of TA loss has been mainly described in melanoma. Melanocytic differentiation proteins (MDPs, e.g. gp100, MART-1, TRP-1, and tyrosinase) have been found to be lost in metastatic lesions in patients with melanoma independently of the treatment with immunotherapy (120122). More recently, loss of the newly identified melanoma associated antigen, melanoma inhibitor of apoptosis protein (ML-IAP) was reported in a recurred intestinal metastasis in conjunction with a lack of lymphocyte infiltration, following immunotherapy utilizing GM-CSF-secreting autologous tumor cells as immunogens (123). In SCID mice, expansion...

Application Of Qrtpcr In Immune Monitoring Of Patients

The original application of qRT-PCR for the measurement of specific T cell responses to tumor antigens was described in a pilot study examining patients immunized with peptides derived from a melanoma tumor antigen (17). This study demonstrated tumor specific CTL directly in the peripheral blood of patients who had undergone immunization and further validated the An important additional application of qRT-PCR is in the monitoring of in vivo tumors during therapy. Previously, macroscopic, microscopic and molecular changes in targeted tumor sites required resection and analysis. This approach would therefore eliminate the ability to sequentially follow an individual lesion prospectively during treatment. We have developed techniques to perform serial fine needle aspirates (FNA) of accessible tumor sites before and during immunotherapy. This proved to be atraumatic to the tumor, while leaving it in situ for clinical observation and immunologic monitoring. Initially these FNAs were...

Circulating TSP1 Can Slow Tumor Growth and Produce Concomitant Tumor Immunity

Circulating levels of TSP-1, whether produced endogenously by tumors releasing high amounts of the protein, or exogenously by daily injections of purified protein, render mice unable to mount an angiogenic response, and also halt the growth of experimental lung metastases (19). When the human fibrosarcoma HT1080, producing high levels of TSP-1, is grown subcutaneously in a nude mouse, the animal develops a high circulating level of human TSP-1 that can reach 10 g mL in plasma. This circulating TSP-1 is able to dramatically reduce the growth of B16 melanoma lung metastases seeded by tail vein injection. Inhibition is probably caused by the inhibition of angiogenesis, because animals treated with TSP-1 become antiangiogenic, in that they are unable to mount a corneal angiogenic response to bFGF TSP-1 has no effect on the in vitro growth rate or cloning efficiency of the melanoma cells forming the metastases and the inhibition of the growth of metastases in vivo is reversible if TSP-1...

Ethanol And Vascular Smooth Muscle Cell Migration

The accumulation of SMC in the intima of arteries is one of the most prominent features of the atherosclerotic plaque and of the intimal hyperplastic lesions which cause restenosis following angioplasty 35,36 , It is increasingly recognized that migration of SMC from the media is a key event in progressive intimal thickening leading to atherosclerosis and restenosis 35-37 , Consequently, there has been extensive interest in defining both positive and negative regulators of this process and many factors have been identified that may play a role. While ethanol has been shown in vitro to differentially influence the migration of neuronal cells 38 and melanoma cells 39 , its effect on SMC migration has not been defined until recently.

Genetic Polymorphisms And Cancer Heterogeneity

Genetic polymorphism is the genesis of the diversity of human beings. Polymorphisms are particularly frequent in genes associated with immune function possibly resulting from an evolutionary adaptation of the organism facing an ever changing environment (16). Although, several genes associated with immune function may bear relevance to tumor host interaction(s) (17), most studies attempting to link human polymorphism to immune responsiveness have been focused on the associations between the Human Leukocyte Antigen (HLA) complex and disease occurrence or response to therapy. However, an extensive analysis of patients with metastatic melanoma treated with systemic interleukin-2 administration

Ist In A Number Of Experimental Settings

Most pertinent to readers of this book, IST has been used to study CTLs directed against cancer antigens. Using a mouse tumor model, Haanen et al. used IST to show that tumor rejection was associated with the infiltration of tumor specific T cells. In human melanoma, T cells specific for the tumor antigen survivin were readily detected in tissue sections from the primary tumor and a sentinel lymph node isolated from a melanoma patient (6). Similarly, in tissues from a breast cancer patient, survivin specific T cells were readily detectable in situ. Importantly, these cells were shown to have functional cytotoxic activity when assayed ex vivo (6).

Proton Teletherapy for APBI

Protons have physical and radiobiological characteristics which differ from those of conventional radiotherapy (photons), and offer a number of theoretical advantages. Dose localization in the Bragg peak provides an ideal characteristic for dose conformation to the target volume, and at the same time reduced dose to non-target tissues (Koehler et al. 1972). This unique dosimetric feature of proton teletherapy makes it an attractive non-invasive modality. The main critical indications are proximity of the target area to critical structures where maximum selectivity of dose distribution is of paramount importance. A general review of proton teletherapy is provided by Orecchia et al. (1998), who have demonstrated success in the treatment of diseases such as uveal melanoma, base of skull chordoma and chondrosarcoma, central nervous system, soft-tissue sarcoma, and prostate cancer. However, the use of proton teletherapy for breast cancer has been very limited.

Human Diseases Associated with Aberrant Splice Site Selection Without Obvious Mutations

A number of diseases have been described that are associated with a change in alternative splicing patterns in the absence of mutations or alterations in trans-acting factors. For example, in schizophrenia, the alternative splicing patterns of the gamma2 subunit of gamma amino butyrate type A receptor (Huntsman et al. 1998), the N-methyl-D-aspartate (NMDA) R1 receptor, and the neuronal cell adhesion molecule (Vawter et al. 2000) were altered. Recent results show that the alternative splicing of tau exon 10 is significantly altered in sporadic Alzheimer's disease (Umeda et al. 2004 Glatz et al. 2006). Changes of alternative splicing patterns have been frequently reported to be associated with cancer development, e.g., Wilms' tumor, breast cancer, melanoma, and prostate cancer (Table 2). Furthermore, EST analysis demonstrates widespread changes of alternative splicing patterns in cancer cells (Xu and Lee 2003) when compared with normal cells. However, these changes have to be...

Anaesthetic problems

Respiratory function may be impaired (Hope et al 1973), and upper airway obstruction and chest deformities can contribute to postoperative respiratory problems. Respiratory failure and subsequent death from pneumonia occurred in a patient following radical cervical lymph node resection for melanoma of the scalp (Jones & Croley 1979). Intrathoracic obstruction may occur. Infiltration of upper airway structures with glycosaminoglycans may cause upper airway obstruction in the perioperative period (Berkowitz et al 1990).

The Impact Of Genetic Variation And Cancer Heterogeneity On Immune Responsiveness

As we previously discussed, genetic background may influence immune responsiveness. However, the genetic background of patients has not been extensively scrutinized as a predictor of immune responsiveness (16). Obvious genetic markers that may affect immune responsiveness are the HLA complex that codes for molecules responsible for antigen presentation to T cells (51). However, correlates between HLA phenotype and treatment outcome or survival failed to provide conclusive evidence that individual variability in antigen presentation may determine immune responsiveness in the context of anti-cancer immune therapy (18 52 53). Others have pointed to other polymorphisms as harbingers of immune responsiveness. For instance polymorphisms of the IL-10 gene appears to be responsible for differential levels of expression of this cytokine in various conditions. Interestingly, individuals with a phenotype associated with low IL-2 production appear to bear an increased incidence of melanoma and...

FGF Receptors and Tumorigenesis

Similar to the FGF ligands, expression of FGFRs is significantly upregulated in a variety of cancer types. For example, the genes for FGFR-1 and -2 were found to be amplified and overexpressed in a subset of breast cancers. In these cases, amplification of FGFR-2 significantly correlated with amplification of the gene for c-myc amplification of FGFR-1 correlated with the amplification of the genes for FGF-3 and FGF-4 (50). The gene for FGFR-2 was found to be amplified in stomach cancer, in which it was isolated as K-sam (40). FGFR-1 expression was found to be upregulated in glioblastoma FGFR-2 was present in white matter and low-grade astrocytomas, but absent in glioblas-toma. Indeed, during progression to the most malignant phenotype of glioblastoma, a gradual shift from FGFR-2 to FGFR-1, with two or three Ig domains, was observed (51). Expression of both FGFR-1 and FGFR-2 was found to be upregulated in gliomas and meningiomas (19). Inhibition of FGFR-1 expression by antisense...

Chemical Enhancers and Inhibitors of Carcinogenesis

The promotional activity of 41 agents was tested with a strain of hybrid Xiphophorus that was genetically predisposed to melanoma (A. Anders et al., 1991a). Thirty of these agents were positive, including the carcinogens MNU and A-ethyl-A-nitrosourea, and 11 were negative. Chemicals that were negative for promoting activity in this test included DEN.

Liver Resection for Colorectal Metastases

In 1963 Woodington and Waugh first reported a 20 5-year survival in 20 patients undergoing liver resection for a variety of malignancies, including colon, stomach, gallbladder, pancreas, and melanoma. Since that time there has been an increasing acceptance of this approach to treat liver metastases, particularly in light of the poor outcome obtained with other treatment modalities. A more accurate understanding of liver structure, based on functional segmental anatomy, as well as advances in operative technique and postoperative care, have resulted in the capability to perform this operation with very low morbidity and mortality.

Structure Based Library Design

Our first example concerns a library designed to find inhibitors of Cathepsin D, an aspartyl protease that has been implicated in tumour metastasis in breast cancer, melanoma metastasis and Alzheimer's disease Kick et al. 1997 . At the outset of the study no potent non-peptidic inhibitors were known. Libraries were designed based on a known aspartyl-protease transition-state mimetic with three positions of diversity as shown in Figure 9-10.

Monitoring vaccination studies

Development is the correlation of clinical efficacy with T cell responses as surrogate markers. There is increasing evidence now from various clinical cancer vaccination trials for a relation between the detection of vaccine-induced T cells by cytokine-based assays and clinical responses (reviewed in 14). Standardization and validation of T cell assays to monitor the induction of specific T cells responses is crucial to reliable monitoring of clinical trials. Several expert workshops have been performed within the EORTC melanoma group and the International Society of Biological Therapy of Cancer (ISBTC) on T cell assay methodology and standardization (15, 16). The simultaneous use of two ex vivo T cell assays including a functional assay for T cell monitoring has been proposed (16). Controls for the quality of the samples as well as for the accuracy and reproducibility of the assay are a prerequiste for clinical T cell monitoring as outlined above.

Novel Method To Identify Tumorreactive T Cells Cd107 Mobilization

A key advantage of the CD 107 technique is the ability to detect tumor-reactive CD8+ T cells without knowing the peptide-MHC target. Since the assay measures T cells which degranulate in response to tumor cells, there is no a priori need to know the actual peptide target which would be required for most current assays. This is an important advantage since only a small number of TAAs have been identified to-date, mostly in the setting of melanoma. This technique may also be useful for immune monitoring of clinical trials involving vaccination with whole tumor cells, tumor-APC fusions, APCs pulsed with tumor lysates or transfected with tumor RNA, or other novel immunotherapeutic strategies in which the exact peptide targets are undefined. In such instances, the same cells used for vaccination could be used as stimulators in the immune monitoring assay to reveal tumor-reactive, cytolytic T cells.

Modulation of TSP1 Production During Tumor Development

Some tumor-suppressor genes support the production of TSP-1. When they are inactivated, the secretion of inhibitory TSP-1 falls off, and, as a result, the cells become more angiogenic. Wild-type p53 supports TSP-1 production in some breast cells (96) and in fibroblasts (27,95), although not in glioma cells (102), where TSP-1 production depends, instead, on an unidentified tumor-suppressor gene on chromosome 10p (26), possibly PTEN MCMAC (103,104). In each ofthe above cases, the phenotype of the cells switches from antiangiogenic to angiogenic upon loss of the tumor-suppressor gene, because of a decrease in the secretion of inhibitory TSP-1. In addition, expression of NM-23 can increase TSP-1 production in melanoma cells (97), suggesting that this metastasis suppressor could in some settings regulate angiogenesis via TSP.

Angiostatin and Endostatin

Recently, O'Reilly et al. (115) identified another antiangiogenic protein isolated from a hemangioendothelioma and called endostatin. Endostatin is a smaller protein than angiostatin, and is a 20-kDA C-terminal fragment of collagen XVIII. Endostatin has been shown to inhibit the growth of the LLC when administered at doses of 10 or 20 mg kg daily by intraperitoneal injection. Similar results were found in animals bearing the T241 fibrosarcoma, the B16 melanoma, and the EOMA hemangioendothelioma.

Organdependent Expression Of Basic Fibroblast Growth Factor By Tumor Cells

Recent clinical observations have noted antiangiogenic effects in vascular tumors, including hemangioma (65-70), Kaposi's sarcoma (71-74), melanoma (75), basal cell and squamous cell carcinoma (76), and bladder carcinoma (77), using recombinant interferons. These tumors have also been documented as producing high levels of bFGF, often detectable in the urine or serum of these patients (78,79). These findings, along with in vivo observations, prompted investigation of whether IFNs could modulate the expression of the angiogenic molecule, bFGF. The authors found that IFN-a and IFN-p, but not IFN-y, downregulated the expression of bFGF mRNA and protein in HRCC, as well as in human bladder, prostate, colon, and breast carcinoma cells (80). The inhibitory effect of IFN-a and -P on bFGF expression was cell-density dependent and independent of the antiproliferative effects of IFNs (80,81). The authors recently confirmed that IFN can inhibit bFGF production in an in vivo model system....

Effect Of pH On Angiogenesis

It is known that the mitogenic response of a variety of cells to growth-stimulating agents are accompanied by an transient increase in Na+ H+ exchange, with a resultant increase in pHj, which suggests that alkalization of the intracellular environment may be an initial signal for cell proliferation, as well as possible cell differentiation. In this connection, Grass et al. (82) reported that cellular differentiation was stimulated by agents that increase pH and was inhibited by agents that block the ATP-dependent H+ pump (Na+ H+ ATPase). The pH in mammalian cells has been demonstrated to vary, depending on the stages of the cell cycle. In tumor cells, the pH of S-phase and G2 M cells was slightly higher than that of G0 G1 cells (83). Taylor and Hodson (84) observed that the growth rate of PMC-22 human melanoma cells in culture was normal at pHe 7.2-6.8 the growth rate was reduced as the medium pH was lowered to below 6.8. When the medium pH was lowered to 6.7-6.4, the cells...

Management of the Axilla

Just as treatment of the primary tumor of the breast has evolved from a single, radical operation for all scenarios to a more directed approach consisting of lumpectomy, the standard axillary dissection is quickly being replaced by sentinel lymphadenectomy. Introduced by Morton and colleagues in 1992 for the treatment of melanoma,39 this technique was quickly applied to breast cancer.4041 Like lymphatic mapping for other disease sites, the sentinel lymph node is identified through the constant anatomic relationship between a tumor and draining lymphatics. Conceptually, each specific area in the breast drains to a sentinel lymph node which may be located anywhere within the axilla or internal mammary chain (Figure 9-10). Larger tumors may have more than one draining lymphatic (Figure 9-11). The sentinel lymph node biopsy continues to be refined and defined for patients with early breast cancer in several studies, it has been demonstrated to yield reliable correlation to an axillary...

Signaling Events Associated with Adenovirus Internalization

While further research is needed to fully characterize Ad cell entry mechanisms, the identification of specific signaling molecules involved in adenovirus cell entry may allow improvements in Ad-mediated gene delivery to cells which lack CAR and or av integrins. For example, ligation of certain growth factor receptors (i.e., epithelial growth factor (EGF)) or cytokines (i.e., tumor necrosis factor alpha (TNFa)) results in activation of remarkably similar signaling pathways as those induced by integrin clustering 101-103 . Li et al. recently investigated whether activation of growth factor receptors could circumvent the need for av integrins CAR in adenovirus-mediated gene delivery 104 , They generated a bifunctional antibody that recognizes the penton base RGD motif (DAV-1) as well as one of several different cytokine or growth factor receptors. Ad vectors complexed with these bifunctional molecules significantly increased PI3K activation in host cells and improved gene delivery to...

Intercellular Surveillance

These and other contactual controls between normal and tumor cells may also explain the previously mentioned observation that many disseminated tumor cells never grow into metastatic tumors. In one experimental model (Naumov et al., 2002), it was found that a significant fraction of injected mouse mammary tumor cells of either high or low metastatic potential persisted as solitary nondividing cells in the liver. Reinoculated to new hosts they were fully tumorigenic. Similar dormancy of solitary tumor cells has been observed with melanoma, squamous cell carcinoma, and prostate carcinoma cells. The awakening of the dormant tumor cells may be accelerated by disturbing the tissue equilibrium, for example, by phorbol esters.

Killing Mechanisms Used In Host Responses To Syngeneic Tumors

It is now clear that killer lymphocytes can use several mechanisms to destroy aberrant self-cells including tumor cells. The most vigorous of these are based on the perforin and Fas pathways, with perhaps a lesser contribution of TNF and related pathways (54). One of the first comprehensive looks at the role of perforin in rejection of syngeneic tumors was carried out by van den Broek et al (55, 56). They looked at rejection of a wide range of lymphoid and non-lymphoid tumors in perforin knockout mice, compared to normal controls. The results varied widely, with no obvious relation to tumor type. A melanoma was equally lethal in mice with or without perforin. A fibrosarcoma grew about ten times more readily in perforin-deficient mice, although both the knockout mice and normal controls developed stable tumors. Both mice rapidly rejected a modified adenovirus-induced tumor. In general, among lymphoid tumors, perforin deficient mice were 100-1000 times more susceptible to some, and...

Tumor Escape And Future Approaches To Cancer Immunotherapy

Extensive immunization trials are on-going worldwide in patients with breast, colon, renal cell, ovarian and prostate carcinomas as well as melanoma and other malignancies. These clinical trials, largely initiated in patients with advanced metastatic disease, have been able to induce clinical responses in not more than 20 of patients. They are unlikely to yield the desired results, if only a proportion of the immunization-induced, TA-specific effector cells survive in vivo. Moreover, if a proportion of specific T cells or DC are preferentially killed, and if the level of apoptosis exceeds that of effector cell influx into the tumor or their generation within the secondary lymphoid sites, the immunization strategies (as currently applied) may prove ineffective. Likewise, it may be counterproductive to generate TA-specific effector cells in a situation where the tumor is resistant to that type of immune cell, i.e., poised to escape specific immune interventions. To avoid additional...

Inhibition of FGF Activity

Another approach to interfere with tumor growth is the ligand-specific targeting of toxins to tumor cells expressing FGFRs. For example, a fusion protein consisting of FGF-2 and saporin, a cell toxin isolated from the plant saponaria, was specifically targeted to FGFRs, and exhibited antitumor activity in vitro and in vivo (112). Recombinant versions of these fusion proteins expressed in Escherichia coli inhibited growth of B16-F10 melanoma cell lines in vitro, and retarded tumor growth and metastasis in vivo (113). Alternatively, fusion of FGF-1 to Pseudomonas exotoxin A resulted in specific cytotoxicity to a variety of tumor cell lines expressing FGFRs, including those of prostate, colon, or breast carcinoma (114). Systemic application in athymic mice grafted with several different tumor cell lines slowed tumor growth, but did not induce complete regression. Probably, the exotoxin attacked the tumor mass, rather than the tumor endothelium (114). Pseudomonas exotoxin FGF-1 fusion...

TSP1 Is a Potent Inhibitor In Vivo

TSP-1 is effective at inhibiting angiogenesis induced by living tumor cells in several settings. Small pieces of mouse melanoma, or human colon carcinoma cut from tumors growing in nude mice and implanted directly into rat corneas, induce vessel ingrowth that is blocked when a pellet containing TSP-1 is interposed between the tumor fragment and the vascular limbus (P. J. Polverini and N. Bouck, unpublished data). Systemic treatment of mice with purified TSP-1 can also be anti angiogenic and inhibit tumor growth. High levels of TSP-1 in the circulation render mice unable to mount a corneal angiogenic response to a pellet containing stimulatory bFGF and halt the growth of experimental lung metastases (19).

Phase Iii Trial Design

The adjuvant setting may ultimately be where Als provide the greatest benefit however, identifying the efficacy of the AI in this setting w ill require a commitment of patient resources, time, and money. The efficacy of adjuvant therapy, following complete surgical resection of a tumor, has been proven for breast cancer, colon cancer, and melanoma. The rationale for adjuvant therapy is to eradicate microscopic disease. In designing a clinical trial in the adjuvant setting for a particular disease, it is important to understand the natural history of patients rendered free of disease by surgery, radiation, and or chemotherapy. As an example, response rates of 85-95 , including 50-60 CRs, can be achieved with combination chemotherapy in limited-stage, small-cell lung cancer (50). Unfortunately, the median survival remains between 12-16 mo. Patients attaining a CR to standard cytotoxic chemotherapy could be considered for a trial randomizing patients between an AI or placebo. The number...

Mechanisms For Protection Of Immune Cells And Prevention Of Tumor Escape

Attention must also be focused on immunized patients' tumor cells susceptibility to immune recognition and destruction. As discussed above, defects in HLA class I antigen expression have been convincingly documented in melanoma large number of malignant lesions of different histotype (20). Although not conclusive, the available evidence suggests the clinical relevance of these defects, since they are associated with a poor course of the disease in several malignancies, are present with increased frequency in malignant lesions of patients treated with T cell-based immunotherapy (20). These findings have been interpreted to indicate the outgrowth of malignant cells which have acquired the ability to escape T cell

Susceptibility To Transitional Cell Carcinoma

Blackfoot Disease and Arsenic-induced Skin Cancer In a cohort study on urinary bladder cancer, mainly transitional cell carcinoma (TCC), in the BFD-endemic area, an increased risk was observed among patients affected with BFD as compared with the unaffected (Chiou et al., 1995). The odds ratio of developing urinary bladder cancer was around four-fold after adjustment for age, sex, cigarette smoking and cumulative arsenic exposure. In our most recent cohort study on TCC in the BFD-endemic and non-endemic areas, an increased risk of developing TCC was observed among patients affected with skin cancer than the unaffected. The odds ratio was around five-fold after adjustment for age, sex, cigarette smoking and cumulative arsenic exposure. In a nested case-control study in the BFD-endemic area, an increased cancer risk was significantly associated with the elevated frequency of chromosome-type aberrations in peripheral lymphocytes (Liou et al., 1999). Both skin cancer and transitional cell...

Carcinogenic Interactions For Ingested Arsenic

Methylation capacity has been hypothesized to play a role in susceptibility to arsenic-induced carcinogenicity. Hsueh et al. (1997) classified subjects from a Taiwanese study according to the percent of arsenic excreted as monomethyl arsonic acid (MMA) in urine and also by cumulative arsenic exposure. These authors found that the multivariate adjusted odds ratios for skin cancer differed in these four groups. Within the low cumulative arsenic exposure group, those with a higher percentage of urinary MMA showed a relative risk of 3.0 compared to those with a lower percentage (

Altered Stem and Progenitor Cell Self Renewal and Cancer Stem Cells

Based on these observations, it is conceivable that similar to the situation in Drosophila, the machinery promoting asymmetric cell division may play an evolutionary conserved role in mammalian tumor suppression. Indeed, mammalian homologues of Baz, Par6, DaPKC, Lgl, and Numb have been shown to regulate asymmetric cell fate determination and tumor suppression. Thus, mammalian aPKC, Par3, and LGN are involved in asymmetric division of basal epidermal progenitor cells of the skin and their dysregulation can lead to skin cancer (Lechler and Fuchs 2005). Moreover, there is evidence for the asymmetric segregation of vertebrate NUMB homologues (Wodarz and Huttner 2003) that seem to act as asymmetric cell fate determinants. Double knockouts of Numb and Numb-like in the mice dorsal forebrain have been found to lead to impaired neuronal differentiation, hyper-proliferation of neural progenitors, and delayed cell-cycle exit (Li HS et al. 2003). In addition, loss of Lgl1 Mlgl Hugl, one of the...

Traumatic disorders of the nail

Nail Diseases With Function

Histological examination is essential to rule out amelanotic melanoma. These are numerous (Figures 9.5-9.8). Trauma-induced Beau's line accompanied by pyogenic granuloma of the proximal nail folds of the affected fingers from trauma on the palm and the arm has been reported. Delayed effects of major trauma include permanent damage of the nail matrix, sometimes with unequal growth of different sections of the nail plate. Damage to the matrix may result in a split extending along the entire length of the nail, or a longitudinal prominent ridge, and may even result in ectopic nail due to the altered position of the matrix following the trauma, Trauma to the proximal nail fold may be responsible for the formation of pterygium. Longitudinal melanonychia following acute trauma is rare in white individuals. Hook nail is observed when the nail bed is shortened after distal section of the bony phalanx. Any traumatic force to the distal phalanx can result in...

Dermoscopy of nail pigmentation

Diagnosis of melanonychia striata is one of the most difficult aspects of clinical dermatology. Melanoma is feared in most situations however, melanoma of the nail apparatus is rare (about 1 of all cutaneous melanomas). The clinical presentation of early nail apparatus melanoma longitudinal pigmentation is shared by many other clinical processes with much more favourable outcomes, such as nail apparatus naevus or lentigo, drug-induced pigmentation, subungual haemorrhage and ethnic-type nail pigmentation. The 'gold standard' of diagnosis remains the pathological examination of the nail matrix biopsy, but the biopsy procedure is usually painful and often results in nail dystrophy.

Glial Cells and Brain Tumors

Medullated Nerve Schwann Cell

A tumor consists of a mass of rapidly dividing cells. Mature neurons, however, have little capacity for mitosis and seldom form tumors. Some brain tumors arise from the meninges (protective membranes of the CNS) or arise by metastasis from tumors elsewhere, such as malignant melanoma and colon cancer. Most adult brain tumors, however, are composed of glial cells, which are mitotically active throughout life. Such tumors are called gliomas.21 Gliomas usually grow rapidly and are highly malignant. Because of the blood-brain barrier (see chapter 14), brain tumors usually do not yield to chemotherapy and must be treated with radiation or surgery.

Associations with an Increased Genetic Risk

173 showed that chronic inhibition of the ETB by the receptor antagonists A-192621 was harmful to vascular remodelling following injury. This is still further supported by the reported inhibition of EDNRB, resulting in induction of VEGF expression in melanoma cells 169 . These actions of endothelin suggest that it plays a major role in development, possibly as a regional morphogen (perhaps via co-coordinated control of genes and signalling pathways) and possibly in conjunction with GDNF as well as laminin-1 downregulation.

Ispinesib and related compounds

Sensitive non-small cell lung cancer, ovarian cancer, hepatocellular cancer, colorectal cancer, head and neck cancer, hormone-refractory prostate cancer, and melanoma. In the ongoing breast cancer study, women with locally advanced or metastatic breast cancer, receive ispinesib as monotherapy at 18mg m2 as a 1-h intravenous infusion for every 21 days. In an interim analysis of Stage 1 data from this two-stage trial, partial responses were reported in three of 33 evaluable patients. Maximum decreases in tumor size ranged from 46 to 68 , and the duration of response from 7.1 to 13.4 weeks. The overall response rate for all 33 evaluable patients was 9 with a median time to progression of 5.7 weeks. The adverse events were manageable, predictable, and consistent with the Phase I clinical trial experience with ispinesib, and ispinesib plasma concentrations were comparable to those observed in the Phase I clinical trial 11,16 .

Intratumoral Microvascular Density

Some investigators have suggested that assessing intratumoral MVD or other markers of endothelial cell proliferation, such as endoglin (34), with serial tumor biopsies over time may offer an insight into the biological activity of a given AI. Unfortunately, the ability to obtain serial tumor biopsies in cancer patients has been difficult. Few tumor types manifest metastatic disease in easily accessible sites. Exceptions include malignant melanoma and Kaposi's sarcoma (KS), which often present with multiple skin lesions. Although there is much enthusiasm for evaluating AIs in patients with HIV-related KS, this disease entity may not behave in the same way as other, more typical, epithelial tumor types. The requirement for serial biopsies has been incorporated into other clinical trials, including those that attempt to determine the development of multidrug resistance (MDR) gene expression over time, as patients are treated with a particular cytotoxic chemo

Incisional biopsy and punch biopsy

Skin Lines

It is essential to have a working clinical diagnosis, but wherever there is doubt the pathologists can provide much more precise information regarding the nature and extent of the lesion. For example, a patch of Bowen's disease (intraepidermal carcinoma) may resemble sclerosing superficial basal cell carcinoma and a biopsy will usually distinguish them. Similarly, what seems to be a dysplastic pigmented naevus clinically may, on the one hand, prove to be benign or, on the other hand, turn out to be a malignant melanoma requiring wide excision.

Acquired longitudinal melanonychia after puberty in a whiteskinned individual requires urgent biopsy

Approximately 2-3 of melanomas in whites, and 15-20 in blacks are located in the nail unit. However, malignant melanoma is rare in black people thus the number of nail melanomas does not significantly differ between these population groups. Most white patients have a fair complexion, light hair, and blue or hazel eyes. There is no sex predominance, although some reports show variable female or male predominance. The mean age at onset is 55-60 years. Most tumours are found in the thumbs or great toes. Melanoma of the nail region is often asymptomatic. Many patients only notice a pigmented lesion after trauma to the area only approximately two-thirds seek medical advice because of the appearance of the lesion pain or discomfort is rare, and nail deformity, spontaneous ulceration, sudden change in colour, bleeding or tumour mass breaking through the nail are even more infrequent. It is useful to remember that a pigmented subungual lesion is more likely to be malignant than benign. If the...

FGF1 and FGF2 in Tumor Development

Extensive studies on the expression of FGF-1 and FGF-2 in tumor biopsies in vivo together with functional studies on tumor cell proliferation in vitro, provided a plethora of evidence for the involvement of FGF-1 and FGF-2 in tumor development. In some cases, expression of FGF-1 or FGF-2 correlated with malignancy, and interference with the activities of FGF-1 or FGF-2 diminished tumor growth and cell transformation (15). FGF-1 and FGF-2 were significantly upregulated in human gliomas, proportional with the degree of malignancy (15). Furthermore, the malignant phenotype of glioblas-toma cell lines could be inhibited by FGF-2-specific antibodies, indicating that FGF-2 utilized an autocrine pathway to promote tumor progression (16). FGF-2 and sometimes FGF-1 are constitutively expressed at high levels in melanomas, but not in normal melanocytes (8). Proliferation and growth in soft agar was inhibited by antisense oligonucleotides to FGF-2 or FGFR-1 in melanoma cell line, indicating that...

Specific Etiologies and Treatments

Drugs NSAIDs Potassium Salicylates Neoplasms Adenocarcinoma Lymphoma Melanoma Infections CMV Small bowel malignancies are rare, accounting for 2 of all GI cancers. Primary small bowel lesions include adenocarcinomas, carcinoid tumors, lymphoma, and leiomyosarcomas. Metastatic lesions may arise from melanoma, Kaposi's sarcoma, lung, breast, and renal cell carcinoma. They are more commonly seen in patients in their fifth to seventh decade of life. Adenocarcinomas are the most common small bowel malignant tumors to cause intestinal bleeding with an incidence approaching 60 (Bashir and Al-Kawas, 1996). In the setting of CD, adenocarcinomas tend to occur distally and are more common in the small bowel than the colon. Endoscopic treatment of small bowel malignancies is highly unsuccessful and associated with the occurrence of a high rate of complications therefore, treatment with surgical resection, if possible, is preferred.

Mutagenetic Tree Models

Some evolutionary processes can be described as the accumulation of nonreversible genetic changes. For example, the process of tumor development of several cancer types starts from the set of complete chromosomes and is characterized by the subsequent accumulation of chromosomal gains and losses, or by losses of heterozygosity Vogelstein et al., 1988, Zang, 2001 . Mutagenetic trees, sometimes also called oncogenetic trees, have been applied to model tumor development in patients with different types of cancer, such as renal cancer Desper et al., 1999, von Heydebreck et al., 2004 , melanoma Radmacher et al., 2001 and ovarian adenocarcinoma Simon et al., 2000 . For glioblastoma and prostate cancer, tumor progression along the mutagenetic tree has been shown to be an independent cytogenetic marker of patient survival Rahnenfuhrer et al., 2005 .

Axis III General Medical Conditions

The second manner in which a general medical condition may be relevant to a mental disorder is that the medical condition may be related to the development of the mental disorder, but not through direct physiological means. For example, an Axis I disorder such as Major Depression or Adjustment Disorder with Depressed Mood might follow in reaction to learning of one is diagnosed with a malignant melanoma (Axis III).

Melanocytic naevus of the nail organ

Naevi may be located at any site in or around the nail organ, and may pose considerable differential diagnostic problems when they cause longitudinal melanonychia. This sign may be due to a focus of functionally active melanocytes (as in ethnic pigmentation), to an accumulation of active melanocytes (as in the Laugier-Hunziker-Baran syndrome), or to a common lentigo, junctional melanocytic naevus, compound naevus or malignant melanoma. Most naevi are of the junctional type. A few barely visible cells or large numbers of distinctly pigmented melanocytes may be seen singly or in clusters within the basal and suprabasal matrix epithelium. Mitoses are absent. A few melanophages may occur in the upper papillary. The nail plate contains intracellular fine melanin granules. Despite clinically obvious pigmentation, pigment visualization under the microscope often requires staining with the Fontana-Masson argentaffin reaction. Suprabasal location of melanocytes is common in the matrix and nail...

From Leprosy To Hansens Disease

Early Signs Leprosy

Medieval attitudes towards the leper were based on biblical passages pertaining to ''leprosy,'' a vague term applied to various chronic, progressive skin afflictions, from leprosy and vitiligo to psoriasis and skin cancer. The leper, according to medieval interpretations of the Bible, was ''unclean'' and, therefore, a dangerous source of physical and moral pollution. Biblical rules governing leprosy demanded that persons and things with suspicious signs of leprosy must be brought to the priests for examination. Leprosy was said to dwell not only in human beings, but also in garments of wool or linen, objects made of skins, and even in houses. Diagnostic signs included a scaly eruption, boil, scab, or bright spot. When the signs were ambiguous, the priest shut the suspect away for as long as two weeks for further observations. When a final judgment had been reached, the leper was instructed to dwell in isolation and call out as a warning to those who might approach him, ''unclean,...

Molecules Cells and Tissues of the Immune Response

Activated leukocyte cell adhesion molecule (ALCAM CD166) is a member of the immunoglobulin (Ig) gene superfamily. It is expressed by activated leukocytes and lymphocyte antigen CD6. The extracellular region of ALCAM contains five Ig-like domains. The N-terminal Ig domain binds specifically to CD6. ALCAM-CD6 interactions have been implicated in T cell development and regulation of T cell function. ALCAM may also play a role in progression of human melanoma.

Are Alterations In The Apoptotic Machinery Determinants Of Drug Sensitivity

Moving further downstream, silencing of APAF-1 has been reported in a large fraction of melanoma cell lines and clinical samples (280). Consistent with prior observations in Apaf -1- - murine fibroblasts and thymocytes (281), the Apaf-1-deficient melanoma cells were reportedly resistant to doxorubicin-induced apoptosis (280). Although the authors concluded that they had identified a major mechanism of drug resistance in melanoma, subsequent observations have called this conclusion into question. In particular, others have not been able to reproduce the frequent Apaf-1 downregulation in melanoma cell lines (282-284) or clinical samples (284).

Dynamic Monitoring Of Anticancer Immune Responses

Determine the occurrence of immune-induced cancer regression in humans (56). The introduction of gene profiling arrays is particularly suited to circumstances when little is known about a biological event to conceive plausible hypotheses. This is clearly the case of immune-mediate cancer rejection. We tested whether global transcript analysis could segregate lesions likely to respond to immunotherapy by obtaining FNA from subcutaneous melanoma metastases prior to immunotherapy (49). This work was based on a previous observation suggesting that cutaneous melanomas can be segregated into two distinct taxonomies based on global transcript analysis (57). Such observation stimulated the question of whether two disease pathologically defined as melanomas had a different biology and consequently, perhaps, different predisposition to respond to immune therapy. However, the original observation was based on the analysis of cell lines or tissue preparations that has been collected a long time...

Essential Components Of An Effective Taspecific T Cellbased Immune Response

Tumor Microenvironment Immune Response

Both the SEREX, T-cell-based and reverse immunology approaches have identified a variety of tumor antigens (TA), which can be broadly classified as tumor antigens that are capable of being recognized by the immunocompetent host (a) cancer-germ line antigens such as MAGE 1 or 3, BAGE, GAGE and many others that are silent in normal tissues, with the exception of germ cells in the testes and ovaries but expressed in a variety of histologically distinct tumors (3-5) (b) differentiation-specific antigens exemplified by melanoma- and melanocyte-associated tyrosinase, MART-1 Melan-A or gp100 (3-5) and (c) unique antigens generated by point mutations in ubiquitously expressed genes, which regulate key cellular functions, such as MUM-1, CDK4, FLICE or b-catenin (3-5) (d) overexpressed antigens, such as p53, MDM2, CEA, which are components of normal cells but in tumor cells are greatly increased in expression (35,25). Despite the fact that the majority of the known TA, with the...

Data Interpretation

Monoclonal or oligoclonal TCR VB families may occur in EBV or CMV-specific T-cell responses and reflect the immunological memory of previous encounters with antigens (19, 20). Some alterations can also be identified in CD4+ T-cells, presumably reacting to common infectious agents, e.g. CMV (21). Due to structural constraints of the TCR interaction with its nominal MHC peptide ligand, some T-cell responses are characterized by a common usage of a TCR VB family, but not with a common CDR3 motif. For instance, the HLA-A2 restricted CD8+ T-cell response targeting the influenza matrix peptide Ml (aa 58-66) shows a preferential usage of the TCR VB17 family (22) which is polyclonal in nature. Other, preferential usage of certain TCR variable families may also be present in the human population. This is difficult to assess, since these studies depend either on the generation of bona fide T-cell clones directed against a single MHC peptide complex, or alternatively on...

Generation Of Tumor Antigen Epitopes

Translated in the third alternative open reading frame (AORF), and a T cell epitope that was recognized by an HLA-A11 restricted, tumor reactive TIL was present within this AORF. A melanoma that expressed a p16INK4a transcript containing a 2 base pair exon 2 deletion that resulted in the translation of the this AORF was also recognized by the HLA-A11 restricted TIL. Frame-shifted CDKN2A products are expressed at high frequencies in certain tumor types (83, 84), and thus this represents a highly shared mutated epitope that could be utilized as a target for immunotherapy in patients bearing certain cancers. Expression of the immunoproteasome, which has a distinct peptide cleavage specificity from the proteasome and which can be induced in a variety of cells by stimulation with interferon gamma (IFN-y), may also affect the processing of certain T cell epitopes. The treatment of tumor cells with IFN-y nearly eliminated the ability of those cells to stimulate T cells that recognize...

Immune Surveillance

The strongest argument for immune surveillance is provided by the increased incidence of a given tumor in immunodefectives. Three types of human malignancies qualify by this criterion. All of them are virus related EBV carrying immunoblastoma, papillomavirus-associated cervical, anogenital, and skin cancer, and HHV-8 carrying Kaposi's sarcoma. The frequency of other tumors does not increase significantly in the immunosuppressed. This is in line with the notion, also supported by research on experimental animals, that spontaneous tumors with no viral involvement are regarded as self by the immune system (with skin melanomas as a possible exception). Immunological attempts to influence such tumors are therefore akin to breaking or circumventing tolerance. Current efforts toward that goal include the inhibition of regulatory T cells the provision of appropriate costimulatory signals the stimulation of proinflammatory cytokines such as IL-1, IL-6, or IL-12 the activation of dendritic...

Case Study Of A Diabetic Patient With Foot Ulcer

Ray Toofani Leg Ulcer Nurse

Malignant melanoma Fig. 4.43 This subungual ulcer failed to heal and was referred to the dermatologists. Biopsy revealed an amelanotic malignant melanoma. Fig. 4.43 This subungual ulcer failed to heal and was referred to the dermatologists. Biopsy revealed an amelanotic malignant melanoma. When the foot failed to heal after 3 months, the patient was referred to dermatology for an opinion (Fig. 4.43). Although the dermatologists were not really suspicious that there was any neoplasia present because the area was not elevated, they felt that it would be wise to check, and a biopsy was arranged. A malignant melanoma was diagnosed and the toe was amputated. The patient is alive and well 3 years later and has regular follow-up appointments with the dermatologists. Malignant melanomas may be amelanotic


Percentage is due to BRCA2 mutations. Initial studies estimated that carriers of the BRCA1 germ-line mutation harbor a lifetime risk for breast cancer of about 85 percent12,13 and a risk for ovarian cancer that ranges between 40 and 66 percent.1213 Carriers of the BRCA2 mutation, on the other hand, have a lifetime risk of breast cancer of about 85 percent, but their risk for ovarian cancer is somewhat lower (10 to 20 ).12,13 Male BRCA2 mutation carriers have an approximate 7 percent lifetime risk for breast cancer. Other cancers occurring in BRCA2 mutation carriers include carcinoma of the pancreas, head and neck, and intraocular malignant melanoma. Males who are harbingers of germline mutations in BRCA1 BRCA2 will have a two- to three-fold increased lifetime risk for prostate cancer.

Disease Atlases

Another set (for the rarer diseases) used the 47 counties. These atlases again showed marked variations in the distribution of disease. For example, cancer rates for the breast, ovary, brain, melanoma of the skin, and non-Hodgkin's lymphoma were lower in the north rates for cancers of the buccal cavity, pharynx, stomach, rectum, cervix and kidney were generally lower in the south. A few pockets of high mortality were evident also for example, oesophageal cancer in Lancashire, and nasal and bladder cancers in some of the London boroughs. Most importantly, these atlases stimulated the formation of new hypotheses of causation, which were tested both by the authors of the atlases and by other independent researchers.


Metastasis has been reported for certain types of fish neoplasms, including nephroblastomas (Masahito et al., 1992), pigment cell neoplasms (Okihiro et al., 1992) and lymphomas (Nigrelli, 1947). Melanomas commonly metastasize in some fish (Fig. 3.1), although this may not occur in all species. There are several reports of metastasis of hepatic neoplasms these and other metastatic neoplasms of fish were reviewed by Machotka et al. (1989). Overall, metastasis in fish may be less common than in mammals because several common metastatic primary tumours in mammals (lung, breast, cervix, prostate and uterus) and some of the most frequent sites of metastases (lungs, lymph nodes and bone marrow) are not present in fish. Many common neoplasms of fish are relatively well differentiated, and this could also be related to their weakly malignant behaviour. Other reasons for the less frequent occurrence of metastasis in fish have been proposed, including differences in the 'lymphatic system'...

Figure 528

Metastatic malignant melanoma involving the kidney. The urinary tract is a common site of melanoma metastases. If not amelanotic, the metastatic nodules are brownish black. Metastatic infiltration of the kidneys is often an incidental finding at autopsy but is a rare cause of functional impairment 68 . Most renal metastases are multiple and bilateral. Glomeruli tend to be spared, possibly because of their lack of lymphatic channels. Pulmonary carcinoma is the most commonly reported form of metastatic solid tumor involving the kidneys, followed by metastatic stomach and breast carcinoma 69 . Metastatic melanoma is an example of a tumor that may be transplanted at the time of cadaver kidney transplantation, with subsequent rapid proliferation in the immunosuppressed recipient tumor rejection may occur with cessation of immunosuppressive therapy 70 (see Fig. 5-37). The presence of renal metastases is often overlooked during life due to the absence of any specific physical or laboratory...

Lumps and bumps

The skin is a common site for neoplastic lesions, but most invade only locally and with treatment usually do not pose any threat to the life of the patient. The exception is malignant melanoma, which is dealt with in chapter 15. This is a rare tumour with a high mortality, and recent publicity campaigns have been aimed at preventing the tragedy of fatal metastases from a neglected melanoma.

Figure 535

Melanoma of the nail region is now better understood since the identification and analysis of acrolentiginous melanoma. It may be localized subungually or periungually with pigmentation and or dystrophy of the nail plate (Figure 5.35). Initial lesions may be mistaken histologically for benign or atypical melanocytic hyperplasia, but serial sections usually reveal the true nature of the disease.

The sun and the skin

People with darkly pigmented skin very rarely get skin cancer. Those of a Celtic constitution, when exposed to strong sunlight in countries such as Australia, get skin cancer very readily. Australia has the highest incidence of skin cancer in the world, with 140 000 new cases per year, and 1200 deaths per year, mainly from melanoma. It is therefore important to understand that there is a variation in skin sensitivity to sunlight. This is rated from one to six (Fitzpatrick classification). Skin type one subjects have red hair and do not tan, burn very easily in the sun and develop skin cancer readily, whereas skin type six subjects have black skin (with an inbuilt sun protection factor of 10) and very rarely develop skin cancer. This is a useful guide in assessing the risk of sun damage and in determining the dose of ultraviolet B in treatment.

Backcross hybrids

(four genotypes resulting in three phenotypes) melanoma melanosis no macromelanophores x-erb B*a - x-erb B*a - - - - - Fig. 3.6. Inheritance of melanoma in hybrids of southern platyfish and swordtails. Fish with the x-erbB*a (Xmrk) oncogene have macromelanophores, but the promoter of this oncogene is repressed by the locus RDtff. Hybrids (F1 hybrids and some backcross hybrids) that are heterozygous for Rm and carry x-erbB*a have melanosis and sometimes develop melanoma when they are adults. Melanomas occur in very young backcross hybrids carrying the oncogene but lacking Rd . (Based on Vielkind, 1976 A. Anders and Anders, 1978 Wakamatsu, 1980 Schartl and Adam, 1992 Zechel et al, 1992 Adam et al, 1993.) The melanomas in Xiphophorus are caused by a dominant tumour locus known as Tu (Ahuja and Anders, 1976 Vielkind, 1976). Several genes that regulate the cell type affected and portion of the body in which neoplasms develop are located on the same chromosome (F. Anders et al., 1984). The...