Breast Cancer Survivors

Chemo Secrets From a Breast Cancer Survivor

Undergoing chemotherapy can be one of the most terrifying things that you go through in your life. One of the most frightening things about chemotherapy is the lack of real information that most people have about it, and the unknown makes it so much more frightening as a result. This eBook, written by a young cancer survivor gives you the real story about what chemo is all about. The most valuable information you can get about chemotherapy is from someone that has already experienced it. This PDF eBook allows you to download and read it as soon as your order it. You can begin your journey of reassurance as soon as you want! Because that's what this is about: chemo does not have to be a terrifying unknown! Other people have gone through it before, and want to help you through it as well! This eBook is the guide through chemo that many people wish they could have had, and now you can have it yourself! Read more here...

Chemo Secrets From a Breast Cancer Survivor Overview

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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 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 al., 1996 McPherson et...

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...

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 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 subsequent risk...

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...

Combination Chemotherapy

A basic limitation of cancer therapy is the resistance of tumors to cytotoxic drugs (I. C. Henderson et al. 1988). Combination chemotherapy developed as a way to overcome resistance. By the 1970s, it had been shown that metastatic breast cancer was moderately sensitive to single-agent chemotherapy (DeVita and Schein 1973). Several groups of cytotoxic agents were identified as active against metastatic breast cancer, including the alkylating agents (cyclophosphamide, thiotepa, L-phenylalanine mustard) the antimetabolites (5-fluorouracil, methotrexate) the vinca alkaloids (vincristine and vinblastine) and the antitumor antibiotics (doxorubicin, mitomycin, and others) (Hortobagyi 2000). Soon after, the superiority of combinations over single-agent drugs was demonstrated. The Cooper regimen, consisting of cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone (CMFVP) and its derivatives (CMF and CMFP), were generally accepted as active and well tolerated. The...

High Dose Chemotherapy

The appropriate dosage for cancer chemotherapy has long been debated within oncology. In 1980, Frei and Canellos argued that the importance of the dose of chemotherapy drugs was insufficiently appreciated. Chemotherapy drugs were so toxic that any suggestion that the dose-response curve was not steep or that lower doses were as effective as higher ones led oncologists to administer lower doses. They argued that the toxicity of antitumor agents was strongly dose related for both tumor and normal cells, and that the dose-response curve was steep for the majority of such agents. A few randomized studies had examined dose as a variable, and most had found a dose-response curve, especially for Hodgkin's disease, non-Hodgkin's lymphoma, oat (small) cell carcinoma of the lung, and acute lymphocytic leukemia (Frei and Canellos 1980). Few of the studies in these sensitive cancers had established proof of principle. Even so, higher doses for these sensitive tumors were at most twice that of...

Adjuvant Chemotherapy

Historically, primary treatment of breast cancer by surgery, or surgery with radiation, assumed that the cancer was physically confined to the breast. But, high recurrence after treatment led clinicians to believe that submicroscopic or occult cancers typically spread from the primary tumor to other areas of the body before diagnosis and primary treatment with surgery and radiotherapy (I. C. Henderson 1985, p. 140). Adjuvant therapy the use of cytotoxic drugs after primary therapy developed as oncologists sought to eradicate occult metastatic disease which otherwise would be fatal (National Institutes of Health NIH 1980, p. 2). Initially, the HDC ABMT procedure was applied to women with metastatic breast cancer. Soon after, it began to be used in the adjuvant setting with patients at high risk of recurrence who, at the time of primary treatment, were found to have cancer cells disseminated to their axillary lymph nodes. Advances in adjuvant chemotherapy were deemed sufficient to...

Concurrent Chemotherapy And Radiation

Radiation alone has been compared with radiation with concurrent cisplatin and 5-FU chemotherapy in an Intergroup study enrolling 129 patients with carcinoma of the thoracic esophagus (45). Eighty-eight percent had squamous histology, 12 had adenocarcinomas. The total radiation dose was 64 Gy for radiation alone and decreased to 50 Gy when delivered with concurrent chemotherapy. The chemotherapy consisted of cisplatin at 75 mg m2 on the first day with continuous infusion 5-FU at 1 gm m2 on days 1-4. Two cycles of chemotherapy were delivered with thoracic radiation during weeks 1 and 5. Two additional cycles were then delivered after radiation during weeks 8 and 11. Concurrent chemoradiation was morbid with 44 severe and 20 life-threatening side effects. Hematological side effects were the most common 33 severe, 13 life-threatening. Mucositis of the oral cavity, pharynx, and esophagus was severe in 26 , life-threatening in 13 .

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...

Benefit of adding chemotherapy to radiotherapy

The first randomized trial in medulloblastoma was conducted by the Southwest Oncology Study Group and is described under Study 9 in this chapter. In this study van Eys et al. evaluated the efficacy of the addition of vincristine (intravenous) and intrathecal hydrocortisone and methotrexate compared to radiation therapy alone. The doses of radiation given were 50 Gy to the primary site and 35 Gy whole brain and spine. Of the 34 children randomized, 8 of the 16 who received chemotherapy died, and 5 of the 18 who did not receive chemotherapy died, therefore showing no benefit to this chemotherapy. There were two toxic deaths and it was identified that the risk of administering intrathecal methotrexate in children with potential for meningeal disease has some risk of developing leukoencephalopa-thy. However, based on the randomized results of the study, there was no benefit to delivering the chemotherapy. Possibly, the toxic death and small number of patients obscured the small benefit of...

Trials to determine best chemotherapy regimen

Several studies have randomized to determine the better of two chemotherapy regimens for treatment of medulloblastoma. One early study (Study 6) was carried out by the POG and reported in 1984. This early study was conducted in the current patients and randomized between MOPP chemotherapy versus the same regimen without nitrogen mustard (OPP) in children with recurrent brain tumors. The main outcome measure was clinical response. This was actually a randomized response study, and not a two-phase trial, therefore the results are not as conclusive. The numbers are very small and demonstrated 4 out of 9 patients with medulloblastoma had complete or Based on these early studies, Study 5 in this chapter, reported by Seltzer et al. for the CCG was conducted between 1986 and 1992. This study compared chemotherapy with an 8-in-1 regimen to adjuvant vincristine, CCNU and prednisone in medulloblastoma. Patients up to age 21 years were eligible in high risk grouping and identified as M1-M4...

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

There is no agreement on whether breast cancer belongs to the tumour spectrum of HNPCC. Watson and Lynch (1993) reported 19 cases of breast cancer (mean age 51 years) in 23 HNPCC families (observed expected ratio 0.9, NS). Risinger performed molecular genetic studies in five cases of breast cancer from HNPCC families, one with an identified mutation in MLH1 (Risinger et al., 1996). In three out of the five tumours, widespread MSI was observed, and in the family with the known mutation, expression of only the mutant allele was observed in the breast cancer tissue. Aarnio reported a SIR for breast cancer in 183 mutation carriers of 1.4 (95 CI 0.4-3.7) (Aarnio et al., 1999). Boyd described a male member of a large HNPCC family affected by breast and colorectal cancer (Boyd et al., 1999). This patient was found to harbour a germline mutation of the MLH1 gene, and the breast tumour exhibited reduction to homozygosity for the MLH1 mutation and MSI. Recently, Scott et al. evaluated the...

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...

Neoadjuvant Chemotherapy

The rationale for preoperative neoadjuvant chemotherapy is based on treating an intact vascular tumor with no reason for treatment induced resistance for a better response rate de novo. There have always been arguments that responses are improved with the fibrotic remodeling of the tumor bed following surgical There have been extensive debates in the literature as to the utility of neoadjuvant chemotherapy in the treatment of any cancer. In locoregionally advanced rectal cancers, neo-adjuvant radiotherapy has been considered superior to surgery alone or followed by adjuvant radiotherapy in terms of risk of locoregioanl relapse (142,143). Neoadjuvant chemotherapy is also used in inflammatory breast cancer as well as osteo-sarcoma (144,145). There are several issues as to the use of neoadjuvant chemotherapy in gastric cancer. The decision for adjuvant treatment is often made based on the final pathological diagnosis and features postoperatively the decision to perform or not a...

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...

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.

Cpg Island Hypermethylation In Breast Cancer Progression And Metastasis

Abstract Breast cancer is the most common malignancy in women and comprises 18 of all female cancers. The incidence of breast cancer increases with age and in the western countries the disease is the single most common cause of death among women aged 40-50, accounting for about a fifth of all deaths in this age group. The advent of mammography screening has led to an increased detection of pre-invasive mammary lesions and a better elucidation of the pathological events that precede the development of invasive breast carcinoma. Invasive breast cancer is classified in two main morphological subtypes ductal carcinoma representing about 80 of breast malignancy, and lobular carcinoma that accounts for approximately 10 of breast cancers. Among pre-invasive breast lesions, the hyperplasia of the usual type (HUT) is morphologically and phenotypically heterogeneous, whereas atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) are homogenous in cell type and marker expression....

From the Normal Breast to Cancer the Concept of Breast Cancer Stem Cell

It is now well established that breast cancer originates from the TDLU, but it is not clear which are the cells targeted by tumorigenesis (6-10). A recent interesting hypothesis based on experimental evidence from tumor subpopulation transplantation and animal models suggests that mammary tumors may derive from adult breast stem cells (2, 11). The involvement of stem cells in carcinogenesis was suggested more than 30 years ago (10, 1214), but only recently the tools of stem cell biology were applied to the study of carcinogenesis (14). Adult stem cells are defined by their ability for self-renewal and differentiation into cell lineages present in the specific tissue. Self-renewal ensures propagation of the stem cell compartment, which sustains morphogenesis, tissue repair and maintenance, whereas differentiation generates the specialized cells that constitute each organ (7, 15-17) (Figure 1A). The adult mammary gland requires stem cells or stem cells like activity to fulfill the...

History Of Cancer Chemotherapy And Reflection Thereon

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

Promoter Hypermethylation Of Cancer Related Genes In Breast Cancer

Cancer is the result from a multistep process characterized by the accumulation of genetic and epigenetic hits leading to uncontrolled growth and ultimately to the acquisition of metastatic potential (Figure 1B). Three types of genes are involved in carcinogenesis oncogenes, tumor suppressor genes (TSGs) and stability (caretaker) genes. These cancer related genes are involved in a series of pathways that control the basic function of the cell proliferation, communication with neighboring cells and with extra cellular matrix, senescence and programmed cell death (apoptosis) (71, 72). It is now becoming clear that there are many fewer pathways than genes, and they cross talk to one another forming a complex network of intracellular signals (72). Gene silencing by CpG promoter hypermethylation can modulate these pathways by acting directly on tumor suppressor genes and stability genes and indirectly on oncogenes through their regulators (Table 1). The analysis of methylation profiles in...

Late Phase Ii Clinical Trial Of S1 In Breast Cancer

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

Chemotherapy treatment

The chemotherapy treatment schema is shown in Table 17.32. Following induction of remission chemotherapy, SR patients received oral 6 mercaptopurine (25 mg m2 day) and two doses of intravenous high dose methotrexate (2 g m2) while HR patients received nine cycles of chemotherapy as consolidation therapy. IR patients, who achieved complete clinical remission after induction of remission therapy, proceeded to phase 2 of the treatment schedule. During this phase of treatment, IR patients were randomized to receive or not prophylactic GCSF. The phase 2 block was count dependent and chemotherapy was withheld or delayed if either the neutrophil count (ANC) and or the platelet count were < 0.2 X 109 l and 50 X 109 l respectively.

Breast Cancer Resistance Protein Bcrp

BCRP is a new member of the ABC transporter superfamily initially cloned from a doxorubicin-resistant breast cancer cell line (MCF-7 AdrVp) selected with a combination of adriamycin and verapamil.229 Two other groups also independently identified this transporter from human placenta230 and human colon carcinoma cells (S1-M1-80),231 and named the protein ABCP (ABC transporter in placenta) and MXR (mitoxantrone resistance-associated protein), respectively. Molecular characterization revealed that BCRP consists of 655 amino acids with a molecular weight of 72.1 kDa. In contrast to P-glycoprotein and MRP1 or MRP2, which contain a typical core structure of 12 transmembrane domains and 2 ATP binding sites, BCRP only has 6 transmembrane domains and 1 ATP binding site (Figure 18.1), and therefore appears to be a half ABC transporter.230 BCRP is the second member of the ABCG subfamily, containing members such as drosophila white, brown, and scarlet genes, and thus, ABCG2 was recommended by the...

Antibiotics red cell transfusions and chemotherapy dose intensity

There were no significant differences in the average duration of fever, antibiotic usage or hospitalization between the two groups (Table 17.54). Patients randomized to receive GMCSF had a greater requirement for packed red cell transfusions (2 units versus 1 unit). Interval between chemotherapy cycles was similar and no differences in

Combined Locoregional And Systemic Chemotherapy

The rationale for combining locoregional and systemic chemotherapy in advanced col-orectal cancer with metastases to the liver only is based on the following issues 1. Locoregional chemotherapy has a well-defined activity in these patients and is possibly superior, as reported above, to systemic treatment (at least when traditional agents are administered intravenously). 2. Again in Germany, Safi et al. (18) included 45 cases in a small controlled clinical trial in which a combination of intraarterial FUDR (0.2 mg kg d x 14 d every 4 wk) and the same drug given intravenously (0.09 mg kg d in the same period) was evaluated in comparison with FUDR administered only intraarterially at the same dose as above. In this study a response rate of 48 was obtained with the combined strategy and the percentage of extrahepatic spread of cancer during therapy seemed of interest in comparison to that observed with locoregional treatment only (33 vs 61 , even though without statistical significance...

Systemic Chemotherapy

In order to understand the current literature in the neoadju-vant and adjuvant settings, a review of chemotherapy agents in the metastatic disease will be discussed. As with many cancers, gastric cancer was thought to be relatively insensitive to chemotherapy. Most agents used in gastric cancer did not induce a complete response, responses in general were poor, and time to progression was short. Table 1 shows a list of singleagent drugs with activity in gastric cancer.

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...

Chemotherapy

Prior to 1985 there was no definitive evidence that chemotherapy could be of benefit in medulloblastoma, other than for the treatment of recurrence. The subsequent evidence for activity is irrefutable, but the overall contribution of chemotherapy to cure of children with medulloblastoma remains relatively modest compared to the strides that were made before 1980 with application of improvements in radiotherapy and surgery. Documentation of the value of chemotherapy for recurrent medulloblastoma was accumulated over many years, from the outcome of small groups of patients with recurrent disease.

Breast cancer

In the scheme proposed for managing varying levels of genetic risk, guidelines might be aimed at the primary care team to ensure that the GP can be confident in reassuring low-risk women (de Bock et al., 1999 Evans and Eccles, 2000). In the hospital-based screening clinic, guidelines and a working knowledge of the relevant literature should allow both patient and clinician to feel confident that a more thorough review of the family tree can help inform a more detailed assessment of risk (The BASO Breast Specialty Group, 1998 Armes et al., 1999) and, if higher risk, in addition to screening, this information can result in onward referral to the genetics specialist. The genetics specialist will use additional information to ensure appropriate use of genetic testing (Couch et al., 1997 Eccles et al., 1998). This, in turn, will allow many of those who appear at first look to be at moderate risk to be reassured that, on closer scrutiny, they appear unlikely to have a significant component...

Data from Chemoprevention Trials Using Antiestrogens

The results from the three TAM chemoprevention trials were reported at interim analysis, and are shown in Table 1. The largest of the three trials, the NSABP P-1 Breast Cancer Prevention Trial, was stopped early, because results of an interim analysis showed a significant reduction in the incidence of BC in women taking TAM, compared to those who took placebo (116). In this trial, over 13,000 women at high risk of developing BC (e.g., women who had greater or equal to the risk of a 60-yr-old women as determined by the Gail model 120 ), were treated with either TAM or placebo for a planned period of 5 yr. At interim analysis, the women had received an average of 4 yr of study drug. The analysis at time of publication demonstrated a 49 reduction in the incidence of BC in the women who took TAM (see Table 1). These results were highly significant, and represent the most convincing evidence that antiestrogens suppress the development or clinical appearance of BC in women without a...

Tam As An Antitumor Agent

TAM is the endocrine agent of choice for the treatment of all stages of BC. However, two features of the drug have set it apart from other anticancer agents. First, adjuvant TAM is the only single agent that confers a survival advantage with a minimum of side effects. Second, women who have had one BC are at increased risk for a second BC in the opposite breast, but TAM is the only agent that has been shown to decrease the incidence of contralateral BC. The process of proving the efficacy of TAM has involved numerous randomized clinical trials, with different designs (plus minus chemotherapy) in different countries over the past twenty 20 yr. Fortunately, it is now easy to evaluate the impact of TAM as a BC therapy. All of the world's randomized clinical trials are periodically reviewed at Oxford, and the resulting reports provide clinicians with an overview analysis as a guide for the standards of patient care.

Proximal Colon Cancer

The hormone receptor status of the proximal colon tumors maybe relevant to our understanding of the tumorigenic process in the colon, as is the case for other hormone-driven cancers. To date, very few studies have examined the patterns of expression of the male or female steroid receptors and their isoforms along the gastrointestinal tract. Interestingly, ERp, which is also the main estrogen receptor expressed in the male urogenital tract, is the predominant estrogen receptor expressed in the colonic epithelium, and its levels of expression have been shown to be reduced in female colon cancers (Widschwendter et al. 2004). It has been proposed that activation by estrogens of this receptor may mediate antimitogenic signals as was observed in breast cancer cells (Cross et al. 2004).

Erbb2

These findings disagree with two other reports (21,24), in which ERBB2 promoter activity did appear to be suppressed by estrogens. It is likely, however, that this reflects differences in the experimental systems used. One study examined the rodent neu promoter activity in NIH-3T3 mouse fibroblasts and CV-1 monkey fibroblasts co-transfected with an ER expression plasmid (21). Because the neu promoter is not well conserved with its human counterpart, e.g., it lacks a TATA box, this may account for the discrepancy. The use of fibroblasts, rather than breast epithelial cells, is probably also significant. The second experimental system also employed the ERBB2 promoter and an ER-positive breast cancer cell line, but transcriptional repression by estrogens could only be shown when ER levels were raised further by co-transfection of an ER expression construct (24). Those authors have more recently (26) localized the estrogen-responsive sequence in their experiments to the binding site for...

Discussion

Consequently, more detailed analyses of clinical specimens, particularly of samples from patients before and after antiestrogen treatment, need to be performed. to determine if estrogens can really regulate EGFR and ERBB2 expression. This has become a pressing issue, given the publicity that has surrounded the administration of TAM prophylatically to women with a genetic predisposition to breast cancer. If these women are to be properly counseled about the relative risks of their genetic inheritance vs the possible side effects of the long-term use of this drug, then it is vital to determine the true in vivo effect of estrogens on the expression levels of these proto-oncogenes.

Conclusions

TAM has been extensively tested in clinical trials of adjuvant therapy for 20 yr. It is clear that TAM benefits the treatment of BC unlike anly other breast cancer agent, as demonstrated in the recent Overview Analysis (Table 3). The value of a long duration of treatment is most important for the premenopausal patient (Fig. 2). This latter finding is new, because the results for premenopausal women could not be ascertained with certainty in earlier overviews. The Oxford Overview Analysis has established the veracity of the laboratory concepts that TAM would be most effective in ER-positive disease, longer duration would be more beneficial, and TAM would prevent primary BC, in this case contralateral disease.

CDKN2A and ARF

The short arm of human chromosome 9, which is lost in many human malignancies, harbors the CDKN2A tumor-suppressor gene encoding two structurally and functionally unrelated tumor suppressors, the p16INK4A and the ARF protein, also referred to as p14ARF. The two alternative transcripts of the CDKN2A locus are initiated from separate promoters, and have distinct first exons, which splice into common downstream exons that are translated in alternative reading frames. Both of these proteins are involved in cell cycle regulation, and exert their effects on two of the most important tumor suppressors, RB1 and TP53. p16INK4A prevents the inactivation of RB1 by blocking the ability of cyclin D-dependent kinases to phosphorylate RB1. The ARF protein activates TP53 by binding to the MDM 2 protein, thus preventing the MDM 2-mediated degradation of TP53. Despite their shared genetic material and close proximity in the genome, these two isoforms are independently regulated, and may be...

Ovarian Cancer

Ovarian cancers can also occur in the context of hereditary cancer syndromes such as HNPCC (Watson and Lynch 1993) and in hereditary breast-ovarian cancer in women with BRCA1 and BRCA2 germ-line mutations (Claus et al. 1996). Silencing of MLH1 and BRCA1, respectively, by aberrant DNA methylation occurs in these syndromes as well as in a small number of sporadic ovarian cancers. Hypermethylation and silencing of the MLH1 gene occurs in 10 of sporadic ovarian cancers (Strathdee et al. 1999,2001), while approximately 17 of all ovarian cancers have methylation of the BRCA1 gene (Baldwin et al. 2000 Catteau et al. 1999 Esteller et al. 2000a, 2001a Rathi et al. 2002 Ibanez de Caceres et al. 2004 Strathdee et al. 2001 Wang et al. 2004). MLH1 hypermethylation is associated with MSI and resistance to chemotherapy (Strathdee et al. 1999). Concordant methylation of multiple genes has been also reported in ovarian cancers. However, it has been proposed that more than one CIMP phenomena may be...

CFTR Mutation Detection by Multiplex Heteroduplex mHET Analysis on MDE

Mutation detection in an integral part of disease diagnosis and patient study. For most Mendelian diseases, multiple mutations may be found in a single gene among a patient population. The type of mutations may vary from large deletions to single-base-pair (bp) substitutions, and different diseases may have different predominant types. For example, large deletions are often found in Duchenne muscular dystrophy (1) and truncation mutation is the predominant type in BRCA1-associated breast cancer (2). Therefore, different mutation detection strategies are required for different diseases.

Beverly A Teicher Series Editor

Oncogene-Directed Therapies, edited by Janusz Rak, 2003 Cell Cycle Inhibitors in Cancer Therapy Current Strategies, edited by Antonio Giordano and Kenneth J. Soprano, 2003 Chemoradiation in Cancer Therapy, edited by Hak Choy, 2003 Fluoropyrimidines in Cancer Therapy, edited by Youcef M. Rustum, 2003 Targets for Cancer Chemotherapy Transcription Factors and Other Nuclear and Nicholas P. Farrell, 2000 Apoptosis and Cancer Chemotherapy, edited by John A. Hickman

Viruses Associated with Inhibition or Suppression of Apoptosis

A lytic infection with Epstein-Barr virus (EBV) causes apoptosis. Expression of BHRF1, a homologue of bcl-2, early in infection prevents TNFa- and FAS-induced apoptotic pathways. This is a means to maximize viral particles. BHRF1 also enables infected epithelial cells to overcome apoptosis induced by y-irradiation and chemotherapeutics. It also provides an alternative mechanism of becoming multidrug resistant during chemotherapy. The latent membrane protein 1 (LMP1), an EBV oncogene, downregulates myc and upregulates bcl-2 and A20 expression, cellular anti-apoptotic genes. This prevents p53-mediated apoptosis and is part of the mechanism of B cell transformation by EBV. LMP1 may also contribute to the establishment of latency. EBV also encodes two polypeptides that interact with p53, EBNA-5 and BZLF1. EBNA-5 may also be able to stimulate cell cycle progression. BZLF1 binds to a region of p53 similar to that by Ad E40RF6 and suppresses p53 transcriptional transactivation. The specific...

Papillary and Follicular Thyroid 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, particularly those with ret-PTC activation (14,15). Likewise, thyroid cancers occurring in Cowden's disease (an autosomal dominant disease with mucocutaneous hamartomas and breast cancer) have a good prognosis (16,17). Another familial syndrome, Carney's complex (spotty skin pigmentation, myxomas, schwannomas, and multiple neoplasias affecting multiple glands) is also associated with thyroid cancer that has a good prognosis (18). Once recognized as familial, these thyroid cancers lend themselves to early diagnosis and treatment at an early stage.

Targets For Fluoropyrimidines

TS inhibition in primary human colon tumors and in liver metastases is retained for at least 48-72 h after a bolus injection of 500 mg m2 5-FU (52,68) in 19 patients responding to 5-FU hepatic artery infusion, TS inhibition was 2-3-fold higher and enzyme levels were 2-3-fold lower than in 21 patients not responding (Fig. 3A). Also in breast cancer patients binding of FdUMP and the effect of CH2-THF decreased during development of resistance (69). These results demonstrate that analysis of biochemical parameters in tumor biopsies obtained at both short and longer time periods after 5-FU administration gives valuable information about the in vivo mechanism of action of the drug in the tumors of patients.

Age of Cancer Incidence

The sixth section examines the different patterns of incidence between the two sexes. Males have slightly more cancers early in life. From approximately age 20 to 60, females have more cancers, mainly because breast cancer rises in incidence earlier than the other major adulthood cancers. After age 60, during the period of greatest cancer incidence, males have more cancers than females, male incidence rising to about twice female incidence. The excess of male cancers late in life occurs mainly because of sharp rises in male incidence for prostate, lung, and colon cancers. Male cancers accelerate more rapidly with age than do female cancers for lung, colon, bladder, melanoma, leukemia, and thyroid. Female cancers accelerate more rapidly for the pancreas, esophagus, and liver, but the results for those tissues are mixed among samples taken from different countries.

Research Methodologies

We relied greatly on the published scientific literature. Typically, we would conduct a Medline search for all citations to a particular clinician-investigator. From that list, which included abstracts, we selected papers pertaining to HDC ABMT for breast cancer and obtained and read the papers. Interviewees often identified important papers and interpreted their importance for us. In addition to the published literature, we obtained and reviewed many documents memoranda, letters, unpublished reports not easily categorized by Medline and that may not be readily accessible to the public. Such documents have sometimes been described as fugitive literature. We interpreted these in the context of when, where, and why they were generated, often relying on our interviewees for help in answering these questions. Cynthia Farquhar, with a research assistant, conducted the analyses of the Health Care Utilization Project database about the utilization of HDC ABMT during 1993-2001. The database...

Details of the study

Therapy for both arms was planned to last 51 days. Local control of the primary and metastatic disease was recommended at week 9. Surgery was used if feasible and radiation therapy was delivered to all sites of the metastatic disease. This was given concurrently with radiation to the primary site. Initial tumor volume received 45 gray with reduced two post-chemotherapy volume to deliver up to 55.8 gray. Radiation was given concurrently with chemotherapy.

Tumour Characterisation

The ability of DCE-MRI to quantify a range of characteristics of the tumour microvasculature has encouraged many investigators to use this technique as a basis for in-vivo staging of tumours. Correlation of DCE-MRI-based features of the tumour microv-asculature with pathology, therapeutic response and prognosis remains the main goal for future work with these techniques. Even early studies were able to demonstrate a clear relationship between rapid and large increases in signal enhancement and high grade malignant behaviour in a range of tumours. Several studies however have also shown significant overlapping of contrast enhancement patterns between benign and malignant tumours (Fig. 1.0). This has been described in breast cancer and fibroadenoma (Kvistad et al. 2000) and prostate cancer and benign prostatic hyperplasia (Barentsz et al. 1999) (Figs. 1.11, 1.12). It is hoped that increased specificity and accuracy in the identification of microvas-cular characterisation parameters will...

Founder effects involving BRCA1 and BRCA2

Specific BRCA1 2 mutations are highly prevalent in population subgroups, such as those identified among Jewish women of central European (Ashkenazi) origin. Approximately 10 of mutations in BRCA1 (Struewing et al., 1997 Bar-Sade et al., 1998 Fodor et al., 1998) found in cases of breast cancer are accounted for by 185delAG and 5382insC mutations. With the BRCA2 mutation, 6174delT, these three mutations together may account for a quarter of all cases of early-onset breast cancer and two-thirds of early-onset breast cancer in the setting of a family Observations suggest that the penetrance of 185delAG (that is, the likelihood that a person with the mutation will actually develop cancer) is significantly greater than the penetrance of 6174delT. This supports the possibility that some breast cancer gene mutations are associated with a higher risk than others, a finding that further complicates genetic counselling in this setting (Struewing et al., 1997). In Icelandic and Finnish...

Categories of Contrast Agents

Arguably the most clinically promising class of non-diffusible agent is the iron-oxide particle (Ultrasmall Particulate Iron Oxides, USPIOs) or monocrystalline iron oxide nanoparticle (MION). Examples include Clariscan (Amersham), Resovist (Schering), and Sinerem (Guerbet). In oncology these have been used in the evaluation of lymph node metastasis (Sigal et al. 2002 Stets et al. 2002) and in one study for estimation of microvascular permeability in breast cancer (Daldrup-Link et al. 2002). Lymph nodes and liver seem to enhance well with particulate iron oxides, which is likely to be due to the sequestering of these agents within cells of the reticuloendothelial system (RES), in macrophages and Kupffer cells, which are plentiful in these tissues. Although not rich in macrophages, brain tumor evaluation has been reported to be superior with the use of these large particles (Enochs et al. 1999).

Using Oligonucleotide Microarrays

One of the strong points of expression profiling is its potential for providing robust molecular signatures. As previously mentioned, the signature provided by multiple markers can sometimes weather sample variability and heterogeneity much better than that provided by a single marker. Indeed, there is hope that gene expression data will allow the detection of a small number of cells diluted in complex mixtures. Martin and colleagues, for example, recently identified a set of 12 genes that allowed high sensitivity detection of disseminated tumor cells in the blood of 77 of patients with invasive breast cancer (56).

Dynamic Contrast Enhanced MRI

Within the class of T2 methodologies, there are two variants T2-weighted and T2*-weighted. The T2*-weighted method is the most routinely used clinical approach to DCE-MRI, where it is most often used to assess cerebral perfusion and blood volume. It has also proven efficacious in clinical breast cancer scanning (Kuhl et al. 1997). Both techniques monitor the passage of a bolus through the microvascular environment however, the T2*-weighted method, being based on a gradient echo technique, is more sensitive to blood vessels with larger diameters. T2-weighting, based on spin echoes, gives sensitivity predominantly to smaller vessels (which arguably therefore provides a closer measure of perfusion at the functional level) and consequently produces a smaller signal change during bolus passage. The advantage of the T2-weighted approach is in assessment of tissues that are typically plagued by susceptibility artifacts due to gas (or bone)-tissue interfaces (e.g., frontal lobes of the brain,...

Current Techniques Used In Medical Genomics

Microarrays has identified gene expression changes associated with breast cancer stages. 2 However, micro-array use as clinical tool is limited by the number of manual steps involved, the time required, cost, and often by the variability between samples and between labora-tories. 3 Current clinical techniques frequently use ''home-brew'' assays and commercial instruments that require analyte-specific reagents (ASRs). In-house validation is essential and all laboratories are required to be CLIA (Clinical Laboratory Improvement Amendments) certified (http www.cms.hhs.gov clia). 4 Clinical laboratories currently identify single nucleotide polymorphisms (SNPs) and other diagnostic mutations using platforms that include allele-specific amplification, chemiluminescent forward dot blot assay, dot blot hybridization, gel-based restriction fragment length polymorphism (RFLP) analysis, oligonucleotide ligation, primer extension, multiplex PCR. Also in use are commercial kits such as mDx...

Validation Studies of Dynamic Contrast Enhanced MRI

There are cheaper and simpler microscopic imaging methods (e.g., light microscopy), other than the EDSX electron microscopy methods. Macromolecu-lar contrast agents containing Gd have been histo-chemically assessed using light microscopy (Saeed et al. 1998). Van Dijke et al. (2002) demonstrated via light microscopy post-in vitro streptavidin staining that even macromolecular contrast agents permeate out of the intravascular space over a period of 1 h in a breast cancer model. However, no current micro

Endoscopic Ultrasound

Because EUS is not capable of distinguishing inflammation from viable residual tumor, it is not accurate in determining which patients are free of disease (60-62). Zuccaro et al. (60) found that EUS correctly predicted a complete response to chemotherapy in only 3 of 17

Primary Nursing Diagnosis

Postoperatively, relieve pain with analgesics and ice packs as needed. Monitor the patient for fever or chills, sore throat, or red or draining wounds, and administer prophylactic antibiotics as prescribed. Treat the patient's reactions to postoperative chemotherapy or radiation therapy as prescribed, by administering antiemetics to control nausea and vomiting.

Dpd In Tumors And Resistance To 5fubased Therapy

DPD activity can be considered as a potential factor for controlling 5-FU responsiveness at the tumoral level. The concept is simple A high level of tumor DPD would metabolize 5-FU to inactive products before cytotoxic nucleotides can be formed. The potential role of DPD for influencing 5-FU activity also concerns new 5-FU prodrugs like UFT or capecitabine, where 5-FU is metabolically produced at the target site. Previous in vitro data revealed that DPD activity in tumor cells was significantly related to 5-FU sensitivity (31) the lower the DPD enzymatic activity, the greater the cytotoxicity. Interestingly, from this experimental study it was shown that DPD activity and thymidylate synthase activity were independent variables significantly correleted with 5-FU cytotoxic activity. Recent studies in human cancer xenografts demonstrated that the efficacy of capecitabine correlated very well with the ratio of thymidine phosphorylase DPD (32). The role of tumoral DPD activity was then...

Brain and Spinal Cord Cancers

The causes of most brain tumors are unknown, but ionizing radiation (high-energy radiation) is a known risk factor. Other possible risk factors include exposure to vinyl chloride, aspartame, and electromagnetic fields, as well as family history. Treatments for brain and spinal cord tumors include surgery to remove the tumor, surgery to place a shunt (a tube used to drain cerebrospinal fluid), radiation therapy, and chemotherapy (American Cancer Society, 2004).

Preclinical Toxicology Studies

An important exception to this occurs with cytotoxic drugs being developed for cancer chemotherapy. These drugs are designed to be toxic, albeit selectively, at the doses that will be used in humans. Doses chosen for Phase I studies are usually doses that were shown to have toxicity, but limited toxicity, in the animal studies. Unlike other drugs and biologic, where the Phase I studies use healthy volunteers, patients in Phase I studies for cytotoxic drugs are usually patients in the final stages of the cancer that will be treated.

The Physiological Roles Of The Bcl2 Family Proteins In Development And Homeostasis

Another key function of apoptosis for multicellular organisms is to maintain cellular homeostasis during adult life. The Bcl-2 family proteins are particularly important in this aspect. For example, many types of stem cells express Bcl-2 for long-term survival (109). Long-lived plasma cells and memory B cells also express a high level of Bcl-2 so that they will be available to counteract any future invasion of the organism (110). This ability of Bcl-2 to maintain cell survival over a long period may be dangerous if it is not under tight control indeed, the abnormal expression of this gene can lead to oncogenesis. A chromosomal translocation (14 18) that results in a deregulated expression of Bcl-2 may be responsible for the etiology of 85 of follicular lymphomas and 20 of diffuse B-cell lymphomas in humans (111). This finding leads to the definition of a new type of proto-oncogene, represented by bcl-2, which does not cause abnormal cellular proliferation but affects cell death (112)....

Characterizing Individual Tumor Biology

The first anti-angiogenic drug tested in our center was a human antibody directed against VEGF (Avastin, Genentech, South San Francisco, CA) (Pham et al. 1998). A significant (p< 0.01) suppression (> 75 ) of MRI-assayed microvascular hyperpermeability, expressed as the coefficient of permeability surface area product (Ktrans), was observed in a human breast cancer (MB-MDA-435) grown in athymic rats following a 1-week course of three 1-mg doses of human anti-VEGF antibody. With appropriate controls, the anti-VEGF antibody was shown to reduce tumor weight, growth rate (Fig. 3.6), and MRI-assayed permeability to the blood pool contrast agent (Fig. 3.7). Other contrast agents have been shown to be potentially useful for the definition of changes in tumor microvessels induced by anti-VEGF antibody treatment. For example, in a human breast cancer rodent model the intermediately sized molecule, gadomer-17, showed significant changes both in permeability (Ktrans) and in fractional blood...

The First Uncertain Steps

Following the discovery of antibiotics for treating bacterial infections, for several decades it was thought that 'safe' antiviral chemotherapy would be difficult if not impossible. The earliest antiviral compounds only emphasized the problems. Marboran was introduced in the early 1960s to treat smallpox and vaccinia its effectiveness was equivocal and its use short-lived. Amantadine and rimantadine were used to treat influenza with relatively little side effects but the influenza virus became resistant

Genotypephenotype associations

1998) for purposes of genotype-phenotype analyses (Marsh et al., 1998b). Of the 37 CS probands, 30 (81 ) were found to carry germline PTEN mutations (Marsh et al., 1998b). Among the 30 mutation-positive probands were two males with breast cancer. Approximately two out of three of all mutations were found in exons 5, 7 or 8. Although exon 5, which encodes the phosphatase core motif, represents 20 of the coding sequence, it harbours 40 of all PTEN mutations in CS. Association analyses revealed that CS families with germline PTEN mutations are more likely to develop malignant breast disease when compared with PTEN-mutation-negative families (Marsh et al., 1998b). Furthermore, non-truncating mutations and those within the phosphatase core motif and 5' region of it appeared to be associated with the involvement of five or more organs, a surrogate phenotype for severity of disease (Marsh et al., 1998b). Another group examined families for germline PTEN mutations and found mutations in only...

Commentary by Katherine Matthay

Neuroblastoma, the most common extra-cranial tumor of childhood, remains a challenge among pediatric tumors, despite the astonishing advances seen in the outcome for children with leukemia over the past 25 years. Fifty percent of children with neuroblastoma present with high risk disease at diagnosis, with 5-year survival below 40 , even with intensive multimodal therapy. In addition, late effects of treatment are particularly important in this tumor, where the peak age incidence is at 2 years. Thus, children with this tumor will be exposed to chemotherapy and radiotherapy at a critical period of growth and development, such that survivors will be very susceptible to late effects of treatment, such as orthopedic deformities, growth delay, cardiac and renal dysfunction, hearing loss and second malignancies. Rapid testing of promising therapies and of means to diminish acute and long-term side effects in a randomized fashion has been difficult, due to the relative rarity of this tumor,...

Dose intensification to overcome resistance to therapy

The demonstration that hematopoiesis could be restored with autologous stem cells allowed the use of much higher doses of chemotherapy with autologous bone marrow support for treatment of solid tumors. The further advance showing that bone marrow tumor cells could be diminished or eliminated using immunomag-netic purging gave credence to the use of autologous marrow support in neuroblastoma, a tumor which is metastatic to bone marrow in 80 of children with high risk stage 4 disease. Early pilot studies showed that responses were seen in resistant patients after high dose melphalan and bone marrow reinfusion, and many subsequent single arm studies in the United States and Europe verified an apparent improvement in outcome for purged or non-purged autologous bone marrow transplantation (ABMT) compared retrospectively to results for chemotherapy.1 Both cooperative pediatric groups in the United States - the Pediatric Oncology Group (POG) and the Children's Cancer Group (CCG) - attempted...

Important Classes of Antiviral Targets and Compounds

Nucleoside and nucleotide analogs play a pivotal role in antiviral chemotherapy. The ultimate target is the viral DNA RNA polymerase which is well conserved within different strains of a particular virus and sometimes within a virus family. For those nucleosides which are activated initially to their monophosphates by a viral enzyme, there is an additional potential for selectivity In general, the viral enzymes are less stringent in their structural requirements than the corresponding host (e.g., human) equivalents. Because the viral polymerase is crucial to the replication of that virus, there are few potential mutations which allow the polymerase to retain full function but reject the antiviral compound. This results in a relatively high genetic barrier (see below).

Overcoming drug resistance with agents using new mechanisms of action

Since the limit oftissue tolerance has been nearly reached with current cytotoxic agents, even with hematopoi-etic support new approaches are required to overcome drug resistance, either by targeting therapy specifically to the tumor or by discovering agents that are non-cross-resistant. The active cytotoxic agents added to the regular armamentarium of chemotherapy for neuroblastoma after 1985 have been the platinum compounds, ifosfamide and the inhibitors of topoiso-merase, the epipodophyllotoxins (topoisomerase II inhibitors) and most recently the camptothecins (topoisomerase I inhibitors).9,10 Yet only one randomized study has been done to test the activity of these agents against the previous standard induction chemotherapy of doxorubicin and cyclophosphamide (Study 4).11 The overall outcome for the two, randomized, continuation chemotherapy regimens in the Castleberry study has not yet been reported. An adjustment must be made to compare the response rate in the phase II window...

John M Walker Series Editor

Methods and Protocols, edited by Emmanuel S. Onaivi, 2006 122. Placenta Research Methods and Protocols Volume 2, edited by Michael J. Soares and Joan S. Hunt, 2006 121. Placenta Research Methods and Protocols Volume 1, edited by Michael J. Soares and Joan S. Hunt, 2006 120. Breast Cancer Research Protocols, edited by

Antiviral Combination Therapy

Virus latency remains an obstacle to successful antiviral chemotherapy for which no solution appears to be in sight. Members of the Herpesviridae are notable for being able to establish latent infections with HSV and VZV, latency is established in neuronal cells. During latent HSV-1 infection, the latency-associated transcript (LAT) of HSV-1 is the only known viral gene expressed. A micro-RNA (miR-LAT), which is generated from the exon 1 region of the LAT gene, reduces the induction of apoptosis and so contributes to the survival of that latently infected neuron. Few, if any, HSV proteins are expressed, so affording little chance for either the immune system or antiviral drugs to control the infection. Latency can be established despite ongoing antiviral chemotherapy although there is some evidence from animal models that famciclovir may be more effective than valaciclovir in reducing the load of latent virus when given very early during experimental infections. It still remains to be...

Minimal residual disease

A phase I study of children with high risk neurob-lastoma after bone marrow transplantation found that an intermittent schedule of high dose 13-cis-retinoic acid (using 13-cis-retinoic acid for 14 days consecutively out of every 28 days) had low toxicity and achieved levels known to be effective against neuroblastoma in vitro. The maximum tolerated dose was 160mg m2 daily, which achieved peak levels of 7 M. This schedule had minimal toxicity, achieved levels that were effective against neuroblastoma cell lines in vitro and resulted in the clearing of tumor cells in bone marrow, as determined by morphologic assessment, in 3 of 10 patients.22 Thus, the second part of the CCG-3891 study (Study 1) examined by prospective randomization, the effect of treatment with 13-cis-retinoic acid using the high dose intermittent schedule after maximal reduction of the tumor with the use of chemotherapy, radiotherapy and surgery, with or without transplantation. There was a significant improvement in...

Acute and late effects of therapy

Study 6 reports the results for the French Society of Paediatric Oncology of an induction chemotherapy protocol, which included a randomized study of two methods of cisplatin administration.26 The goal of this randomization was to determine whether changing cisplatin from a 1-hour daily infusion for 5 days to a continuous 5-day infusion of the same total dose would diminish renal or ototoxicity. A previous European pilot study had shown activity of the high dose cisplatin-etoposide regimen, but an associated high incidence of renal impairment, since 7 of 15 patients developed significant decreases in creatinine clearance.27 This is of concern both acutely during induction, then for later ability to tolerate myeloabla-tive chemotherapy, and long term, for development of late effects, including renal deficits or ototoxicity. Overall, renal toxicity was lower in both treatment arms than expected, with only 8 of patients in the continuous infusion arm and 18 in the bolus arm having a...

Questions for future studies

The most important questions to address continue to be in the categories above, but with the emphasis on control of both local and late metastatic recurrence. Since dose intensity is close to the limits of tolerance, the emphasis should be either on ways to deliver dose intensity without increasing toxicity, or on agents with new mechanisms of action and on eradication of minimal residual disease. Increased dose intensity in the setting of myeloablative therapy might be accomplished by comparing a repetitive myeloablative consolidation to a single course. Adding agents with new mechanisms of action include comparing standard therapy to therapy with the addition of new immune modulators or new combinations of retinoids or anti-angiogenic agents in combination with chemotherapy. Treatment of minimal residual disease post-myeloablative consolidation will be studied in a randomized fashion both in the ENSG and the COG studies testing the addition of anti-GD2 monoclonal antibody to...

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....

Dihydropyrimidine Dehydrogenase

Binations with other chemotherapeutic compounds have been developed because of its limited efficacy when used alone. More recently, prodrugs of 5-FU were invented that can be administered orally. In particular, for patients suffering from advanced colon or breast cancer, oral administration can significantly improve the quality of life. Cancer Chemotherapy Polymorphisms in DPD, TPMT, UGT1A1 DPD

Genetic Considerations

Breast cancer is a feature of several cancer syndromes including Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, Bloom syndrome, Werner syndrome, ataxia-telangiectasia, and xeroderma pigmentosum, but these account for less than 1 of all breast cancers. More familiar to most people are the nonsyndromic breast cancer susceptibility genes, which account for 5 to 10 of breast cancer cases. The two most widely known genes are BRCA1 and BRCA2, both tumor suppressor genes. Lifetime risk of becoming affected by breast cancer for mutation carriers has been estimated at between 60 and 88 . Breast cancer is considered a complex (multifactorial) disorder caused by both nongenetic and genetic factors. Several genes have been shown to contribute to susceptibility. These include the tumor suppressor gene CHEK2.

Thiopurine Smethyltransferase

Childhood acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and can be cured in most cases via chemotherapy. ALL is treated by a combination of various drugs however, 6-mercaptopu-rine (6-MP) is one of the drugs required to maintain remission. It is mandatory to adjust 6-MP dosage according to the toxicity of 6-MP, which is mainly caused by the accumulation of the active metabolite 6-thioguanine triphosphate (6-TGTP) via the metabolite 6-thioinosine-monophosphate (6-TIMP metabolic pathway shown in Fig. 2). 6-MP is an antimetabolite, which has to be activated to its triphosphate in order to be incorporated into DNA. On the other hand, 6-MP, but also 6-TIMP, can be inactivated by the enzyme TPMT to their inactive methylated metabolites 6-methylmecaptopurine (6-MMP) or 6-methylthioinosinemonophosphate (6-MTIMP). Thus decreased TPMT activity may lead to accumulation of the active 6-MP metabolite, and increased activity may lead to ineffective drug concentrations....

Gender Ethnicracial And Life Span Considerations

Breast cancer is predominantly a disease of women over 40, with incidence rates increasing with age. Annual incidence of breast cancer is less than 60 per 100,000 below age 40 100 per 100,000 by age 50 and nearly 200 per 100,000 at age 70. Only 1 of breast cancer affects men, and it usually occurs when they are over the age of 60. The case of the elderly with breast cancer is essentially the same as with younger patients. While white women have a higher frequency of breast cancer, African Americans are more likely to die from the disease this is attributed to late detection of the cancer and perhaps more aggressive tumors.

Somatic PTEN alterations in sporadic tumours

Sporadic counterpart tumours of CS are breast, thyroid and endometrial carcinomas. While a broad range of cancer cell lines harbour a high frequency of intragenic PTENmutations and homozygous PTENdeletions (Li et al., 1997 Teng et al., 1997), this does not hold for non-cultured neoplasias. While breast cancer can occur in up to 50 of females affected by CS, somatic intragenic PTEN mutations in non-cultured primary adenocarcinomas of the breast are very rare (Rhei et al., 1997 Singh et al., 1998 Feilotter et al., 1999). In one study of 54 unselected primary breast carcinomas, only one true somatic mutation was noted (Rhei et al., 1997). Even when selected for 10q23 hemizygous deletion, only 1 out of 14 samples had a somatic intragenic mutation (Bose et al., 1998). However, the 10q region has not previously shown prominent loss of heterozygosity in breast cancers. Yet, deletions in the region of PTEN occur in 30-40 of primary breast carcinomas (Bose et al., 1998 Singh et al., 1998...

Sage Uses In Human Genome Mining And Annotation

In breast cancer studies, epithelial populations from normal breast epithelium and ductal carcinoma in situ (DCIS) lesions were obtained and analyzed with SAGE. Various chemokine and cytokine genes, such as HIN1, leukemia inhibitory factor (LIF), interleukin (IL)-8, and growth-related oncogene (GRO), were observed to have a decreased expression in DCIS when compared with normal tissue. Several transcripts were also identified as specific for DCIS an example of this is psoriasin, an S100 binding protein (30). It was also reported that promoter methylation is the main mechanism by which expression of the gene HIN1 is silenced in many DCIS and invasive breast cancer lesions. This gene is a small cytokine with no homology to other genes, and it is likely to be involved in growth control (31). The p53 gene target 14-3-3 had also been shown previously by SAGE to exhibit lower expression in breast carcinoma cells in vitro due to hypermethylation when compared to normal epithelial cells (32)....

Stamp I Stamp Ii Stamp Iii Stamp Iv Stamp V

A The letter sequence in a combination regimen corresponds to the sequence in which the individual chemotherapy drugs are administered. disease, suggesting that the dose-response curve would be steeper in the adjuvant (or early-stage) setting than in the metastatic setting. This appeared to be true for the CMF regimen in breast cancer treatment, but results differed for pre- and postmenopausal women (Hortobagyi 2000, p. 588). Dose intensification received a powerful stimulus from several articles published in the mid-1980s. In 1984, Hryniuk and Bush lamented Combination chemotherapy has failed to cure advanced disease, patients who have received adjuvant chemotherapy continue to relapse, and chemotherapy has not dramatically increased survival in Stage IV disease. Manipulations of doses, schedules, and combinations do not seem to improve results. Combination chemotherapy of breast cancer appears to have reached an impasse (1984, p. 1281). Their review of metastatic breast cancer...

What Is Multistage Progression

I focus on how the dynamics of progression within individuals affects the age-onset patterns in populations. Biochemical changes that do not affect rates of progression can be ignored in dynamical analyses, even though they may be very important for understanding physiological changes and for analyzing which drugs succeed or fail in chemotherapy.

Individuals with chronic disease

Blood-borne cancers or those that are treated with chemotherapy or radiation are immuno-suppressive conditions that lead to susceptibility to opportunistic infections (Bow, 1998 Zinner, 2000). Neutropenia is the marker for infection risk and may be constant or periodic, depending on the duration and intensity of the cancer treatment regimen (Safdar and Armstrong, 2001). Again, the elderly are particularly vulnerable to the toxic effects of cancer treatment and the risk for infection is more pronounced (Repetto, 2003).

Bone Marrow Transplantation

Bone marrow transplantation is an offshoot of whole organ transplantation.2 Allogeneic BMT involves infusing marrow cells from an immunologically compatible donor to the patient being treated. It had been applied therapeutically mainly to hematologic disorders and was described as curative for severe immunodeficiency, aplastic anemia, thalassemia, and leukemia and lymphoma (Hansen et al. 1989). Autologous BMT involves extracting a patient's marrow, preserving it through a freezing process, treating the patient's cancer with HDC, and reinfusing the patient's marrow cells in the hope that the hematologic and immunological capability depleted by chemotherapy will be restored. The success of allogeneic transplantation in dealing with acute leukemia resistant to standard chemotherapy led investigators to use autologous transplantation against other cancers responsive to chemotherapy and radiation. Canellos (1985) compared the relative merits of allogeneic versus autologous BMT for treating...

Therapeutic Opportunities

Cancer is a disease that is extremely heterogeneous, in which many different tumor types can arise from virtually any tissue. Numerous proto-oncogenes have been identified, which, when mutated or aberrantly expressed, can contribute to the transformed phenotype. Despite the complexity of cancer genetics, there are fundamental characteristics shared by all cancers, regardless of tumor origin. The deregulation of most growth-promoting oncogenes triggers apoptosis in an otherwise normal cell (reviewed in ref. 92) (see Chapter 12). As a consequence, the suppression of apoptosis is a fundamental and requisite change in all cancer cells, regardless of origin (93). Apoptosis is also the primary means by which radio- and chemotherapy modalities kill cancer cells (reviewed in ref. 94). The discovery that the Bcl-2 oncogene functions as an inhibitor of apoptosis revolutionized cancer biologists' concepts of tumor initiation and progression, identifying apoptotic inhibition as a key event in...

Commentary by Ross Pinkerton

Hepatoblastoma (HBL) and malignant germ-cell tumors (MGCT) have a number of common features with regard to the questions that need to be addressed in their management. Both have subgroups in which the prognosis with current treatment strategies is good, namely localized HBL where complete resection is feasible after non-intensive chemotherapy, and MGCT arising in the testis or ovary, where cure rate is high even with lung metastases. For these subgroups it is appropriate to determine whether chemotherapy with fewer early and late sequelae can maintain high cure rates. In contrast, those with non-localized HBL or extra-gonadal MGCT require more intensive treatment to try and improve outcome.

Malignant germcell tumors

Randomized trials in adults with good-risk testicular teratoma have shown that cisplatin-based chemotherapy provides a small but significant relapse-free advantage. Some of these studies have again used a smaller dose of carboplatin than the UKCCSG. It would seem appropriate that the European and American groups consider a randomized trial to assess the role of carbo-platin as there is no doubt about the significant hearing loss seen with cisplatin, particularly in this very young age group. There is also the possibility that cisplatin exacerbates bleomycin lung toxicity. The SIOP group has recently reached a consensus of risk grouping in MGCT which could be applied in such a study. For the poorer-risk groups, such as those with extra-gonadal primaries and high aFP level, the addition of IVAd (ifosfamide, vincristine, doxorubicin) to PVB requires evaluation. High-dose chemotherapy with stem cell rescue has been introduced in relapse protocols following practice in adults. To date no...

Adjuvant Radiation Alone for Esophagus Cancer Pre Operative Radiation

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 statistical significance for the pre-operative radiation alone arm. Arnott reported the results of a meta-analysis evaluating pre-operative radiotherapy in esophagus cancer from the Oesophageal Cancer Collaborative Group (19). This analysis of five randomized trials included 1147 patients. With a median...

Postoperative Chemoradiation

There is little data on the use of combination chemotherapy together with radiation after resection of esophageal cancer. There exists the general perception that these patients are too frail after surgery to tolerate the morbidity of such aggressive adjuvant therapy. Noting that neither postoperative radiotherapy nor chemotherapy alone provide a survival benefit after curative esophagectomy for esophageal squamous cell carcinoma, Tachibana and colleagues devised a prospective randomized trial to compare postoperative chemotherapy with chemo-radiotherapy (32). Patients were randomized to receive cisplatin and 5-FU chemotherapy alone or together with 50 Gy to the mediastinum after surgery. The 5-yr survival rates were 50 after chemoradiation vs 38 after chemotherapy alone but this was not significant (p 0.97). Further, locoregional failure rate was not affected by mediastinal irradiation 18 vs 17 . The authors concluded postoperative radiotherapy administered concurrently with...

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

Concurrent Chemoradiation Radiation Dose Escalation

Seeking to improve outcome in the use of chemoradiation for esophagus cancer and recognizing the greater than 40 local failure rate seen with its prior chemoradiation regimen, the Radiation Therapy Oncology Group (RTOG) developed two studies evaluating the benefit of increasing local therapy by increasing the radiation dose. RTOG 9207 was a phase I II trial adding endoluminal brachytherapy to boost the site of the tumor in addition to the 50 Gy external beam dose used in the prior trial. Here, patients could receive boost with either HDR brachytherapy with three fractions of 5 Gy each or low-dose rate brachytherapy with a single boost fraction of 20 Gy. This study enrolled 49 patients (92 squamous, 6 adenocarcino-mas). With a median follow-up of 29 mo, 3-yr survival was 29 but toxicity was felt to be unacceptably high with 6 life-threatening strictures and 12 fistulas. The authors concluded with the following advice use caution in employing esophageal brachytherapy when used in...

Dynamic Contrast Enhanced Imaging

It has been shown that accurate characterisation of the AIF requires a temporal resolution in the order of a second (Henderson et al. 1998). Furthermore, following bolus injection of a typical clinical dose of contrast agent the T1 of the blood may decrease by more than an order of magnitude (Fritz-Hansen et al. 1996). Monitoring such large changes in relaxation rate requires an imaging sequence with a good dynamic range (Fig. 5.2). Competing directly with this requirement is the need to monitor much smaller changes in T1 at the level of the tissue. The location of the AIF, in relation to the tissue of interest, and the extent of that tissue dictates the requirements for spatial coverage. Finally, it is rare to identify a local feeding artery to provide an AIF but the closer the AIF is to the true tissue arterial supply the more accurate the subsequent modelling (Calamante et al. 2000). However, the spatial resolution of the images places a minimum diameter on the artery to be imaged....

Palliative Therapy For Esophagus Cancer Surgery And Radiation

Radiation alone or in combination with chemotherapy has also been used for palliation of advanced esophageal cancer. Rosenberg has described the use of palliative radiation to relieve both dysphagia and pain in up to 80 (59). Wara reviewed the University of California, San Francisco experience of radiation alone for 169 patients with squamous cell carcinoma of the esophagus (60). In this group of patients, 66 achieved significant relief of dysphagia for 2 mo or longer. Median length of survival was 7 mo. Similar palliative response rates were seen for tumors of the upper, middle, and lower esophagus. Coia evaluated swallowing function in 120 patients receiving concurrent chemoradiation (61). He found an improvement in dysphagia occurring by a median of 2 wk in 88 . There was no difference in dysphagia relief between patients with squamous cell or adenocarcinoma histologies. Patients with distal third tumors had both earlier and greater frequency of initial dysphagia relief than...

Transcriptional Regulation

In addition to cell-cycle-related events, chronic exposure of malignant cells to various anticancer agents can result in increased expression of TS that is controlled at the transcrip-tional level. Work by Scanlon et al. (48) demonstrated that selection of human ovarian cancer cells in cisplatin led to the development of cross-resistance to 5-FU. They found that cisplatin-resistant cells expressed 3- to 4-fold higher levels of TS when compared to wildtype parental cells. Moreover, the increased level of expression of TS was not associated with TS gene amplification but rather was the direct result of an increased transcriptional rate. A series of adriamycin-resistant human breast cancer MCF-7 and human colon cancer DLD-1 cells were established by Chu et al. (49) to investigate the process of multidrug resistance, and characterization of these cell lines revealed that they were cross-resistant to the fluoropyrimidines, 5-FU and FdUrd. Of note, these resistant cell lines had not...

Genetic Engineering and Society

A more immediate set of risks are the problems of confidentiality and discrimination associated with the newly developed capability to test for genetic predisposition to certain diseases. As mentioned previously, a gene has been discovered that predisposes women to breast cancer. Women who test positive for this gene can protect themselves by aggressive monitoring or by preemptive surgery. However, insurance companies may refuse to issue life or health insurance to women who possess this gene although not all will actually contract the disease. As a result, many women whose family history suggests that they might have the gene refuse to be tested.

Translational Regulation

Several groups have described rapid increases in TS enzyme levels in various in vitro, in vivo, and clinical experimental model systems following short-term exposure to the fluo-ropyrimidines (8,9,55,56). Although the underlying mechanism(s) for the enhanced expression of TS in response to 5-FU was not well characterized in these initial studies, several possibilities were proposed including increased transcription of TS-specific sequences, enhanced stability of TS mRNA, increased efficiency of TS mRNA translation, and enhanced stability of TS protein. Because this observation represented a potentially important mechanism for the rapid development of resistance to 5-FU chemotherapy in the clinical setting, significant research efforts have focused on elucidating the critical biochemical and molecular events that control the 5-FU-mediated acute induction of TS. Studies by Keyomarsi and Pardee (57) showed that treatment of human breast cancer MCF-7 cells with the folate-based...

Reduced dose of cranialspinal radiotherapy to improve longterm morbidity

The goal of most therapeutic trials in brain tumors is not only to cure the child, but also to provide a meaningful quality of life. This is of paramount concern. These concerns explain the continued study with the hope of providing therapy with reduced dose cranial spinal radiation. In fact, the recently completed study conducted by the Children's Oncology Group (COG) for average risk medulloblastoma included much more aggressive post-radiation chemotherapy given after 24 Gy to the cranial-spinal axis. This same issue was explored in Study 7 in this chapter, reported by Deutsche et al. for the combined CCG and POG. This study was conducted from 1986 to 1990 and randomized good risk patients between full and reduced dose cranial radiation. Unlike the European studies, stringent staging was a requirement for study entry. This staging included myelography, MRI, CSF cytology, bone marrow examination and bone scan. The good risk group was required to have posterior fossa tumors that were...

Important issues for future studies

Despite these randomized trials, several important questions concerning the best use of radiotherapy and chemotherapy for treatment of medulloblastoma still need to be explored. And, as is usually the case in clinical trial outcomes, the results have also led to more questions being asked than were answered by the trials themselves. These include 1 Does reducing the dose of cranial-spinal irradiation with chemotherapy provide adequate survival rates and improve neuropsychological outcome, neuroendocrine outcome, physical and physiological growth, overall quality of life and survival 2 Will a reduction in volume provided by conformal radiotherapy techniques (including proton radiation)13 be used to improve control of the tumor bed and simultaneously decrease the morbidity of normal tissue to decrease late hearing loss without jeopardizing tumor control to enable on increase in the use of radiosensitizing chemotherapy that will offer better tumor control without increasing hearing loss...

Recent data from the Dutch HNPCC registry

A total of 34 cases of breast cancer were identified in the 138 families - 7 in families associated with an MLH1 mutation and 12 in families with an MSH2 mutation. The mean age at diagnosis of breast cancer was 50.6 years (range 26-74 years). The distribution of the ages at diagnosis is depicted in Figure 5.2. The risk of developing breast cancer was equal to the risk in the general population in the Netherlands.

Posttranslational Regulation

Further evidence for posttranslational regulation of TS comes from the work of Key-omarsi and Pardee (11), who investigated the differential expression of TS protein and TS mRNA levels in human breast cancer MCF-7 cells in response to lovastatin treatment. Lovastatin synchronized the cells in the G1 phase of the cell cycle, and synchrony was followed for several cycles. During the first three cell cycles, the levels of TS protein were induced by up to 10-fold during the S phase and returned to baseline during the subsequent G1 phases. During the first G1 phase, the levels of TS mRNA were barely detectable. However, they increased markedly by 10-fold upon entry into the S-phase and remained at relatively high levels during the next few cycles. Thus, although TS protein expression varied with the cell cycle, TS mRNA expression remained at a constant level following the initial lag in the first G1 phase. Given the differential levels of expression of TS protein and TS mRNA, it was...

Vancomycinresistant E Faecium

The streptogramin, quinupristin dalfopristin is being used in multiple trials for treatment of gram-positive infections, including those caused by vancomycin-resistant E. faecium. Undoubtedly, this latter organism will prove a significant problem in immunocompromised patients. Two such cases of life-threatening infections in the setting of severe immunosuppression, one in a patient with chronic renal failure on peritoneal dialysis who developed vancomycin-resistant E. faecium peritonitis and the other in a severely neutropenic patient with lymphoma who was receiving chemotherapy were seen at the consulting service at Stanford.

Unsupervised Learning Clustering

Unsupervised learning approaches, such as clustering, can be very useful when the underlying structure of the data is unknown however, they have the disadvantage, if unguided, of sometimes producing results that may or may not be relevant to distinctions in the data that are biologically relevant. Clustering often rediscovers already known subclasses or differences if these distinctions are predominant (e.g., estrogen receptor positive vs negative breast cancers). However, this approach can also discover unanticipated relationships, and clustering methods have been used with relative success in a number of cancer classification problems. In practice, it is often challenging to interpret clusters that result from unsupervised learning in cancer datasets. A general methodology for clustering is shown in Fig. 2. Similar studies have recently been described for the subclassification of various tumor types including breast cancer (17,18), lung cancer (19), and melanoma (20).

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