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 Overview


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Cutaneous Malignant Melanomas

Bittner et al. (2001), in a study involving 11 different institutions, brought modern molecular techniques to this important type of cancer, whose incidence is rising steeply. Melanomas have no histopathologic, molecular, or immunochemical markers to differentiate subsets of patients. There are few known recurring genetic or cytogenetic changes in these tumors, and non-surgical treatment is notoriously ineffective in cases of advanced disease. With a clever visual clustering of gene expression data for 31 patients, 19 were concentrated in the major cluster, whereas the rest were distributed A substudy examined cell lines from very invasive malignant melanomas of the uvula, together with the cutaneous melanomas. The molecular assays were combined with bioassays. First, a simulated scratch wound was made in plated cells, to see whether the cells would grow out, how far they would migrate, and how rapidly they moved away from the initial site. The cells from the invasive lesions migrated...

Mucosal malignant melanoma

Fig. 3.69 Primary laryngeal mucosal malignant melanoma. This hypercellular proliferation shows an admixture of epithelioid and spindle-shaped cells. The epithelioid cells have a solid and nested growth, while the spindle-shaped component has a fascicular growth pattern. Fig. 3.69 Primary laryngeal mucosal malignant melanoma. This hypercellular proliferation shows an admixture of epithelioid and spindle-shaped cells. The epithelioid cells have a solid and nested growth, while the spindle-shaped component has a fascicular growth pattern.

Melanoma Tumor Antigens

Tumor-reactive lymphocytes derived from patient peripheral blood or found to infiltrate metastatic melanoma lesions have been grown in vitro,1 permitting the cloning of melanoma antigens recognized by T cells2,3 (Table 20.1, Figure 20.1). The antigen called MAGE (melanoma antigen E) defined a family of antigens not previously identified. MAGE-1 and members of its multigene family were present on melanomas and other tumors as well as testis and placenta but no other normal tissue.4 A second group of antigens is the melanosome-related differentiation proteins. MART-1 Melan A was defined via recognition by cytotoxic T lymphocyte (CTL) clones from melanoma patient peripheral blood and by tumor-infiltrating lymphocytes (TIL).5 MART-1 is expressed by virtually all metastatic melanoma lesions, and also by melanocytes, but not normal tissue. The nonamer sequence AAGIGILTV and decamer EAAGIGILTV, representing amino acid residues 27-35 and 26-35 of MART-1, respectively, bound most strongly to...

Interferon Alpha A Cytokine That Is an Effective Adjuvant Treatment for Melanoma

Interferon-alpha, a biologic compound that has both antipro-liferative and immune modulatory activity in vitro and in vivo, has been tested in a number of Phase II studies in metastatic melanoma, yielding response rates of 10 to 25 with a small proportion of complete responses (CRs) and median survival of 6 to 9 months.42,43 Response rates appeared to be dose related. These modest results, however, have led to a number of trials of high-, moderate-, and low-dose interferon as adjuvant treatment in patients with resected intermediate (stage IIB and IIC) and high-risk (stage III lymph nodal) melanoma. In Europe, low-dose extended-duration regimens have been tested with fixed doses of 3 million units m2 for up to 3 years. A total of seven well-conceived randomized trials have compared low-dose interferon to a control arm, usually observation (Table 20.2). For patients with high-risk disease, no differences in overall and relapse-free survival were observed in those six European and one...

Activity of Recombinant Interleukin 2 IL2 for Metastatic Melanoma

Shown to mediate regression of melanoma and renal cell cancer and has activity in patients with non-Hodgkin's lymphoma. It was approved by the FDA for metastatic melanoma due to a multicenter Phase II experience of 270 patients with a 16 response rate and a median survival of 12.2 months.61,62 Survival of metastatic melanoma after treatment with highdose IL-2 is associated with development of autoimmune thy-roiditis and vitiligo, as well as the height of the lymphocyte rebound that occurs after cessation of treatment with IL-2 (Table 20.4). When given at the FDA-approved dosage and schedule of 600,000 international units kg every 8 hours as an intravenous bolus, IL-2 was quite toxic, and it is not recommended for use in an inpatient hospital setting unless given by medical and nursing personnel experienced in its use. IL-2 could be beneficial in a variety of different ways. It could drive the expansion of tumor-specific T cells that are activated by the vaccine. It may also be...

Evidence That Cell Vaccines Might Be Beneficial in Melanoma

Cell-based vaccines for melanoma have been evaluated in trials since the 1970s (Table 20.5). Melacine, consisting of two lyophilized melanoma cell line lysates administered with the Ribi adjuvant, and Canvaxin, consisting of three irradiated and frozen intact cell lines administered with bacille Calmette-Guerin (BCG), have been shown to mediate regression in a small proportion of patients with stage IV disease, in the range of 5 to 10 .102-105 Melacine was shown to have a 7 response rate in a small Phase II randomized trial with a survival no different from multiagent chemotherapy102 and has been tested in a large randomized Phase III trial as adjuvant therapy for patients with resected stage II melanoma compared with an observation arm.104,105 For all patients as randomized, there was no difference in overall and disease-free survival, but for patients who were HLA-A2 positive, a relapse-free survival advantage was seen, indicating that the More current developments in this field...

Development of Peptide Vaccines for Melanoma

Peptides of 8 to 10 amino acids are derived by intracellular cleavage of a variety of proteins, and are selectively conducted by the TAP transporter mechanism to the endoplasmic retic-ulum where they bind nascent class I molecules and are presented on the surface of the cell in association with class I molecules for interrogation by T cells. Because peptides are the smallest unit recognized by T cells, they might be useful as vaccine immunogens in the proper MHC class I context for recognition by T cells. A MAGE-3 HLA-Al-restricted peptide in aqueous solution was used to treat 39 patients with metastatic melanoma, of whom 26 finished four treatments every 4 weeks.112 Four PR as well as 3 CR were seen, often with a prolonged time to attain response 2 complete respon-ders had a duration beyond 2 years. The full-length MAGE-3 gene encoding the same peptide was chimerically linked to an H. Flu protein as adjuvant and used to vaccinate 35 patients in a Phase I trial with adjuvant...

Primary cutaneous malignant melanoma

Primary cutaneous malignant melanoma arises from the melanocytes found in the basal layer of skin. These cells produce melanin pigment and are responsible for producing the tanning response after exposure to ultraviolet radiation. 33 of patients with familial melanoma have mutations of CDKN2A The incidence of melanoma in the UK is around 10 new cases per 100 000 per year approximately 6000 patients annually. Primary melanoma of the skin presents as a growing, irregular brown or black lesion on the skin. Important features to alert clinical suspicion include an irregular outline to the lesion irregular pigmentation containing shades of brown, black, and red and, occasionally, oozing or crusting. Most melanomas are around 5 mm in diameter when first recognized but a small number are identified at an earlier stage. They may arise on previously normal skin or on a previously apparently benign melanocytic naevus. The current UICC staging of melanoma divides the tumour into four stages....

Malignant Melanoma ICDO87203

The majority of conjunctival melanomas arise within primary acquired melanosis with atypia. Development of a melanoma in a pre-existing naevus or de novo is possible, but uncommon 44, 61 . In malignant melanoma clusters of atypical melanocytes are present in the stroma (Figs. 10.14, 10.15). The melanocytes are most frequently epithelioid, but can also be spindle-shaped or bizarre. The intraepithelial component shows large, atypical melanocytes, often without ascending cells. This differs from skin melanocytic lesions, where ascending melanocytes can be very helpful in diagnosing a malignant melanoma. These cytological characteristics do not seem to influence prognosis. Depth of the tumour, however, does have prognostic value thickness less than 1.5 mm means a low risk of metastatic disease.

Dna Repair And Skin Cancer

Ultraviolet Light and Skin Cancer Ultraviolet Light and Skin Cancer It is important to guard against skin cancer. For example, apply sunscreen before prolonged exposure to sunlight. It is important to guard against skin cancer. For example, apply sunscreen before prolonged exposure to sunlight. main cause of mutations that trigger skin cancer. Skin cancer is the most common type of cancer in the United States. Each year, about 1 million Americans get skin cancer. DNA Repair Enzymes and Skin Cancer Treatments Some organisms do not get skin cancer. One reason is that these organisms have a DNA repair enzyme called photolyase Some researchers want to try to use gene therapy to insert the gene for photolyase in people that are at high risk for skin cancer. Gene therapy is a technique in which a defective gene is replaced with a normal version of the gene. Ongoing studies of DNA repair enzymes may help develop gene therapy and other types of cancer treatments in humans.

Levodopa in Patients with a History of Melanoma

Levodopa is an intermediary metabolite in the synthesis of melanin. For this reason, there has been long-standing concern that this medication might potentially promote the growth of melanoma. While melanoma obviously occurs in patients on levodopa therapy, there is no evidence that the incidence differs from that in the general population (96-99), other than that there seems to be a higher risk for melanoma in patients with PD, even without levodopa treatment (100). In studies of patients with melanoma, levodopa exposure is rare (101). Thus, although the package insert warns that levodopa should not be used in patients with melanoma or suspicious skin lesions (102-105), there is no clinical evidence to support this admonition (106-109). Nonetheless, in patients with PD and a history of melanoma, it would seem prudent to both defer levodopa therapy until other medications prove inadequate and to monitor closely for recurrent melanoma.

Longterm behavior of murine melanoma B16 F10 explants on CU

B16 F10 murine melanoma cells possess a highly metastatic potency when injected to mice. Tumor explants (1-2 mm3) layered on semi-solid culture medium were covered with 0.7 cm2 CU or AN69 pieces and cultured for 14 days. Proliferation, adhesion, and migration of sorting cells were assessed from the cell layer developed around each explant. Surface area and cell counts after trypsin-EDTA detachment kinetics can give thus a good evaluation of cell behavior 31 . Proliferation and migration of melanoma cells were significantly reduced on CU as compared to AN69. Onto CU, cells appeared to secrete a thick extracellular matrix and to be much more adherent than onto AN69. Moreover, on CU, cells were highly charged in melanin while they remained mostly un-colored onto AN69. These observations suggest cell differentiation on CU (Figure 3.9).


Mucosal melanomas fortunately are rare. Mucosal melanomas of the oral cavity and head and neck areas have not been as well characterized as their cutaneous counterparts (90). Certainly, the paucity in melanoma in mucosal surfaces, accounts for less than 1 of all cases of melanomas, contributes to this lack of understanding. Mucosal melanomas as a rule tend to present at a higher stage and are more aggressive than cutaneous melanomas. With oral melanomas, the incidence is very low, in the order of 1.2 cases 10 million per year. Overall, the most common sites for mucosal melanomas are head and neck (55 ), followed by the anal rectal region (24 ), female genital tract (18 ), and urinary tract (3 ) (90). In the literature, about one-half of all melanomas that occur within the oral nasal region are located in the oral cavity (48 ) (90). The survival rate for mucosal melanomas is much less than that of cutaneous melanomas, likely due to a more prominent vertical growth phase in mucosal...

Malignant Melanoma

Uveal tract melanoma detail of an epithelioid lesion Fig. 10.24. Retinoblastoma a detached retina with small blue consisting of cells with a large amount of eosinophilic cytoplasm round cell proliferation Fig. 10.22. Uveal tract melanoma detail of an epithelioid lesion Fig. 10.24. Retinoblastoma a detached retina with small blue consisting of cells with a large amount of eosinophilic cytoplasm round cell proliferation

Uveal Melanoma

Rpe Hyperplasia

Although uveal melanoma is generally a disease of adulthood, it is occasionally diagnosed in children 15 . It is a variably pigmented elevated mass that shows slow progression (Fig. 8.21). If it is not treated early, it has a tendency to metastasize to liver, lung, and other distant sites. Most advanced tumors are treated by enucleation. Radiotherapy of local tumor resection can be employed for less advanced tumors. Fig. 8.21. Choroidal melanoma with shallow subreti-nal fluid and documented growth in a 16-year-old boy

Molecular Basis Of Thyroid Cancer

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

Tissue Plasminogen Activator

Tissue plasminogen activator (tPA) enzyme dissolves blood clots and is therefore used for the treatment of myocardial infarction and thrombolytic occlusions. Alternative products that were available, such as urokinase and streptokinase, were less specific and could cause general internal bleeding and other side effects. A means of producing tPA had been sought for many years but production levels from endothelial cells were too low to form a production process. Even a rich in vivo source such as the human uterus only yielded 1 mg tPA 5 kg uterus (0.01 mg purified tPA uterus) (Griffiths & Electricwalla 1987). Some tumour cell lines, such as the Bowes melanoma, secrete tPA at a higher rate (0.1 mg l) (Cartwright 1992), but this was still considered uneconomical for production, and at the time was considered unsafe, coming from a human melanoma. tPA was thus an ideal product for recombinant enhancement as it was a high-activity low-concentration product with a huge clinical demand....

Spindle Cell Carcinoma

The diagnosis of a SpCC is based on the demonstration of an invasive or in situ SCC and a malignant spindle cell component. However, when a SCC component cannot be demonstrated, the diagnosis is more difficult, and the SpCC must be distinguished from a number of benign and malignant processes, such as spindle cell sarcomas, nodular fasciitis, inflammatory myofibroblastic tumour and malignant melanoma. Negative reaction for S-100 protein and HMB45 helps to distinguish SpCCs from malignant melanomas 96 .

Lymphoepithelial Carcinoma

Differential diagnosis includes malignant lymphoma, in particular diffuse large B-cell lymphoma, as well as malignant melanoma and rhabdomyosarcoma. Differentiation is achieved by the use of appropriate im-munohistochemical staining. The vast majority of LECs are positive for cytokeratin and negative for leukocyte common antigen as well as other lymphocyte antigens. Cytokeratin positivity has been reported in rare lymphomas 123 , but leukocyte common antigen positivity in the tumour cells of LECs has not yet been reported. A negative reaction to S-100, HMB-45 and melan-A helps to differentiate LECs from malignant melanomas.

Surgical Resection of Regional Lymph Nodes

The regional lymph nodes represent the most prevalent site of metastasis for solid tumors. Because of this, the involvement of the regional lymph nodes represents an important prognostic factor in the staging of the cancer patient. For this reason, the removal of the regional lymph nodes is often performed at the time of resection of the primary cancer. Besides staging information, a regional lymphadenectomy provides regional control of the cancer. Examples of this are patients with melanoma who have tumor metastatic to lymph nodes. It is well documented that the removal of these regional lymph nodes can result in long-term survival benefit in approximately 20 to 40 of individuals depending upon the extent of nodal involvement. Hence, the removal of regional lymph nodes can be therapeutic. 42). Based on these trials, the more-extended lymphadenec-tomy appears to result in more accurate staging of patients at a cost of increased morbidity. For nonvisceral solid tumors such as melanoma,...

Type I And Type Ii Tumors Are Characterized By Unique Molecular Features

Braf And Kras Mutually Exclusive

In the transmission of growth signals into the nucleus (18). Oncogenic mutations in BRAF and KRAS result in constitutive activation of this pathway and contribute to neoplastic transformation. Recent studies (14,19) have demonstrated that KRAS mutations at codons 12 and 13 occur in 35 of invasive low-grade serous carcinomas and 33 of borderline tumors (atypical proliferative tumor and intraepithelial low-grade carcinoma), but not in high-grade serous carcinomas. Similarly, BRAF mutations at codon 599 occur in 30 of low-grade serous carcinomas and 28 of borderline tumors, but not in high-grade serous carcinomas (19). Accordingly, mutations in either KRAS or BRAF were found in 65 of invasive low-grade serous carcinomas and in 68 of serous borderline tumors (atypical proliferative tumors and intraepithelial low-grade serous carcinomas). In contrast, neither of the genes is mutated in high-grade serous carcinomas (Fig. 2). It is of interest that BRAF mutations were found only in tumors...

Sentinel Lymph Node Biopsy

Metastasize to one or more sentinel nodes in the regional lymph node basin(s) as defined by the anatomic distribution of lymphatic vessels present within and adjacent to the tumor (Figure 4.6).34 One can determine whether the lymph node basin is involved with tumor by removing the sentinel lymph nodes and performing careful histologic examination of the nodes. Negative sentinel nodes predict fairly accurately that the remaining nodes within that basin will also be uninvolved with tumor, thereby avoiding the need for a regional lym-phadenectomy and its attendant complications. This method has become the standard of care for staging patients with invasive breast cancer or melanoma (greater than 1 mm thickness) and is increasingly being evaluated in other malignancies such as head and neck, lung, gynecologic (i.e., cervical cancer), and gastrointestinal malignancies (i.e., colorectal and gastric cancers). The sixth edition of the American Joint Commission on Cancer staging guidelines has...

Metastatic Disease In The Orbit

Metastatic tumors constitute approximately 3 of all orbital diseases and 10 of orbital neoplasms in most series.23'34-36 The prevalence of ocular and orbital metastasis in patients with cancer varies from 0.7 to 12 , depending on whether the analysis was clinical or performed in autopsy series.37-39 The frequency of the site of origin parallels the general incidence of tumors.40 The most frequent primary organs are breast in women, and lung and prostate in men, and cutaneous melanoma. However, metastases from a large variety of tumors have been reported to occur in the orbit (Table 4.2).23 The spatial and tissue location of metastasis within the orbit is variable. Frequency analysis suggests that tumors from different primary sites tend to metastasize predominantly within certain tissues of the orbit. The orbit is bordered by bone and contains fat and muscle tissues. Melanoma has a strong tendency to metastasize muscle (41-76 of the cases), whereas thyroid and prostate carcinomas...

Phase I Maintenance of Quiescence by the Basement Membrane

Ing FGF2 to its high-affinity cell surface receptors. Consistent with this model, it was shown using an antisense approach that blocking of perlecan expression by colon carcinoma cells attenuated their growth, which correlated with a reduction in their responsiveness to FGF-7. Furthermore, antisense-mediated inhibition of perlecan expression in tumor xenografts of colon carcinoma cells or allografts of mouse melanoma cells showed a reduced capacity for tumorigenesis and the promotion of neovascularization in nude mice. Perlecan-mediated potentiation of growth factor action may occur via sites on either or both of the gly-cosaminoglycan chains and the core protein. At the cell surface, cell-associated proteoglycans such as perlecan are proposed to contribute HS chains in the formation of a ternary complex with two FGF1 molecules, and one growth factor receptor chain, to activate the growth factor receptor. Perlecan's HS chains can also serve as reservoirs or binding sites for other...

BOX 41 Extraocular Muscle Involvement in Orbital Metastasis and Dissemination

Breast carcinoma Cutaneous melanoma Neuroblastoma Lung carcinoma Carcinoid tumor Seminoma muscle.44,45 Some tumors are discrete like metastasis of melanoma, breast carcinoma, and renal carcinoma (Box 4.1), whereas others are diffuse like lobular carcinoma of the breast and carcinomas with a scirrhous fibroblastic response.46 Regarding location, a recent study combining the data from published series and case reports suggests that the lateral and the superior orbit are the most commonly affected quadrants for metastatic tumors.23,35 Melanoma, squamous cell carcinoma Melanoma

BOX 42 Clinical Presentations of Orbital Metastases

Metastatic melanoma to the orbit constitutes a unique situation because of the long delay from onset and treatment of the primary tumor and the first appearance of metastasis. It may manifest in one of four clinical settings from an excised cutaneous lesion, in association with an active skin melanoma, with history or evidence of a spontaneously regressed melanoma, or from an occult primary site. Most patients present with widespread metastatic disease at the time of ocular manifestions.48 The survival after the diagnosis of metastastic disease is poor the average time from diagnosis to death is 4 months (range 2-6 months).23 In addition, a patient with a metastastic melanoma may have had a spontaneously regressed cutaneous melanoma that was unnoticed, or an occult primary melanoma.49 This scenario most likely explains findings of metastatic melanoma without an apparent primary lesion or in an unknown primary. The long delay between the origin of the primary tumor and the first...

Studies Of The Gene For Rb

Diagnosis, agreeing with other studies and indicating the rarity of late mortality due to Rb.31 Nine hundred nineteen (57 ) of the 1603 patients had unilateral disease. The most common second primary malignancies were bone and soft tissue sarcomas, followed by cutaneous melanoma and brain tumors. When the relative risk of mortality was calculated, it was found to exceed the expected rates 300-fold for malignant tumors of bone and soft tissues,32-34 100-fold for melanoma, and 24-fold for brain tumors. At 40 years of follow-up, the cumulative mortality for all SMNs was 26 3.5 (expected 1.3 ) for bilateral Rb and 1.5 0.7 (expected 1.1 ) for unilateral Rb. In the bilateral Rb patients, external beam radiotherapy (EBRT) further increased the risk of mortality (Figure 5.1). The cumulative mortality from SMNs among patients who received radiotherapy was 30.3 4.8 as opposed to 6.4 3.8 for those who did not receive EBRT. Acute leukemias have also been reported among the patients who survive...

Sinonasal Undifferentiated Carcinoma

The two main differential diagnoses of SNUC are small cell (neuroendocrine) carcinoma (SCC) and high-grade olfactory neuroblastoma (ONB). All three entities may share some clinical and light microscopic features. However, SNUC and SCC show a marked immunoreactivity for cytokeratins that is not seen in ONB, and SNUC lacks the neuroendocrine immuno-reactivity seen in SCC and ONB. Most lesions categorised in the past as grade IV ONB are now considered to be either SNUC or SCC. This is important because SNUC and SCC have a worse prognosis than ONB. In addition, SNUC needs to be distinguished from other primary sinonasal tumours, such as solid adenoid cystic carcinoma, microcytic malignant melanoma, cylindrical cell carcinoma, primary sinonasal nasopharyn-geal-type undifferentiated carcinoma, lymphoma and others (Table 2.2).

Second Stage of Wound Healing

The fact that macrophages predominate in this stage is important because they also produce TNF (tumor necrosis factor), growth factors, enzymes, and other related compounds. In normal wound healing, these compounds help kill pathogens, degrade damaged tissue, and stimulate the growth of vascular (endothelial) cells required for normal angiogenesis. In the case of cancer, however, these compounds can stimulate cancer cell proliferation, angiogenesis, invasion, and metastasis. Indeed, one study reported an increased risk of melanoma metastasis in mice after an intense inflammatory reaction.36 In the next chapter, we discuss ways to inhibit the angiogenic effects of TNF and other growth factors produced by macrophages.

Production Of Phytoene In Mammalian Cells

Phytoene, which is detectable in human blood, was proved to suppress tumori-genesis in skin cancer models. It has been suggested that the antioxidative activity of phytoene may play an important role in its mechanism of action. To confirm the mechanism, more precise study should be carried out. However, phytoene becomes unstable when it is purified, and thus is very difficult to examine its biological activities. Therefore, stable production of phytoene within target cells was tried. As phytoene synthase encoding gene, crtB, has already been cloned from Erwinia uredovora,13 we used it for the expression of the enzyme in animal cells. Plasmids encoding phytoene synthase were transfected into NIH-3T3 cells and expression was determined by Northern blot. These cells expressed a

Vascular Endothelial Growth Factor

Structural alterations of FGFRs may play a role in human tumorigenesis. FGFR1 is highly expressed in the brain (41) but the shorter (2 Ig-domain) form of FGFR1 is more abundant in some CNS glioblastomas (42). Anti-sense targeted interruption of FGFR1 reduces malignant melanoma cell proliferation and differentiation (43). FGFR2 exon switching has been observed to accompany prostate cell transformation (44).

Lowfield Intraoperative

Between March 1996 and July 2001, we performed intraoperative MRI in 330 patients. Histopathologic examination revealed pituitary adenoma in 61, craniopharyngioma in 26, glioma in 106, cavernoma in 18, and other diagnoses in 54 patients (including chordoma, gangliocytoma, germinoma, lymphoma, melanoma, meningioma, metastasis, neurocytoma, pinealoma, primitive neu-roectodermal tumor, and subependymoma). For remaining 65 cases, either resective or disconnective epilepsy surgery was carried out for nonlesional conditions (n 40), or procedures were performed in which intraoperative MRI was used as an online control during catheter or electrode placements (n 25). Among the 330 procedures, there were 240 craniotomies, 59 transsphenoidal approaches, and 31 burr hole procedures.

Vitamin D And The Cancer Connection

The role of vitamin D in cancer prevention perhaps has been known for more than 50 years. Although excessive sun exposure has been documented to increase the risk of skin cancer, research conducted starting as early as 1936 has proved this population of patients with skin cancer to be at a lower risk for other types of cancer. Sun exposure has been correlated with decreased incidence of certain types of cancer such as cancers of the prostate, breast, and colon. Individuals residing in the U.S., which lies in the northern latitudes, have a risk for cancer incidence which is two to three times higher than the risk of cancer incidence of people living in sunnier, equatorial parts of the world.40 This intriguing observation by Apperly40 was followed by several epidemiological studies that demonstrated an inverse relationship between 25-(OH)D3 levels and cancer risk and

Ras Mutations In Thyroid Cancer

Although Ras mutations are infrequent in papillary thyroid carcinomas, somatic mutations in B-Raf were recently identified in these tumors (Kimura et al., 2003 Cohen et al., 2003). B-Raf mutations were discovered in a wide range of human tumors only last year (Davies et al., 2002 Rajagopalan et al., 2002). Intriguingly, mutations in B-Raf were found in cancers that typically harbor Ras mutations, such as malignant melanomas, colorectal tumors and ovarian cancers. The most frequent B-raf mutation (V599E) results in the insertion of an acidic residue close to a site of activating phosphorylation in the kinase domain. Recombinant B-RafV559E exhibits increased kinase activity, suggesting constitutive activation of signaling pathways similar to those activated by Ras. Moreover, unlike activated Raf-1 mutants that stimulate transformation through an autocrine mechanism involving Ras, the effects of B-RafV559E on cell transformation were Ras-independent (Davies et al., 2002). The same B-Raf...

Role Of Nk Cells In Host Defense Against Disease

The ability to selectively depress NK activity by administration of anti-asialo GM1 in vivo has provided a good opportunity to evaluate in detail the role of NK cells in control of metastases. Gorelik, et al. 49 showed that mice treated with this antiserum developed increased numbers of pulmonary metastases after intravenous inoculation of either B16 melanoma or Lewis lung carcinoma cells. In addition, the treated mice also developed many metastases in the liver, an organ, which previously showed completely resistance to the metastatic spread of these tumour lines.

Nk Cells In Therapy Of Cancer

Immunotherapy with adoptively transferred activated NK cells and cytokines has been used mainly for patients with advanced malignancies in the hope of capitalizing on the well-documented antimetastatic activity of NK cells. The earliest clinical trials were performed with LAK cells and high-dose IL-2 in patients with metastatic melanoma or renal cell carcinoma 79 , The results of these trials have been only mildly encouraging in that the rate of objective clinical responses achieved was about 20-30 79 , However, it is important to note that these responses, some of long duration (> 2 years), were achieved in patients with metastatic diseases unresponsive to conventional therapies. The LAK cells for the adoptive cellular therapy were autologous and mainly contained IL-2-activated NK cells 29 , More recently, clinical trials with purified NK cells, selected and expanded in vitro from patients' PBMNC, have been done on the hypothesis that transfer of a selected subset of highly...

Differential diagnosis

AC may be confused for a TC, paragan-glioma, malignant melanoma, and medullary thyroid carcinoma. The AC is distinguished from the TC by the presence of larger cells, prominence of nucleoli, mitoses, necrosis, pleomor-phism and angiolymphatic invasion. AC is positive for cytokeratin, CEA and calci-tonin, whereas the paraganglioma is negative for these markers. Malignant melanoma is positive for HMB-45 and tyrosinase and negative for synapto-physin and cytokeratin. Separating AC from metastatic medullary thyroid carcinoma (MTC) may be more problematic since both tumours are positive for synaptophysin, calcitonin and CEA. Clinical and imaging studies to detect the presence or absence of a mass in the larynx or thyroid may offer some assistance. Although the serum calcitonin level is almost invariably elevated in metastatic MTC and usually negative in AC, rare cases of laryngeal AC associated with elevated levels of serum calci-tonin have been reported 2409 . Reliance on this test to...

Endometrioid Type I Carcinoma

PTEN is located on chromosome 10q23.3, a region of the genome that undergoes loss of heterozygosity in approx 20-30 of endometrioid carcinomas and 30-80 of tumors having intragenic mutation (1). In addition, mutations have been detected in approx 20 of hyperplastic lesions, both with and without atypia, suggesting that mutations in PTEN occur relatively early in the pathogenesis of endometrioid carcinoma (2,3). This is in contrast to other tumor types (e.g., prostate cancer, melanoma, and gliomas), in which PTEN is believed to be inactivated later in their development. Initially, based on sequence homology, it was believed that PTEN encoded a dual specificity protein phosphatase. It was later shown that in vitro it had lipid phosphatase activity (4). Presently, its most well-documented substrate is the lipid molecule phosphatidylinositol 3,4,5-triphosphate. This lipid molecule is an important second messenger that regulates the phosphorylation of a protein...

Vascular Connexins in Pathologic Conditions

Vascular endothelium has the capacity to form gap junctions with circulating cells such as neutrophils expressing Cx43 and macrophages expressing Cx37. Such interactions may be significant in the development of inflammation, particularly since inflammation increases Cx43 expression in endothelial cells and leukocytes 12 . In contrast, myoen-dothelial cell-cell communication is downregulated in inflammation. The gap-junctional role in inflammation is also indicated in that gap junction inhibitors promote vascular leak and transvascular cell migration 13 , suggesting that gap junctions help maintain vascular barrier function. Tumor cell extravasation might also be regulated by gap-junctional communication, since melanoma cells expressing high levels of Cx26 are able to communicate with vascular endothelium and are more metastatic than cells that lack connexin expression. Interestingly, since Cx26 is believed to be incompatible with Cx37, Cx40, and Cx43, the melanoma cell-endothelial...

Immune System In Cancer Treatment

The immune system's postulated role in preventing cancer by destroying cancer cells, along with other evidence, tells us it can also help destroy cells of established cancers. Its ability to do so, referred to as antitumor immunity, involves both the innate and adaptive immune systems. For example, recent evidence suggests the immune system may be capable of detecting the protein products of oncogenes on the cell surface immune responses to the HER-2 neu protein and mutated ras and p53 gene products have been re-ported.20,21 In addition, antibodies against the patient's own tumor have been identified in the sera of some patients with soft-tissue sarcoma, malignant melanoma, ovarian carcinoma, and lung cancer.22

Immune Evasion by Tumors

The immune system must recognize a cancer cell as foreign before it can be destroyed. If the immune system is able to recognize a substance as foreign, that substance is referred to as being antigenic. One might expect the immune system to have trouble recognizing tumors as foreign, but in fact most tumor cells appear to be strongly antigenic. Unfortunately, recognition of a foreign substance does not necessarily ensure that an immune reaction will take place. Although most human tumor cells are apparently strongly antigenic, they are only weakly immunogenic. (The ability of a foreign substance to evoke an immunologic reaction in a host is called its immunogenicity.) Therefore, rejection of the tumor is difficult, even with a fully functioning immune system. Recent investigations have reported that a few cancers, such as melanoma and kidney cancer, are more strongly immunogenic, but even these often escape destruction by the immune system. The low immuno-genicity of most tumors may be...

Forensic DNA phenotyping

Special attention has been addressed to genetic markers determining the colours of hair, eyes and skin, mainly because animal models have been studied for decades and many genes involved in the regulation of melanin synthesis have been identified. Melanin is a complex polymer synthesized from the amino acid tyrosine via a number of toxic intermediates (Rees, 2003 Nordlund et al., 2006). The synthesis is performed in specialized compartments (organelles known as melanosomes) in the melanocytes to protect the cell from the destructive intermediates. The mature melanosomes filled with melanin are transported from the melanocytes to keratinocytes in the skin and hair, where melanin shields the body from damaging UV light. The regulatory mechanisms involved in melanocyte differentiation, melanin synthesis and melanosome transport are very complicated and not fully understood, and since genetic variations in any of the dozens of regulatory and functional proteins involved in these processes...

Rakesh Kumar MD Ayse Mavi MD Gonca Bural MD Abass Alavi MD

Malignant melanoma is diagnosed in more than 40,000 patients annually in United States 1 . It is most common cause of death from cutaneous malignancies. The incidence of malignant melanoma is increasing when compared with other malignancies. In most cases, melanoma is curable by surgical excision if diagnosed in early stages of the disease. Six percent to 10 of patients, however, show detectable metastases at the time of diagnosis, and 16 of patients develop metastases over time 2,3 . Among the patients who develop metastases over the time, 70 initially develop regional metastases, whereas 30 progress directly to distant metastases 3 . The prognosis is linked directly to the initial stage at diagnosis. The patients who present with locally advanced or metastatic disease at the time of diagnosis have a poor prognosis, but the multi-disciplinary treatment approach improves the prognosis. The 10-year survival after lymphadenectomy for palpable regional lymph node metastasis is 24 2 ....

Angiosarcoma ICDOcode91203

Primary angiosarcomas of the larynx are exceedingly rare, with only a few well-documented reports. Despite the fact that nearly 50 of all angiosarcomas occur in the skin and superficial soft tissues of the head and neck, angiosarco-ma accounts for less than 0.1 of all head and neck malignancies. Laryngeal angiosarcoma is twice as frequent in men with a mean age at presentation in the 7th decade of life. Symptoms are non-specific previous radiation exposure is frequently noted. The supraglottis is affected more frequently, specifically the epiglottis, where an increasing size is associated with a worse clinical outcome. Tumours demonstrate the typical histomorphologic features of angiosarco-ma in other soft tissue sites. Tumour cells are consistently positive with Factor VIII-related antigen, CD34, and CD31. Contact ulcer, haemangioma, acantho-lytic squamous cell carcinoma and mucosal malignant melanoma are the principle differential diagnostic considerations. Surgical excision is the...

Epidemiological Studies

Lower selenium levels were found in serum collected from American subjects 1 to 5 years prior to diagnosis of cancer as compared to those who remained cancer free during this time.20 This association was strongest for gastrointestinal and prostatic cancers. Evidence that low serum selenium is a prediagnostic indicator of higher cancer risk was subsequently shown in studies conducted in Finland21 and Japan.22 In further case-control studies, low serum or plasma selenium were found to be associated with increased risk of thyroid cancer,23 malignant oral cavity lesions,24 prostate cancer,25 esophageal and gastric cancers,26 cervical cancer mortality rates,27 and colorectal adenomas.28 A decade-long prospective study of selenium status and cancer incidences indicated that initial plasma selenium concentration was inversely related to subsequent risks of both nonmelanoma skin cancer and colonic adenomatous polyps.29 Patients with plasma selenium levels less than 128 ng ml (the average...

Lymphangiogenesis and metastatic spread of cancer cells

Vessels and or via newly formed lymphatic capillaries. This is indeed the basis of the sentinel lymph node biopsy and indicates the particular importance in surgical management of cancers including breast, melanoma, and others. However, not all tumours metastasise to the regional lymph nodes first. Furthermore, the presence of a metastasis in a lymph node does not necessarily mean that the tumour cells have been arrived via the lymphatic vessels (137). Tumour cells may pass directly into the blood vascular system through veno-lymphatic communications. The mechanisms determining whether regional lymph nodes or other sites first develop metastases remain poorly understood. In fact, most disseminated tumour cells have a limited lifespan in bloodstream. While many surviving cancer cells remain dormant in the host tissues, only a few develop into clinically detectable micrometastases. However, identification of those occult tumours cells, and prevention of their re-growth would be of great...

Schwannoma and Neurofibroma

Fibroblastic Proliferation

Feature of sinonasal schwannomas is the lack of tumour encapsulation that determines an apparently infiltra-tive growth pattern 36, 108 . Immunohistochemically, sinonasal schwannoma is intensely reactive for S-100 protein 108 . The differential diagnosis includes other spindle cell lesions of the sinonasal mucosa, like juvenile angiofibroma, solitary fibrous tumour and leiomyoma. Particular care should be taken when evaluating cellular schwannomas with a predominance of Antoni type A areas, which should not be confused with malignant spindle cell neoplasms, like fibrosarcoma, leiomyosar-coma, malignant peripheral nerve sheath tumour, and spindle cell melanoma.

Classification Based On Gene Expression

Classification of disease states using cDNA microarrays, which provide expression measurements for thousands of genes simultaneously, has become a key application of expression data and has had many successes including the following cancer examples rhabdomyosarcoma 18 , colon cancer 19 , lymphoma 20 , breast cancer 21 , and melanoma 16 . Classification based on gene expression data can separate samples into different classes using a variety of methods such as neighborhood analysis with p-value with random permutation 22 , TNoM score 23 , and neural network 24 .

Discussion And Future Directions

A case study by Kim et al. 27 investigated whether the network of interactions that regulate gene expression can be modeled by existing mathematical techniques. As an attempt to determine whether certain biological behavior could be captured in a Markov chain model, a small network based on microarray data observations of a human cancer, melanoma, was built and simulated by a Markov chain. The Markov chain is a widespread statistical methodology to enable estimation of complex models via simulation, in particular, in the context of a biological system. This required developing criteria to select a small set of genes from which to build a Markov chain and developing a method to construct transition rules from microarray data. As it would be unrealistic to study all genes in one regulatory network because of the limit

Well Circumscribed Solid Orbital Lesions

Hemangioma appears to have a homogeneous, isointense to slightly hyperintense signal with respect to the vitreous, and a hypointense signal with respect to the orbital fat.4 On T2-weighted images, the tumor has a high signal intensity with respect to the orbital fat (Table 10.1). Heterogeneity in tumor signal may be related to the presence of calcified phleboliths, which produce signal void on T1- and T2-weighted images and may mimic vessels with high blood flow. Other well-circumscribed solid lesions that can conceivably have identical MR characteristics include neurile-moma, neurofibroma, fibrous histiocytoma, and he-mangiopericytoma.4,6,26 However, less common well-circumscribed orbital lesions such as lympho-proliferative disorder, metastasis from skin melanoma or carcinoid tumor, capillary hemangioma, orbital varix, rhabdomyosarcoma, and extraocular extension of intraocular malignancies may also present with the same nonenhancing MR features as cavernous hem-angioma (Table...

Tumours of the cerebral hemispheres intrinsic

Any malignant tumour may metastasise to the brain. Malignant melanomas show the highest frequency (66 of patients) this contrasts with tumours of the cervix and uterus where < 3 develop intracranial metastasis. The most commonly encountered metastatic intracranial tumours arise from the bronchus and the breast of patients with carcinomas at these sites, 25 develop intracranial metastasis. - melanoma

Uva Protection 51 Effects of UVA

Data from animal studies suggest that sunscreens prevent development of skin cancer, and that UVA protection may be as important as UVB protection in that respect 18 . As noted earlier, energy in the UV wavelengths has also been shown to cause changes in the skin immune response. Moyal, who evaluated the level of protection by two broad-spectrum sunscreens with the same SPF, but with different UVA protection factors, against acute solar-simulated UV radiation-induced immunosuppression in humans, found that the sunscreen with the higher UVA protection factor was substantially more protective 8 . Perhaps the most important reason for the need for high levels of UVA protection is that SPF is determined by using solar simulators that typically lack the relative levels of UVA power found in sunlight at most latitudes and may overestimate the degree of sun protection actually received 19 . Calculations made by using solar spectra and sunscreen transmission spectra show that products...

End Organ Arrest Organ Directed Metastasis

Postintravasation, tumor cells migrate to the sites of metastasis. Clinical and experimental observations suggest that metastatic destinations are selective for specific tissues159 for example, among others, breast and prostate cancers preferentially metastasize to bone,160 colorectal cancer to the liver,161 and skin cancer to the lung.162 Hart and Fidler examined the organ biases of B16 melanoma metastases. In the whole animal, B16 cells spontaneously form metastases within the lung and ovaries. The investigators intravenously injected B16 cells into mice bearing syngeneic pulmonary, ovarian, and renal subcutaneous implants.168 Hart and Fidler found that B16 tumors do not develop randomly rather, they formed selectively within the implanted lung and ovarian tissue, and not within the kidney tissue. Thus, it would seem that some special interaction between circulating B16 cells and the pulmonary and ovarian tissue dictates the metastatic bias.

Immediate Pigment Darkening

The IPD test produces rapid results with low doses of UVA. However the response is highly variable and difficult to reproduce accurately. Its clinical significance is low because the action spectrum for IPD differs widely from action spectra for erythema and tanning 3,4,21 , nonmelanoma skin cancer 5 , and pho-toelastosis 6 . Further, the test is performed using human subjects with skin types III and IV, who are less sun sensitive than types I and II and are not the individuals who have the greatest need for sun protection. (The sun-reactive skin types were characterized by Fitzpatrick 22 .) In addition, the low UVA doses involved may conceal the effects of sunlight on the photostability of the product (see later).

Recombinant Interleukin 12 IL12

Secreted by activated dendritic cells, IL-12 produces several effects that could enhance an antitumor T-cell response, including the induction of a T helper cell type 1 (Th1) response and the production of g-interferon.66 Recombinant IL-12 protein given to cancer patients at the maximum tolerated dose (MTD) in a Phase II trial produced unacceptable toxicity.67 However, based on animal models, the administration of doses well below the MTD should be sufficient for use of this agent as a tumor vaccine augmentation strategy.68,69 Gajewski and colleagues conducted Phase I69 and Phase II clinical trials70 in melanoma patients combining subcuta-neously injected IL-12 with a peptide-pulsed PBMC-based tumor vaccine. The IL-12 was given at a dose well below the MTD three times every other day after each vaccine. Toxic-ity was acceptable, and two patients (10 ) had CRs. In other trials reported by Cebon et al.,71 melanoma patients were treated with IL-12 in combination with a tumor vaccine...

Blocking AntiCTLA4 Antibody

CTLA.4 binding to its ligand, CD28, delivers an inhibitory signal to T cells.98,99 Removal of this potential inhibition is the rationale for administering a blocking anti-CTLA.4 monoclonal antibody in combination with tumor vaccines. Phan et al. conducted a clinical trial involving patients with metastatic melanoma.100 Patients were treated systemically Hodi et al. also tested the anti-CTLA.4 antibody in melanoma and ovarian cancer patients, observing no objective tumor regressions.101 However, this was a single-dose trial and was not combined with a tumor vaccine. Tumor biopsies from three of the patients obtained after antibody administration revealed extensive tumor necrosis, providing compelling evidence that the antibody has the potential to produce a clinical effect. Interestingly, the tumor necrosis was only observed in patients who had previously been immunized with a GM-CSF-modified vaccine.

Dendritic Cell Based Vaccines

Dendritic cells (DC) are the most potent cells known in humans that prime and stimulate T-cell responses, and they are highly specialized cells which process and present antigens to immune cells. DCs have been grown from a variety of precursors, including peripheral blood monocytes, as well as selected CD34+ progenitors, and a number of cytokines and maturing stimuli have been used to generate human DC ex vivo for clinical trials of adoptive transfer after pulsing with antigen. Nestle and colleagues intravenously administered mature monocyte-derived DC cultured in vitro with IL-4 and GM-CSF and pulsed with tumor antigen peptides and or tumor lysate to patients with stage IV melanoma.117 Five CR or PR were observed in 16 patients,118 and the trial has been extended to a larger multicenter Phase II trial. Seven patients with metastatic melanoma received gp100 and MART-1 peptide-pulsed monocyte-derived DC.119 DC were administered intravenously four times at 3-week intervals in escalating...

Adoptive Transfer of CTL

CD8+ T-cell clones specific for MART1MelanA or gp100 were administered to 10 stage IV melanoma patients by Yee and colleagues.125 Adoptively transferred T-cell clones persisted in vivo in response to low-dose IL-2 treatment, trafficked to tumor sites, and eliminated antigen-positive tumor cells. Mixed response or stable disease was observed in 8 of 10 patients for up to 21 months. Selected peptide-specific, tumor-reactive CD8+ T-cell clones derived from tumor-infiltrating lymphocytes were administered intravenously to 12 patients with stage IV melanoma after a nonmyeloablative conditioning regimen, followed by differing doses of IL-2.126 Although no objective responses were seen, the same authors then administered oligoclonal populations of mixed CD4 and CD8 T cells to 13 patients after treatment with the same nonmyeloablative chemotherapy regimen.127 Persistence of the transferred T cells for up to 7 months occurred and was associated with their proliferation in vivo and trafficking...

Downmodulation of MHC

A number of small-scale assessments of MHC class I expression and its loss by metastatic melanomas have been conducted using IHC staining, indicating that loss of class I expression confers a worse prognosis.129-134 The majority of melanomas show normal staining for the nonpolymorphous class I A, B, C determinants, without evidence for allele-spe-cific deletion or downregulation. Less than 10 of tumors show deletion of the beta-2 microglobulin gene, resulting in complete loss of class I expression. Approximately 10 to 40 of tumors demonstrate a decrease in class I staining or with antibody MA 2.1 recognizing class I allele A2 due to downregulation of mRNA expression or gene deletion causing absent expression of that allele. Fourteen primary melanomas were examined in one study, with MHC allele loss seen by IHC in 20 .131 In a study of 48 metastatic lesions from 39 patients, loss of HLA class I expression of more than 50 was seen and was associated with a poorer clinical outcome.132...

The Tumor Microenvironment Is Toxic to T Cells

Blocking tumor-specific B7-H1 molecules from binding to their ligands on activated T cells improved the efficacy of antitumor T cells in preclinical models,139,140 suggesting a therapeutic approach. IL-2 at high doses produces significant clinical responses in some cancers and is being tested in combination with tumor vaccines.59,60 The B7-H1-mediated negative effect on T-cell function is overcome in the presence of exogenous IL-2.64 A very low dose IL-2 regimen has been shown to result in the prolonged persistence of transferred T cells in melanoma patients.65 This dose of IL-2 is sufficient to saturate IL-2 receptors in vivo.141 Therefore an immune augmenting effect of IL-2 can potentially be achieved with minimal toxicity.

Th2 Skewing of the TCell Repertoire

IL-12 secreted by activated dendritic cells produces several effects that could enhance an antitumor T-cell response, including the support of a Th1 response this suggests a possible approach to preventing the Th2 switch induced by tumors. Recombinant IL-12 protein given to cancer patients at the maximum tolerated dose (MTD) in a Phase II trial produced unacceptable toxicity.66 However, based on animal models, the administration of doses well below the MTD should be sufficient for use of this agent as a tumor vaccine augmentation strategy, as previously sug-gested.67,68 Gajewski et al. conducted phase I69 and Phase II clinical trials144 in melanoma patients combining subcuta-neously injected IL-12 with a peptide-pulsed PBMC-based tumor vaccine. The IL-12 was given at a dose well below the MTD, every other day after each vaccine for three injections. Toxicity was acceptable, and 2 patients (10 ) had complete responses. In other trials reported by Cebon et al.,71 melanoma patients were...

Other Malignant Neoplasms

Poorly differentiated plasmacytoma must be differentiated from other lymphoid neoplasms and from other malignant tumours, such as malignant melanoma and carcinoma. This is achieved by appropriate immunohis-tochemical analysis plasmacytoma, in contrast to lymphoma, does not express CD45 and immature B- and T-cell markers 351 . It also does not express antigens characteristic of malignant melanoma (i.e. S-100 protein, HMB-45 and melan-A), carcinoma (cytokeratins) and neuroendocrine neoplasms (i.e. synaptophysin, chromogranin). Primary malignant melanoma (MM) of the larynx is extremely rare less than 60 cases have been described in the literature. They represent 3.6 to 7.4 of all mucosal melanomas of the head and neck 6, 185, 212, 379 . The treatment of choice is complete surgical excision. The prognosis of primary laryngeal MM is poor, similar to primary mucosal malignant melanoma in general, with an average survival of less than 3.5 years 260, 379 .

Metastases to the Larynx

Metastases to the larynx from distant primary tumours are uncommon, accounting for less than 0.5 of all laryngeal neoplasms. Metastases to the hypo-pharynx and trachea are even less common. The most common source is malignant melanoma (Fig. 7.15), followed by renal cell carcinoma. Other tumours with proven laryngeal metastases include cancer of the breast, lung, prostate, colon, stomach and ovary 24, 74, 105, 154, 267, 296 . The rare occurrence of metastases to the larynx seems to be related to the terminal location of this organ in the lymphatic and vascular circulation. Laryngeal metastases are most commonly located in the supraglottic and subglottic regions, presumably due to their rich vascular supply 24, 133 . They can be divided into those located in the soft tissue (metastases from melanoma and renal cell carcinoma) and those located primarily in the marrow spaces of the ossified laryngeal cartilage (metastases from breast, prostate, and lung cancer).

Molecular Markers Of Tumor Recurrence Or Progression

The importance of detecting metastases earlier has not been clarified in thyroid cancer, a disease that typically follows an indolent course. However, for patients with malignant melanoma, amplification of tyrosinase mRNA from sentinel lymph node tissue removed at surgery correlates with development of metastatic melanoma and subsequent prognosis (63, 64). With time, it is likely that early detection will result in better prognosis. The development of markers of aggressiveness, such as p53 mutation analysis, may provide additional predictive data that will help clinicians stratify patients for appropriate treatment paradigms. Other markers derived from cDNA array analysis may also be particularly useful in the future.

The Global Cancer Burden

Estimates of the global cancer burden have been made for 1975, 1980, 1985, and 2000.18 These estimates include all forms of cancer except nonmelanoma skin cancer, poorly registered on incidence statistics and infrequently fatal. In 2000, cancer deaths among men totaled 4.7 million, and an estimated 5.3 million new cases were diagnosed, an increase of 1.5 million from 1985, lung cancer being the most common form of cancer in men, with an estimated 902,000 new cases in 2000. The estimated number of lung cancer cases has increased by 35 over the 5-year period covered by these estimates. Other cancers showing notable increases are colorectal, prostate, bladder, melanoma, and lymphoma, particularly non-Hodgkin's lymphoma. Some increases may be due to better surveillance or impaired precision in the estimation of rates but likely have a real etiologic component.

Immunohistochemical Stains

Melanoma, hemangiopericytoma, most sarcomas, neurofibroma Schwannoma, neurofibroma, glioma, melanoma, lacrimal gland tumors (+ ), Primary melanoma, metastatic melanoma (+ ), lymphangioma (+ ) Primary melanoma (normal melanocytes are HMB45 negative), lymphangioma, metastatic melanoma (+ ) Metastatic melanoma Juvenile xanthogranuloma (JXG), Langerhans cell histiocytoses, lacrimal tumors (+ ) Fibrous histiocytoma, JXG, sarcomas, schwannoma, melanoma, granular cell tumor Squamous cell carcinoma (K14, 17, 19), Merkel cell carcinoma (K8, 18, 20), basal cell carcinoma (+ ), lacrimal gland carcinoma (+ ), sarcomas (+ ), hemangioma (K18), metastatic melanoma (K8, K18)

DNA Sequencing and Antibody Gene Microarray

Immunohistochemi-cal algorithm for identifying malignant pleomorphic tumors including melanoma, liposarcoma, spindle cell squamous cell carcinoma (SCC), leiomyosarcoma, rhabdomyosarcoma, malignant fibrous histiocytoma (MFH), and malignant peripheral nerve tumors (MPNST). FIGURE 12.11. Immunohistochemi-cal algorithm for identifying malignant pleomorphic tumors including melanoma, liposarcoma, spindle cell squamous cell carcinoma (SCC), leiomyosarcoma, rhabdomyosarcoma, malignant fibrous histiocytoma (MFH), and malignant peripheral nerve tumors (MPNST).

Nonmalignant Skin Disease

Viral warts occur in more than 50 of transplant recipients, usually in sun-exposure areas. The causative agent of warts is the Human Papilloma Virus (HPV) of which there are 18 different subtypes. Type 5 may predispose to squamous cell carcinoma of the skin. Warts and skin cancer often appear in the same patient. Genital warts (condyloma acuminata) result from sexual transmission of a Human Papilloma Virus (HPV). The lesions are often resistant to therapy with topical preparation. Further, the lesions may recur after surgical removal, fulguration, cryotherapy, or laser therapy. Both condylomata and cervical neoplasias occur with an increased incidence following transplantation and often appear together in the same patient.

Posttransplant Malignancies

The incidence of lymphomas, skin cancer, and Kaposi's sarcoma does appear to be significantly increased in posttransplant recipients. Skin Cancer Skin cancer occurs at a frequency up to twenty times greater in posttransplant recipients than in the general population. While basal cell carcinoma is more common in the general population, squamous cell carcinoma seems to occur more frequently in transplant recipients. In addition, melanoma occurs more frequently in transplant recipients. In general, whatever the type of skin malignancy that occurs, it tends to take a more aggressive course in the transplant recipient than in the nonimmunocompromised individual. Early detection and aggressive management should be incorporated in all long-term follow-up of transplant recipients. Sun exposure should be dissuaded and regular complete skin evaluations should be employed.

Receptors and Signal Transduction

In primary cultures of melanoma cells, binding of a-MSH to its receptor stimulates the activation of adenylate cyclase and the phosphorylation of a 34-kDa molecule. This step is blocked by phorbolesters, suggesting that protein kinase C might be involved in the signal transduction of a-MSH.

Biological Effects

The general function of MSH is the regulation of epidermal pigmentation. Activation of MC-1 receptors preferentially found in melanocytes and melanoma cells affects the distribution of melanin. The functional significance of this action centers on protective color changes in lower vertebrates - amphibians, reptiles and fishes. These species are able to change the number and size of the secretory granula of their epidermal melanocytes to adapt their body color to the background. MSH has also been identified in the skin of mammals (including humans). However, the involvement of MSH in pigmentation of the skin in higher vertebrates has not been demonstrated, although some evidence indicates that MSH in higher vertebrates, including humans, may affect hair color (rodents) and skin pigmentation. An example of a feasible relationship is given by the inverse correlation between susceptibility to sunburn, photo-ageing and skin cancer and the ability of an individual to tan after sun exposure....

Clinical features

Tests of synthetic function, e.g. serum albumin levels and the prothrombin time, may be normal despite extensive metastatic involvement. Alpha-fetoprotein (AFP) levels may be slightly to moderately elevated but very high concentrations are more consistent with a diagnosis of hepatocellular carcinoma 904 . Carcinoembryonic antigen (CEA) levels, which are raised in as many as 90 of patients with metastases from colorectal carcinoma, can be useful in monitoring patients after primary tumour resection. However, CEA levels do not correlate well with prognosis 2043, 1821 . Computed tomography (CT), using both contrasted and non-contrasted images, can also serve as a screening tool. The administration of intravenous contrast permits the detection of tumours as small as 0.5 cm in diameter 1763 . Most metastases display decreased vascularity in comparison to the surrounding hepatic parenchyma and appear as hypodense defects. Tumours that are hypervascular (e.g. melanoma, carcinoids...

Non Related Neurotransmitters

To the mitogenic signaling of the nAChR, the m3AChR has an anti-proliferative function in lung cancer cells, and furthermore increases E-cadherin-mediated adhesion 173 . However, acetylcholine is also expressed in lung cancers and functions as an autocrine growth factor 174 . Thus, if the results are validated that the acetylcholine receptors subtypes have opposite effects on lung cancer cell proliferation, the balanced signaling seems to privilege the pro-mitogenic function of the nicotinic receptors. In contrast, the m3AChR promotes the growth of colon cancer cells 175 . Interestingly, the m3AChR is expressed in normal prostate tissue and well-differentiated tumors, whereas less-differentiated tumors show a loss of m3AChR expression 176 , and the expression of mAChR in melanoma plays a role in the tumor progression towards infiltration and metastasis formation 172 .

Conclusions and Future Directions

Since 1991, when the first report of detection of circulating cells in melanoma was published,61 investigation of the clinical relevance of occult tumor cells in blood, bone marrow, and other sites has eluded many teams of investigators. The challenges in development and validation of RT-PCR assays aimed at expression of a normal gene (rather than a mutated, translocated, or chimeric gene) are significant and have undoubtedly led to much confusion within this field. Little standardization of these assays has yet occurred, making comparison of results of the various studies difficult. Carefully designed and controlled multicenter clinical studies are needed to further clarify the utility of this approach for any tumor or sample type. The International Union Against Cancer (UICC) staging protocol was recently revised to include molecular results in some of the categories, at this point largely to facilitate data gathering.62

Invitro and Animal Studies

Cells in mice. , In the other two, rectal administration of 45 mg kg two times per day of a polyenzyme formula (WOBE-MUGOS) reduced metastasis and increased survival of mice with transplanted melanoma and lung cancer cells.210,221 Doses were rectally given to improve absorption. The equivalent human dose is roughly 870 milligrams per day.

Protecting the staff from radiation exposure

Non-ionizing radiation from the lower-frequency range of the electromagnetic spectrum includes ultraviolet (UV) light (wavelength, 10-400 nm). Wavelengths below 200 nm do not pose a hazard as they are absorbed by air, and atmospheric ozone provides protection from wavelengths below 290 nm. Wavelengths of 280 to 320 nm (UV-B) have been associated with skin cancer (these effects are enhanced by UV-A which has wavelengths of 320-400 nm). Although minimal levels are observed from fluorescent lighting or from units where UV is used to limit bacterial contamination, care must be taken in neonatal units where such lights are used in the treatment of jaundice.

Differential diagnoses

(immunoblasts, plasmablasts and plasma cells). On immunostaining, the large cells usually consist of a mixture of B- and T-cells, and there is no immunoglobulin light chain restriction. As a rule of thumb, infectious mononucleosis has to be seriously excluded before making a diagnosis of DLBCL in young patients. Some cases of DLBCL (especially those in the tonsil) can exhibit deceptively cohesive growth and a sharp interface with the uninvolved mucosa, closely mimicking poorly differentiated carcinoma or malignant melanoma. Marked irregular nuclear foldings and amphophilic cytoplasm, if present, should point more towards a diagnosis of lymphoma. Appropriate immunostains can readily solve this diagnostic problem. Anaplastic plasmacytoma can be difficult to distinguish from DLBCL, including the plasmablastic variant. An important clue to the diagnosis is the presence of coarsely clumped 'clock-face' chromatin in the few differentiated cells that are present. There are often intermingled...

Plasmodium falciparum Malaria

CD36 is an 88-kDa membrane glycoprotein of 471 amino acids with two hydrophobic regions near the amino and carboxyl terminals that serve to anchor the molecule to the plasma membrane (Figure 2). It is expressed on a wide variety of cell types, such as microvascular endothelial cells, erythroblasts, monocytes, platelets, striated muscle cells, adipocytes, and mammary epithelial cells. The natural lig-ands of CD36 include collagen, TSP-1, both native and oxidized low-density lipoproteins (LDLs) and high-density lipoproteins (HDLs), and apoptotic neutrophils. These receptor-ligand interactions can lead to diverse cellular and biological responses including uptake of apoptotic bodies, TGF-b activation, fatty acid transport, and endothelial cell apoptosis. CD36 was first identified as a receptor for IRBCs indirectly by the inhibition of adhesion of IRBCs to C32 melanoma cells and endothelial cells by the anti-CD36 monoclonal antibody OKM5. Direct evidence was obtained subsequently by...

Health Databases In Saskatchewan

Linkage can be made to the Saskatchewan cancer registry, which is required to record all persons diagnosed with cancer, including non-melanoma skin cancers and in situ cancers, and suspected as well as confirmed cancers. A lag time of 6 months exists from date of diagnosis to availability of the data.

Antibody Immunoconjugates

Cell-mediated cytotoxicity can be highly effective against tumors in vitro and in animal models. Im-munocytokines (Davis and Gillies 2003 Lode and Reisfeld 2000) have shown remarkable success in activating and redirecting effectors to human tumors. The majority of these studies have focused on NK, NKT, T cells (Davis and Gillies 2003), and granulo-cytes (Metelitsa et al. 2002). They are active in ADCC in vitro activating effector cells appropriately through their cytokine receptors. In vivo administration of the ch14.18-IL-2 fusion protein induces long-term anti-tumor immunity (Davis and Gillies 2003 Lode and Reisfeld 2000), and provides greater protection against localized or metastatic murine neuroblas-tomas than does treatment consisting of the identical amounts of ch14.18 antibody and IL-2 given as separate molecules (Lode et al. 1997). Following initial successes with IL-2 and GM-CSF immunocytokines, constructs containing other cytokines have also been tested with encouraging...

Prognosis and predictive factors

The prognosis for oral melanoma is poor with an overall median survival of about 2 years and 5-year survival of less than 20 122,170,1085 . Stage is a predictor of survival but even localized tumours (stage I) show a 5-year survival of less than 50 . Depth of invasion (Breslow thickness and Clark's levels) is of limited value in oral lesions. This is due to lack of adequate studies and the fact that most oral melanomas are deeper than 4 mm at presentation 1085,1843,2080 .

Antioxidant Effects of Isoflavones Flavones Flavonols and other Phenols

Unfortunately, very few animal antitumor studies have been conducted on flavones and fla-vonols. As discussed previously, one study on luteolin reported that it inhibited growth of human breast cancer cells in mice. Another mouse study found that intraperitoneal administration of 25 and 50 mg kg apigenin inhibited growth and metastasis of transplanted melanoma cells.26 The equivalent human oral dose is about 1.2 and 2.5 grams per A low oral dose (the human equivalent of 290 milligrams) did not affect metastasis of melanoma cells in mice (the same dose of curcumin was inhibitory).32 Intraperitoneal administration of 25 and 50 mg kg inhibited growth and metastasis of transplanted melanoma cells in mice.26 The equivalent human oral dose is about 1.5 and 3.1 grams per day. A number of rodent studies have suggested that soy or isolated isoflavones could also inhibit progression of established cancers in vivo. Again, in studies on soy, additional components may have been active. In one...

Efficacy of Risk Reduction Sun Exposure

Exposure to the sunlight has been implicated in the high incidence of skin cancers, which most commonly include cutaneous melanoma, basal cell carcinoma, and squamous cell carcinoma.38-40 There is no direct evidence, however, that personal sun protection behaviors can reduce the incidence of melanoma, and evidence that sun protection behaviors modify the incidence of other skin cancers is mixed.41,42 For example, a randomized controlled trial of daily sunscreen use in a general population in Australia showed no effect on risk of basal cell carcinoma over 5 years of intervention and follow-up.43 Another randomized controlled trial, however, of sunscreen applied daily to the head, neck, hands, and arms reduced the number of new squamous cell carcinomas over a 5-year period.44 A third randomized trial observed that sunscreen use decreased the incidence of, and increased the regression rate of, solar keratoses.45,46

Gene Based Medical Care

Although the incidence of breast cancer is lower for African American and Hispanic women, their mortality rates are higher than for Caucasian women. Most traditional cancer drugs help less than half of patients, exposing them to the toxic side effects without the prospect of improving their health. Herceptin is a drug designed to treat metastatic breast cancer whose tumors are shown to express abnormally high amounts of the protein called HER2. For these patients, up to 30 of women with breast cancer, Her-ceptin can bind to HER2, slowing tumor growth. Herceptin is one of four drugs in various developmental stages that attack tumors with overactive cancer genes. Intended for a variety of cancers, brain, melanoma, prostate, breast, and lung, they will be prescribed only after first verifying cancer gene overactivity. For women of color, the use of this drug could be very beneficial, especially because their cancers are detected later and they therefore experience higher mortality rates....

Incidence and origins

Although rare in clinical practice, gallbladder and extrahepatic bile duct metastases were encountered in 15 and 6 of cases respectively in an autopsy study of melanoma patients 373 . Indeed, malignant melanoma accounts for more than 50 of all reported cases of gallbladder and intrabiliary metastases 100 . Other metastatic lesions include carcinomas of the kidney, lung, breast, ovary and oesophagus 35, 1674, 2085 some examples result from transcoelomic spread in the setting of peritoneal carcinomatosis. The gallbladder and extrahepatic bile ducts may also be involved by direct extension from carcinomas of the pancreas, stomach, colon and liver. Malignant melanoma Primary malignant melanoma is exceedingly rare in the gallbladder. Junctional activity in the epithelium adjacent to the tumour, absence of a primary melanoma elsewhere in the body and long term survival are important features to distinguish primary from the more commonly occurring metastatic melanoma. However, junctional...

Histologic Type of Metastases and Immunohistochemical Features

Nearly any histologic type of malignancy can present as a metastasis to the cervical lymph nodes, but metastatic SCC is by far the most common tumour to do so. In cases of metastases of an unknown primary tumour to the cervical lymph nodes, 80-85 are of this histologic type (Table 9.3). Undifferentiated carcinomas, adenocarcinomas, thyroid carcinomas, melanoma, rhabdomyosarco-mas and sialocarcinomas are the other neoplasms that often metastasise to cervical lymph nodes. Adenocarci-nomas, undifferentiated carcinomas and thyroid carci-

Effectiveness of Physician Counseling Sun Exposure

Patient's use of sun protection behaviors or on subsequent development of skin cancer is not yet known.89 A randomized trial of a community-based, multiintervention program, including office-based counseling by physicians, showed that the intervention increased sun protection behaviors in the intervention towns.90 More parents recalled receiving advice to use sun protection behaviors in the intervention towns, giving some indirect evidence that the increased use of sun protection behaviors was due to more physician counseling. The United States Preventive Services Task Force concluded, in October 2003, that there was insufficient evidence to recommend for or against routine counseling by primary care clinicians to prevent skin cancer.91

Cancer Therapy And The Immune System

Several proteins that stimulate subsets of lymphocytes involved in various aspects of the immune response are now produced by recombinant DNA techniques. The pharmacology of these lymphokines as potential anticancer agents is being investigated. Interleukin (IL) 2, originally described as a T-cell growth factor, induces the production of cytotoxic lymphocytes (lymphokine-activated killer cells, or LAK cells). IL-2 produces remissions in 10 to 20 of patients with melanoma or renal cell carcinoma when infused at high doses either alone or with lymphocytes that were previously harvested from the patient and incubated with IL-2 in vitro.

In Vitro MRS applied to some other cancers

There has been some application of in vitro MRS to other cancers, such as malignant melanomas and a variety of thyroid neoplasms. 15.7.1 Malignant melanoma Melanoma metastases to lymph nodes have been analyzed using proton MRS by Lean et al 61 . The ratio of 1.8 to 2.5 ppm (containing lipid, lactate and other metabolites) to choline (3.2 ppm) was significantly higher in excised benign lymph nodes compared to those containing melanoma. Thompson et al. 62 suggest that techniques such as in vivo proton MRS hold great promise for assessment of sentinel nodes in patients with melanoma (p. 147S). 61 C.L. Lean, R. Bourne, J.F. Thompson, et al., Rapid detection of metastatic melanoma in lymph nodes using proton magnetic resonance spectroscopy of fine needle aspiration biopsy specimens, Melanoma Res. 13, 259-261 (2003). 62 J.F. Thompson, J.R. Stretch, R.F. Uren, V.S. Ka, R.A. Scolyer, Sentinel node biopsy for melanoma Where have we been and where are we going Ann. Surg. Oncol. 11 (Suppl.),...

Recommendations of Professional Groups Sun Exposure

Effective in reducing skin cancer but that the evidence does not support physician counseling about SPBs with every patient.107 ACPM concluded that evidence does not support advising patients to use chemical sunscreens and that their use may actually increase the risk of malignant melanoma.108

Aetiologyepidemiology pathology

A mixed group of cancers with a high metastatic potential. The reason the primary site remains undetected may be due to spontaneous regression (well recognized in melanoma) or mucosal sloughing, but in most cases is probably due to the unusual metastatic potential of the tumour. The pattern of metastatic disease is often very different from cases where the primary site is known e.g. lung cancer causes bone metastases 10 times more often when the primary site is known than when the lung cancer is occult. Appearances of adenocarcinoma and squamous carcinoma are similar irrespective of their site of origin and light microscopy rarely provides further clues. The diagnosis of undifferentiated malignancy should be made with caution as a high proportion will turn out to be lymphomas and further staining is essential. Poorly differentiated carcinoma may also be confused with seminoma, amelanotic melanoma, and epidermal carcinoma.

Methods Of Classifying Data

So, what is all this debate about As you may have already deduced, clustering and classifying are synonymous terms that refer to (1) the grouping of objects into sets on the basis of their similarities and (2) the differentiating between sets on the basis of their differences. For example, all clinicians know that they can classify their patients on bases other than diagnostic patients who come in only when they're on death's doorstep those who make appointments every time a new pimple appears, convinced that it is the first sign of melanoma those who blindly follow any advice given those who won't take their medications, no matter how often they're told to do so and so on. How would a clinician go about classifying these patients on a more objective basis

Genetic susceptibility

Familial atypical multiple mole melanoma (FAMMM) is associated with germline mutations in the p16 tumour suppressor gene on 9p. Affected individuals have an increased risk of developing both melanoma and pancreatic carcinoma 601, 1127, 1285, 2097 . The lifetime risk for developing pancreatic carcinoma is about 10 .

Lnvitro and lnvivo Anticancer Studies

Animal studies have reported that flaxseed can reduce cancer risk as well as the volume of established tumors. In one study, a 5 percent flaxseed diet given to rats decreased the number of breast tumors induced by a high fat diet and a carcinogen urinary enterodiol and enter-olactone excretion increased.83 In another study, oral administration of SD at about 8 mg kg (equivalent to a 5 percent flaxseed diet) inhibited growth of established breast cancer in rats during the late stages of carcino-genesis (greater than 50 percent reduction in tumor volume). This inhibitory effect correlated with the degree of urinary lignan excretion, indicating that flax lignans may have been partly responsible.92,93 A 5 percent flax-seed diet also reduced the lung metastasis of melanoma cells injected into mice, as well as tumor volumes.94 In another study with melanoma cells, oral administration of SD also reduced the number of lung metastases in mice. Again, tumor volumes were decreased.79 The 5...

Primary Acquired Melanosis

Malignant melanoma detail of the nested, atypical Fig. 10.16. Mucopolysaccharidosis this cornea showed no abnor-melanocytes without maturation in the stroma malities on H& E staining, but colloidal iron showed deposits of Fig. 10.15. Malignant melanoma detail of the nested, atypical Fig. 10.16. Mucopolysaccharidosis this cornea showed no abnor-melanocytes without maturation in the stroma malities on H& E staining, but colloidal iron showed deposits of

Summary of Research and Conclusions

In 14 in-vitro studies, emodin inhibited proliferation of a variety of cancer cell lines, usually at concentrations of 2 to 76 M, often below 40 mM.117-121 Only three animal antitumor studies have been conducted in these, emodin inhibited tumor growth and or increased the survival of mice with transplanted leukemia, melanoma, and breast cancer cells.122,123,124 In one, emodin acted synergistically with the chemotherapy drug Taxol, besides inhibiting tumor growth on its own. In-vitro studies have also reported synergistic effects with chemotherapy drugs (see Chapter 23).

Pathologic Histologic and Immunohistochemical Features

Which are the pacemaker cells of the gastrointestinal tract. This association suggests that these cells are the common origin of GISTs.4 The expression of CD 117 is the most specific marker for GIST.30 However, it is not pathognomonic, as other malignant neoplasms, including malignant melanoma, seminoma, sarcoma, and some leukemias, may also express CD 117.6 Fortunately, the distinction between GISTs and other tumors that express CD 117 can be made histologically. Approximately 70 to 80 of GISTs also express CD34, which is a hemopoietic progenitor cell antigen. GIST may also express smooth muscle antigen in approximately one-third of cases, but it is rarely reactive to desmin, present in true smooth muscle tumors, and S-100 immunostaining, present in schwannoma.

Administering Different Types and Dosages of Cytokines and Their Effects on Sleep

IL-2 that is also used as a therapeutic agent for treatment of various forms of cancer has been shown to produce partial remission in some patients with renal cell carcinoma or metastatic melanoma. It has also some neuropsychiatric side effects corresponding to symptoms associated with depression, such as fatigue, increased sleepiness and difficulty sleeping, irritability, anorexia, weight loss, and apathy (Krigel et al. 1990 Collier and Chapman 2001).

Metastases To Pelvic Viscera

Malignant melanoma may also metastasise to the pelvic viscera or subcutaneous soft tissues. Typically lesions are of intermediate or high signal on T1-weighted images. The high signal is due to the paramagnetic effect of intra-lesional melanin. Lesions may be of mixed high and intermediate signal on T2-weighted images. Large lesions may undergo central necrosis.

Gastrointestinal haemorrhage

Acute blood loss in gastrointestinal cancers is less common than chronic bleeding resulting in iron deficiency. It can occur as the presenting feature or in the terminal phase of illness in the heavily pre-treated patient. Haemorrhage occurs most often from the primary tumour or as a result of its local extension. Previous chemotherapy and clotting factor deficiency, in the case of hepatic impairment, may exacerbate bleeding. Endoluminal metastases are a rare cause of acute blood loss and metastases to the small bowel can occur in malignant melanoma.