Cancer Causes and Treatment

Do I Have Cancer

This ebook from medical practitioner and family doctor Dr. Parajuli gives you all of the signs and symptoms that you need to know in order to catch cancer in the very early stages and protect yourself from it. You don't have to worry about if you have cancer anymore, and better yet you don't have to spend thousands of dollars to make sure of that either! All it takes is a bit of knowledge and you are on your way! This book also teaches about other aspects of cancer patients, such as how to live with different kinds of cancer, how to prepare yourself mentally to accept this reality if it IS a reality for you, and how to deal with doctors and insurance companies. This book is easy to read and in PDF format, so you don't have to worry at all about reading it. Make it easy on yourself! More here...

Do I Have Cancer Overview

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This is one of the best e-books I have read on this field. The writing style was simple and engaging. Content included was worth reading spending my precious time.

As a whole, this book contains everything you need to know about this subject. I would recommend it as a guide for beginners as well as experts and everyone in between.

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....

Anaplastic Thyroid Cancer

In the past, ATC comprised about 5-10 of thyroid cancers (24) but in recent years has accounted for about 2 of all thyroid cancers (8). In a review of 475 patients with this disease reported in six large studies, the mean age was 65 yr, with only a slight female predominance (24). ATC is almost never seen before age 20 yr. It evolves from well-differentiated tumors (24) which may slowly transform into ATC (25). One report, for example, described a 61-yr-old man who developed follicular cancer pulmonary metastases 12 yr after initial surgery, which transformed over several years into ATC (as shown by serial biopsies ) (26). Some appear to arise de novo (27), but many are well-differentiated tumors that slowly transform into ATC (24). One study (28) found elements of differentiated cancer in almost 90 of ATC specimens, which often came from persons previously treated for well-differentiated thyroid cancer, underscoring an important adverse effect of late or incomplete treatment of...

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...

The Role of Thyroid Radiation in Causing Thyroid Cancer External Irradiation

The only environmental factor known to increase the risk of thyroid cancer is irradiation. The risk of developing papillary thyroid cancer after therapeutic external radiation, used in the past to treat children with benign head and neck conditions, is well known (30). Exposure before the age of 15 yr poses a major risk that becomes progressively larger with increasing doses of radiation between 0.10 Gy (10 rad) and 10 Gy (1000 rad). The incidence of thyroid cancer begins increasing within 5 yr of exposure and continues unabated for 30 yr, after which it begins to decline (30). After thyroid radiation exposure, females are more likely than males to develop thyroid cancer, and it is more prevalent among those with a family history of thyroid cancer (30). Radioiodine-Induced Thyroid Cancer Most early studies suggested that 131I was unlikely to induce thyroid cancer (31). A large U.S. study, for example, reported a slight elevation of thyroid cancer mortality following treatment of...

Studies of familial breast cancer

It has been recognized for many years that there is an association in certain families between breast and ovarian cancer. The risk for epithelial ovarian cancer was found to be significantly elevated in patients with first-degree relatives affected with breast cancer (twice the population risk) (Muderspach, 1994 Claus et al., 1996). Similarly, the risk for breast cancer was found to be elevated in patients who had first-degree relatives with ovarian cancer. Following international studies of large families with an excess of both early-onset breast cancer and of ovarian cancers, Mary Clair King's group demonstrated linkage between inherited susceptibility to early-onset breast cancer and a polymorphic marker on chromosome 17q21.3 (Hall et al., 1990). Predisposition to breast and ovarian cancer was also found with this locus in many families around the world, but it was also clear that other families existed with an excess of early-onset breast cancer that did not segregate with this...

Age of Cancer Incidence

Perturbations of the genetic and environmental causes of cancer shift the age-specific curves of cancer incidence. We understand cancer to the extent that we can explain those shifts in incidence curves. In this chapter, I describe the observed age-specific incidence patterns. The following chapters discuss what we can learn about process from these patterns of cancer incidence. The first section introduces the main quantitative measures of cancer incidence at different ages. The standard measure is the incidence of a cancer at each age, plotted as the logarithm of incidence versus the logarithm of age. Many cancers show an approximately linear relation between incidence and age on log-log scales. I also plot the derivative (slope) of the incidence curves, which gives the acceleration of cancer incidence at different ages. The patterns of acceleration provide particularly good visual displays of how cancer incidence changes with age, giving clues about the underlying processes of...

Genes implicated in breast cancer predisposition

More than 500 sequence variations have been identified in BRCA1, and of these, more than 80 of all BRCA1 mutations are frameshift or nonsense mutations that alter the codon reading frame and result in a 'stop' codon producing a premature protein termination (Futreal et al., 1994 Gayther et al., 1995 FitzGerald et al., 1996 Szabo and King, 1997 Liede et al., 1999). Genetic susceptibility to breast cancer is thought to occur when one BRCA1 allele is inactivated in the germline cancer Collaborative studies by the Breast Cancer Linkage Consortium (BCLC) have examined multiple families with germline mutations in BRCA1 and BRCA2 to establish the penetrance of mutations in these genes and the risks of other cancers (Ford et al., 1994 Ford et al., 1998 Puget et al., 1999a) (Figure 2.1). These studies suggest that carriers of mutations in BRCA1 have an associated cumulative breast cancer risk of 80-85 by age 80 years. Once affected with a first breast cancer, such gene carriers have a...

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...

Microarrays As Target Identification Tools In Cancer

Microarrays constitute a group of technologies characterized by the common availability of measuring hundreds or thousands of items, including DNA sequences, RNA transcripts, or proteins, within a single experiment using miniaturized devices. Hybridization-based methods and the microarray format constitute together an extremely versatile platform provided for both static and dynamic views of DNA structure, as well as RNA and protein expression patterns in cultured cancer cells and tumor

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...

Breast Cancer and Its Treatment

It is the second leading cause of cancer death among women (representing 15 of all cancer deaths), compared to 25 of cancer deaths from lung cancer (American Cancer Society ACS 2004). Estimated deaths from breast cancer in 2003 were 39,800 for women and 400 for men. Mortality rates for breast cancer declined significantly in recent years, mostly among young women, both white and black, falling 1.4 annually in 1989-1995 and then at a rate of 3.2 annually. Survival for women with breast cancer varies as a function of the stage of the disease at diagnosis. The ACS data show 5-year relative survival rates of 86 for all stages, 97 for local, 78 for regional, and 23 for distant (or metastasized) cancers. The ACS, relying on the SEER staging system of the National Cancer Institute, defines local-stage tumors as cancers that are confined to the breast regional-stage tumors have spread to surrounding tissue or nearby lymph nodes and distant-stage tumors have...

Common Types Of Childhood Cancer Leukemia

Leukemia is a cancer involving the blood-forming cells. It typically affects the white blood cells, but it can also affect other types of blood cells (i.e., red blood cells or platelets). Leukemia initially develops in the bone marrow (i.e., the inner part of the bones where blood cells are produced) and then spreads to the blood. Once in the blood, the leukemia can spread to the lymph nodes, the central nervous system (i.e., the brain and spinal cord), or other organs. Symptoms of leukemia include fatigue, pale skin, infection, easy bleeding or bruising, bone pain, swelling of the abdomen, swollen lymph nodes, swollen thymus gland, headaches, seizures, vomiting, rashes, gum disease, and extreme weakness (American Cancer Society, 2004). Leukemia is identified as being either acute (growing quickly) or chronic (growing slowly). Children with leukemia are typically diagnosed with an acute form of the disease. Acute leukemia is divided into two types, (1) acute lymphocytic leukemia...

Brain and Spinal Cord Cancers

Brain and spinal cord tumors are the second most common childhood cancer, accounting for 21 of all childhood cancers (American Cancer Society, 2004). Brain tumors involve the brain structures either by growing on or in a structure, or by causing pressure on brain tissues (Armstrong & colleagues, 1999). Possible symptoms of brain tumors include epileptic seizures and pressure within the skull, which may result in headaches, nausea, vomiting, or blurred vision. Some children experience crossed eyes and double vision as a result of the pressure, and some children lose their vision totally. Symptoms of skull pressure in school-age children include decreased school performance, fatigue, personality changes, and headaches. In younger children, symptoms include irritability, decreased appetite, developmental delays, and losing previously acquired intellectual and motor skills infant symptoms include increased head size, vomiting, and failure to thrive. Possible symptoms of spinal cord...

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...

Clinical cancer genetic management

The two most serious, and established, component tumours in CS are breast cancer and non-medullary thyroid cancer for affected females and males. Endometrial cancer is now believed to be a component of CS as well. Patients with CS or those who are at risk of CS should undergo surveillance for these three cancers. Beginning in their teens, these individuals should undergo annual physical examinations, paying particular attention to the thyroid examination. Beginning in their mid-twenties, women with CS or those at risk of it should be encouraged to perform monthly breast self-examinations and to have careful breast examinations during their annual check-ups. The value of annual imaging studies is unclear as no objective data are available. Nonetheless, we usually recommend annual mammography and or breast ultrasounds performed by skilled individuals in at-risk women, beginning at age 30 years or 5 years younger than the earliest breast cancer case in the family, whichever is earlier....

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...

Pathogenesis of Estrogen ReceptorPositive and Negative Breast Cancer

Importance of Estrogen and ER in Genesis of Breast Cancer Effect of Estrogen on Normal Gland Development Estrogen Receptors ER Expression During Breast Cancer Evolution Genesis of Breast Cancer Evolution of ER-negative Breast Cancers Studies Supporting Hypothesis that ER-negative Cancers Arise from ER-positive Precursors Studies Supporting Hypothesis that ER-negative Cancers Arise

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...

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...

Clinical pathological and outcome characteristics of BRCArelated ovarian cancer

Clinicopathological characteristics of ovarian tumour have been evaluated in familial aggregation of ovarian cancers or among patients with BRCA1 2 germline mutation (hereditary ovarian cancer). Few data are available for ovarian cancer associated with other inherited genetic syndromes and will not be discussed further here. This whole topic is discussed in detail in Chapter 7. Early age of onset is often considered to be a hallmark of most of the hereditary cancers. As discussed above, in some studies the average age of onset for familial or hereditary ovarian cancer was significantly lower (about 5 years) than that of ovarian cancer in the general population (Bewtra et al., 1992 Lynch et al., 1993 Piver et al., 1993a Muto et al., 1996 Rubin et al., 1996 Zweemer et al., 1998 Boyd et al., 2000). This significant difference in age of onset has not been found consistently (Narod et al., 1994a Chang et al., 1995 Auranen et al., 1997 Stratton et al., 1997 Johannsson et al., 1998 Gayther...

Definitive Radiation Alone For Esophagus Cancer

Radiation oncologists often complain that definitive radiation for esophageal cancer is limited only to the patients the surgeons do not want either because the tumors are too locally advanced or the patients are felt too frail to tolerate surgery. Whether this is true or not, what is true is radiation therapy alone is rarely curative in the treatment of esophageal cancer. In his review of radiotherapy in the management of squamous cell carcinoma of the esophagus, the British surgeon Earlam reported a 1-yr survival rate of 18 and a 5-yr survival of 6 after radiation (34). Interestingly, Earlam was a strong proponent of an MRC trial comparing surgery alone Radiotherapy alone has been used for early-stage eso-phageal cancer including patients medically unfit for surgery. Sykes reported on the use of radical radiation of 45-52.5 Gy in 15 or 16 fractions over 3 wk in 101 patients with tumors no longer than 5 cm. In this series of relatively favorable tumors, the median survival was 15 mo...

Accelerated Hyperfractionated Radiotherapy Alone For Esophagus Cancer

During a fractionated course of radiotherapy, surviving cancer cells can continue to divide. In fact, radiobiologists and clinicians have observed tumor clonogens actually begin dividing at an increased rate during the course of radiotherapy. This accelerated repopulation can occur around the fourth week of standard once-a-day fractionated radiotherapy (41). In an attempt to deal with this tumor regrowth, clinicians have attempted to shorten or accelerate the course of radiation. Decreasing total treatment time by using hyperfractionated (more than one treatment per day) radiation may improve results when using radiation alone for esophagus cancer (42). Institut Gustave Roussy has used this approach delivering 65 Gy over 4-5 wk (median treatment duration 32 d) for 88 patients ineligible for surgery. Of these patients, 64 did receive neoadjuvant chemotherapy before radiation. Three-year Fig. 6. Long-term survival benefit of chemoradiation over radiation alone for esophagus cancer...

Palliative Therapy For Esophagus Cancer Surgery And Radiation

Recognizing that all esophagus cancer patients are not good candidates for curative therapy, surgery still has a long-established history for providing effective palliation of dysphagia with either bypass surgery or esophagectomy. Mannel performed bypass surgery on 124 patients with unresectable esophagus cancer (57). Peri-operative mortality was 11 and was increased in patients undergoing colonic bypass and patients with large tumor load. Of those surviving surgery, 89 could eat a normal, unrestricted diet on discharge and 82 of survivors had complete and durable dysphagia relief. The most common complication was sepsis due to anastomotic leakage in the neck. Median survival after surgery was only 5 mo. Segalin et al. (58) reviewed their experience of surgery for palliation of advanced esophageal cancer. Resection was performed in 156 patients. Successful palliation was achieved in 78 41 were able to eat an unrestricted diet (scored as excellent) and 37 were able to eat a normal diet...

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...

Chemotherapy For Esophageal Cancer

The use of chemotherapy combined with surgery and or radiation for locoregional disease has been discussed. Still, as many as 50 of patients with esophagus cancer will present with metastatic disease. Further, most patients treated with curative intent will ultimately develop locoregionally recurrent or metastatic disease. Most single agents of chemotherapy have response rates of 15-25 against esophagus cancer (Table 3) (65). The use of chemotherapy in this population is palliative with most patients receiving therapy living less than 1 yr. Any hoped for benefit from therapy, therefore, must be weighed against the potential morbidity of side effects in these patients with limited life spans. Certainly patients with good performance status and limited weight loss are the best candidates for further therapy. Combination chemotherapy generally has higher response rates but may have greater toxicity. In a randomized phase II trial, the combination of cisplatin plus continuous infusion...

Do ovarian and breast cancer belong to the tumour spectrum of HNPCC

Watson and Lynch (1993) evaluated the frequency of cancer in 1300 high-risk members of 23 extended kindreds with HNPCC. They reported 13 cases of ovarian cancers (mean age at diagnosis 40 years) in these families, while 3.6 were expected on the basis of the general population incidence (observed expected ratio 3.5, P < 0.001 ). Vasen compared the risk of developing ovarian cancer between carriers of an MLH1 mutation (n 124) and carriers of an MSH2 mutation (n 86) (Vasen et al., 1996). He reported relative risksof 6.35 (95 CI 0.89-45.1) and 7.97 (95 CI 1.1-56.6) for MLH1 and MSH2 mutation carriers, respectively. Aarnio assessed the incidence of cancer in a large series of mutation carriers (predominantly MLH1 mutations) (n 360 183 women, 177 men) known at the Finnish HNPCC registry (Aarnio et al., 1999). He reported a standardized incidence ratio (SIR) for ovarian cancer of 13 (95 CI 5.3-25) and a cumulative ovarian cancer incidence of 12 by age 70 years. In conclusion, several...

Er Expression During Breast Cancer Evolution

An elegant case-control study (42,43) has examined ER and progesterone receptor (PR) expression in patients with invasive BC, compared to benign breast disease controls. Those authors found that elevated ER expression in benign epithelium was a significant risk factor for BC development, and also suggest that overexpression of ER in TDLUs augments normal estrogen sensitivity. Since prolonged estrogen exposure is an important risk factor for BC, abnormal ER expression in the benign epithelium may contribute to and increase the risk of progression to cancer.

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...

Comparative Genomic Hybridization In Cancer Cytogenetics

Genetic alterations associated with neoplasia have been well defined in hematological malignancies by both classical and molecular cytogenetics.1-5'6-1 In contrast, there is significantly less information known about the cytogenetics and molecular cytogenetics of solid tumors. This is because of technical difficulties in the production of metaphase spreads from these tumor cells. Karyotype analysis requires viable, proliferating cells that can be arrested in the metaphase stage of the cell cycle. Cytogenetic analysis of these tumors is often hampered as many solid tumor cells fail to proliferate in vitro. For those tumors that do divide and produce metaphase spreads, the quality of the metaphase spreads is often inadequate to allow for recognition of banding patterns. There is also the question of the significance of the cytogenetic data derived from in vitro tumor cell culture as small subclones in vivo may take advantage of the in vitro conditions and thus the nonproliferating cells...

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...

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...

Methylationassociated Silencing In Cancer Progression Involves Abnormal Histone Modifications

It has been widely proposed that the hypermethylated CpG islands will attract methyl-DNA binding activities that will later recruit corepressor complexes that modify the structure of the chromatin to produce a transcriptionally silenced state (18, 38). The presence of different changes in the acetylation, methylation and phosphorylation status of histone, the denominated histone code (39), is fundamental to the determination of the active or silenced status of any given gene. Regarding tumor progression, chromatin immunoprecipitation (ChIP) assays using two antibodies against anti-acetylH4 and anti-dimethylK4 H3 that have been related with transcriptional activation in the mouse skin carcinogenesis model show a drastic loss of acetyl-H4 and dimethylK4-H3 in hypermethylated CpG island promoters, whilst there is significant enrichment in the unmethylated CpG islands in both modifications (25). For instance, the MLH1 promoter that is unmethylated and actively transcribed in all cell...

Cancer Is a Genetic Disease

The role of somatic mutations in cancer was debated for many years. Witkowski (1990) puts that historical debate in context with a comprehensive time line of developments in cancer research interleaved with developments in basic genetics and molecular biology (see also Knudson 2001). Here, I mention a few of the highlights that provide background for evaluating theories of progression and incidence. Boveri (1914, 1929) often gets credit for the first comprehensive theory of somatic genetic changes in cancer progression (Wunderlich 2002). Tyzzer (1916) used the term somatic mutation to describe events in cancer progression. In the 1950s, Armitage and Doll (1954, 1957) cautiously described the stages of multistage progression as possibly resulting from somatic mutations but perhaps arising from other causes. Burdette (1955), in a comprehensive review of the role of genetic mutations in carcinogenesis, tended to oppose the central role of mutations in progression. In (1969), Fould's...

Pathology of breast cancers in mutation carriers

There are a number of published studies indicating that breast cancers arising in mutation carriers are of higher grade than sporadic cancers (Bignon et al., 1995 Jacquemier et al., 1995 Eisinger et al., 1996 Marcus et al., 1996). Eisenger et al. studied 27 BRCA1-associated breast cancers from 14 families and compared these to sporadic breast cancers, matching for grade. They found an excess of grade III carcinomas in the BRCA1-associated group. Marcus et al. reported the first large series of the pathology of BRCA1-related tumours. They had 90 BRCA1-related breast cancers assigned to the group on the basis of linkage to chromosomes 17q and or the presence of ovarian cancer and male breast cancer. The control set comprised 187 predominantly non-familial cases. They reported that BRCA1-associated tumours were more likely to be of medullary or atypical medullary type, to be of higher grade, to be aneuploid, and to have a higher tumour cell proliferation rate. When adjusted for age, the...

Molecular pathology of BRCAl2associated breast cancers

Since its discovery in 1960, oestrogen receptor (ER) has become an important prognostic and predictive marker for breast cancer (Osborne, 1998). ER expression is inversely correlated with tumour grade (Henderson and Patek, 1998) hence, BRCA-associated tumours, which are more often of a higher grade than those of sporadic breast cancer, would be predicted to be more often ER-negative. Many studies have shown low levels of ER expression in familial breast cancers (Johannsson et al., 1997 Osin et al., 1998a,b Robson et al., 1998 Armes et al., 1999). This is also true when ER expression in fiRCA-associated tumours is compared with a grade-matched control group (Osin et al., 1998a). In contrast, the expression of ER in BRCA2 tumours appears to be similar to that in sporadic breast cancer tumours (Osin et al., 1998a,b). The detection of ERs immunohis-tochemically does not necessarily reflect their functional competence, and a percentage of cancers expressing ER are known to be resistant to...

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).

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...

Grading and staging of familial ovarian cancers

The first report on BRCA1-associated ovarian carcinoma found that, overall, the tumours were of higher grade and higher stage than their historic age-matched controls (Rubin et al., 1996). However, grade I stage I tumours have been observed, suggesting that loss of differentiation occurs in parallel with spread of disease. These findings have been largely reproduced by a number of other groups (Aida et al., 1998). Werness et al. (2000a) and Boyd et al. (2000) also found fewer low-grade carcinomas in the mutation carriers. Zweemer et al. (1998) and Pharoah et al. (1999) found that a greater number of high-stage (III IV) cancers and fewer low-stage (I) cancers occurred in individuals with BRCA1 and BRCA2 germline mutations. Shaw et al. (1999) also studied a familial ovarian cancer group comprising BRCA1 and BRCA2 carriers and reported that they had a higher grade of cancer than their sporadic counterparts. However, Berchuck et al. (1998) found that, although the BRCA1 cases in their...

Carcinogenicity Mutagenicity Studies

The toxicity and carcinogenicity of sodium hypochlorite has been examined extensively. Both published and unpublished studies have repeatedly demonstrated this ingredient's safety, and failed to raise any significant questions regarding acute toxicity or carcinogenicity. A number of studies that examine sodium hypochlorite's carcinogenic and mutagenic potential have been investigated by both in vitro and in vivo methods. One of the most common worldwide uses of chlorine and chlorine containing compounds (including sodium hypochlorite) is as a disinfectant for drinking water. This use has led a number of investigators to examine the carcinogenicity of chlorinated water. Hasegawa et al. 30 examined the effects on rats of a 104-week administration of sodium hypochlorite in drinking water at levels of 0.05-0.2 . No significant increase in incidence of any tumors was observed, leading the investigators to conclude that sodium hypochlorite showed no carcinogenic potential. Kurokawa examined...

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).

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...

Folate Deficiency And Cancer

The biochemical manifestations of a folate deficiency can be seen in a decreased supply of S-adenosylmethionine and then in loss of methylation of CpG islands as well as a decrease in dTMP and a rise in the dUMP pool, which has been shown to result in misincorporation of deoxyuridine (du) into DNA. Recently, Ames and colleagues showed the significant extent of misincorporation of dU into DNA in folate-deficient patients (9) and, like others (10), speculated on the consequences. The protective effects of adequate folate, and of genetic polymorphisms altering the composition of the intracellular folate pool, with regard to the risk of colon cancer and perhaps other carcinomas has also been recently reviewed (11,12). Recent work by James and her colleagues have also shown that cells transformed in vitro are more tumorgenic in vivo (13).

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...

Cpg Island Hypermethylation And Lung Cancer Invasion And Metastasis

Abstract Invasion and metastasis are biological hallmarks of malignant tumors, and metastases are the major cause of cancer deaths. Invasion and destruction of BM is the earliest step in the multi-step process of metastases and it is the earliest morphological feature of invasive tumors. Disruption of organization or integrity of the basement membrane (BM) is a key histologic marker of the transition of a tumor from an in situ carcinoma to an invasive carcinoma. A fundamental and important question is what causes in situ cancers to become invasive even though cancer cells at the preinvasive and invasive stages are morphologically similar. One of the well-established mechanisms for invading and destroying BMs is by matrix metalloproteinases (MMPs), which are up regulated during invasion and metastasis. Developing molecular markers that mark the transition of in situ cancers to invasive cancer are very important because they may predict cancer for those who are at highest risk or those...

Gallbladder and Biliary Duct Biliary System Cancer

Gallbladder cancer and biliary duct cancer are relatively rare and account for fewer than 1 of all cancers. In 2005, over 3200 cases will be diagnosed and almost 2000 people will die of this cancer. Gallbladder cancer occurs five times more often in Native Americans than in whites and is more common in white females than in African American females. Most cancers of the gallbladder and biliary tract are inoperable at the time of diagnosis. If the cancer has been found incidentally at the time of a cholecystectomy, longer survival may be possible. More than 75 of gallbladder cancers are nonpapillary adenocarcinomas and approximately 6 are papillary adenocarcinomas a small number are squamous cell, adenosquamous cell, mucinous, or small cell carcinomas. Papillary cancers have a better prognosis and grow along the connective tissue and blood vessels they are not as likely to metastasize to the liver and lymph nodes. Adenocar-cinomas occur most frequently at the bifurcation in the common...

Molecular Genetics Of Colon Cancer

Colorectal cancer is a well-defined clinical model for studying the molecular events of tumor development and progression. There is a linear progression, during which the neoplasm develops from hyperplastic epithelium in aberrant crypt foci through adenoma to carcinoma and metastasis (28). This sequence reflects the accumulation of specific genetic alterations. It is thought that five to seven genes must be altered sequentially in order for cancer to develop (10). Two separate sequences of molecular pathogenesis have been postulated for colorectal cancer, based upon observations in families with inherited predisposition to colorectal cancer (Fig. 1). The first model is derived from observations initially made in patients with FAP. Family members with this condition (which accounts for 1-2 of colorectal cancer) inherit an inactivating mutation in the adenomatous polyposis coli (APC) gene. Inactivation of the second allele (occurring in about 1 of 106 colorectal epithelial stem cells)...

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...

And Epidemiology Of Prostate Cancer

The vast majority of malignant tumors of the prostate are epithelial and termed adenocarcinomas. The prostate normally has several types of epithelial cells. Basal cells are located between the luminal cells and the basement membrane and form a continuous layer in the non-neoplastic gland. This cell layer may also contain a stem cell compartment that differentiates into luminal cells. Neuroendocrine cells are androgen-independent cells dispersed throughout the basal layer and are believed to provide paracrine signals that support the growth and function of luminal cells. The luminal cells are androgen-dependent and produce prostatic secretory proteins. Prostate adenocarcinomas have features of both basal and luminal cells, raising controversy as to the cell of origin (4). A likely possibility is that most cancers are derived from the ill-defined stem cell compartment. The prostate develops through budding of epithelium from the urogenital sinus into the surrounding mesenchyme....

Cancer Causing Chemicals

References to cancer have been found in the annals of human disease since ancient times, but the disease's association with carcinogen exposure is a relatively new concept. Sir Percival Potts, a British physician who lived in the eighteenth century, was the first to suggest that the induction of cancer might be linked to agents in the environment. Potts had observed high rates of scrotal and nasal cancer among England's chimney sweeps, men who were exposed to accumulated fireplace soot during their work. After some careful studies, Potts suggested correctly that exposure to soot caused the high cancer rates, providing the impetus for identifying other carcinogens present in the environment. In retrospect, it was fortuitous that soot was acknowledged as one of the first carcinogenic agents. Soot is a complex mixture of chemicals that arises from the combustion of organic material. As scientists and physicians separated soot's individual components, it became clear that chemicals called...

Experimental Biology Of Prostate Cancer

Several excellent reviews of the molecular biology of prostate cancer are available, and only a few of the more common molecular alterations and their potential significance are highlighted here (4,12). The analysis of chromosomal alterations in cancer has identified many changes reflecting loss or gain of function of particular genes. Consistent allelic loss is expected to reflect the location of putative tumor suppressor genes. Loss of heterozygosity at chromosome arms 8p, 10q, 13q, and 17p are frequent events in prostate cancer, and losses at 6q, 7q, 16q, and 18q also occur. Gains of genetic material are expected to reflect the location of oncogenes. In prostate cancer, gains at 8q and 7 are fairly common. Individual genes at these loci have not been definitely assigned a role in prostate cancer, but several reasonable candidate genes have been proposed based on their location and functional properties. One of the more common events in early prostate cancer development is loss of...

Results Of Gene Expression Analysis Of Prostate Cancer

The subset of genes expressed in normal and neoplastic prostate tissue has been estimated based on theoretical and practical considerations. These studies are beginning to define the prostate cancer transcriptome and a possible role for some genes in critical processes. The Cancer Genome Anatomy Project (CGAP) of the National Cancer Institute was designed to identify genes responsible for cancer by sequencing of cDNA clones representing RNA from normal, precancerous, and malignant cells (http cgap.nci.nih.gov ). Currently, there are 17,040 genes identified in the 139,041 ESTs from prostate libraries listed in CGAP. These resources have been combined with independent data to identify 15,953 prostate-specific EST clusters in the prostate expression database (http www.pedb.org ) (37). This is believed to represent about 50-75 of the prostate transcriptome. An additional estimate, based on combining publicly available SAGE data, predicted 37,000 genes in the prostate transcriptome (38)....

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...

Identification of individuals with a genetic predisposition to cancer

The basic aims of genetic management for breast and ovarian cancer risks are To identify individuals who are at a significantly increased genetic risk of inherited cancer To provide advice and counselling to individuals about their risks of developing cancer To provide patients affected with cancer that is associated with a genetic predisposition with appropriate genetic counselling and management Given the growing awareness and demand for advice on familial aspects of cancer and the limited resources available to meet this demand, primary care and breast clinics should be provided with guidelines to resolve enquiries relating to inherited aspects of common cancers. The specialist services should be reserved for known familial forms of the more common cancers (only a minority of the total caseload), for other high-risk situations, and for cases where primary care professionals themselves consider specialist referrals to be desirable (Emery et al., 1999a). The main roles of primary...

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)...

Clinical Features In Hereditary Breast And Ovarian Cancer Syndrome

BRCA mutations occur in approximately 20 of families with inherited susceptibility to breast cancer. Personal and family characteristics associated with an increased likelihood that a BRCA mutation will be identified are listed in Table 3. Breast cancers in BRCA1 carriers often have medullary features, are more likely to be poorly differentiated with high mitotic rates and S-phase fraction, lack an in situ component, have low estrogen and progesterone receptors score, and node-positive. BRCA2 tumors are more histologically heterogeneous and more likely to be estrogen-receptor-positive. For BRCA1 carriers, breast cancer survival rates are similar to those for sporadic cancer patients when controlling for stage. The lifetime risk for second primary breast cancers in BRCA-mutation carriers with breast cancer is 40-60 , with 5-year risk estimates of 22-31 . The lifetime risk for male breast cancer in BRCA2-mu-tation carriers has been reported to be approximately 6.3 . 1 The average age of...

Genetic Testing And Counseling In Hereditary Breast And Ovarian Cancer Syndrome

Genetic testing for HBOC has become generally accepted as part of standard clinical practice and should be offered to any patient that has personal or family history features suggestive of HBOC (Table 3) and when genetic testing results could influence the medical management of that patient or the patient's family members. Clinical laboratories employ a variety of molecular techniques to detect germline mutations in BRCA1 and BRCA2 in a peripheral blood sample (Table 4). The sensitivity of molecular testing for BRCA cancer-predisposing mutations is Table 1 Syndromes associated with hereditary breast and or ovarian cancer Hereditary cancer syndrome ovarian cancer BRCA2 Hereditary diffuse gastric cancer Hereditary nonpolyposis colorectal cancer Breast, ovarian, colon, and prostate cancer Breast, ovarian, prostate, pancreatic, bile duct and gall bladder, stomach cancer, and malignant melanoma Soft-tissue sarcomas, breast cancer, brain tumors, acute leukemia, and other epithelial and...

Screening In Hereditary Breast And Ovarian Cancer Syndrome

Although overall population screening reduces breast cancer mortality by 25-40 in women between the ages of 50 and 70 years, no data are available on the outcomes of interventions to reduce risk in HBOC syndrome. No data are available to demonstrate that surveillance for ovarian cancer in high-risk women reduces mortality 3 because transvaginal ultrasound and CA-125 lack sensitivity and specificity. However, recommended screening in BRCA gene mutation carriers includes monthly breast self-examination starting at age 18, semiannual clinical breast examination and annual mammography starting at age 25, and starting at age 30-40, semiannual transvaginal ultrasound with color Doppler, serum CA-125, and pelvic examination. Several studies have shown that in women with germline BRCA1 and BRCA2 mutations, breast cancers are likely to occur as interval cancers 4 and that standard mammography is more likely to be negative than in women at low or moderate risk. 5 Recent data suggest that...

Chemoprevention In Hereditary Breast And Ovarian Cancer Syndrome

Women who desire risk reduction intervention for breast cancer have the option of chemoprevention with tamoxifen therapy (20 mg day for 5 years) or prophylactic surgery. The National Surgical Adjuvant Breast and Bowel Project prevention trial in healthy women 35 years and older with a 1.7 or greater cumulative 5-year risk for developing breast cancer demonstrated short-term reduction in risk of developing estrogen-receptor-positive breast cancer by 49 . The utility of tamoxifen for breast cancer risk reduction in women under the age of 35 years is unknown and current evidence-based data regarding tamoxifen breast cancer risk reduction in BRCA gene mutation carriers are insufficient. Women with BRCA1 mutations who develop breast cancer have estrogen-receptor-negative tumors in approximately 80 of cases, whereas women with BRCA2 mutations who develop breast cancer have estrogen-receptor-positive tumors in 80 of cases. Therefore, the use of tamoxifen for breast cancer prevention in...

Breast Cancer and Angiogenesis

In solid tumours, growth beyond a millimetre cannot occur without vascular support (Folkman 1996). Transgenic animal tumour model experiments have shown that progression from an in-situ to invasive cancer is accompanied by the onset of angiogenesis (Rak et al. 1995). There are a number of clinical examples where vascularization has been related to tumour progression (e.g., in the change from breast ductal carcinoma in-situ to invasive cancer (Gilles et al. 1995) Bose et al. 1996). Immunohistochemical techniques show changes consistent with this observation for example, expression of the endothelial cell-specific tyrosine kinase receptor, Tie-2 (TEK) is increased during the transition from benign to invasive breast cancer (Bernsen et al. 1998). The most potent pro-angiogenic factor in breast tumours is vascular endothelial growth factor (VEGF), initially termed vascular permeability factor due to its hyperpermeable effect on vessels (Senger et al. 1983). VEGF leads to endothelial cell...

Tumortargeted Anticancer Prodrugs And Their Biochemical Basis

One of the challenges in anticancer prodrug design is the identification of cancer-associated biochemical processes that can be utilized to release anticancer drugs from prodrugs. The obvious advantage of this approach is its high selectivity. Ideally, the cancer-associated biochemical processes do not or barely occur in normal cells. Two cancer-related features that have been extensively used for anticancer prodrug design are hypoxia and metastasis. Anticancer prodrugs based on the biochemical processes associated with hypoxia and metastasis have demonstrated high selectivity in killing cancer cells.3-5 In addition, enzymes with elevated activities in cancer cells, such as p-glucuronidase, prostate specific antigen, and cytochrome P450, have also been exploited for anticancer prodrug design. Further, the enzyme selected to activate an anticancer prodrug can be enhanced or delivered to tumor sites through gene expression gene-directed enzyme prodrug therapy (GDEPT) 6-8 or...

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.

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...

Cpg Island Hypermethylation Changes During Prostate Cancer Progression And Metastasis

The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Abstract Recent studies have implicated the dysregulation or maladaptation of epigenetic mechanisms to be a central feature of prostate carcinogenesis. Hypermethylation of CpG islands (CGI), clusters of CpG dinucleotides frequently found at gene regulatory regions, has been demonstrated to be one of the most frequent somatic genome alterations associated with prostate carcinogenesis. A few recent studies have explored the role of CGI hypermethylation during prostate cancer progression from the early precursor lesions to distant metastases. This chapter will focus on the time course of CGI hypermethylation changes that occur at each step during the development and progression of prostate cancer in an effort to understand how these epigenetic changes contribute to the formation of prostate cancer metastases. We will begin by giving an overview of the epidemiology, natural...

Human genetic polymorphisms that influence the propensity towards gastric cancer development

Although H. pylori strain-specific constituents clearly influence disease outcome, these factors are not absolute determinants of virulence. Most persons colonized with disease-associated H. pylori strains remain asymptomatic and H. pylori cag+ toxigenic strains are related to both duodenal ulcer disease and distal gastric cancer, two mutually exclusive disease outcomes (l90). The inability of bacterial virulence components to completely account for pathologic outcomes has highlighted the need to explore host factors that may influence diseases, particularly gastric cancer. The critical components that regulate the H. pylori-induced cascade to carcinogenesis are (1) the presence of the bacterium, (2) the concomitant inflammatory response, and (3) a reduction in acid secretion, because inflammation that involves the acid-secreting gastric corpus increases the risk of developing gastric adenocarcinoma by inducing hypochlorhydria and atrophic gastritis (l9l). A host effector molecule...

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...

Cancer genetics services

A survey of cancer genetics services, particularly in relation to breast cancer, in 34 European countries was undertaken as part of a BIOMED II Demonstration Project - 'Familial Breast Cancer, an Audit of a New Development in Medical Practice in European Countries' - and the results have been published in detail (Hodgson et al., 1999, 2000). There was considerable variation between the current status of such services in the different countries. The UK, the Netherlands, Belgium and the Scandinavian countries were the first to develop these, profiting from relatively high levels of gross national product and healthcare funding. However, much of the initial funding was provided by research charities. Other countries with active service development are France, Austria, Italy and Germany, but in these countries genetic counsellors are not yet accepted as having a role in service development. Israel, Poland and Ireland are also actively developing these services, including the acceptance of...

Application Of Dna Microarrays To The Study Of Bladder Cancer

The main advantage of DNA arrays is that they allow the study of the multiple tran-scriptional events that take place when normal urothelium is transformed into tumor tissue in single experiments. Expression profiling using cell lines has been used to gain an insight into the molecular events associated with the disease. An example of how the technology can be applied to the discovery of gene functions and pathways in bladder cancer is provided by the following study. Tumor cell growth inhibition mediated by genistein was induced in the susceptible bladder tumor line TCCSUP. Expression The following study provides an example of the functional classification of genes applied to bladder cancer, relating the expression patterns of p53-mediated apoptosis in resistant tumor cell lines vs sensitive tumor cell lines. The ECV-304 bladder carcinoma cell line was selected for resistance to p53 by repeated infections with a p53 recombinant adenovirus Ad5-cytomegalovirus (CMV)-p53. Its expression...

Using Human Bladder Cancer Specimens

There have been few reports dealing with molecular classification of bladder cancer expression profiling using DNA microarrays. The most extensive one has monitored the expression patterns of superficial and invasive tumor cell suspensions prepared from 36 normal and 29 bladder tumor biopsies using oligonucleotide microarrays containing 6500 genes. This study also analyzed pools of cells made from normal urothelium as well as pools of tumors of different stages such as pTa grade I and II and pT2 grade III and IV bladder cancer specimens (34). The pooling approach may smooth out individual differences, but on the other hand, it can dilute strong intensities of relevant genes that may differentiate specific groups with different prognosis. Single cell suspensions were prepared from cooled biopsies immediately after surgery following a procedure previously used for the preparation of bladder tumors for flow cytometry (45). Single-cell suspensions can be inspected under the microscope to...

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...

Other Applications Of Microarrays In Bladder Cancer Research

Oligonucleotide microarrays have also been used to analyze gene mutations in tumor samples for the presence of mutations in the TP53 tumor suppressor gene, which is a valuable predictor for bladder cancer outcome (34). The traditional manual dideoxy sequencing has been compared with the much faster microarray sequencing on a commercially available chip and the concordance between methods was 92 . DNA samples extracted from 140 human bladder tumors were subjected to a multiplex-PCR before loading onto the p53 GeneChip (Affymetrix, Santa Clara, CA, USA). Each of the 1464 gene chip positions corresponded to an analyzed nucleotide in the p53 gene sequence. If there is a heterozygous or homozygous mutation, the oligonucleotide probes will hybridize differently from the wild-type sequence and reveal a signal that detects this particular base change. It is possible to detect either a wild-type sequence or a mixture of wild-type and mutant alleles. The system is almost free from interference...

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...

Weibull Analysis of Carcinogen Dose Response Curves

Peto et al. (1991) provided the most comprehensive experiment and analysis of carcinogen dose-response curves. In their analysis, they compared the observed age-specific incidence of cancer (the response) over varying dosage levels. They described the incidence curves by fitting the data to the Weibull distribution. They also related the Weibull incidence pattern to the classic Druckrey formula for carcinogen dose-response relations. The Druckrey formula summarizes the many carcinogen experiments that give linear dose-response curves when plotting the median time to tumor onset versus dosage of the carcinogen on log-log scales (Druckrey 1967). I discussed the Druckrey equation, the data from Peto et al.'s study, and some experimental results from other carcinogen experiments in section 2.5. Here, I summarize the theory that ties the Weibull approximation for incidence curves to the Druckrey equation between carcinogens and tumor incidence. For carcinogen experiments, Druckrey and...

Microbial and host inflammatory genotypes and gastric cancer risk

An important question raised by these studies focused on immune response gene polymorphisms is whether H. pylori strain characteristics can further augment cancer risk exerted by host genotypes. To directly address this, Figueiredo et al. stratified H. pylori-infected subjects on the basis of both high-expression IL-1P polymorphisms and virulence genotype of their infecting H. pylori strains (202). Odds ratios for distal gastric cancer were greatest in those persons with high-risk host and bacterial genotypes, and in persons with high-expression IL-1P alleles that were colonized by H. pylori vacA s1-type strains, the relative risk for gastric cancer was 87-fold over baseline (202), indicating that interactions between specific host and microbial characteristics are biologically significant for the development of gastric cancer. On the basis of these case-control studies in human populations, it is apparent that H. pylori are able to send and receive signals from their hosts, allowing...

Association of HPVs with Human Cancers

Certain types of HPVs, such as type 16,18, 31 and 33, are associated with human anogenital cancers, and are referred as high-risk HPVs. These cancers include cervical cancers in women and penile cancers in men. The advent of Pap smears, which provide early detection of cervical cancer precursor lesions in women, has led to a significant decrease in deaths due to cervical cancer in countries where there is good access to health care. Nevertheless, cervical cancer remains a leading cause of death by cancer among women. More than 95 of cervical cancers are associated with infection by the sexually transmitted, high-risk anogenital PVs. HPV DNA can be detected in these cancers and cells derived from these cancers. The viral DNA is commonly found to be integrated into the cellular genome. The sites of integration appear relatively random with regard to the host genome, but specific with regard to the viral genome. Integration leads to the disruption of the 3' portion of the viral early...

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.

Carcinogen Dose Response

Lung cancer incidence increases with roughly the fourth or fifth power of the number of years (duration) of cigarette smoking but with only the first or second power of the number of cigarettes smoked per day (dosage). The stronger response to duration than dosage occurs in nearly all studies of carcinogens. Peto (1977) concluded The fact that the exponent of dose rate is so much lower than the exponent of time is one of the most important observations about the induction of carcinomas, and everyone should be familiar with it and slightly puzzled by it In this section, I first summarize the background concepts and two studies of duration and dosage. I then consider five different explanations. The most widely accepted explanation is that cancer progresses through several stages, causing incidence to rise with a high power of duration, but that a carcinogen usually affects only one or two of those stages in progression, causing incidence to rise with only the first or second power of...

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).

Current State Of Molecular Biology Of Pancreatic Cancer

A brief review of the current understanding of the genetic alterations associated with pancreatic cancer will help set the stage for a more detailed discussion of gene expression in pancreatic cancer. The last decade has seen a dramatic increase in our understanding of the molecular biology of pancreatic cancer, with pancreatic cancer now considered one of the better characterized neoplasms at the genetic level. Recent advances include the identification of the precursor lesions of invasive pancreatic carcinoma, known as pancreatic intraepithelial neoplasias (PanINs) (4-6). Just as there is a progression in the colorectum from normal epithelium, to adenoma, to infiltrating carcinoma, so too is there a genetic progression in the pancreas from normal duct epithelium, to PanINs, to invasive duct adenocarcinoma (7). This progression has been shown to be associated with the accumulation of multiple genetic alterations, including activating point mutations in the K-ras gene, telomere...

Cessation of Carcinogen Exposure

Lung cancer incidence of continuing smokers increases with approximately the fourth or fifth power of the duration of smoking (Doll and Peto 1978). By contrast, incidence among those who quit remains relatively flat after the age of cessation (Doll 1971 Peto 1977 Halpern et al. 1993). In 1977, Richard Peto (1977) stated that the approximately constant incidence rate after smoking ceases is one of the strongest, and hence most useful, observational restrictions on the formulation of multistage models for lung cancer. Peto argued that, in any model, the observed constancy in incidence after smoking has stopped suggests that smoking cannot possibly be acting on the final stage of cancer progression. There could, for example, be a particular gene or pathway that acts as a final barrier in progression and resists the carcinogenic effects of cigarette smoke. In 2001, Julian Peto (2001) reiterated Richard's argument The rapid increase in the lung cancer incidence rate among continuing...

Rus To Direct Therapy For Rectal Cancer

RUS is useful in planning a treatment approach once rectal cancer has been staged. In an earlier study by Faigel and Lee (2), of 29 patients with rectal adenocarcinoma who were initially suggested to undergo low anterior resection or abdominoperineal resection (APR), 9 (31 ) patients were able to undergo local excision once staged with EUS. This also impacted those patients who were originally to undergo neoadjuvant chemotherapy and radiation therapy. Of 29 patients, 6 initially planned to undergo chemo radiotherapy, an additional 3 patients (N 9 31 ) underwent preoperative chemo radiation after staging EUS. Similarly, Winde et al. (18) reviewed 50 patients with rectal adenocarcinoma, with EUS confirmed stage T1N0, who were randomized to operative treatment either with local surgical excision or low anterior resection. The 5-yr survival (96 ) and local recurrence rate (4.2 ) were equal in both surgical treatment arms. However, the number of hospital days was much less (5.7 vs 15.4 d,...

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

Should the management of familial ovarian cancer differ from that of sporadic ovarian cancer

The management of familial ovarian cancer (FOC) is currently essentially the same as for sporadic ovarian cancer, but is FOC biologically different from sporadic ovarian cancer and should we be managing it differently There is some conflicting evidence. Greggi examined eight families with two or more first-degree relatives affected with epithelial ovarian cancer (EOC) among a series of 138 consecutive ovarian cancer patients. No significant difference was detected in clinical and pathological features between sporadic and familial cases. Papillary serous adenocarcinoma was the predominant histological type. However, in three high-risk families, EOC tended to develop at a younger age compared with other familial cases and with sporadic cancers, and nulliparity was less frequent in the familial group (Greggi et al., 1990). Similarly, Bewtra identified 37 FOC patients from FOC syndrome kindreds with documented cancers of the ovary, breast, colon or endometrium in two or more first-degree...

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...

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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