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10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

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Papillary and Follicular Thyroid Cancer

Derived from follicular epithelial cells, papillary and follicular thyroid cancers comprise the majority of thyroid malignancies and have the best prognosis of the various thyroid cancers however, they account for nearly 70 of all thyroid cancer deaths (Table 1) (8). They are the only tumors that respond to radioiodine (131I) therapy and that synthesize and secrete thyroglobulin (Tg), a sensitive tumor marker, which in the absence of normal thyroid tissue identifies small amounts of persistent tumor that can be promptly treated. Familial Papillary Cancer About 5 of papillary cancers are inherited as an autosomal dominant trait, the gene for which is still unknown (10,11). They have a less favorable prognosis than sporadic papillary cancer (12,13), unless they occur in the setting of certain syndromes such as familial adenomatous polyposis (Gardner's syndrome), for example, in which thyroid cancer occurs at a young age as bilateral, multicentric tumors with an excellent prognosis,...

Hurthle Cell Follicular Cancer

Oxyphilic cells, termed Hurthle cells, which contain large amounts of acidophilic cytoplasm with numerous mitochondria, may constitute most of a follicular cancer. Some think this is a distinct entity and others believe it is a variant of follicular cancer (19), it has an unfavorable prognosis (Table 1) (20). Hurthle Cell Papillary Cancer About 2 of papillary cancers have Hurthle cells (21), which in some cases are familial (22). Compared with typical papillary cancers, they have higher recurrence and mortality rates, similar to oxyphilic follicular cancer (21,23).

Services for cancer genetics

Cancer genetics is a new field and the organization of services in this area may be initiated by clinical genetics services or through oncology and other departments, where individuals with a special interest in cancer genetics arrange to see individuals with a family history of cancer, estimate their cancer risks and arrange surveillance and genetic testing as appropriate. In many parts of Europe, cancer genetics clinics have been established for many years, and most specialized genetic counselling for cancer susceptibility is organized from genetics centres. However, the organization and quality of such services vary, depending on the economic status and healthcare systems of the country. There is increasing awareness that education and referral guidelines for primary care physicians are important. This would allow a collaborative relationship to be developed with primary healthcare services, helping them act as gatekeepers for the prioritization of referrals for genetics services....

Family history as an indicator of predisposition to breast cancer

A history of breast cancer among relatives has been found, in epidemiological studies, to be an indication of breast cancer risk. Familial breast cancer is characterized by a younger age at diagnosis than sporadic forms, increasing numbers of affected family members, an increased risk of bilateral breast cancer, and a strong association with ovarian cancer. Table 2.1. Genetic syndromes associated with breast cancer susceptibility Table 2.1. Genetic syndromes associated with breast cancer susceptibility Site-specific hereditary breast cancer Breast ovarian cancer If a woman has a first-degree relative (mother, sister or daughter) who has developed breast cancer before the age of 50 years, her own risk of developing the disease is increased two-fold or greater, and the younger the relative the greater is the risk. If a woman has two first-degree relatives with the disease, her risk may be increased four- to six-fold, and again, the younger the relative the greater is the risk (Claus et...

FollowUp of Papillary and Follicular Thyroid Cancer

Performing a whole-body scan and measuring serum Tg is the standard of care in the follow-up of patients with differentiated thyroid cancer (1,84), although DxWBS before 131I therapy is usually unnecessary. The panel of experts that formulated the National Cancer Center guidelines for thyroid cancer could not reach consensus on recommending a DxWBS in lieu of RxWBS during evaluation (39). A retrospective study (85) of 76 patients undergoing follow-up after initial thyroid ablation found that two consecutive negative DxWBSs had a greater likelihood of predicting relapse-free survival than did one such study however, serum Tg was not measured under TSH stimulation, which is a considerably more sensitive test than DxWBS (86,87). A study of 256 patients (88) found that a 2-5-mCi 131I DxWBS performed 6 mo to 1 yr after thyroid ablation did not correlate with the serum Tg but only confirmed the completeness of thyroid ablation, suggesting that DxWBS is unnecessary in this setting patients...

The Need For Biomarkers In Bladder Cancer

Bladder tumors are pathologically stratified based on stage, grade, tumor size, presence of concomitant carcinoma in situ, and multicentricity.1-2-1 The chances of tumor progression are augmented with the increase of these pathological variables. Pathologically, most bladder tumors are transitional cell carcinomas. There is, however, increasing recognition of the prognostic importance associated with the metaplastic variants displaying squamous and glandular differentiation as part of their clonal evolution. The power of these histopathological variables and the tumor node metastases (TNM) categorization, in defining the clinical subtypes of bladder cancer and predicting the clinical outcome of individual patients, has certain limitations. Within each stage, it has been very difficult to identify clinically useful parameters that can predict risk of disease recurrence or progression. Numerous biological markers have been described for bladder cancer, some correlating with tumor stage...

Bladder Cancer Studies Using In Vitro Models

Expression profiling using bladder cancer cell lines has been used to gain insight into the molecular events associated with clinical disease states, assigning potential functional roles to novel genes in both tumorigenic and tumor progression processes. Certain studies have focused on gene and pathway discovery associated to genistein 10 or 5-aza-2'-deoxycytidine 11 exposure. Other reports describe the functional classification of genes comparing the expression patterns of p53-mediated apoptosis in resistant tumor cell lines versus sensitive tumor cell lines using cDNA arrays, 12 or the expression patterns of a metastatic variant cell line to the respective parental invasive cells. 13 Many molecular targets involved in bladder cancer progression have been identified in these studies. Comprehensive analyses using clinical specimens will also elucidate the clinical utility of these targets as biomarkers for patients with bladder cancer. An attempt to tumor subtypes classification of...

Bladder Cancer Studies Using Clinical Specimens

Microarray analyses have been used to correlate changes in the expression of specific genes and groups of genes within distinct bladder subclasses. Such signature genes would ideally provide a molecular basis for classification, yielding insight into the molecular events underlying different clinical bladder cancer phenotypes. The first report monitored the expression patterns of superficial and invasive tumor cell suspensions prepared from individuals and pools of normal and bladder tumors of tumors of different stages such as from pTA grade I and II and pT2 grade III and IV bladder cancer specimens. 15 Hierarchical clustering of gene expression levels grouped bladder cancer specimens based on tumor stage and grade. The most significant functional genes included those involved in cell cycle, cell growth, immunology, adhesion, transcription, and protein metabolism. Superficial papillary tumors showed increased transcription factor and ribosomal levels, as well as proteinase encoding...

Mouse Skin Multistage Carcinogenesis Model That Unmasks Epigenetic Lesions Responsible For Metastasis

Cancer Epigenetics Laboratory, Molecular Pathology Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain Abstract Although there is a wide range of accepted models of tumorigenesis involving genetic lesions, the timing and hierarchy of epigenetic alterations associated with tumor progression and metastasis are still poorly understood. In this regard, the best characterized mouse carcinogenesis system, the multistage skin cancer progression model, has recently been used to identify epigenetic alterations during tumor progression and to provide decisive information about how epigenetic lesions precede metastasis. This model reveals a progressive global loss of genomic methylcytosine that is associated with the degree of tumor aggressiveness and that occurs in the context of increasing numbers of hypermethylated CpG islands of tumor-suppressor genes during the most malignant stages of carcinogenesis. DNA microarrays coupled with demethylating drug treatments confirm the...

And Animal Models Of Human Cancer

Recent SAGE studies were performed using a p53 null mouse model of mammary epithelial in vivo preneoplastic progression. This led to the identification of several new and unsuspected targets directly or indirectly dysregulated by the absence of p53 in normal mammary epithelium in vivo. These studies also allowed us to analyze the dramatic physiologic effects of hormonal treatment in mammary gland differentiation (45) (database available at In other studies using a mouse model of skin carcinogenesis, the gene expression profile of squamous cell carcinomas induced by UV-light has been compared with that of normal skin (46). In summary, since its inception, the use of SAGE has grown dramatically. The numerous publications using this methodology for a multitude of applications have validated the approach and demonstrated the power of this methodology for the analysis of global gene expression. As discussed, it was used in numerous cancer-related studies and has been particularly useful...

Alternative Pathways to Colorectal Cancer

Figure 3.3 Genetic changes in HNPCC progression. Approximately 2-4 percent of colorectal cancers follow this pathway. Figure 3.3 Genetic changes in HNPCC progression. Approximately 2-4 percent of colorectal cancers follow this pathway. Most colorectal tumors have either MSI or CIN, but not both. Some form of accelerated mutation may be needed for progression to aggressive colorectal cancer (Jass et al. 2002a Kinzler and Vogelstein 2002). Individuals who inherit defects in MMR develop hereditary nonpoly-posis colorectal cancer (HNPCC) as well as other cancers that together make up Lynch's syndrome (Boland 2002). Some of the genetic steps in HNPCC progression and the rates of transition between stages differ from the classical pathway (Figure 3.3). In another study, Rajagopalan et al. (2002) found that 61 percent of 330 colorectal tumors had either a BRAF or K-RAS mutation, but a tumor never had mutations in both genes. Mutually exclusive mutation of these genes supports the suggestion...

Adjuvant Radiation Alone for Esophagus Cancer Pre Operative Radiation

There have been five randomized trials evaluating the benefit of pre-operative radiation in resectable esophageal cancer (14-18). Most patients in these studies had squamous cell histology. Pre-operative radiation therapy was not shown to improve respectability. Gignoux did show a decrease in local failure rate with the addition of 33 Gy pre-operative radiation 67 after surgery alone vs 46 after combined therapy (15). Nygaard reported an improvement in overall survival in patients receiving pre-operative radiation (18). These results are tempered by the fact that this was a four-arm study pre-operative chemotherapy, pre-operative radiation, pre-operative chemora-diation, or surgery alone. Three-year survival was significantly higher in the pooled groups receiving pre-operative radiotherapy with or without chemotherapy 18 vs 5 (p 0.009). In this series, 48 patients received pre-operative radiation alone and had a 20 survival rate at 3 yr. Still, this apparent benefit did not reach...

Hereditary nonpolyposis colorectal cancer

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder associated with germline mutations in five mismatch repair genes MSH2, MLH1, PMS1, PMS2 and MSH6 (Lynch and de la Chapelle, 1999). The protein products of HNPCC genes are key players in the correction of mismatches that arise during DNA replication. Mismatch repair (MMR) deficiency gives rise to microsatellite instability (MSI). MSI results from repetitive non-coding DNA sequences of unknown function found throughout the genome. Loss of MMR function may also result in mutations in the coding regions of genes involved in tumour initiation and progression, e.g. APC, KRAS, TP53 and TGFbRII. The so-called 'Amsterdam criteria' are often used to make a clinical diagnosis of HNPCC. According to the classical Amsterdam criteria (Amsterdam criteria I), there should be at least three relatives with colorectal cancer, one relative should be a first-degree relative of the other two, at least two successive...

Genesis Of Breast Cancer

Estrogen and progesterone and their receptors, ER and PR, are clearly important in the genesis of BC. These hormones control the proliferation and differentiation of normal mammary ECs, and also are critical regulators of the growth of ER-positive BC cells. However, peptide growth factors (GF), receptors, and tumor suppressor genes are also important for the genesis of BC. These include GFs, such as epidermal growth factor (EGF), transforming growth factor a, heregulins, and insulin-like growth factors (IGFs), and their receptors, such as EGFR, erb-2, -3, and -4, and IGFR and the tumor suppressor genes, p53, Rb, BRCA1, and BRCA2. These proteins and their role in breast carcinogenesis are discussed later in Chapter 5, and in recent reviews (44). However, it should be noted that many of these GFs and GFRs are altered in more undifferentiated cells, which typically do not express ER. For example, breast cells that express high levels of erbB-2 typically are ER-negative (45). A similar...

The Gastritiscancer Sequence

Based on epidemiological and pathological information, Pelayo Correa proposed a model of gastric carcinogenesis known as Correa's cascade (1). He originally described the sequence as starting with chronic gastritis, which evolved to atrophy and intestinal metaplasia (IM). The metaplastic epithelium, as in Barrett's, can become dysplastic and these cells can lead to invasive malignancy. The discovery of the pathogenic role of Helicobacter pylori places it at the site of initiation of From Endoscopic Oncology Gastrointestinal Endoscopy and Cancer Management. Edited by D. O. Faigel and M. L. Kochman Humana Press, Totowa, NJ This model is a very useful way to approach the gastric cancer process. But the progression is not invariable. For example, chronic active gastritis may lead to duodenal ulcer, not gastric cancer. Diet, sanitary conditions, and genetics play a major role in gastric cancer development. Their impact is most likely related to the development of atrophic gastritis as well...

Breast and ovarian cancer in other hereditary colorectal cancer syndromes

Cancer of the breast and ovaries has also been observed in two hereditary colorectal cancer syndromes associated with hamartomatous polyposis, i.e. the Peutz-Jeghers syndrome and Cowden syndrome. Peutz-Jeghers (PJ) syndrome is characterized by hamartomatous polyps in the small bowel and pigmented macules of the buccal mucosa and lips (Vasen, 2000). The syndrome is caused by germline mutations in STK11 LKB1, a serine-threonine kinase located on chromosome 19. The PJ syndrome is associated with an increased risk of developing cancer. The most frequently occurring cancers are cancer of the colon and breast. A retrospective study for determining cancer risk in PJ families assigned a relative risk (RR) for breast cancer or gynaecological cancer of 20.3 (Boardman et al., 2001). The mean age at diagnosis of breast cancer was 39 years. Recently, Giardello and others performed an individual patient metaanalysis to determine the relative risk (RR) of cancer in patients with PJ syndrome compared...

Gastric Cancer Staging

Various classification systems have been developed for the staging of gastric cancer. The two most commonly used in clinical practice include the Japanese Gastric Cancer Association system and the International Union Against Cancer American Joint Committee on Cancer system (Tables 1 and 2) (2,3). The assessment of the extent of local tumor involvement or T category of both of these systems is essentially identical and they only vary in the method of assignment of nodal status. T1 lesions (Fig. 1) invade either the mucosa or submucosa (first three EUS layers), T2 lesions (Fig. 2) invade the muscularis propria (fourth EUS layer) or subserosa (not defined on EUS), T3 lesions (Fig. 3) penetrate the serosa (fifth EUS layer), and T4 lesions invade adjacent organs. Outcome studies have shown that stage at diagnosis correlates with survival (Table 3).

Eus In Early Gastric Cancer

The subset of T1 gastric lesions confined to the mucosa or submucosa has traditionally been referred to as early gastric cancer. T1 lesions confined only to the mucosa are candidates for curative endoscopic mucosal resection, whereas those that invade the submucosa usually require surgical resection owing EUS Studies Evaluating Accuracy in Determining T Category When Staging Gastric Cancer (1,10-22) EUS Studies Evaluating Accuracy in Determining T Category When Staging Gastric Cancer (1,10-22)

Gastric Cancer And Eusguided

There is limited literature concerning the use of FNA as an adjunct to standard gastric cancer endoscopic evaluation. The potential role for EUS-FNA in the evaluation of gastric cancer includes sampling of enlarged lymph nodes, particularly lymph nodes that would confirm metastatic disease, and also sampling of ascitic or pleural fluid and FNA of liver lesions. Mortensen et al. reported with EUS-FNA, they were able to confirm metastatic disease in eight gastric cancer patients with enlarged mediastinal (n 3) or para-aortic (n 5) lymph nodes (35). Chang et al. (36) reported diagnosing malignant ascites and malignant pleural effusion with EUS-FNA in one gastric cancer patient and malignant pleural effusion in another gastric cancer patient. In the first patient, neither the effusion nor the ascites were noted on prior CT scan. EUS-guided FNA of suspected liver metastases in patients with gastric cancer has also been described, although data are currently limited in this regard (37).

Role of Hepatitis B Virus in Liver Cancer

A consequence of chronic HBV infection is the development of hepatocellular carcinoma (HCC). Although viral DNA integration is not required for genome replication in hepadnaviruses, the large majority of tumors contain viral DNA sequences inserted into chromosomal DNA. The mechanism for DNA integration is not known. The pattern of integrated viral DNA generally reflects a clonal origin of the tumor and indicates that DNA integration is an early event in the development of HCC. Therefore, it has been proposed that viral DNA integration could play an active role in the progression of liver cancer, i.e. through the activation of proto-oncogenes as it occurs with certain retroviruses. Contrary to expectations, extensive analyses of DNA samples obtained from human HCCs failed to reveal any common integration sites for HBV sequences. However, analyses of DNA samples obtained from woodchuck HCCs identified a pseudogene of N-myc 2 as a major target for viral DNA integrations in this animal...

Primary care in the cancer genetics service for Wales

Guidelines were drawn up and distributed to all GPs in Wales by the National Assembly for Wales (Box 9.1). Crucially, the guidelines were developed in a multidisciplinary fashion - initially in conjunction with the cancer lead clinicians, public health representatives, voluntary groups, patient groups and GPs. Multiple meetings were required over an 18-month period and all decisions were taken to and endorsed by the Royal College of General Practitioners, the GP committee of the BMA, and the appropriate government committees. Key to our work with the GPs was a series of focus groups, as outlined in Box 9.2, giving a real sense of ownership to the primary care groups. Setting up a cancer genetics service Referral guidelines Breast cancer 1 first-degree relative with male breast cancer A first-degree relative with bilateral breast cancer Note breast cancer can also be inherited through the paternal side of the family Breast ovarian cancer Minimum 1 of each cancer in first-degree...

Classification of Cancer Types

The term cancer is general, in that it represents a large group of related diseases that arise from neoplasms. A neoplasm is classified by the type of tissue in which it arises and the stage to which it has progressed. Neoplasms are also called tumors. Not all tumors are cancerous. A tumor that grows in one place and does not invade surrounding tissue is called benign. In contrast, invasive tumors are called malignant. These are cancerous. ESTIMATED NEW CANCER CASES AND DEATHS IN THE UNITED STATES 2000 ESTIMATED NEW CANCER CASES AND DEATHS IN THE UNITED STATES 2000 *(the American Cancer Society's Clinical Oncology, Lenhard R.E., Osteen R.T., Gansler T., 2001) *(the American Cancer Society's Clinical Oncology, Lenhard R.E., Osteen R.T., Gansler T., 2001) Estimated new cancer cases and deaths in the United States in 2000. Adapted from Lenherd, 2001.

Development of benchmarks for the regional cancer genetics service

Box 9.3 Benchmarks being piloted for cancer genetics service provision EQ Cancer genetics clinics per million EQ A Referrals per million cancer type A Proportion of referrals getting a clinic appointment with a counsellor at a cancer genetics clinic EF Numbers seen in clinic (e.g. cancer genetics clinic) Talks given per month (total) (counsellor cancer genetics clinic)

H pylori vacA and Carcinogenesis

An independent H. pylori locus linked with pathologic outcomes such as ulcer disease and gastric cancer is vacA, which encodes a secreted bacterial toxin (VacA) (154-159). When added to epithelial cells in vitro, VacA induces multiple structural and functional alterations in cells, the most prominent of which is the formation of large intracellular vacuoles (160). There is a strong correlation between vacuolating cytotoxin activity and the presence of cagA. However, vacA and cagA map to two distinct loci on the H. pylori chromosome, and mutation of cagA does not affect toxin production, indicating that expression of the two proteins is independent (161). H. pylori strains that possess a type s1 m1 vacA allele are associated with an increased risk of gastric cancer (172-175) and enhanced gastric epithelial cell injury (176,177) compared to vacA s2 m2 strains. The relationship between s1 m1 alleles and gastric cancer is consistent with the distribution of vacA genotypes throughout the...

Deregulation and Cancer

Deregulation of cell cycle control proteins plays a key role in the development of cancer. Overactivation of proteins that favor cell cycle progression, namely cyclins and CDKs, and the inactivation of proteins that impede cell cycle progression, such as CKIs, can result in uncontrolled cell proliferation. In human tumors, it is genes encoding the proteins that control the transition from the G1 to the S phase that are most commonly altered. These genes include those for cyclins, CKIs, and pRb. Such mutations overcome the inhibitory effects of pRb on the cell cycle, causing cells to have a growth advantage. In some cancers, this occurs after the direct mutation of the pRb gene, resulting in the protein's loss of function. In a larger set of cancers, pRb is indirectly inactivated by the hyper-activation of CDKs. This may result from over expression of cyclins, from an activating mutation in CDK4, or from inactivation of CKIs. There is much evidence to suggest that cyclins can act as...

Guidelines for risk estimation in individuals with a family history of cancer

Calculation of risk of breast cancer In families where there is no clear-cut Mendelian genetic predisposition, empirical risks for breast cancer may be calculated based on the age at diagnosis of breast Table 11.1. Importance of genetic predisposition to breast cancer Table 11.1. Importance of genetic predisposition to breast cancer Age at onset of cancer (years) cancer in first-degree relatives in studies carried out by Houlston et al. (1991) in the UK and by Claus et al. (1996) in the USA. Where more than one relative is affected various studies have produced figures for the relative risks to individuals (Table 11.1 Murday, 1994). For the majority of individuals with a family history of cancer, no specific gene mutations will have been identified as being causative. In such cases, data from epidemiological studies must be used to calculate the risks to relatives of those affected with cancer. Where a single relative is affected with breast cancer, data from the Claus et al. (1996)...

Tumor Activated Anticancer Prodrugs Based on Hypoxia

Hypoxia appears to be a common and unique property of cells in solid tumors and is a target for tumor-specific activation of anticancer prodrugs.4 It is now well known that solid tumors often contain an inefficient microvascular system, and part of solid tumors exists under a hypoxic condition.12 Hypoxia can be classified into two broad types chronic and acute. Chronic hypoxia occurs in cells that are distant from their blood supply and suffer low oxygen tension permanently. Acute hypoxia results in cells experiencing temporary cessation of blood flow. Hypoxia is a major problem in radiotherapy and chemotherapy.13,14 The cyto-toxic effects of radiation require the presence of oxygen. In chemotherapy, hypoxia reduces the distribution of chemotherapeutic agents. Further, hypoxic cells receive not only a reduced amount of oxygen but also a low supply of nutrients, which causes them to stop or reduce their rate of progress through the cell cycle. Since most anticancer agents are more...

Clinical And Molecular Pathologic Features Of Bladder Cancer

Molecular epidemiology studies of bladder cancer have contributed to the modern viewpoint of tumorigenesis mainly based on associations with environmental exposures and DNA damaging agents. Bladder cancer was one of the first neoplastic diseases to be found associated with an industrial chemical exposure (14). It has also been related to genotypic characteristics of individual polymorphisms, such as the fast acetylator phenotype (15). In addition, bladder cancer is one of the first tumors in which early stage disease is treated with immunotherapy (16). The early diagnosis of bladder cancer is increasing, particularly in superficial preinvasive stages due to simplified procedures such as the use of flexible cystoscopy. Pathologically, most bladder tumors are transitional cell carcinomas. There is, however, increasing recognition of the prognostic importance associated with the meta-plastic variants displaying squamous and glandular differentiation as part of their clonal evolution....

Of Dna Microarrays For Bladder Cancer Analysis

Several types of samples are available to study bladder cancer by expression profiling. Normal urothelia and tumor tissues can be obtained by transurethral resection, cystectomy, or cystoprostatectomy. Due to the close monitoring of bladder cancer patients, sequential biopsies obtained over time allow addressing critical issues related to tumor progression and response to treatment. Optimal results are achieved by handling tissue promptly and either extracting RNA immediately from fresh aliquots or deep freezing in liquid nitrogen in either tubes or using cryomolds and embedding medium. This latter format allows verification of histopathological characteristics, since it represents a frozen tissue block. It also provides adequate samples for tissue microdissection if required. Bladder cancer offers an additional source of material for tumor profiling studies based on direct access to exfoliated tumor cells through urine samples and bladder washes. This approach has not been reported...

Expression Profiling And The Study Of Bladder Cancer

Microarray-based gene expression profiling has found a number of important applications in the study of carcinogenesis and cancer biology. Broadly speaking, these applications can be described as gene and pathway discovery, functional classification of genes, and tumor classification. Tumor classification is one of the most exciting and potentially most powerful applications of expression profiling with DNA microarrays. Major goals for improving cancer treatment include the early and accurate diagnosis of tumor type and determining the extent of the disease. The traditional approach to tumor classification is based on clinicopathological criteria. It is expected that the integration of gene expression patterns, as determined by DNA microarrays, will provide a better means for classifying tumors into biologically meaningful and clinically useful categories. In addition, expression profiling of well-curated tumor specimens has the potential of identifying target genes for novel...

Nsabp Rectal Cancer Adjuvant Trials

This protocol was designed to explain the role of postoperative chemotherapy and radiotherapy in the treatment of patients with resected Stage II or III rectal cancer (20). Between November 1977 and October 1986, 555 eligible patients with follow-up entered. They were stratified by age, gender, and stage and randomized to receive entirely no further treatment, MOF (as in the treatment arm of C-01 and control arm of C-03), or radiation therapy. At 5 yr of follow-up, patients who received MOF demonstrated an overall improvement in DFS (p 0.006) and in survival (p 0.05) compared to the group treated by surgery alone. Gender was the primary stratification variable contributing to the DFS and survival benefit from chemotherapy however, to a lesser extent, age and stage also interacted. The benefit for chemotherapy, both in DFS (29 vs 47 , p< 0.001) and survival (37 vs 60 , p 0.001) was restricted to males, with the greatest benefit occurring in the younger age groups. This age benefit...

Rodent Mammary Cancer

The same hormones that are important for normal growth are also involved to varying degrees in the development of BC. PRL's role in rodent mammary cancer is well established (59). Multiple pituitary isografts in mice result in large amounts of PRL secreted into the circulation. Subsequently, there is a significant increase in the incidence of spontaneous mammary tumors (60). There is a direct correlation between serum PRL levels and susceptibility of various rat strains to induction of tumors by chemical carcinogens (61). Both N-methyl(-N-nitrosourea-) and 1,2-dimethylbenz(a)anthracene-induced tumors in rats are dependent on PRL for sustained growth (62). There is a direct correlation between drug-induced hyperprolactinemia and increased tumor growth and hypo-prolactinemia and retarded tumor growth in rodents (63,64).

Prostate Cancer Angiogenesis

Tumour hypoxia is thought to be the likely explanation for the induction of angiogenesis in prostate cancer (Izawa and Dinney 2001). Hypoxia induces vascular endothelial growth factor (VEGF) transcription via hypoxia-inducible factor-1 (Zhong et al. 1999). VEGF is a recognised stimulus of neoan-giogenesis in tumours, and is also a potent tissue permeability factor (Dvorak et al. 1995). Androgens seem to regulate VEGF expression in prostate cancer cells and prostatic fibroblasts (Joseph et al. 1997 Levine et al. 1998). It has been shown that VEGF is produced in abundance by the secretory epithe lium of normal, hyperplastic, and tumorous prostate glands (Jackson et al. 1997 Ferrer et al. 1998). The physiological role(s) of VEGF in the prostate is poorly understood and target cells may include cells other than the vascular endothelium. With respect to the vasculature, it is clear that VEGF is required for vascular homeostasis in the prostate gland and maintains the high fraction of...

Metastatic Prostate Cancer

Very few studies have described CGI hypermethylation patterns in metastatic prostate cancers, due to the difficulty in obtaining metastatic cancer tissue. Surgical resection of metastatic deposits of prostate cancer does not enhance survival from the disease significantly. Therefore, most patients with refractory, metastatic prostate cancer are not candidates for further surgical intervention. Therefore, the few studies that have examined CGI hypermethylation patterns in metastases obtained these specimens from autopsy cases of patients who died from refractory prostate cancer or from the small group of patients undergoing surgical resection of bone metastases to alleviate symptoms or monitor for response to novel therapies. Over a 7 year period, we systematically collected metastatic prostate cancer specimens at autopsy from 28 men who died of refractory prostate cancer. One to six anatomically distinct metastases from a wide array of sites, including bone, lymph node, liver, adrenal...

Post 131I Cancer Risks

The increased risk of thyroid cancer after thyroid irradiation in childhood has been recognized for nearly 50 years 70 . Thus, a major concern of 131I therapy relates to the risk of thyroid cancer. Detractors of 131I therapy point to the increased rates of thyroid cancer and thyroid nodules observed in young children exposed to radiation from nuclear fallout at Hiroshima or after the Chernobyl nuclear reactor explosion. The thyroid gland is unique in its developmental sensitivity to malignancy following radiation exposure. Individuals older than 20 years of age do not have an increased risk of thyroid cancer when exposed to low-level thyroid irradiation 71-73 . Yet, when individuals are less than 20 years of age at the time of low-level thyroid irradiation, the thyroid cancer risks increases the younger one is 71-73 . In addition to age, the radiation dose plays a major role in cancer risk 70-73 . The risk of thyroid cancer and thyroid nodules is highest with exposure to low or...

For Cancer and Cardiovascular Diseases

Anticancer Drugs is More Efficacious Than Monotherapy Inhibition of Prenylation Radiosensitizes Human Tumors FTI-277 Induces Apoptosis by Blocking the PI-3 Kinase AKT-2 From Farnesyltransferase Inhibitors in Cancer Therapy Edited by S. M. Sebti and A. D. Hamilton Humana Press Inc., Totowa, NJ

Hereditary Nonpolyposis Colon Cancer

HNPCC is an autosomal dominant disorder that may be responsible for up to 5 percent of colon cancers. The genetic mutation leading to the abnormality is the mutation of DNA mismatch repair genes. Individuals with this mutation have up to an 80 percent chance of developing colon cancer. At least five genes are involved in this syndrome.

Molecular Mechanisms In The Generation And Propagation Of Aberrant Dna Methylation Patterns In Prostate Cancer

In our discussions thus far, we have been continually alluding to a fundamental paradox concerning CGI hypermethylation in prostate cancer initiation and propagation DNA methylation processes appear to be dysregulated enough to cause hypermethylation of CGIs at multiple genes yet, the same DNA methylation processes have high enough fidelity that they can maintain the acquired changes in CGI hypermethylation through every step of prostate cancer initiation and progression. This observed paradox would suggest that the CGI hypermethylation changes in prostate cancer are not due to a total dysregulation of the DNA methylation machinery, with subsequent loss of discrimination and fidelity in which CGI sequences are stochastically hypermethylated. Rather, it appears that certain CGI sequences are targeted for hypermethylation resulting in silencing of the corresponding genes. One possibility is that targeting these genes for CGI hypermethylation provides a growth advantage for these cells...

Management Of Rectal Cancer By Location

The development of techniques of coloanal reconstruction (23) has enabled surgeons to offer a sphincter-preserving surgery to carefully selected patients with cancers of the low rectum. This procedure involves a complete dissection of the rectum down to the levator musculature using an abdominal approach. A transanal approach is then used perform a distal rectal mucosectomy. A hand-sewn anastomosis is then performed between colon and the anal mucosa at the dentate line. This approach is often coupled with neoadjuvant chemoradio-therapy to provide downstaging of the disease before operation (24,25). In addition to coloanal anastomosis, it is also possible to perform stapled anastomoses in many patients with low tumors. One technical refinement that has been added to the procedure in recent years is the use of a colonic J-pouch to improve the reservoir function of the neorectum (26). In addition to technical precision, successful sphincter preservation in the patient with low rectal...

New Markers For Ovarian Cancer Diagnosis

Although we, and others, have identified many highly expressed genes encoding secreted proteins in ovarian carcinomas, we collectively lack the evidence at this time that these proteins are detectable in the serum of patients with ovarian cancer. Mok and coworkers have recently described one of the first examples of this type of translational diagnostic research, in which their observation of an overexpressed gene in ovarian carcinoma has led to the identification of the encoded protein in the serum of ovarian cancer patients (47). The authors previously described the overexpression of prostasin, a secreted protease originally identified in human seminal fluid, in ovarian carcinoma-derived cell-lines compared to those obtained from normal ovarian epithelium. IHC showed that the prostasin protein is expressed in ovarian tissues, albeit at significantly higher levels in the cytoplasm of ovarian carcinoma cells. Consistent with this observation, the authors demonstrated by ELISA that the...

Effect Of Human Chorionic Gonadotropin Treatment On Mammary Gland Development And Carcinogenesis

The direct association of BC risk with nulliparity, as well as the protection afforded by early first full-term pregnancy, have been in great part explained by experimental studies. This and other laboratories have demonstrated that mammary cancer in rodents can be induced with chemical carcinogens, such as dimethylbenz a anthracene (DMBA) or N-methyl-N-nitrosourea only in the young nulliparous females completion of pregnancy prior to carcinogen exposure prevents carcinoma development (7,12-15,19,20, 28,29). This preventive effect has been attributed to the differentiation of the mammary gland induced by pregnancy. In the DMBA model, the authors have successfully reproduced this effect by treating virgin rats with human chorionic gonadotropin (hCG) (28-32).

Adjuvant Therapy For Largebowel Cancers

Surgery remains the primary curative modality for treatment of colorectal cancers. However, many patients will relapse and die of recurrent colorectal cancer in spite of complete gross tumor removal. The risk of relapse following surgery correlates with stage of disease, and ranges from approx 20 to 30 for stage II disease (Tx, N0) to 50-80 for stage III disease (Tx, N+). For patients with rectal cancer, a recent meta-analysis demonstrated that local tumor recurrence was highly correlated with both the depth of tumor penetration and the number of regional lymph nodes involved by metastatic disease (96). There is consensus that adjuvant therapy is indicated for most patients with stage III cancers of the colon or rectum and stage II cancers of the rectum. Opinion is divided whether patients with stage II colon cancer derive sufficient benefit to warrant adjuvant therapy on a routine basis, although a recent trial involving more than 3000 patients demonstrated a 3 absolute benefit in...

Pre Vs Postoperative Radiation Therapy For Rectal Cancer

The timing of radiation in relation to surgery has been extensively debated. The benefit from postoperative therapy has been demonstrated by the landmark trials of the Gastrointestinal Tumor Study Group (GITSG), National Surgical Adjuvant Breast and Bowel Project (NSABP), and North Central Cancer Treatment Group (NCCTG) (117-119). The principal argument for postoperative therapy is that the patient is accurately staged for the selection of adjuvant therapy. With pre-operative therapy, patients who are thought to be stage II or III but really have stage I disease are over-treated.

Combined Modality Adjuvant Therapy Of Rectal Cancer

Postoperative combined-modality therapy with chemotherapy and irradiation for patients with stages II or III rectal cancer has been recommended for decades, partly based on the results of randomized clinical trials performed by the GITSG, NSABP, and the NCCTG. The GITSG trial randomized 227 patients following surgical resection for rectal adenocarcinoma to one of four treatments no adjuvant therapy, postoperative radiotherapy, postoperative chemotherapy (fluorouracil and semustine methyl-CCNU ), or a combination of radiation therapy and chemotherapy. The recurrence rate was highest among the control patients (55 ) and lowest among the patients receiving a combination of adjuvant radiation and chemotherapy (33 ). Time to tumor recurrence was significantly prolonged by combined radiation and chemotherapy as compared with resection alone (p < 0.009), though overall survival did not differ significantly among the treatment groups (117). NSABP protocol R-01 randomized 555 postoperative...

Psychological distress associated with genetic counselling for breastovarian cancer

Relevant psychological issues have been raised and discussed regarding hereditary breast cancer (Lerman and Croyle, 1994). A point to note is that much of the current research work in this area is theoretical, and a variety of measures and inclusion criteria are used that make comparison between studies difficult. As studies have used different assessment tools for measuring psychological distress, apparent prevalence rates for distress vary (Hopwood et al., 1998), which has implications for clinicians who provide genetic counselling. A variety of measures are used. Some are specific to anxiety or depression (e.g. Hospital Anxiety and Depression Scale - Zigmond and Snaith, 1983 Beck Depression Inventory - Beck and Steer, 1987 State-Trait Anxiety Inventory - Spielberger et al., 1983), others assess more general psychiatric distress (e.g. General Health Questionnaire -Goldberg and Williams, 1988), and others are cancer specific, or can be adapted to be so (Cancer Worry Scale - Lerman et...

Peutz Jeghers Syndrome and Cancer Risk

Peutz-Jeghers syndrome is a hereditary cancer-susceptibility syndrome, as evidenced by the development of malignancies in the great majority of patients during their lifetimes, the early age of cancer diagnosis in these family members compared to the general population, and the occurrence of cancers in related individuals in these families. Although the polyps in PJS patients are restricted to the gastrointestinal tract, the malignancies that arise in these families can be found in a variety of organ sites, including the gastrointestinal tract. The gastrointestinal malignancies can occur anywhere in the mucin-secreting portion of the luminal GI tract as well as in the pancreas. Interestingly, although foci of dysplasia can be found in larger Peutz-Jeghers polyps, the hamartomatous polyp of Peutz-Jeghers syndrome is typically a benign neoplasm. Most gastrointestinal cancers are believed to arise from coexisting adenomatous polyps. Nongastrointestinal tumors occur in the skin, thyroid,...

AID in Immunodeficiency and Cancer

1DNA Editing Lab, Clare Hall Laboratories, London Research Institute Cancer Research UK South Mimms, EN6 3LD, UK E-mail svend.petersen-mahrt cancer.org.uk The impact of the discovery of AID, with its associated function as a DNA deaminase, has been seen throughout diverse fields of studies. These include basic biochemistry, immunology, genetics and even epigenetics. Importantly, understanding the function, regulation and mechanism of AID's importance is also seen to have a direct impact on patient care. Broadly speaking, there are those patients that have an immune affliction due to mutations or even complete absence of AID (discussed in the first part of this chapter), and those patients that suffer ed from unregulated expression of AID, which can manifest itself as cancer (discussed in the second half of the chapter). Chapter 9 of this book will look at the effect of unregulated AID expression during an immune response and how this can lead to autoimmunity. Although basic research...

History Of Cancer Chemotherapy And Reflection Thereon

Originally, cancer chemotherapy started with nitrogen mustard, a derivative of poisonous gas yperite, a by-product in World War II. The pharmacological action of nitrogen mustard consists in cytotoxicities (e.g., leukopenia, diarrhea, and stomatitis) to the organism, and attempts were made to utilize these toxicities to obtain anticancer activity. Namely, the modality consisted in cancer therapy using toxicities to the organism that were inherent to nitrogen mustard. From the standpoint of establishing cancer chemotherapy that is ideally based on the premise that only the tumor should be attacked with the least damage to the organism, therefore, we cannot but consider that the approach was the tail wagging the dog (misoriented rescuing). A concept of high-dose chemotherapy, i.e., an anticancer agent fails to be effective unless provoking considerable adverse reactions, still remains at present when half a century has elapsed since the introduction of nitrogen mustard. The concept of...

Hereditary breastovarian cancer families

Prior to the detailed characterization of BRCA1 (and the discovery of BRCA2), a number of studies focused on individuals with a proven family history of breast and ovarian cancer, two reported rates of interest (definite or probable) in a genetic test being approximately 95 (Lerman et al., 1994 Struewing et al., 1995). A third study (Julian-Reynier et al., 1996) found a similar rate amongst unaffected women with at least one first-degree relative (FDR) affected, but a lower rate of interest (76 ) in affected women. Struewing et al. (1995) added a note regarding the fact that their sample was made up of people involved in linkage studies (some having given blood), and that this was possibly a factor in the high rate. Lerman et al. (1994) suggested that the request rate for tests among low-risk women would be high, based on a telephone poll of FDRs of women with ovarian cancer. Lerman et al. (1995), in a similar study that examined the FDRs of breast cancer Attitudes about genetic...

Gender Specific Gene Methylation Profiles in Four Hormone Driven Cancers

Sex steroid hormones play a pivotal role in the development of several female and male malignancies. Women experiencing prolonged exposure to or having high circulating levels of estrogen are at increased risk for breast, endometrial, and ovarian cancers. Various aspects of the ovarian reproductive function represent well-established risk factors for these types of cancers. Aside from these cancers that develop from cells that are established physiologic targets of female hormones, epidemiological studies have also described several other human cancers that have higher frequencies in women, including the cancers that develop in the proximal colon. The hormonal link of this malignancy is just starting to be elucidated. CpG island hypermethylation is one of the earliest somatic alterations to occur during cancer development. Many genes are also abnormally methylated in female cancers, and specific DNA methylation profiles of these cancers have already been described. In order to compare...

Modulation Of Pglycoprotein In Cancer Treatment

A major reason for the failure of chemotherapy treatment to cure human cancers is the ability of tumor cells to become resistant to several anticancer drugs simultaneously. Many mechanisms are known to contribute to MDR in tumor cells, of which the presence of multidrug efflux pumps is only one. Three ABC family members, Pgp, MRP1 (ABCC1), and BCRP (ABCG2), are likely to be the major drug efflux pumps expressed in human cancers.195 Tumor cells are notoriously heterogeneous, and correlations between drug resistance and the expression of efflux pumps have been difficult to establish. Some tumors express Pgp before chemotherapy treatment (e.g., colorectal and renal cancers), while in others, expression increases after exposure to MDR drugs (e.g., leukemias, lymphomas, myeloma, and breast and ovarian carcinomas). In general, patients with Pgp-positive tumors respond less well to chemotherapy and have a poorer outlook and long-term survival. There is strong evidence linking Pgp expression...

Is There a Relationship between Cancer Associated DNA Hypomethylation and DNA Hypermethylation

Hypomethylation of some DNA sequences and hypermethylation of other sequences has been found in rat hepatocarcinomas and human breast, colon, and prostate adenocarcinomas.45,76 72 Given the prevalence of both of these types of changes in cancers when they have been studied individually, they probably coexist in the vast majority of cancers but simply have not yet been documented to be simultaneously present. Hypermethylation of the GST P promoter and hypomethylation of LINE-1 repeats were found in some of the same prostate adenocarcinomas but no significant association was observed between these two types of epigenetic changes in this kind of cancer.41 Recently, in collaboration with Peter Laird and Emerich Fiala, we have shown that global DNA hypomethylation, satellite DNA hypomethylation, hypomethylation of a promoter, and hypermethylation of CpG island-promoters are present concurrently in many Wilms tumors.75 Global hypomethylation was significantly associated with Sat2...

Cancer and Tumor Angiogenesis

VEGF receptors obviously play a critical role in cancer because of their active regulation of angiogenesis and vascular permeability (see above reviews). There is also some evidence that they may have a more direct role in some cancers by regulating the proliferation or survival of the tumor cells. For example, VEGFr1 Flt1 has been reported to have the potential to transform cells when appropriately activated (Maru et al., 1998). In endothelial cells over-expressing VEGFr1 Flt1, PlGF binding has been shown to stimulate cell proliferation (Landgren et al., 1998). The specific ligands for VEGFr1 Flt1 (PlGF and VEGFB VRF) also induce the secretion of urokinase plasminogen activator (uPA) from endothelial cells (Landgren, 1998 Olofsson et al., 1998). Activation of the uPA is considered to be important for the invasive growth and metastasis of tumor cells (Conese and Blasi, 1995 Schmitt et al., 1995). Thus, these observations suggest that aberrant expression and or activation of VEGF...

Late Phase Ii Clinical Trials Of S1 In Advanced Gastric Cancer

According to the same schedule as that of the clinical pharmacological study, the late phase II clinical trial of S-1 was conducted subject to patients with advanced or recurrent gastric cancer at a dose of 40 mg m2, basically with four or more courses, each of which consisted of twice-a-day (once each after breakfast and dinner), 4-wk consecutive oral administration and of 2-wk withdrawal. The results of the late phase II clinical trials, which were reported by two groups, i.e., one of Sakata et al. (31) and another of Koizumi et al. (32), are summarized in Table 6 the overall response rate was 44.6 (45 101). As shown in Fig. 12, the survival curve was based to consider that MST was 244 d. Adverse reactions of a total of 362 patients in the late phase II clinical trials are shown in Table 7 the incidence of adverse reactions (> G3) was Response Rates in the Late Phase II Clinical Trial of S-1 (Gastric Cancer) Response Rates in the Late Phase II Clinical Trial of S-1 (Gastric Cancer)

Late Phase Ii Clinical Trial Of S1 In Colorectal Cancer

The response rate of S-1 for colorectal cancer in the early phase II clinical trial was as modes at 16.7 (Table 4). However, the response rate was 25 in patients without prior chemotherapy, thus warranting further research on this disorder. The late phase II clinical trial of S-1 was conducted to evaluate the efficacy and toxicities in patients with metastatic colorectal carcinoma. Sixty-three patients with measurable metastatic colorectal carcinoma were enrolled in this clinical trial. None of the patients had received chemotherapy prior to this clinical trial, except the adjuvant setting. S-1 was administered orally at a standard dose of 80 mg m2d, twice daily for 28 consecutive days followed by 14-d withdrawal. This regimen was maintained until when the disease progressed, an intolerable toxicity developed, or the patient refused the drug. As shown in Table 8, the overall response rate was 35.5 . As shown in Fig. 13, the median survival time was 378 d. The main adverse reactions...

Late Phase Ii Clinical Trial Of S1 In Breast Cancer

This clinical trial was conducted to examine the antitumor activity and toxicities of S-1. Eligibility required advanced and or recurrent breast cancer which was verified by histopathological or cytological evidence. However, postoperative adjuvant chemotherapy for advanced or metastatic cancer, which was conducted six or more months prior to this clinical trial, was not counted as a regimen. S-1 was administered orally at a dose of 40 mg m2, with at least four courses, each of which consisted of twice-a-day (once each after breakfast and dinner) 28-d consecutive oral administration and of 14-d withdrawal two courses were repeated every 6 wk unless the disease progressed. As shown in Table 10, there were six complete response cases and 28 partial response cases among 81 cases which were evaluable for response, with an overall response rate of 42.0 . As shown in Fig. 14, the median survival time was 910 d. The adverse events that were assessed to be Grade 3 or Response Rate in the Late...

Late Phase Ii Clinical Trial Of S1 In Lung Cancer

The objective of this clinical trial was to examine the antitumor activity and toxicity profile of S-1 in patients with stage Illb or IV lung cancer who underwent no treatment prior to the onset of this clinical trial. Sixty-two patients were enrolled in this clinical trial, and 61 patients were treated with S-1. Fifty-nine patients were eligible for the analysis of response and toxicities. S-1 was administered orally at a dose of 40 mg m2, twice daily, i.e., once after breakfast and once after dinner. One course consisted of 28-d consecutive oral administration and of subsequent 14-d withdrawal. This regimen was repeated in four courses unless the disease progressed. Twenty-two patients with stage IIIb lung cancer and 37 patients with stage IV lung cancer were enrolled in this clinical trial. As shown in Table 11, the response rate per protocol set was 22.0 (13 59). As shown in Fig. 15, the median follow-up was 281

Cancer markers and AID

One of the hallmarks of neoplastic cells is that they no longer express a 'normal' set of genes. In the past decade, tumor markers have become valuable diagnostic tools in understanding cancer progression, as well as providing information for patient care. These 'markers' though, are not always involved in the actual molecular biology of tumor formation progression, but can represent a bystander effect. Unlike transformed oncogenes (i.e. proto-oncogenes that have altered protein structure, sequence, modification or expression) DNA deaminases can induce their oncogenic potential (mutation of a cytosine) as part of their 'normal' activity. They can be activated by stress, hormones and other environmental signals, and return to 'un-stressed' levels subsequently -even in a transformed cell. Regardless, with DNA deaminases being both mutagen and oncogene, a number of cancers (especially of B cell origin) have been analysed for their expression of AID and potential prognostic association....

Cancer and risk status

Up to 18 of the family members offered testing were affected with cancer (B), with two papers (W and M-H) concentrating only on pre-symptomatic testing, and one further work (S) not specifying what proportion of individuals contacted had a diagnosis of cancer. In most cases, the uptake amongst affecteds and unaffecteds is either directly reported or deducible from the data provided. Unsurprisingly perhaps, every paper that provided complete data on cancer status showed a higher rate of utilization of counselling (H) or testing in affecteds than in unaffecteds, except where data were only available for study participants (BB), where a rate of 79 was reported for both groups. J-R reports the lowest figures in each group, while L consistently reports the highest (23 vs 56 and 69 vs 74 unaffecteds and affecteds respectively). This may once more reflect differences in recruitment methodology. J-R, M-H and H provide the best descriptions of the chance of each unaffected individual...

DNA Methylation in Urological Cancers

Urological cancers are a diverse group with different alterations of DNA methylation. In all urological cancers, DNA hypermethylation of specific genes has been described. In contrast, methylation of repetitive sequences is often diminished, resulting in decreased overall methylation levels (global hypomethylation). Altered imprinting is also found. Tes-ticular tumors are derived from more or less immature germ cells whose methylation patterns they often reflect. Subtypes can be distinguished by the extents of global hypomethylation and hypermethylation. Renal cell carcinomas typically display hypermethylation restricted to specific genes important for tumor development and progression. By comparison, methylation patterns are more severely disturbed in prostate and bladder cancers in which hypermethylation of multiple genes coexists with genome-wide hypomethylation. Causes of altered methylation may also differ. Hypermethylation could be incidental in renal cancers, but is more likely...

Example Involving Multidrug Resistance of Anticancer Agents

The investigations to be exemplified in this case have been directed toward studying the SAR associated with biological transporter systems with the hope of establishing a database of transportophore relationships that might be generally applicable toward enhancing the selection and or development of efficacy leads from any other type of data set. To provide immediate relevance to this long-term project, it has initially focused on the P-glycoprotein pump (Pgp)126,127 that is associated, in part,128,129 with the development of multidrug resistance (MDR)130,131 during cancer chemotherapy. Pgp is a 170-kD transmembrane glycoprotein that serves as an energy-dependent unidirectional efflux pump having broad substrate specificity. In humans it is encoded by the MDR gene, MDR1, whose classical phenotype is characterized by a reduced ability to accumulate drugs intra-cellularly, and thus the deleterious impact of Pgp activity on cancer chemotherapy.132-136 By way of practical example, the...

An Overview of Urological Cancers

Urological cancers constitute a diverse group of tumors different in origin, biology, clinical course and treatment options (Fig. 1). Testicular cancers are usually diseases of younger men. Most share a common origin from germ cells that have become aberrant at different stages of development. Unlike many other carcinomas, they respond well to chemotherapy. The more common urological malignancies befall older people. This is most evident for prostate carcinoma which is now the most prevalent lethal cancer of older men in industrialized countries. This adenocarcinoma is derived from the secretory epithelium of the gland. Organ-confined cases can be cured by surgical removal of the prostate (prostatectomy) or by radiotherapy. Since testosterone is essential for the proliferation of normal and many transformed prostate cells, many locally advanced and metastatic tumors respond to androgen deprivation, although this treatment is not curative. Because of the difficulty to clinically...

Conclusion Pelvic Radiotherapy for Rectal Cancer

There is no doubt that the addition of (chemo)radia-tion increases the risk of fecal incontinence and other sequelae. On the other hand, this treatment modality decreases the risk of local recurrence and may also increase survival 11 . Further studies are needed to clarify which rectal cancer patient needs neoadjuvant therapy and how functional outcome can be improved by improving the quality of both radiotherapy and surgery. Hopefully, in the future, we will have much more specific methods to select patients who will benefit from neoadjuvant therapy and identify patients with the highest risk of functional problems.

Fecal Incontinence Associated with Radiotherapy for other Cancers

Several studies have shown that radical radiotherapy for both prostate cancer and bladder cancer is associated with an increased risk of fecal incontinence 21-24 . After 2 years, bowel frequency, fecal urgency, and fecal incontinence were increased in 50 , 47 , and 26 of patients, respectively 24 . These functional deficits were associated with a reduction in resting anal pressures, squeeze pressure, and rectal compliance 24 . With a medium observation time of 29 months after radical radiotherapy for urinary bladder cancer, about 55 of the patients experienced impairment in bowel function, including urgency, incontinence, and use of pads 22 . These changes had a moderate or severe impact on the performance of daily activity in 29 of patients. Physiological studies suggest that the impaired function, also for bladder cancer, is due to a combination of sphincter weakness and changes in rectal function. For patients with cervical cancer treated with surgery and external radiotherapy,...

Cancer Cachexia Influence of n3 PUFAs

In patients with cancer, weight loss indicates a poor prognosis and a shorter survival time. Cancer cachexia involves a massive loss of body weight, with extensive breakdown of both body fat and skeletal muscle, often, but not always, accompanied by anorexia (DeWys, 1985). Metabolic studies have shown that increased free fatty acid mobilization occurs prior to weight loss in cancer patients (Costa, Bewley, Aragon, & Siebold, 1981) and weight loss is not reversed by parenteral nutrition thus, the weight loss associated with cancer cachexia is different from simple starvation (Brennan, 1977). Although not fully understood, it appears that the most likely model for the development of cancer cachexia is based on increased cytokine production. Interleukin-1p (IL-1P), an endogenous pyrogen, is a cytokine released by activated macrophages and monocytes that mediates local and systemic responses to inflammation. Peripheral or central administration of IL-1 p produces decreased food and...

Adjuvant Therapy Of Pancreatic Cancer

Although operative results have improved dramatically over the past 20 yr owing to better staging, improved surgical techniques, and advances in peri-operative care, the overall outcome for pancreatic cancer is still very disappointing. The number of patients amenable to therapeutic resection is less than 20 . Even for those patients with complete resection, the median survival is only around 20 mo with high recurrence rates both locally and distantly. For the past 20 yr, numerous studies have been performed in an effort to identify effective adjuvant (postoperative) therapy that could improve the long-term survival of resected patients. Case series from several institutions, although nonrandomized, also support a beneficial role for adjuvant 5-FU chemotherapy and radiation therapy in patients undergoing resection of pancreatic carcinoma (77,78). In contrast, a multi-institutional study conducted in Europe (ESPAC-1) suggested that chemoradiation was of no benefit following resection...

Criteria for Causal Relationship between Virus and Cancer

Although there are numerous animal models for viral oncogenesis, only in rare cases is the virus sufficient by itself for tumor induction. In those systems, experimental infection may lead to sizeable tumors within a few weeks, thus leaving no doubt about the etiologic role of the particular pathogen. In humans, none of the viruses incriminated as being oncogenic appear to be independent of other factors. Many years, and often several decades, pass by before tumors develop from primary infection in a small number of infected individuals. Monoclonal tumors arise from the pool of virus-infected cells. This suggests that the virus is, at best, one of several factors that together increase the probability of a cell undergoing malignant transformation. Possible co-factors are chemical or physical carcinogens. Furthermore, the oncogenic activity of the virus may be restricted to a specific genetic background of the patient or to a susceptible stage of cell development. These complex...

Global View of DNA Methylation Alterations in Urological Cancers

The results presented in the previous section suggest that although hypermethylation of some genes (VHL, DBCCR1) occurs only in specific urological cancers, many genes are subject to DNA hypermethylation in several tumor types (Table 1). Such genes may interfere with universal properties of tumor cells, such as uncontrolled proliferation (CDKN2A) or decreased adhesion (CDH1). Nevertheless, some genes of general importance in human cancers seem to become hypermethylated never (PTEN) or rarely (RB1). The molecular basis for this difference has begun to be addressed by studies on Moreover, several genes, like CDKN2A, are inactivated by hypermethylation, point mutation, or homozygous deletion in different human cancers, but the contribution of each mechanism differs widely.73 The molecular basis for these differences is also unknown. Beyond the investigation of individual genes, several new methods developed recently aim at surveying methylation changes in cancers (see other contributions...

Hypermethylation During Breast Cancer Progression

Although the past decades of research have shed new light into the epigenetic mechanisms involved in breast carcinogenesis, it is still difficult to establish a precise timing for promoter hypermethylation of the cancer related genes involved in mammary carcinogenesis. This is due to two

Thyroid And Cancers Of The Head And Neck

Thyroid cancer is generally associated with a favorable prognosis. However, advanced local involvement and distant metastases incur significant mortality. Curative resection improves the prognosis in advanced thyroid cancer (21). Thyroid cancers that have invaded the esophageal wall as far as the muscular layer require a full thickness resection, although cancers that invade only the adventitia can be managed with a simple shaving (22). Although CT and MRI are able to detect esophageal invasion, these modalities are insufficient for a precise determination of depth. Because the thyroid is near the esophagus, the gland can be detected by EUS through the esophageal wall. EUS has been used successfully for diagnosing depth and extension of thyroid cancer (see Fig. 10). A study published recently compared EUS with esophagography and MRI in 59 patients in whom esophagopharyngeal invasion by thyroid cancer was suspected (large tumors with poor mobility). The diagnostic specificity and...

Causes of Altered DNA Methylation in Urological Cancers

The causes of altered methylation may be distinct in different cancers (Fig. 2). In some cancers, apparently aberrant methylation may in fact largely reflect the methylation pattern of the affected stem cell. Thus, different germ cell tumors display methylation patterns at imprinted genes corresponding to distinct stages of germ cell development.8,10,14 Conversely, failure to set up proper methylation patterns of mature cells may underlie blocked differentiation. Clear-cell renal carcinomas may exemplify a group of cancers displaying a limited number of methylation changes. Some of these could be caused by incidental errors for which there is strong selection during tumor development because they lead to inactivation of crucial tumor suppressor genes such as VHL. Others such as CA9 hypomethylation62 may be secondary to alterations in transcriptional activators. In contrast, advanced prostate and bladder cancers are typically characterized by severely disturbed DNA methylation patterns...

Possible Mechanisms Of Anticancer Effects

Because PA is ubiquitous to every mammalian cell, it is not surprising that it has a cancer protective effect on different tissues, in different experimental models and under various conditions. However, the mechanisms of PA action are not clear and are open to conjecture. The inhibition of enzymes within the digestive tract may lead to inhibition of digestion and absorption of dietary components 69,70 Figure 14.3(A) . PA may bind to enzymes necessary for starch digestion or, alternatively, it may also reduce the rate of digestion and absorption of starches Figure 14.3(B) either by hydrogen binding to starch 12,71 , binding to proteins that starch is bound to 12,70 or by binding amylase or enzyme cofactors such as Ca2+ 4 . Studies suggest that PA may slow starch digestion and absorption in vivo 72,73 . Such undigested and unabsorbed starch may reach the colon where it may either contribute to fecal bulk and increase the dilution of potential carcinogens, or it may be fermented to...

Plots of Cancer Incidence at Different Times and Places

The following plots show cancer incidence and acceleration patterns at different time periods and in different countries. In some cases, the acceleration plots fluctuate between countries because of the nature of the data, which may have small numbers of cases at early or late ages. Thus, it is best to focus only on the broad trends in the acceleration plots, particularly those patterns that recur in different years and in different locations. For example, prostate cancer shows a remarkably strong and linear decline in acceleration beginning in midlife (Figure A.2). Some cancers show midlife peaks in acceleration, for example, colon and bladder cancer (Figure A.4). Cervical cancer has an acceleration close to zero throughout life, with higher fluctuations outside the USA probably caused by smaller samples for those other countries (Figure A.12). However, cervical cancer in the USA follows different patterns of acceleration in different ethnic groups (not shown), emphasizing that...

Role of EGFLike Peptides in Ovarian Carcinogenesis

EGF-related peptides and their receptors may be involved in the autonomous proliferation of ovarian carcinoma cells, and may play a role in ovarian carcinogenesis (401, 432-440). EGF and TGF-a stimulate the growth of several human ovarian carcinoma cell lines (441,442). The stimulatory effects of EGF and TGF-a are accompanied by changes in cell cycle distribution, as detected by flow cytometric analysis (443). Like TGF-a, AR is also mitogenic, but has less pronounced effects on proliferation (444). The growth of some ovarian carcinoma cells can be inhibited by EGF, which suggests that the EGF effect is not only dependent on concentration, but also on different postreceptor events in various cell lines (445). Neutralizing Abs directed against EGF or TGF-a can inhibit ovarian cell proliferation in cells that possess functional EGFR, suggesting a major role of TGF-a EGFR autocrine growth mechanisms in primary Ocs, but also in OC cell lines and in xenotransplants (441,446-448). Individual...

DNA Methylation in Colorectal Cancer

In this chapter, it is pointed out that colorectal cancer is a heterogeneous disease. The case is early acquisition of DNA instability. DNA hypermethylation is likely to be of critical importance in driving this pathway. Inhibition of apoptosis is conceived as the first step. Thereafter, methylation of one of several DNA repair genes would result in a state of tolerated hyper-mutability. It remains to be shown whether this model applies to a small subset of colorectal cancers or in fact explains the great majority given the overall low risk of progression for an individual adenoma initiated by mutation of APC. Colorectal cancer is not only an important disease in terms of its frequency and contribution to human suffering but also because it provides an instructive model for neoplasia in general. There are two reasons why colorectal cancer has served as a successful model. First, the precancerous stages present as mucosal lesions (polyps) that can be identified and removed with...

Studies of gene therapy for breast and ovarian cancer

Over the past 10 years there has been a large amount of research into gene therapy for ovarian and breast cancer. It is important to appreciate that many of these studies have only been involved in cell culture or animal models and have yet to be studied in human subjects. Others have proven initially successful in pre-clinical models but have failed to show a benefit in the treatment of humans. Unfortu Correction of genetic mutation in cancer cells The p53 tumour suppressor gene encodes a protein in response to DNA damage that leads to cell cycle arrest at the G1 M phase and may result in apoptosis or DNA repair. Mutation of this gene is found in about half of ovarian and breast cancers (Kohler et al., 1993 Vogelstein et al., 2000) and is associated with a decrease in sensitivity to chemotherapy along with aggressive tumour behaviour. Reintroduction of the wild type p53 gene is therefore a potential mechanism for treatment of chemoresistant tumours. Using this approach, Kigawa et al....

Incidence and death rates of thyroid cancer and lymphoma

About 17,000 new cases of thyroid cancer are diagnosed annually in the United States, making it about 14th in incidence among malignancies (6). It occurs at all ages but is most common among middle-aged and postmenopausal women (Fig. 1). The lifetime risk of developing thyroid cancer is about 1 (0.65 for women and 0.25 for men) (7), and death rates are less than 10 (1200 deaths occurred among 135,000 thyroid cancer patients in 1998) (6). However, both the incidence and mortality rates vary substantially among the different forms of thyroid cancer (Table 1) (8). Incidence and 10-Year Relative Survival of 53,856 Patients with Thyroid Cancer Incidence and 10-Year Relative Survival of 53,856 Patients with Thyroid Cancer Proportion of all cancer Type of thyroid cancer

Eus In The Followup Of Anal Cancer

The treatment strategy of anal cancer was changed in the early to mid-1980s when several authors reported excellent T Primary anal cancer Description Fig. 8. (A) Endoscopic appearance of anal cancer, biopsies confirm squamous cell carcinoma. (B,C) Rectal endoscopic ultrasound confirms that this is T2N1 stage, with involvement of the internal anal sphinter (U), and disruption of the external anal sphinter anteriorly and a single round, hypoechoic, malignant-appearing perirectal lymph node (anal cancer is seen to invoive the lymph node). T Primary anal cancer Description

Models For The Development Of Prostate Cancer Metastases

The mechanisms underlying the dissemination of primary prostate cancer and establishment of metastatic deposits is a topic of great interest since these lesions are ultimately responsible for the vast majority of prostate cancer deaths. It is clear from clinical observations that prostate cancers have a predilection to metastasize to a distinct set of anatomical organ systems, such as lymph node, bone and liver. The first formal hypothesis suggesting an explanation for the non-random distribution of sites to which primary cancers metastasize was proposed by Stephen Paget in 1889 (111, 112). His seed and soil hypothesis suggested that factors in the target site environment promoted the growth of cancer cells there, much like fertile soil would promote the growth of seeds. A modern view of this hypothesis would suggest two possibilities i) that the target site microenvironment would either promote cancer cells to change and adapt when they reach the target site and then establish a...

Effects Of Cancer On The Heart

Pericardial Effusion Fluid Removal

Pericardial involvement is a common sequelae of cancers that have invaded the pericardial space by Finally, even when cancers do not directly involve the heart, the treatment may have cardiac effects, despite remission or even cure of the primary malignancy. Chemotherapeutics of the vincristine class (adri-amycin, daunorubicin, and others) are notorious for causing dilated cardiomyopathy as a side effect in some patients. The anti-HER2 monoclonal antibody, her-ceptin, is often used in combination with anthra-cyclines, and appears to cause heart failure, particularly in patients who are older or have other cardiac risk factors. Thus, the ejection fraction should be followed serially in these patients. Radiation therapy to the mediastinum can cause radiation pericarditis, which may be eventually evolve into constrictive pericarditis exposure to such radiation also associated with accelerated coronary artery disease in cancer survivors.

Carcinogenicity testing the Ames test

The great majority of carcinogenic substances, that is, substances that cause cancer in humans and animals, are also mutagenic in bacteria. This fact has been used to develop an initial screening procedure for carcinogens instead of the expensive and time-consuming process of exposing laboratory animals (not to mention the moral issues involved), a substance can be tested on bacteria to see if it induces mutations. The Ames Test assesses the ability of a substance to cause reverse mutations in aux-otrophic strains of Salmonella that have lost the ability to synthesise the amino acid his-tidine (his-). Rates of back mutation (assessed by the ability to grow in a histidine-free medium) are compared in the presence and absence of the test substance (Figure 11.23). A reversion to his+ at a rate higher than that of the control indicates a mutagen. Many substances are procarcinogens, only becoming mutagenic carcinogenic after metabolic conversion by mammals in order to test for these, an...

Cancer Drug Discovery and Development Beverly A Teicher Series Editor

Matrix Metalloproteinase Inhibitors in Cancer Therapy, edited by Neil J. Clendeninn and Krzysztof Appelt, 2000 9. Tumor Suppresor Genes in Human Cancer, edited by David E. Fisher, 2000 8. Farnesyltransferase Inhibitors in Cancer Therapy, edited by Said M. Sebti and Andrew Hamilton, 2000 7. Platinum-Based Drugs in Cancer Therapy, edited by Lloyd R. Cancer and Other Diseases, edited by J. Silvio Gutkind, 2000 5. Apoptosis and Cancer Chemotherapy, edited by John A. Hickman and Caroline Dive, 1999 4. Antifolate Drugs in Cancer Therapy, edited by Ann L. Jackman, 1999 3. Antiangiogenic Agents in Cancer Therapy, edited by Beverly A. Teicher, 1999 2. Anticancer Drug Development Guide Preclinical Screening, Clinical Trials, and Approval, edited by Beverly A. Teicher, 1997 1. Cancer Therapeutics Experimental and Clinical Agents, edited by Beverly A. Teicher, 1997

Familial Breast Ovarian Cancer

Familial Breast and Ovarian Cancer This book surveys the profound and far-reaching ramifications that have arisen from the very significant advances in our understanding of the genetic basis of familial breast and ovarian cancer. Written by international experts from Europe and North America, it provides the busy clinician with a contemporary and wide-ranging guide to the latest developments in the diagnosis, genetics, screening, prevention and management of familial breast cancer. In this rapidly advancing field, this book provides an unrivalled source of information, including sections on ethical and insurance issues and the different cultural aspects of breast cancer. The use of recently devised cancer genetics clinics and different referral criteria and patterns to these clinics are also detailed. This accessible book will be of immense value to all clinical geneticists, oncologists and healthcare professionals involved in screening and counselling programmes.

Multistage Progression in Colorectal Cancer

Colorectal cancer provides a good model for the study of morphological and genetic stages in cancer progression (Kinzler and Vogelstein 2002). Various precancerous morphologies can be identified, allowing tissue samples to be collected and analyzed genetically. Figure 3.1 shows the morphology of normal colon tissue. The epithelium has about 107 invaginations, called crypts. Cells migrate upward to the epithelial surface from the dividing stem cells and multiplying daughter cells at Figure 3.2 Morphology of colorectal cancer progression. This classical pathway is characterized by traditional adenoma morphology, slow progression, high adenoma carcinoma ratio, frequent chromosomal instability and aneuploi-dy, and rare microsatellite instability. Particular genetic changes often associate with morphological stage, suggesting that the genetic changes play an important role in driving progression. Approximately 50-85 percent of colorectal cancers follow this pathway. Redrawn from Figure 3...

Cpg Island Hypermethylation Changes During Prostate Cancer Initiation And Progression

Prostate Examine

In 1994, Lee et al. demonstrated that hypermethylation of CGI sequences within the regulatory region of GSTP1, which encodes the pi-class glutathione S-transferase (GST) enzyme, is an extremely frequent feature of human prostate cancer (49, 50). Since that initial study, numerous groups have independently corroborated these findings using a wide array of techniques applied to numerous prostate cancer DNA sources, including prostatectomy specimens, prostate autopsy specimens, prostate biopsy specimens, prostate secretions, and various bodily fluids from prostate cancer patients. Furthermore, GSTP1 CGI hypermethylation appears to be an extremely specific finding for prostate cancer as it is not characteristic of normal prostates or benign prostatic hyperplasia. The GST enzymes catalyze the detoxification of carcinogens and reactive chemical species via the conjugation of glutathione. It has been hypothesized that loss of this detoxification agent in prostate cells might make them...

Ch Emoprevention A Rational Approach To Fight Cancer

Cancer is the end-stage manifestation of heterogeneous and chronic disease processes. Over the last several decades, a search for a cancer cure has largely been focused on developing chemotherapeutic agents, radiotherapy, and surgical intervention. Nonetheless, the incidence and mortality of cancer, in general, are still increasing. The number of cancer-related deaths is expected to double in the next 50 years despite current advances in cancer prevention and treatment 1 . In fact, the aforementioned conventional strategies, largely implemented after the diagnosis of cancer at the advanced stage, have been proven unsatisfactory to cure cancer. This is because the malignant lesions exhibit heterogeneity in terms of genotypic and phenotypic characteristics, which makes it impractical to find a specific molecular target for the defined cure for cancer. Moreover, many of the clinically approved cytotoxic drugs exert deleterious effects on the normal tissues, thereby devastating the...

Clinical Manifestations Of Colorectal Cancer

A major goal of global expression analysis is to provide information that supports an enriched system of classification, either alone or in conjunction with clinical and genetic data. To place this effort in perspective, we sketch the clinical behavior of colon cancer and outline the major clinical-pathological classification systems. Colorectal cancer principally affects those older than 40 yr of age, although it occurs occasionally in adolescents (18). Ninety percent of tumors are found in people older than 50 yr. The incidence rate varies about 20-fold in different parts of the world, with the highest in the West and the lowest in India (19). Migration from a low to a high incidence region is associated with an increase in disease risk. This suggests that the environment (probably the diet) can influence the incidence of colorectal cancer (20), although the occurrence of cancer predisposition syndromes (accounting for about 5 of all cases of colon cancer) such as familial...

Testing for Carcinogenicity and Teratogenicity

Carcinogenic potential can be detected by three types of tests long-term carcinogenicity studies, rapid screening tests, and biomarkers. Long-term tests are the most definitive. These generally use mice or rats and last the lifetime of the animals (18 and 24 months, respectively). Two or three dose levels are usually used, the highest being the maximum tolerated dose'' (MTD). The MTD is estimated from 90-day studies and is chosen so as not to produce severe noncarcinogenic toxicological effects or to reduce significantly the life of any organisms that do not develop tumors. The other doses are typically one-fourth to one-half of the MTD. The number of tumors is recorded by animal (location, whether benign or malignant, the presence of any unusual tumors), the number of animals with tumors, the number of tumors per animal, the number of tumor sites, and the time to onset. In the United States, a set of minimum test standards for carcinogenicity has been developed by the National...

Retroviruses and Cancer

Retroviruses are among several types of viruses that can induce cancer in the host organism. So-called slowly transforming viruses are exemplified by human T-lymphotropic virus (HTLV), which causes leukemia (a type of blood cancer) in humans. These viruses induce malignancy by a process called insertional mutagenesis. The initial event is thought to be retroviral integration near, and subsequent activation of, a cellular oncogene (c-onc). Examples of c-onc include genes for growth factors, protein kinases, and transcription factors. Harold Varmus and Michael Bishop won the Nobel Prize for physiology or medicine in 1989 for their contributions to the discovery of oncogenes. Acutely transforming retroviruses contain a viral oncogene (v-onc) and induce polyclonal cancers (that is, many different cancer cells are derived in multiple transforming events) at high efficiency within a short time frame (weeks). The v-onc are derived by incorporation and modification (that is, by deletion of...

Combination Therapy Of Ftis Or Ggtis With Cytotoxic Anticancer Drugs Is More Efficacious Than Monotherapy

Evidence from our research and that of others (46-48) indicated that FTIs' antitumor effect is often cytostatic and reversible. This suggested that combination therapy may be beneficial. Furthermore, there are several reasons why combination therapy with FTIs or GGTIs and other clinically used anticancer drugs with different mechanisms ofaction may prove to be more beneficial than monotherapy. First, because a tumor is made up of a heterogeneous population of cells with different genetic alterations, treatment with more than one agent may avoid resistance of the tumor to a single drug. Second, Ras has been shown to induce resistance to radiation and some cytotoxic agents. Therefore, inhibition ofK-Ras prenylation may sensitize human tumors to cytotoxic agents or radiation (see Chapter 12). On the other hand, treatment with cytotoxic agents may also alter tumor cells such that they become even more sensitive to FTIs or GGTIs. To explore these possibilities we have implanted sc...

Ipsi and contralateral breast cancer recurrences

Lumpectomy followed by radiation therapy, i.e. the conservative management of breast cancer, has been accepted as a standard of care for the majority of women with early breast cancer. Long-term follow-up data have consistently shown a risk of ipsilateral breast tumour recurrence (IBTR) of 0.5-2 per year (Recht et al., 1988 Fourquet et al., 1989 Kurtz et al., 1989 Fisher et al., 1991 Veronesi et al., 1995), but breast cancer survival was not significantly affected by IBTR when compared with patients undergoing a radical mastectomy (Haffty et al., 1991a Fisher et al., 1995 Jacobson et al., 1995 Veronesi et al., 1995 Winchester et al., 1997). Early age of onset is associated with an increased risk of IBTR (Schnitt et al., 1984 Haffty et al., 1991b de la Rochefordiere et al., 1993), but an association was not consistently found when the patient reported a positive family history of breast cancer (Chabner et al., 1998 Harrold et al., 1998). Young age at primary breast cancer diagnosis, a...

Melanoma Pancreatic Cancer Syndrome

Melanoma susceptibility has also been reported in conjunction with gastrointestinal cancer and breast cancer, and an excess of pancreatic carcinoma is frequently being observed. Comparison of CDKN2A mutation-positive and -negative melanoma families showed an increased risk of pancreatic cancer in the mutation-positive group. 11 Interestingly, the increased risk for pancreatic cancer seems to be restricted to only some of the CDKN2A mutation-positive families, implying other genes and or environmental factors are responsible for modifying the penetrance of this tumor type. Disentanglement of these issues is of utmost importance because of the high mor- tality associated with this cancer and the lack of routine surveillance for it. Whether the correlation with other cancers is restricted to pancreatic cancer only or also involves different cancers remains to be answered by large-scale analysis of cancer history in melanoma families.

Familial ovarian cancer

Familial aggregation of ovarian cancer has been variably defined as occurring when (1) two first-degree relatives have ovarian cancer, or (2) the proband has ovarian cancer as well as one or more of her first- or second-degree relatives (Lynch and Lynch, 1992). Case-control studies designed to estimate the relative risk of developing ovarian cancer associated with a family history of the disease are summarized in Table 4.1. In a meta-analysis of case-control and cohort studies on family history and risk of ovarian cancer, the relative risk for all first-degree relatives was 3.1 (95 CI, 2.6-3.7), 1.1 (95 CI, 0.8-1.6) for mothers of cases, 3.8 (95 CI, 2.9-5.1) for sisters and 6.0 (95 CI, 3.0-11.9) for daughters, respectively (Stratton et al., 1998). In another study, the risk increased with the number of first-degree relatives affected (Kerber and Slattery, 1995). Initial work suggested that women who have one first-degree relative affected by, or who died of, ovarian cancer were at...

Nsabp Colon Cancer Adjuvant Trials

The NSABP historically has included Stage II and Stage III colon cancer patients in all its adjuvant chemotherapy trials. Four such trials (C-01, C-02, C-03, and C-04) are described below. From November 1977 through February 1983, 1166 patients were entered into the NSABP's first randomized adjuvant clinical trial for patients with resected Stage II and Stage III colon cancer (12). Patients were stratified by stage, gender, and age to receive either MOF (MeCCNU, vincristine, and fluorouracil), BCG, or no further treatment. At 5 yr, disease-free survival (DFS) and survival for patients who received MOF were better than for patients treated by surgery alone (58 vs 51 , p 0.02 and 67 vs 59 , p 0.05, respectively). When patients who received BCG alone were compared to those who were treated with surgery alone, there was no significant difference in 5-yr DFS (56 vs 51 , p 0.09), but there was a 5-yr survival advantage in the BCG-treated group (67 vs 59 , p 0.03). Subsequent analysis...

Pathology of ovarian cancers in mutation carriers

All studies performed to date indicate that carcinoma is the most common histological diagnosis observed in BRCA1- and BRCA2-associated ovarian cancer. Most of the information available on familial ovarian cancer is based on BRCA1-linked disease because, unlike familial breast cancer patients, BRCA1 germline mutations are approximately four times more common than BRCA2 mutations in ovarian cancer patients (Gayther et al., 1999 Boyd et al., 2000). All five subtypes of malignant epithelial ovarian neoplasms have occurred in BRCA1 mutation carriers. Even a case of a malignant transitional cell carcinoma - a very rare entity -has been found to occur in an individual carrying a BRCA1 mutation (Werness et al., 2000a). It is generally agreed that the frequency of endometrioid and clear-cell carcinoma occurring in BRCA1 mutation carriers is similar to that of sporadic cases (Rubin et al., 1996 Stratton et al., 1997 Aida et al., 1998 Berchuck et al., 1998 Johannsson et al., 1998 Zweemer et...

Multiplestage Design In Cancer Trials

As was discussed in Section 6.6, in phase II cancer trials, it is undesirable to stop a study early when the treatment appears to be effective but desirable when the treatment seems to be ineffective. For this purpose, a multiple-stage design is often employed to determine whether an experimental treatment holds sufficient promise to warrant further testing (see, e.g., Fleming, 1982 Simon, 1989 Chang et al., 1987 Therneau et al., 1990). The concept of a multiple-stage design is to permit early stopping when a moderately long sequence of initial failures occurs. Chow et al. (2003b) provided tables for sample size calculation for two-stage designs such as minimax design, Simon's optimal two-stage design, and flexible two-stage design and three-stage designs such as optimal three-stage design and flexible design for single-arm phase II cancer trials.

The Role of Membrane Complement Regulatory Proteins in Cancer Immunotherapy

1Tumor Immunobiology Program of the James Graham Brown Cancer Center, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA, jun.yan louisville.edu Abstract. Anti-tumor monoclonal antibody therapy represents one of the earliest targeted therapies in clinical cancer care and has achieved great clinical promise. Complement activation mediated by anti-tumor mAbs can result in direct tumor lysis or enhancement of antibody-dependent cellular cytotoxicy. Chemotaxis of phagocytic cells by complement activation products C5a is also required for certain cancer immunotherapy such as combined P-glucan with anti-tumor mAb therapy. However, high expression levels of membrane-bound complement regulatory proteins (mCRPs) such as CD46, CD55 and CD59 on tumors significantly limit the anti-tumor mAb therapeutic efficacy. In addition, mCRPs have been shown to directly or indirectly down-regulate adaptive T cell responses. Therefore, it is desirable to combine...

Might There Be Deleterious Consequences of Introducing DNA Hypomethylation in the Genome As a Cancer Therapy

The DNA methylation inhibitors 5-azacytidine, 5-aza-2'-deoxycytidine (decitabine), and 5,6-dihydro-5- azacytidine have been used as cancer chemotherapeutic agents in clinical trials on various neoplasms, including refractory acute leukemia 89 myelodysplastic syndrome 90 advanced non-small cell lung cancer 91 malignant mesothelioma 92 accelerated or blast phase of chronic myeloid leukemia 93 advanced ovarian or cervical carcinoma 94,95 malignant melanomas and colorectal, head and neck, and renal carcinomas.96 For solid tumors, usually little or no clinical efficacy and often no disease stabilization was seen, but many toxic effects were observed.89,91,94-9 Combination therapy on malignant mesothelioma, which showed a low response to 5,6- dihydro-5-azacytidine alon,92 did not improve the response rate (17 ) and increased the toxicity.97 There has been considerable attention recently to testing the efficacy of treatment of high-risk myelodysplastic syndrome (MDS) with 5-azacytidine or...

Molecular Diagnosis Of Cancers

The molecular diagnosis of cancers relies on biomarker molecules that are produced in higher than normal levels either directly by tumor cells or by the response of the human body to the presence of cancers. Detection of the biomarkers in a patient's body fluids can serve as the first step in cancer diagnosis and provide critical information to doctors as to whether or not a biopsy is needed. Tumor markers can be proteins or hormones. Some classic tumor markers include a-fetoprotein (AFP), carcinoembryonic antigen (CEA), and prostate-specific antigen (PSA). They are usually not very specific to a particular cancer as the level of one tumor marker can be elevated by more than one type of cancers. Another problem is that the presence of cancer does not necessarily cause a detectable level of tumor markers, especially in the early stages. Extra caution is thus needed in some cases to avoid false negatives. With a better understanding of the genetic basis of cancers, some biomol-ecules...

TrWeighted Breast Cancer DCEMRI

A large body of literature has shown that breast cancer enhance earlier and to a greater extent than benign breast diseases on Trweighted DCE-MRI. This difference is most marked in the early period (1-3 min) after bolus contrast medium administration (Kaiser and Zeitler 1989 Flickinger et al. 1993 Gilles et al. 1993 Boetes et al. 1994). However, other investigators have demonstrated that there is an overlap in the enhancement rates of benign and malignant lesions (Heywang et al. 1989 Fobben et al. 1995 Stomper et al. 1995). Thus, any kinetic parameter used for tissue characterisation has to take into consideration the relative contrast medium behaviour in different tissues.