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! More here...

Chemo Secrets From a Breast Cancer Survivor Overview


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MAGEA3 Marker Function in Breast Cancer Patients Sentinel Node Evaluation

There have been attempts to detect occult cancer cells by RT-PCR, with tyrosinase in malignant melanoma cases and with MAGE-A3 in breast cancer cases. In recent investigations by Wascher et al. (2001), 77 AJCC stage I-IIIa breast cancer cases were analyzed. The results of this study are summarized in Table 3.

Is Intraoperative SLN Staging Possible in Breast Cancer Cases

As long ago as in the 1970s, our group developed our system of intraoperative axillary node staging in breast cancer cases by staining frozen sections of the nodes and simultaneously investigating imprint cytologies taken from the cut surface of each node (Schauer 1977, 1981). The correspondence between histology and cytology results was 98 . This method was immediately adopted by numerous national and international cooperative groups. The disadvantage of this strategy (one aim of which is to avoid two sessions of surgery) was that for each case we needed one pathologist, one cyto-

Ehrlich and Chemotherapy

It was Paul Ehrlich who, in this context, most clearly grasped the historical opportunity and who most clearly defined a program for chemotherapy. Born in comfortable circumstances in Upper Silesia in 1854, Ehrlich followed his Gymnasium education with study of medicine at several universities, finally taking his medical degree at Leipzig in 1878. After nearly a decade of service as physician at the Charit Hospital in Berlin, and two years in Egypt recovering from a bout of tuberculosis, Ehrlich returned to Berlin and accepted a position at Koch's Institute. There he helped Emil von Behring develop effective therapeutic serums, especially the new diphtheria antitoxin.9 Serums, or antitoxins, were prepared by extracting the liquid part of the blood, or serum, from animals inoculated with a specific bacterium. This serum contained antibodies produced by the animal in response to the infection and could be used to treat humans infected with the same type of bacterium, a kind of therapy...

Chemotherapy resistance takes on many forms

Until recently, the mainstay of treatment for metastatic colorectal cancer has been fluorouracil-based therapy with no demonstrable survival benefit (10). The recent emergence of more effective poly-chemotherapy regimens for colon cancer has resulted from combining conventional 5-fluorouracil (5-FU)-based therapy with relatively new compounds that exert their effects through unrelated mechanisms of action. This improvement in treatment response is evidenced by the results from phase III clinical trials that combine 5-FU and leucovorin with the cytotoxic agents irinotecan (11,12) or oxaliplatin (13,14). These advances have correlated with improvements in survival of patients with metastatic colorectal cancer from less than 12 mo (15) up to between 17 and 22 mo (16). Further progress in improved treatment response has resulted by combining these poly-chemotherapy regimens with targeted therapeutics such as epidermal growth factor (EGF) inhibitors (cetuximab) or vascular endothelial...

Altered regulation of apoptosis provides potential mechanism for chemotherapy resistance

There are two principal modes of action by which chemotherapy agents affect the cell either direct blockage of a vital cellular process or induction of programmed cell death (apoptosis) (37). Recently, it has also been shown that some chemotherapy agents induce a permanent cell cycle arrest that resembles the replicative senescence seen in the aging of normal cells this represents a more cytostatic rather than tumoricidal approach (3840). It is not clear to what extent the three are, separately or together, responsible for the cytotoxicity effects of chemotherapy however, increasing data suggest that apoptosis is one of the principle tumoricidal mechanisms of response (41-44). It follows that interference with the apoptotic response to drug therapy provides a viable defense against the damaging effects of cancer therapies (45,46). As a result, over the past decade, increasing attention has focused on the development of new therapeutic targets that either singly or in conjunction with...

Role of Apoptosis in Chemotherapy Response and Resistance

Apoptosis plays an important role in the equilibrium of normal tissue homeostasis. This equilibrium is often disturbed in cancer cells through inactivation or inhibition of the apoptotic response pathways and an upregulation of mitotic activity. Suppression of apoptosis via a variety ofmechanisms represents a means by which cancer cells might be rescued from the killing effects of chemotherapy. In the process of apoptosis, the fate of cells is dependent on the intracellular response involving sensors and an extensive network of transmitters regulated by positive and negative factors. Central to this response is the role of a series of apoptotic executors called cysteine-aspartyl-specific proteases (caspases) (47). Two principle pathways are involved in apoptosis the extrinsic or death receptor-mediated pathway and the intrinsic or mitochondrial pathway (see Fig. 1). The extrinsic pathway functions via activation of membrane-linked death receptors and is initiated by the binding of...

Targeting transcription factors to enhance chemotherapy sensitivity

Highly attractive targets for drug design are the transcription factors, which are upreg-ulated in a large variety of human cancers. In addition, there are only a few transcription factors reported (compared to the number of oncogenes, for example) (69). The potential advantages of targeting a transcription factor in cancer cells are as follows (1) A variety of dysregulated signal transduction pathways might be effected by targeting a single transcription factor and (2) targeted therapy effective in one form of malignancy might be equally effective in many types of malignancy. There are three major groups of transcription factors the steroid receptors, the resident nuclear proteins, and the latent cytoplasmic factors (70). Exemplified in the steroid receptor group, one finds the estrogen receptors in breast cancer and the androgen receptors in prostate cancer. Drugs targeting

The Prospects of Chemotherapy

Looking back in 1955 at what he called the immense vogue for mercurachrome in the 1920s, British physician Lawrence P. Garrod marveled that so many people seriously believed the compound to be an efficient intravenous antiseptic. His own explanation, that the episode was a case of therapeutic fraud, is surely mistaken. The vogue for mercurachrome emerged from, and placed in sharp relief, several features of the medical world of the 1920s. It expressed the intense desire of researchers, physicians, and patients alike for some defense against the relentless suffering and death associated with bacterial infections. It expressed even more clearly an optimism, motivated in part by Ehrlich's program, in part by other successes of chemotherapy, and in part perhaps by the spectacular impact of insulin against a very different kind of disease, that such a thing as bacterial chemotherapy was even possible. And it expressed, or was made possible by, a lack of settled consensus on principles,...

The Nature of Chemotherapy

For Domagk and his chemist-collaborators Mietzsch and Klarer, the invention of Prontosil was a momentous event, marking a watershed in their careers as much as in the history of medicine. It is not surprising that all three subsequently wrote accounts of the investigations that resulted in Prontosil. Domagk and Miet-zsch, in particular, each wrote about their early collaboration, Domagk in several articles of the mid-1930s, and Mietzsch in a series of publications of the early 1950s. These articles are useful not only for reconstruction of the process that led to Prontosil, but still more for what they reveal about how each party, medical researcher and chemist, viewed the nature of chemotherapeutic research and for what these views, in some ways contrasting and contradictory, tell us about the nature of chemotherapy as an entity and its place in the system of industrial innovation that had emerged at I.G. Farben. disease, and the chemical agents used in treatment. The aim of the...

What is the mechanism for enhanced activity of chemotherapy in combination with avastin

The mechanism for the enhanced activity of chemotherapy with the addition of Avastin is not completely understood. There are several potential mechanisms by which an anti-angiogenic agent might enhance antitumor activity in combination with a standard chemotherapy for colorectal cancer. First, the activity of Avastin in killing endothelial cells could potentially impede the angiogenic repair of tumors after initial cytoreduction of tumor cells by chemotherapy and might kill poorly oxygenated tumor cells that are highly dependent on the vasculature. Second, antiangiogenic agents might mediate a pruning effect on tumor blood vessels that might allow for better penetration of chemotherapy (14). As a result, a decreased interstitial fluid pressure could enable better penetration of chemotherapy and allow higher intratumoral drug levels. Third, antiangiogenic therapy might syner-gize with chemotherapy in killing endothelial cells. Perhaps the choice of a cytotoxic agent that has...

Can Radiotherapy or Chemotherapy be at Least Partly Replaced by More Accurate Stagerelated Surgical Treatment

Because seminomas, in contrast to NSGCTs, spread preferentially by the lymphogenic route, this category would presumably be most suitable for primary lymphatic control. At the moment it seems that there is no need to establish a sentinel node concept, because radio- and chemotherapy programs seem to be optimal. The treatment protocols applied are roughly as follows therapy (28 Gy). Stage II a disease with limited retroperitoneal lymph node metastasis treatment by retroperitoneal radiotherapy, or alternatively systemic chemotherapy with carboplatin. Stage II b, III disease with bulky retroperitoneal lymph node involvement or distant metastases systemic chemotherapy including cisplatin and etoposide as the standard approach. After exclusively paraaortic radiation, even with follow-up periods in excess of 5 years, the incidence of pelvic lymph node relapses remained below 4 (Sedelmayer et al. 1999). However, radiotherapy, especially with the late vascular changes it causes through...

Expression and amplification oerbB2 in breast cancer

Amplification of erbB2 was studied extensively in breast and ovarian cancers and found to correlate with lymph node involvement and relapse-free survival, and also overall survival of patients (Slamon et al., 1987, 1989). This relationship has not been borne out by some subsequent studies, such as those by Ali et al (1988), Zhou et al. (1989) and Kury et al. (1990). The expression of the protein appears to be associated with tumour grade (McCann et al., 1991 Tervahauta et al, 1991). Studies using immunohistochemical methods show that erbB2 protein expression does not differentiate between invasive and in situ breast carcinomas (Moe et al, 1991 Porter et al, 1991). McCann et al (1991) detected no correlation between over-expression of erbB2 protein and lymph node status. But McCann et al. (1991) have themselves stated that over-expression of the oncoprotein was significantly related to shorter disease-free survival. Furthermore, over-expression of the protein in node-positive patients...

Chemotherapy and Endocrine Therapy Regimens

Classification according to risk factors for patients with node-negative breast cancer (modified according to Goldhirsch et al. 2003) Table 3. Adjuvant systemic treatment for patients with operable breast cancer (modified according to Goldhirsch et al. 2003) Table 3. Adjuvant systemic treatment for patients with operable breast cancer (modified according to Goldhirsch et al. 2003)

Pros and Contras of Tamoxifen for Breast Cancer Prevention

Comments on the International Breast Cancer Intervention Study (IBIS-1) report (Sept 14, p 187, 2002) criticize the underestimation of tamoxifen's benefit in breast cancer prevention and the lack of important explanations for tamoxifen-related mortality rates (Cykert 2003). In addition, Caine et al. (2003) recommend thrombosis prophylaxis and doubt whether patients at risk should receive ta-moxifen in the first place. In the authors' reply, Cu-zick for IBIS reflects on the overall reduction in breast cancer by one third (N.B. similar results in the IBIS group and in European trials), but emphasizes that there is a serious need for thrombosis prophylaxis.

Chemotherapy Regimens for Non SmallCell Lung Cancer

Surgery and radiotherapy remain the best treatment options for resectable non-small-cell lung cancer (NSCLC). The role of adjuvant chemotherapy in successfully resected NSCLC is still highly controversial. Whereas the largest trial (IALT, International Adjuvant Lung Cancer Trial) (see Tona-to 2002) showed a small but significant survival benefit for patients treated with cisplatin-based chemotherapy, the Italian trial (ALPI) (see Alexa-nian and Torri 2000) and the UK trial (Big Lung Trial) (see Evans 2004) did not show any significant differences. In patients with unresectable tumors combination chemotherapy is the cornerstone of treatment. Patients with a good performance status benefit more from the combination therapy than patients with a poor condition. New drugs have been evaluated (taxanes, gemcitabine, vinorelbine). Up to now there is no standard therapy regimen, but therapies should be platinum based. Tables 20-23 show combination chemotherapy regimens frequently used for the...

Cox2 inhibitors in combination with chemotherapy

Not only augment the antitumor efficacy of various chemotherapeutic drugs (40) but also improve their antimetastatic efficiency (157). A study by Trifan et. al. (158) showed that celecoxib enhanced antitumor efficacy of irinotecan while reducing diarrhea, a serious side effect of this drug. Thus, as in the case of radiotherapy, combining selective COX-2 inhibitors with chemotherapy has a high potential to increase therapeutic gain. Using human A431 tumor xenografts in mice, we recently reported that celecoxib enhanced the antitumor efficacy of docetaxel or radiation and that the greatest effect was achieved when all three agents were combined (Fig. 5) (159). Mechanistically, the improvement of antitumor efficacy of chemotherapeutic agents by COX-2 inhibitors is commonly attributed to the augmentation of apoptotic cell death. However, other mechanisms, the same or similar to those involved in augmentation of tumor response to radiation, are likely to be involved here as well. It is...

Criteria for Clinical and Histopathological Sentinel Node Evaluation Breast Cancer

Recurrence rates in cases with breast cancers in central or retroareolar locations and treated by mastectomy or lumpectomy are still under discussion. The authors concluded that lumpectomy is a reasonable treatment option for selected patients with central or retroareolar breast cancers. On the basis of these still preliminary results - which are based on a relatively small number of cases - it can be concluded that in selected cases with subareolar cancers regardless of the surgical option (mastectomy or lumpectomy) sentinel node labeling is a helpful strategy for further decision making. Recently, Macmillan et al. (2001) tried to test the relative benefits of the sentinel node concept and of the four node axillary sampling technique already tested 10 years ago by the Rotterdam group and now called 4 NAS, in breast cancer. This approach has already been abandoned throughout the world in view of the possibility of skip metastases or metastases bypassing these nodes. Macmillan's group...

Differential Diagnosis of Very Sharply Delineated Breast Cancers

These round nodes often correspond to specific subtypes of breast cancer but for diagnosis of a fibroadenoma large foci of sclerosing adenosis (with and without microcalcifications) must be delineated. Fig. 55. Bifocal breast cancer in the upper lateral quadrant of the left breast in a 48-year-old woman. Strong enhancement at the site of injection of the labeled contrast solution. 99mTc of one parasternal lymph node was visible after 30 min, and weak labeling of two additional nodes in the region of the upper part of the mammaria interna chain. In the later phase (1.5 h after injection of contrast solution) an infraclavicular node is also weakly labeled

Chemotherapy Agents

Cisplatin is currently the most widely used anticancer drug, and unfortunately, it is cochleotoxic. The toxicity of cisplatin is synergistic with that of gentamicin (Riggs et al., 1996), and high doses of cisplatin have been reported to cause total deafness. In animals, cisplatin ototoxicity is related to lipid peroxidation, and the use of antioxidant agents is protective (Rybak et al., 2000). Some chemotherapy medications also have central nervous system toxicity, which can be confused with vestibulotoxicity.

Breast Cancer

The international literature makes it clear that early experience was gained in the treatment of breast cancer and malignant melanoma, whereas experience of SLN diagnosis of other primaries is still limited. Three routes of contrast solution injection (subdermal, peritumoral, intratumoral) have been compared for SLN detection in breast cancer cases, and the intratumoral route, initially used and propagated by Giuliano et al. (1995), Kapteijn (1996), and Nieweg et al. 1997 has now been generally rul Fig. 2. Injection profiles differ for various cancers in different organs. For breast cancer the tracer fluid is usually given by the subcutaneous or peritumoral route injection, depending on the depth at which the tumor is located. Most of the tracer fluid should be injected in the suspected direction of flow to the sentinel node(s). This figure shows peri-tumoral labeling in a deeply located primary (four-spot Fig. 2. Injection profiles differ for various cancers in different organs. For...

Oncogenomics Handbook

Biomarkers in Breast Cancer Molecular Diagnostics for Predicting and Monitoring Therapeutic 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 Proteins, edited by Apoptosis and Cancer Chemotherapy, edited by John A. Hickman and Caroline Dive, 1999

The Sentinel Node Concept Related to Main Tumor Types and Subtypes Applicability in Daily Routine Work

Breast 177 Role of PET in Breast Cancer and Systemic Metastasis in Breast Cancer Patients 182 of Breast Cancer Localization of the SLNs in Multifocal and Multicentric Breast Cancer . 205 No Need for Discussion of SLN-Dependent Chemotherapy Strategies . . 298 Can Radiotherapy or Chemotherapy be at Least Partly Replaced Adjuvant Chemotherapy Regimens for Breast Cancer 504 Chemotherapy Regimens for Lung Cancer Chemotherapy Regimens for Gastric

Precipitating Factors

There are causes of infarction other than acute atherothrombotic coronary occlusion. Prolonged vasospasm can induce infarction, and spontaneous dissections are becoming more commonly appreciated, especially in pregnant females. Other conditions can also cause the death of cardiomyocytes and lead to a biochemical signal of myocyte damage, but should not be confused with myocardial infarction. These include (1) trauma that may precipitate myocardial contusion (2) toxic reactions to chemotherapy agents, such as Adriamycin, or myocardial depressant substances released with sepsis (3) heat-induced injury after cardioversion (4) increases in wall stress with impairment of subendocardial perfusion caused by severe hypo- or hypertension and or (5) injury caused by catechol-amine release in patients with acute neurological catastrophes. Pulmonary embolism is another common cause of biomarker increase.

Definition of the Sentinel Lymph Node and Basic Principles of Detection

This staging procedure has been developed for the following tumor categories breast cancer (already used in many clinics, but in others still in development) malignant melanomas (already well developed) lung tumors gastrointestinal tumors and head and neck tumors (discussion and preliminary approaches in progress). In addition, new approaches for tumors of the pelvis (cervix, penis, bladder, prostate, etc.) are also under discussion, as is node labeling of neuroendocrine tumors. Is investigation of the sentinel node really significant in avoidance, for instance, of extended axilla revision in breast cancer patients (levels I and II) in sentinel node-negative cases

Reference genomes provide anchors for biological information

A key aspect of research in genetics is associating sequence variations with heritable phenotypes (39). The most common variations are SNPs, which occur approximately once every 100-300 bases in the human genome. Comprehensive SNP maps (The Cold Spring Harbor SNP collection http dbSNP, http SNP ) can facilitate the cataloging and profiling of the unique sets of changes in different diseases. The availability of high-quality and high-density SNP maps has been enabled genome-scale correlations studies between SNPs and precancerous conditions (40,41), drug resistance in chemotherapy (42,43), cancer susceptibility (44,45), and drug response (46-49). This approach has the promise of significantly advancing our abilities to understand and treat cancer. A comprehensive review of the current SNP-related resources can be found at Human Genome Variation Database website

Chromosomal abnormalities in cancer

Chromosomal and DNA ploidy is an important parameter which has served as a marker of prognosis in breast cancer (Hedley et al., 1987 Clark et al., 1989 Ferno et al., 1992 Grant et al., 1992 Wenger et al., 1993), as well as in other forms of cancer such as pancreatic adenocarcinoma (Porschen et al., 1993), melanoma (Karlsson et al., 1993), endometrial cancer (Rosenberg et al., 1989), and gastric leiomyosarcoma (Suzuki and Sugihira, 1993). An image cytometric study carried out in the authors' laboratory on breast cancer aspirate cells has also revealed a highly significant relationship between ploidy and prognosis (see Table 2) (G. V. Sherbet et al., unpublished data). Nevertheless, it should be noted that a dissenting view has been expressed with regard to the significance of aneuploidy as a prognostic indicator (Lanigan et al., 1992 Lipponen et al., 1992). Aneuploidy may be a consequence of cells entering the S-phase of the cell cycle prematurely. This can be inferred from the close...

Oncogenes as anticancer drug targets

Cancer therapy directed at specific, frequently occurring molecular alterations in signaling pathways of cancer cells has been validated through the clinical development and regulatory approval in the recent years (6). An example of an approved therapeutic agent is Herceptin trastazumab, a humanized antibody directed against the product ofthe HER2 neu oncogene, which is amplified in approx 20 of advanced breast cancer and encodes a receptor tyrosine kinase. Another example is the small-molecule drug Gleevec imatinib, which inhibits the BCR-ABL tyrosine kinase and the c-kit tyrosine kinase receptor, and is currently used for treatment ofchronic myelogenous leukemia and gastro-intestinal cancer. It is anticipated that a wave of sophisticated smart drugs directed at activated or over-expressed oncogene products identified through genomic and proteomic techniques will fundamentally change the treatment of all cancers (6). Tumor suppressor genes obviously represent more difficult targets...

Techniques used for identification of oncogenic amplifications

Retroviruses had incorporated a number of cellular oncogenes. Several of these genes were shown to have undergone activating alterations in human cancer. Another approach was to directly identify and characterize genetic alterations in human cancer by using cytogenetic methods. This led to the discovery of oncogenic fusion proteins resulting from recurrent breakpoint fusions between different chromosomes. One famous example is the BCR-ABL fusion, which occurs in CML (chronic myeloid leukemia) as a result ofthe fusion ofthe chromosomal regions 9q34 to 22q11 (13). Other oncogenes were identified as components of cytogenetically detectable amplifications of genetic material in the form of double minutes and homogenously staining regions (HSRs) (14). The increase of gene dosage by DNA amplification is a common genetic mechanism for upregulating gene expression. DNA amplification has been detected in response to exposure to cytotoxic drugs (15-17) or during tumorigenesis (18). Therefore,...

What is the value of research

Baum (1986) explained that the surgeon who carries out mastectomy for early breast cancer for 10 years and then switches to lumpectomy for the next 10 years, because custom and practice have changed, is in fact conducting a research project involving 'haphazard allocation'. The surgeon's patients are not receiving the best known treatment, they are receiving the treatment that she thinks is best on the basis of unreliable data. Because the surgeon is acting solely in what she believes to be the best interests of her patients, and her intentions towards them are unmixed with the desire to gain knowledge which will not be of direct benefit to them, the ethics of her behaviour have not, in the past, been openly questioned. Whilst few would deny the need to demonstrate greater certainty than subjective observation allows, the attitude of the surgeon to the individual patients in the trial might nevertheless then be open to rebuke, because arguably she is not doing her best for each one,...

Validation of digital karyotyping results

Functions similar to known oncogenes (e.g., kinases, transcriptions factors) represent the most promising candidates for playing a causal role in the detected amplification event. Primer pairs neighboring these genes should be used to screen genomic DNAs isolated from tumors of a larger number of patients (> 50) in order to determine the frequency ofthe gene-amplification event in a particular type of cancer. This analysis will also define the smallest, amplified consensus region. Other types oftumor can be included in the analysis. Several of the classic oncogenes show moderate frequencies of amplification in a given tumor type for example, c-myc and HER2 neu are amplified in approx 20 of all breast cancer cases analyzed (19). For certain genes, an alternative to amplification can be activation by point mutation. Therefore, genes found to be amplified by Digital Karyotyping should be analyzed for point mutations in tumors showing no amplification. Interphase FISH using a...

Quantitative Measurements

Another source of inaccuracy is the distribution of FDG in different body compartments. Fat, for example, has a lower FDG uptake than other tissues. Therefore, FDG uptake in tumors will be overestimated in heavy patients. To correct for these effects the use of the lean body mass or the body surface area has been suggested (Zasadny et al. 1993 Kim et al. 1996). However, when these correction methods were applied in a study population of breast cancer patients no better results were obtained than with other SUV approaches to differentiating between benign and malignant breast tissue (Avril et al. 1997). As a result of the competition between the transport of endogenous glucose and FDG molecules into the cell, FDG uptake in tissue is sensitive to variations in blood glucose levels. In patients with lung cancer a markedly decreased FDG uptake (41.8 15 ) was found when plasma glucose levels were about double those recorded in fasting conditions (Langen et al. 1993). The lumped constant...

By Utilizing Both the EST Database and the Human Genome Sequence

In this approach, we identify EST clusters that are breast-specific or prostate cancer-specific, as described in the previous approach, and then align the assembled cluster sequence into the human genome using the Golden Path human genome browser (http We then analyze a region about 180 kb in size around the locus of the identified genomic sequences for genes predicted to encode membrane proteins using different gene-prediction programs. After the identification of the candidate genes, we experimentally validate the finding as described earlier and then isolate a full-length cDNA and obtain its sequence and that of the predicted protein. Two new members of the ABC transporter superfamily have been identified using this approach, one of which is a potential target for immuno-based therapy of breast cancer. Expressed sequence tag database analysis followed by genome analysis using a gene-prediction program as described earlier identified a specific breast cancer gene...

Identification of Genes Encoding Membrane Proteins by Generating a Membrane Associated Polyribosomal cDNA Library

Unlike for prostate cancer, the EST mining approach did not identify many breast cancer candidate genes. Taking advantage of the fact that there are many breast cancer cell lines that accurately reflect the properties of the parental cancer (which is not the case with prostate cancer), we decided to use breast cancer cell lines to search for new membrane-associated proteins. Our strategy was to isolate membrane-associated polysomal RNA from several phenotypically diverse breast cancer cell lines with different properties such as ER positive, ER negative, erbB2 positive, and erbB2 negative. This RNA, which is enriched in transcripts encoding membrane and secreted proteins, was then used to generate a large high-quality cDNA library with an average insert size of 2 kb. We call this library MAPcL (Membrane Associated Polyribosomal cDNA Library). Sequencing of900 clones confirmed that the library was greatly enriched for the desired mRNAs. The cDNA library was then subtracted with RNA...

Diagnosis of Lymph Node Metastases

PET offers particular advantages in evaluating lymph nodes. When CT is applied the size of the lymph nodes is a determining factor, although even lymph nodes that are normal in size can be tumor involved, just as lymph nodes can be non-specifically enlarged. In detection of breast cancer and melanoma and in the mediastinal staging of lung cancer, FDG-PET is clearly superior to conventional imaging modalities. In principle, PET permits the recognition of positive lymph nodes regardless of size, but has limited sensitivity in detecting microscopically small tumors. Spatial resolution is an important factor, as existing PET scanners do not have sufficiently high resolution to enable detection of micrometastases. The further development of PET scanners and new imaging processes should, however, improve the spatial resolution in the future.

Monitoring Effects of Therapy

The quantitative assessment of tumor metabolism by FDG-PET is a unique means of monitoring the response of malignant tissue to therapy. Various studies have shown that the reduction of tumor glucose metabolism precedes a reduction in tumor volume (for a recent overview see Weber et al. 2000). In addition, a reduction in FDG uptake may be quantified more easily than reduction of tumor size, which is conventionally assessed by measuring the maximum diameter of the tumor mass. Weber at al. (1999, 2000) have shown high repro-ducibility of the FDG signal, indicating that tumor glucose utilization rate is stable without therapeutic interventions. Monitoring the effects of therapy consists in predicting response to therapy by repetitive measurements of tumoral glucose metabolism and assessing response to therapy by measuring the metabolic activity of any residual masses. Various studies have shown that repetitive measurements of tumoral glucose metabolism early after the onset of therapy...

Systemimmanent Properties of PET to Support the Sentinel Node Concept

Finally, it must be pointed out that PET is superior to CT and MRI at least in some circumstances. Its advantages are described in the part of the book relating to the different cancer entities see Chapters 2l-27 for value of PET in staging cancers of the breast, thyroid, aerodigestive tract, lung, esophagus and gastrointestinal tract for evaluation specifically of breast cancer see work by Smith et al. (l998) and Crippa et al. (l998), which is cited with more detail in Chapter 2l . In addition, it must be emphasized that PET detects only cancer-infiltrated lymph nodes, which can be identical with the sentinel node(s), but in the case of breast cancer a positive PET excludes any possibility of avoiding complete axillary revision. Complete axillary revision (levels I and II) must be carried out without fail in all cases, and in some supplementary FNAC should also be performed for greater certainty.

Peripheral Structural Changes Resulting from Surgical Ablation

Current treatment protocols for tumors involving structures of the peripheral speech mechanism include surgery, radiotherapy, or chemotherapy, alone or in combination. The choice of modality usually depends on tumor location, disease stage, cell type, and other factors. Each treatment modality is associated with some additional morbidity that can significantly affect structure, function, cosmesis, and quality of life. Surgery carries a clear potential for anatomical and physiological changes that may directly alter speech and swallowing, while at the same time creating significant cosmetic deformities. Similarly, radiotherapy is commonly associated with a range of side effects. Radiation delivered to the head and neck affects both abnormal and normal tissues. Salivary glands may be damaged, with a resulting decrease in salivary flow leading to a dry mouth (xerostomia). This decrease in saliva may then challenge normal oral hygiene and health, which may result in dental caries...

Genetics And The Ethical Legal And Sociological Debate

The author starts by describing the well-known general objection towards the use of new technologies in modern medicine based on the fear of dehumanization of clinical practice. Fagot-Largeault then pinpoints several precise examples of the use of genetics in medicine, aiming at a thorough response to the general objection mentioned above. One of the many convincing examples she presents in the paper is that of the use of a genetic screen to rule out unnecessary chemical therapy in the treatment of certain kinds of breast cancer. She concludes that small signs like these give us a glimpse of how genetic technologies can be introduced into clinical practice, for the benefit of patients, and without leading to any major anthropological collapse.

Detection and Radiological Imaging

The problem of locoregional recurrences is also especially important when the patients are treated by breast-conserving surgery, because locoregional recurrences occur even in approximately 10 of cases where primaries are small (pT 1a-1c) and homogeneous radiation therapy has been delivered to the remaining breast. When all operable breast cancers are considered together, the locoregional recurrence rate increases to ranges of up to 35 (Rauschecker et al. 2001). node approach is one such theme, challenging medical doctors working in a broad field of cancer diagnosis and treatment its application is currently in the course of being extended from melanoma and breast cancer to head and neck cancers, gastrointestinal cancers, and both male and female urogenital cancers and now involves nearly all surgical disciplines. When in breast-conserving therapy protocols axillary revision with postoperative complications (bleeding infections, seroma formation, lymphede-ma etc.) can be largely...

The Pedigree Is A Costeffective Tool For Genetic Diagnosis And Risk Assessment

Linda's grandmother and two aunts died of breast cancer. Did the cancer occur in Linda's maternal or paternal grandmother Are the aunts the sisters of Linda's mother or Linda's father The exact relationship of these affected relatives to Linda, their ages at death, and if the breast cancer was unilateral or bilateral can make a critical difference in your clinical assessment of Linda's risk for developing breast cancer. Instead, using the associative icons of a pedigree, the relevant family and medical information can be recorded quickly and precisely, in an easily interpretable format. A family pedigree is a tool for

Microsatellite instability in cancer progression

Microsatellite instability has been encountered in several forms of human cancer, e.g. in colonic (Aaltonen et al., 1993 Ionov et al, 1993 Thibodeau et al., 1993 Patel et al., 1994), endometrial (Risinger etal, 1993 Burks etal., 1994), gastric (Han etal, 1993 Peltomaki etal., 1993 Seruca et al., 1995 Dossantos et al., 1996), pancreatic (Han et al., 1993), and oesophageal cancers (Meltzer et al., 1994). This abnormality was not found in cancers of the breast, lung or testis (Peltomaki et al, 1993), but recent reports do cite microsatellite instability in these tumours. MI may occur infrequently in sporadic and in familial breast cancer (Jonsson et al., 1995) and at a high frequency in invasive lobular breast carcinoma (Aldaz et al., 1995). Merlo et al. (1994) has stated that it occurs frequently in small cell lung carcinoma. Adachi et al. (1995) found no MI in small cell lung carcinoma, but did find MI in about one-third of non-small cell lung cancers. Instability of microsatellite...

Efforts at Optimization in mNanocolloid Mediated Sentinel Node Localization

Van Dongen's group (Gommans et al. 2001) tried to optimize 99mTc-nanocolloid sentinel node detection in breast cancer cases by improving the count rate by use of higher specific concentrations of 99mTc-colloidal albumin, with increased radiochemical labeling efficiency and stability. The particle size of colloidal albumin was tested by dynamic light scattering at angles of 30.2 , 62.6 , and 90 . For labeling under nitrogen a maximum acceptable concentration of 10 MBq p.g was found, which complies with the specifications of the manufacturer, when the labeling was carried out in vacuum vials 2.5-fold radiochemical labeling efficiency over the entire period was achieved, and a significant improvement (P < 0.002) was found in vivo.

Seeking Guidance

This is true for both minor conditions and serious illnesses. For example, a study on female breast cancer survivors revealed that women who participated in support groups lived longer and experienced better quality of life when compared with women who did not participate. In the support group, women learned coping skills and had the opportunity to share their feelings with other women in the same situation. There are a number of directories that list additional medical associations that you may find useful. While not all of these directories will provide different information, by consulting all of them, you will have nearly exhausted all sources for patient associations. Rehabilitation. Rehabilitation services help people adjust to the effects of cancer and its treatment. Physical rehabilitation focuses on recovery from the physical effects of surgery or the side effects associated with chemotherapy. occupational or vocational therapy helps people readjust...

Histo and Cytopathological Diagnosis

In breast cancer the diagnostic results obtained by radiodiagnosis (mammography, MRI) can be supplemented or complemented by the use of fine-needle aspiration cytology (FNAC) before SLN labeling takes place. Breast cancer Table 3. Analysis of breast cancer cases classified as stages I-IIIa (AJCC system Wascher et al. 2001) Table 3. Analysis of breast cancer cases classified as stages I-IIIa (AJCC system Wascher et al. 2001)

Retrospective Evaluation of the Significance of SLN Located Mediastinally or Along the Mammaria Interna by Radioimaging

Eubank et al. (2001) conducted a retrospective investigation into the question of mediastinal or internal mammary metastases in breast cancer patients, using FDG-PET and CT in 73 consecutive patients with recurrent or metastatic breast cancer. Both CT and FDG-PET were carried out within 30 days of each other. Suspicion of IM node involvement by locore-gional cancer spread seems to be an important point in implication of this node group in the radiotherapy field of treatment and or adjuvant chemotherapy treatment protocols.

Inclusion and Exclusion Criteria for Sentinel Node Investigation

These criteria are very important they have been intensively evaluated for breast cancer and also for malignant melanoma, but for many other cancers only rare certified results are available. In breast cancer cases, as a rule it makes sense to look for the SLN only when the diagnosis of the primary is secure according to mammography and or MRI or has been confirmed at least cyto-logically. This can be achieved by punch or aspiration biopsy, perhaps including evaluation of so-called prognostic factors such as ER and PR status, c-erbB2 overexpression, mutated p53 expression or vimentin expression (Domagala et al. l990). In breast cancer series with vimentin coexpression, Domogala et al. found an association with low or missing estrogen and or progesterone receptor expression and high proliferative activity measured with the antibody Ki-67 (l990a), a worse prognosis even in node-negative cases (l990b) and an association with a high degree of malignancy (l990 c). In cases with...

Pedigree Can Help Distinguish Genetic from Other Risk Factors

A pedigree can be just as useful in determining that a condition is not genetic as in establishing that a condition is inherited in a family. This is particularly true for common complex health conditions such as mental illness, heart disease, and cancer. For example, Jean is a 42-year-old premenopausal woman with unilateral breast cancer. Her mother is healthy at age 65 years, but Jean's maternal grandmother, Pamela, died of breast cancer at age 63. This limited family history may raise your initial suspicion for a familial breast cancer. Yet when you take an extended family history, you find that Jean's mother has three healthy sisters between the ages of 68 and 72 years. You also find that Pamela had two sisters who were cancer free in their mid-70s when they died of heart disease. This negative family history is just as important as the positive family history of cancer in risk assessment and determining cancer screening protocols.

Do You Wish To Know When And How You Will

FJ - I think that one can't generalize reactions vary from one individual to the next. I don't know if one can speak of rights here. In contrast, I believe that if one were to tell people at age 20, you will die on this day, at this time, that would make their life harder. AFL - Granted, but in real life things are less specific than this. One cannot predict death so precisely, but one can say to a woman, for instance, you are genetically predisposed to breast cancer. Is that harmful to her, would it ruin her life

Associations and Seizures and Epilepsy

This is true for both minor conditions and serious illnesses. For example, a study on female breast cancer survivors revealed that women who participated in support groups lived longer and experienced better quality of life when compared with women who did not participate. In the support group, women learned coping skills and had the opportunity to share their feelings with other women in the same situation.

Refractory Hyponatremia with Lung Cancer

Past history is significant for schizophrenia diagnosed 15 years ago and for oat cell carcinoma of the left lung diagnosed 3 years ago with the patient subsequently undergoing left pnuemonectomy followed by chemotherapy. One month prior to this admission, CT scan of the chest and abdomen revealed recurrent oat cell carcinoma of the left hemithorax that is currently being treated by radiotherapy. CT scan of the head at the time revealed no evidence of brain metastasis. Physical examination revealed a confused, agitated, and moderately obese white female. Vital signs temperature 36.7 C, respiratory rate 24, blood pressure 150 90 mm Hg, pulse 104 bpm. Slight ankle edema was noted, but the remainder of the physical examination was unremarkable. Relevant laboratory investigations at admission revealed the following

Pedigree Can Help Identify Medical Screening Needs for Healthy Individuals

Nancy. (Tay-Sachs disease is an autosomal recessive neurodegenerative disease leading to death usually by the age of 5 years. Approximately 1 in 30 Ashkenazi Jews carries this mutation as compared to 1 in 300 individuals of non-Ashkenazi heritage.) Serum cholesterol screening can be considered for someone with a strong family history of coronary artery disease. For a person with a significant family history of colon cancer, colonoscopy should be offered at a younger age than usual (Burke et al., 1997b). A young woman with a strong family history of breast cancer should have screening mammography (or possibly breast ultrasounds) at an earlier age than is usually recommended (Burke et al., 1997a).

Use of Liposomes for Radioimaging Within the Sentinel Node Concept

Localization of SLN in dependence on primary localization, organizational structure of individual lymphatic network, and tumor size. a Scenario I Localized in lower axillary node(s). This is the scenario encountered in 90 of cases of breast cancer in which metastasis develops. b Scenario II Localized in paraglandu-lar lateral lymph node(s). This is a rare localization of the sentinel node, being encountered together with other atypical localisations in approximately 8 of cases. c Scenario III Localized in the parasternal lymph node chain. This localization is encountered especially when the primary is located centrally or medially. Any of these localizations can be encountered, separately or in combination

Cancer Drug Targets Identification

Membrane proteins are common drug and antibody targets (86). The three postgen-omics mechanism-based cancer drugs and antibody, Gleevec, Herceptin, and Iressa, are all targeted against membrane proteins (87-89). These therapeutic successes have led to efforts to adopt cutting-edge technology such as mass-spectrometry-based proteomics to speed up the traditional one-molecule-at-a-time-based approach for cancer therapeutic targets discovery. The most recent achievement is potential therapeutic targets identification by a comprehensive proteomic analysis using the breast cancer cell membrane (90). In this study, tandem mass spectra were searched against a comprehensive database using the SEQUEST search program, resulting in the identification of tumor-cell-specific plasma-membrane-associated novel proteins. Among them are many highly abundant proteins such as her2 neu and rare unique proteins such as BCMP101, showing a wide dynamic range of breast cancer membrane proteins. Three unique...

Bottom mentality See bottom

Brain cancer Any primary cancerous tumor in the brain. Brain cancer is relatively rare. There are many different types of brain tumors, only some of which are cancerous. A malignant tumor can spread to other parts of the brain although a benign brain tumor does not spread, it can be equally devastating because the skull cannot expand to accommodate the mass growing inside. Some benign tumors become malignant. Two types of brain cancer affect HIV-infected people primary CENTRAL NERVOUS SYSTEM (CNS) LYMPHOMA and metastatic systemic lymphoma in the brain. Other brain cancers are extremely rare in HIV patients. The symptoms of a brain tumor can vary, depending on the part of the brain affected. The most frequent signs of a brain tumor are subtle changes in personality, memory, and intellectual performance that may not be noticed. A common symptom is a headache, not necessarily persistent or severe. Nausea and vomiting unrelated to food consumption occur in about a quarter of people with a...

Taking A Family History Is A Way To Establish Client Rapport And Facilitate Patient Decisionmaking

Your patients are more likely to comply with your medical advice if they trust you and have a relationship with you. The process of taking a medical-family history provides an excellent opportunity to establish rapport with a client. A clear picture of family dynamics and the patient's life experiences usually unfolds while taking a patient's medical-family history. These family relationships and life experiences will have an impact on a patient's decisions about medical care and genetic testing. Compare Amanda, a healthy 37-year-old pregnant woman who has experienced 10 years of infertility, with Beth, who is also 37 years old but has two healthy children. Both women have the same age-related risk to have a child with a chromosome anomaly, yet each woman may make different choices about genetic testing during her pregnancy. Or consider two 45-year-old women who each has a mother who died of breast cancer at age 38 years. Their genetic risk assessments (drawn from factual empiric risk...

P53 cancer progression and prognosis

Over-expression of p53 protein was reported in > 50 of breast cancers (Horak et al., 1991). Mutations of the gene are also common (25-40 incidence) in sporadic breast cancer, with the frequency of G-T transversions generally higher than expected, and these occur predominantly in the conserved exons 5-8. In many cases mutation of one allele is also accompanied by deletion of the second allele. In summary, p53 mutation characterises a highly aggressive form of the disease, associated with poor prognosis in both node-positive and node-negative patients (Lemoine, 1994). But, in contrast to colon cancer, these tend to be early events. It may be that the distinction lies in the fact that in tumorigenesis in the colon results from mutations in a series of genes, including the DCC gene, which produce a progressive alteration in the phenotype and p53 may have a complementary role (see page 172). Abnormalities of rb, another suppressor gene that actively regulates cell cycle progression, are...

Subcellular localisation of p53 protein

Be exclusively nuclear or cytoplasmic, or a mixture of both (Faille et al., 1994). Non-Hodgkin's lymphomas show virtually exclusive (90 out of 96 samples) nuclear staining (Pezzella et al., 1993a). Its localisation in breast cancer was described as predominantly cytoplasmic (Horak et al, 1991). Both the nucleus and the cytoplasm may be stained in melanomas (Weiss et al., 1993 Parker et al., 1994a). In the light of the interactions of p53 with cellular proteins (see page 31), it seems likely that the subcellular localisation patterns seen in tumours might be suggestive of the pathways by which wild-type and mutant proteins might be functioning. Moll et al. (1992) carried out sequence analysis of p53 cDNAs from breast cancers showing cytoplasmic staining and found wild-type alleles in six out of seven specimens. In contrast, where nuclear staining of p53 was encountered, missense and nonsense mutations were found. Furthermore, a sample of normal lactating breast tissue also showed...

The foundations of dutybased thinking

It was said earlier that the duty-based principle to be applied to research on humans is that of benefiting and not harming the research participants. Applying the principle involves subjecting research procedures to scrutiny against this yardstick. It is helpful, in doing this, to separate research into therapeutic and non-therapeutic types, because different levels of benefit and harm can be expected and justified in each. Therapeutic research is research which is conducted in the context of clinical care the participants in the research project are patients expecting to be treated for their illness as well as to help the researcher gain knowledge which can be generalized. In this context some harm to the research subject might be expected, but it would be experienced as a necessary part of the therapy, and would be outweighed in the individual research subject by the therapeutic benefits he may enjoy from the treatment, be it experimental or standard. For example, treatment for...

Sources Of Phytoestrogen And Estrogenic Effects

There are several in vitro test systems, including cell-proliferation assays and reporter gene assays, that are used to evaluate the estrogenic activity of natural compounds. The cell-proliferation assay, also called the 'E-screen,' measures the ability of a compound to stimulate the proliferation of human estrogen dependent breast cancer cell lines, such as MCF-7 and T47-D. The reporter gene assay is used to check the capability of a compound to activate the transcription of an estrogen-sensitive promoter. Application of these tests to phytoestrogens has clearly demonstrated that coumestrol is the most active of the phytoestrogens and binds as strongly as 17-p-estradiol to both ERs. Differences in estrogen-binding affinity have suggested that phytoestrogens, and in particular the isoflavones, are weakly estrogenic but induce distinct patterns of ER agonist or antagonist activities that are cell context- and promoter-dependent, suggesting that these compounds may induce...

Good Practice in Combined Use of Dye and mTclabeling Procedures

Depending on the localization of the primary, for instance in breast cancer cases (subcutaneous, centrally in the gland, prefascial), patent blue solution is injected subdermally or peritumorally in a volume of 0.2 ml in subdermal or 4 aliquots of 1,52 ml in deep pertumoral injections (quantities vary in the published literature, and different reasons are given for larger and smaller quantities).

Target identification

Some of the anticancer strategies are directed against proteases that facilitate several steps in cancer progression. The major proteases are matrix metalloproteases, cathepsins, and the mast cell serine proteases. Assay of actual enzyme activity, and not messenger RNA levels or immunoassay of protein, is ideal for identifying proteases most suitable for drug targeting. Proteases are particularly suitable for functional proteomic screening. This has been achieved by an automated microtiter plate assay format that was modified to allow for the detection of major classes of proteases in tissue samples (15). The results show that matrix metalloproteases are localized to the tumor cells themselves, whereas cathepsin B is predominantly expressed by macrophages at the leading edge of invading tumors. Such an analysis serves to identify proteases whose activity is not completely balanced by endogenous inhibitors and that might be essential for tumor progression. These proteases are logical...

SLN Investigation by Pathologists in Cooperation with Cytopathologists

In recent years the working formula has been When pathologists investigate the SLN intensively and do not find any metastatic settlement investigation of the other approximately 12 lymph nodes (average in German breast cancer studies) or even more (usually after revision of the axilla) can be omitted. Pathologists bear a much heavier responsibility, especially in breast cancer cases, because false-negative results caused by insufficient investigation of the node(s) can lead to axillary recurrence with a fatal outcome.

Selective Estrogen Receptor Modulators

These new drugs, sometimes called designer estrogens, appear to affect blood lipids in much the same way that estrogen does but possibly without the increased risk for breast cancer and endome-trial cancer associated with hormone replacement therapy. Raloxifene (Evista), one of these drugs, has been shown to decrease levels of LDL, but unlike estrogen does not reliably elevate HDL cholesterol, though it may increase one of the HDL subfractions. Also unlike estrogen, raloxifene doesn't elevate triglyceride levels. Raloxifene is approved for osteoporosis prevention, and recent preliminary studies suggest that it may be effective at reducing breast cancer risk. Like estrogen, however, it does increase the risk of blood clots in the legs. Overall, I don't use raloxifene as a pri- 33. mary treatment for lipid problems, but if a woman needs a drug to treat her osteoporosis, raloxifene's generally favorable effects on lipids make it a reasonable choice. If further trials show that this drug...

Mdm2 and tumour progression

In breast cancer, no correlation is seen between clinico-pathological and biological parameters and mdm2 protein levels (Marchetti et al., 1995b), where amplification of the gene may be a rare event (Quesnel et al., 1994b McCann AH et al., 1995). Co-amplification of certain oncogenes, and of growth factor and oestrogen receptor genes has also been reported, e.g. Wnt-2, myc, ras, erbB2, etc. (Fontana et al., 1994 Habuchi et al., 1994 Marchetti et al., 1995b). This only emphasises the importance of examining the significance or functions of the genes which are co-amplified with mdm2.

Transactivation of growth factor receptor genes by p53

Epidermal growth factor receptor (EGFr) expression has long been regarded as an indicator of malignancy in certain forms of human cancer. Therefore, it is of considerable interest that high EGFr expression has often been found to accompany p53 abnormalities. EGFr over-expression has shown significant correlation with p53 mutation status in oesophageal carcinomas (Esteve et al, 1993). p53 over-expression is strongly correlated with EGFr expression in breast cancer (Horak et al., 1991). Wright et al. (1991) found that p53 and or EGFr over-expression was strongly associated with invasive transitional cell carcinoma of the bladder, but there was no statistically significant association between p53 and EFGr expression. Amplification of c-erbB2 was found together with mdm2 amplification in breast cancer (Fontana et al., 1994). Overexpression of p53 and erbB2 has been reported in breast cancer (Horak et al., 1991 Tsuda et al, 1993), in bladder cancer (Moch et al., 1993), and in...

Operationoriented Requirements for the Detection of the SLNs

E Breast cancer, located in the upper outer quadrant, already near to the axillary tail or in the axillary tail has a very short distance to the lymph nodes of the axilla (level I). In consequence separate measurement of radioactivity using the gammaprobe can hardly have been possible

Diagnostic Evaluation

Laboratory evaluation of platelets is particularly important in patients with cancer because disease and treatment, including chemotherapy and radiotherapy, can be myelosuppressive. The patient's coagulation status should be assessed because liver dysfunction and treatment of and prophylaxis for thromboembolism are common in the cancer population.

Confounding Factors In Recognizing Patterns Of Inheritance

Ceptions, the pedigree should extend at least three generations to include the patient's grandparents, parents, siblings, half siblings, nieces and nephews, children, grandchildren, and aunts and uncles (see Chapter 3). Remember to record the ages, sex, and health information of both affected and unaffected relatives. Information on unaffected relatives is just as important as information on affected relatives. For example, if you take a history of a 50-year-old woman diagnosed with unilateral breast cancer at age 42 years, and she has four sisters cancer-free in their 60s, you are more likely to consider this cancer a sporadic occurrence than to suspect an autosomal dominant inheritance pattern. The expression of a syndrome may be influenced by the sex of an individual even when the gene is located on a non-sex chromosome. This is called sex-influenced or sex-limited gene expression. For example, it may be difficult to recognize families with an inherited breast cancer susceptibility...

New strategies for discovery of accessible tumor targets

One widely used approach to reducing sample complexity has been to study tumor cells that have been isolated and grown in culture. Unfortunately, both enzymatic mechanical tissue disassembly and growth in culture contribute to phenotypic changes that alter native cellular function and protein expression (36). Direct comparisons of protein expression have revealed < 25 similarity between primary tumor cell biopsies vs cultured, clonally selected prostate tumor cell lines vs patient-matched microdissected cell-populations-derived biopsy specimens (37). For example, in vitro caveolin-1 expression is downregulated in transformed cell lines and in various cultured human cancer cell lines, and induced expression greatly retards tumor cell growth (38-44). Yet, in vivo, caveolin-1 can be highly expressed in tumors and is associated with increased tumor cell survival, aggressiveness, metastatic potential, suppression of apoptosis, acquisition of multidrug resistance, and resistance to...

Are the Technical Conditions for SLN Detection Satisfactory14

Investigations of Breast Cancer Cases As a Basic Parameter In the year 2001 there was still a high degree of uncertainty about the safety of the SLN concept in breast cancer treatment many institutions are involved in clinical, partly multicenter, studies, but definitive results answering the most important question, that of the false-negative rate and its implications, are not yet available. which, because of early stromal invasion that has not been detected histologically, the disease cannot be safely resected, even when the Van Nuys (Silver-stein et al. 1995) or Holland (Holland et al. 1994) classification of DCIS following identification of high-grade types (see also International Consensus Conference (2002) is applied, the results of Cox et al. (1998) are of special interest. These authors had 87 cases with noninvasive ductal breast cancer (DCIS) in their series of 466 cases. In 4 of these cases (4.6 ) cancer-positive SLNs were found. This rate is in keeping with most percentages...

Depending on Quality of Sampling

The Swedish Cameco syringe has long been used in many European countries and also in other continents (Fig. 1). Ultrasound guidance supports the success of the puncture, which may for instance take the form of confirming a diagnosis of breast cancer. This syringe is also often used

Cyclins cell cycle progression and cyclins as protooncogenes

Buckley et al. (1993) found higher expression of one or more of cyclins A, Bl, Dl or E in seven out of 20 breast cancer cell lines cyclin Dl was over-expressed in five out of 20 cell lines. Of 124 breast cancer biopsies investigated, 56 specimens showed higher cyclin D gene expression compared with normal breast tissue. Amplification of chromosome llql3 which contains the bcll PRADl (cyclin Dl) together with EMS1, (and hstl and int2 only rarely expressed in breast cancer) genes has been reported (Faust and Meeker, 1992 Schuuring et al., 1992). Schuuring et al. (1992) observed that 1 lql3 amplification showed a positive association with lymph node involvement and significantly shorter relapse-free interval and on this basis have suggested that this may be a predictor of diminished survival in operable breast cancer. Elevated cyclin D1 expression has also been reported in a Bcell non-Hodgkin's lymphoma called mantle cell lymphomas (Bosch et al., 1994 Yang et al., 1994), squamous cell...

Case 1 A Middle Aged Man with Widespread Cancer

In his mid-50s, a successful executive had incurable cancer of the kidney with lung metastases, for which chemotherapy was not very effective. He was hospitalized because of vomiting, which was improving with intravenous fluids and medicines to control his nausea. His urologist asked me to see him for general medical evaluation and help with his long-term care.

Cyclobut G See lobucavir

Cyclophosphamide (CY) An immunosuppressive drug that at high doses has been used in cancer chemotherapy regimens. In low doses, the drug has well-documented immunomodulatory properties and has been used to treat several immune disorders, including lupus and Wegener's granulomato-sis. In people with HIV, cyclosphosphamide is most commonly used in combination therapy for AIDS-related lymphoma. CY has a greater suppressive effect on b cells than on t cells, and CD8 cells are more sensitive to the drug than other T cell subsets. CY is an alkylating agent, which means that it works by attaching to biologically important molecules such as DNA and RNA, interfering with cell growth and division. Alkylating agents are toxic to rapidly dividing cells, like those in a tumor or in the bone marrow (where blood cells are continually being replaced). CY is one of the most widely used chemotherapy drugs, in part because its toxi-city is more specific to malignant cells and less likely to cause severe...

David Ljungman MD and James C Cusack Jr MD

Chemotherapy Resistance Takes on Many Forms Altered Regulation of Apoptosis Provides Potential Mechanism for Chemotherapy Resistance Targeting Transcription Factors to Enhance Chemotherapy Resistance toward chemotherapy remains one of the principle obstacles to the effective treatment of malignancies. As our knowledge of mechanisms involved in cancer biology expands, new molecular targets emerge. This chapter aims to overview the major resistance mechanisms, in order to identify potential targets appropriate for developmental therapeutics. An emphasis on the role of transcription factor NF-kB in colorectal cancer is presented as an example of how targeted therapies may advance from the bench to the bedside. Key Words Chemotherapy resistance apoptosis transcription factors NF-kB proteasome inhibition combination chemotherapy.

Alterations in Drug Transport and Metabolism

One common type of resistance involves actively pumping out cytotoxic compounds from cancer cells. Notable substrates for this mechanism include anthracyclines, vinca alkaloids, and taxanes. Increased drug efflux might be mediated by the ATP-binding cassette (ABC) transporter proteins including P-glycoprotein (Pgp), multidrug resistance (MDR) protein (MRP-1), and breast cancer resistance protein (BCRP) (17). MDR1 has been found to be overexpressed in many resistant cancer cells (18), whereas high levels of Pgp expression in chemotherapy na ve cancer cells has been found to negatively impact patient survival (19). Expression of BCRP leads to a reduction in the intracellular accumulation of adriamycin doxorubicin and CPT-11 (20,21). Interestingly, expression of BCRP is actually induced by CPT-11 exposure (20). Circumvention of BCRP-mediated resistance to camptothecins in vitro has been demonstrated using nonsubstrate drugs or the BCRP inhibitor GF120918 (22). MDR1 is only one of many...

Case 3 A 70Year Old Man with Widespread Cancer

On his return from a well-known medical center where this patient had been receiving chemotherapy for widespread cancer, the retired executive's wife called to ask that I become his physician. The initial treatment had failed, an experimental drug was being offered with less than 25 percent chance of success, and he was having ongoing pain that medicine poorly controlled. Stopping chemotherapy had not been considered. The adult children lived at least three hours away by plane. Prior to this call, he had no primary physician in his hometown. On my first visit to his home, we concentrated on pain control, and I prescribed ibuprofen, a mild but often effective drug when given regularly several times a day. Subsequent visits concentrated on achieving better pain control using morphine, on helping him understand his illness (he knew that the prognosis was poor), and on addressing alternative ways of treating the progressive malignancy, including more chemotherapy. He declined the latter.

Therapeutic Approaches Involving Regulatory Proteins of Apoptosis

Overview ofkey apoptotic pathways. The extrinsic death receptor-mediated pathway (at left) is activated by ligand-receptor interaction. Examples known to induce apoptosis are the Fas-ligand (FasL) binding the membrane-bound Fas receptor or the tumor necrosis factor-a (TNF-a) binding a TNF receptor (i.e., TNF-R1). A death-inducing signaling complex (DISC) is formed on the cytoplasmic side of the membrane consisting of the intracellular end of the receptor called the death domain, a series of adaptor proteins (i.e., Fas TNFRSF6 -associated via death domain FADD ) and the inactive precursor of a cysteine-aspartyl-protease (caspase) procaspase-8 or -10. This triggers a proteolytic cascade involving conversion of procaspase-3, -6, or -7 into active caspases. These effector caspases act on various death substrates to induce apoptosis. In some cells, the stimulus is too weak to result in a cascade this way and the pro-apoptotic protein Bid communicate the signal to the mitochondria,...

Handling and Consequences in Cases with Primaries in the Lateral Quadrants

The high degree of variability in breast cancer location in the lateral quadrants is well known. Cancers can be located extremely far laterally in the axillary tail and even in the lower level of the axilla. These in some cases extreme lateral positions result in radiation interference between the labeled primary and the labeled axillary sentinel node.

Ehrlichiosis human monocytic

Preliminary evidence suggests that infection caused by the E. chaffeensis bacteria may become more severe than other ehrlichia infections. The severity of ehrlichiosis may also be related in part to the health of the child's immune system. Patients with compromised immunity caused by corticosteroids or cancer chemotherapy, HIV infection, or removal of the spleen appear to develop more severe disease.

Kipl gene expression in neoplasia

Polymorphisms relating to kipl G A transition at codon 109 in one case and T G transversion in 26 of breast cancer DNA samples and 31 out of 80 normal individuals were detected by Ferrando et al. (1996), but they found no somatic mutations of the gene. These initial studies, albeit a few in number, suggest that kipl alterations may be rare events in the pathogenesis of cancer. There are no studies on the involvement of kip2. But Matsuoka et al. (1995) point out that kip2 region of the human chromosome may be involved in sporadic and with the familial cancer syndrome - the Beckwith-Wiedemann syndrome.

The AKT Signaling Pathway

Growth factors, oncogenic Ras, and integrins could activate this survival pathway. Once activated, the phosphatidylinositol-3 kinase (PI3K) facilitates the conversion of PIP2 to PIP3, which then activates the transcription factor AKT. This has been shown to promote transcription of antiapoptotic Bcl-XL and inactivate Bad, caspase-9 and FKHRL1 (an inducer ofmany proapoptotic factors) (83). A tumor suppressor, phosphatase and ten-sin homolog (PTEN), is regulatory and counteracts AKT by phosphorylating PIP3. AKT is constitutively activated in a wide range of tumors such as prostate, liver, lung, ovary, and breast carcinomas (84). Also, this pathway has been observed to cause resistance to chemotherapy one example is inhibition of cisplatin-induced apoptosis in ovarian carcinoma through phosphorylation ofthe proapoptotic Bad. Treatment with either the AKT inhibitor wortmannin or exogenous expression of a dominant-negative AKT sensitized the cells to cisplatin (85). Another successful...

Monitoring health outcomes

For the moment it is a fact of life that the measurement of process is usually our best mechanism for predicting rather than measuring outcome and thus quality of care, but it does require that we measure quality by degree of adherence to very clearly defined and agreed standards. Unfortunately, these are only available in a limited number of clinical instances. For example, the percentage of premenopausal women with node-positive breast cancer receiving chemotherapy or the percentage of patients with myocardial infarction receiving thrombolysis within a set time. Medical managers need to make clear judgments about the validity of the criteria that are going to be used as gold standards of quality. This in turn leads back not only to the validity of EBM as a process but also to an awareness that bureaucratisation of the process can lead to the original measure being misrepresented or inappropriate. For example, concerning the management of breast cancer, when breast conserving surgery...

Clinical Management and Prognosis

Primary lymphomas of the thyroid are rare and typically occur in the setting of chronic lymphocytic thyroiditis. Because advances in subclassifying these lymphomas are recent, it is difficult to separate the clinical course of thyroid MALT lymphomas from DLBCL based upon published studies. Depending upon the subtype and stage of the lymphoma, most patients are treated with radiotherapy or with combined radiotherapy and chemotherapy. Results of 5-year survival rates range from 13 to 92 , but in most studies the average 5-year survival is 40 to 60 . Stage at diagnosis appears to be the most important predictive factor, and for those patients in whom the lymphoma is confined to the thyroid gland, the recurrence rate is low.

Accuracy of SLN Biopsy in Patients with Large Primaries

Now, however, with the developing tendency to perform preoperative down-staging by means of chemotherapy (CMF or anthracycline-containing regimens in c-erbB2- and or p53-positive cases) the chance that breast-conserving surgery will become possible increases (McCready et al. 1988 Bo-nadonna et al. 1990 Schwartz et al. 1994 Botti et al. 1995 Fisher et al. 1997, 1998 Kling et al. 1997 Cunningham et al. 1998 Kuerer et al. 1998). In this context, it must be emphasized that it is of critical importance to perform axillary lymph node staging before chemotherapy is started, for the following reasons To avoid extended axilla revision before chemotherapy-induced down-staging of the primary the team working in the Mayo Clinic and the Philadelphia University Hospital has recently tried to eval

Significance of Pathohistological Analysis of SLN and NonSLN for Occult Metastasis Conclusions Drawn from Recent

If occult metastasis is considered more likely to be present in SLN, this search will shift a proportion of women currently considered lymph node negative into the group of lymph node-positive patients, with the consequence of adjuvant chemotherapy for these patients (Weaver et al. 2000). Chemotherapy regimens are discussed in Chapter 33 at the end of this book. It has been suggested that occult disease that is not histologically confirmed may be a predictor for the approximately 25 of lymph node-negative patients who develop recurrences (Weaver et al. 2000). But the data obtained in different investigations, which could give an idea of the significance of occult disease, are contradictory and discussion on this point has sometimes been controversial (Fisher et al. 1978 Bussolati et al. 1986 Friedman et al. 1988 International Breast Cancer Study Group 1990 Chen et al. 1991 Galea et al. 1991 Neville et al. 1991 Byrne et al. 1992 de Mascarel et al. 1992 Clayton and Hopkins 1993 Elson et...

TNF Receptors and Trail Apo2L

Recombinant human TRAIL (10 mg kg administered once daily for 7 d) (97). One of the most exciting features of TRAIL therapy is the strong positive interaction effect of TRAIL with chemotherapeutic agents or ionizing radiation. TRAIL treatment has been shown to sensitize tumor cells derived from acute leukemia, breast cancer, lung cancer, colon cancer, prostate cancer, and melanoma to chemotherapeutic agents (98-105). In an in vitro setting, TRAIL has been shown to induce apoptosis in normal primary hepatocytes (106). In light of this observation, it remains to be seen whether TRAIL therapy offers a margin of safety in humans, as is seen in mice and monkeys.

Treatment and Monitoring

Currently available drug therapy focuses on suppression of bone resorption. Because of the relationship between estrogen and bone resorption, hormone replacement therapy was for many years the first therapeutic option. But this changed in 2002 when data from the Women's Health Initiative suggested increased risks of breast cancer, coronary artery disease, stroke, and pulmonary embolism with a combined estrogen-progesterone formula. Although these risks were not found with other estrogen therapies, there was concern that for many women the risks outweighed the bone benefits. For these women, and when hormone therapy is contraindicated, there are other options. The bisphospho-nates are probably the most frequently prescribed drugs for the treatment of osteoporosis and osteopenia. Alendronate, the most widely used of the class, acts by inhibiting farnesyl diphosphate synthase within the osteoclast, causing the cell to undergo premature apopto-sis. Second- and third-generation...

Communicating through the media

There are great dangers in trying to use the media as a vehicle for manipulating rather than communicating, because it is so unpredictable and unreliable. It is, however, an unfortunate reality that the upward channels to the NHS Executive and government are so tenuous that often only pressure from the media has any effect. Health stories are part of their stock-in-trade, readily carried without much attempt at checking the facts or putting them in context, partly one suspects because of the corrupting effect of deadlines and the desire for a scoop. Bricks can indeed be made without straw if they need only last a day or two. Transparently inaccurate or overstated items display an eerie lack of basic knowledge about medicine, for example one day both the Independent and the Daily Mail announced that Australian scientists have developed the first nano-machine which will enable doctors to provide an instant diagnosis of virtually all known diseases, and on another occasion BBC Radio 4...

Patients And Their Families Need Time

It takes time to deal with a difficult child, parent, or dilemma, to adjust to an illness, and to accept advice. We cannot always expect an immediate change in an opinion or behavior. We cannot, overnight, cope with the impact of a diagnosis of cancer, heart disease, or other chronic illness. Nor can we decide quickly about having major surgery, undergoing chemotherapy, or declining treatment. It takes time to come to grips with a need to change our style of living eating or work habits or a nicotine addiction. Patients and families think things over between visits to the physician, think about their physician's advice, ruminate, and talk things over with others. What goes on behind the scenes is substantial. They do homework they read, they search the Internet, they may even get another medical opinion on their own.

Head and Neck Introduction

As in the diagnostic approach adopted in breast cancer, and because of the good accessibility of cervical and facial lymph nodes, ultrasonography is the first step in the staging of naso-pharyngeal and oral cavity cancers. Additional examinations performed in most patients are CT, MRI and 18F-FDG-PET (see also section contributed by Avril et al. in this chapter). The sensitivity in detection of enlarged lymph nodes is relatively high, while the specificity in prediction of metastatic involvement depends principally on the size and shape of the lymph nodes or the intensity of glucose metabolism. The Sinerem method might be the first diagnostic method to provide histological information (defects in cancer-infiltrated lymph nodes).

A2mtsl protein and HSPs in cell proliferation

For instance, HSP28 is highly expressed in quiescent keratinocytes compared with their proliferating counterparts (Honore et al., 1994). In mitogen-stimulated human B lymphocytes HSP28 induction coincides with peak proliferation and the onset of arrest of growth (Spector et al., 1992). HSP28 appears to be regulated in human leukaemic HL-60 cells when they are induced to differentiate by retinoic acid, since a transient increase of HSP28 levels occurs upon exposure to retinoic acid with concomitant Gi arrest (Spector et al, 1994). The expression of HSP27 is related to the state of differentiation in cervical cancer and its expression in breast cancer is considered to be an indicator of good prognosis (see Ciocca et al., 1993). Thus, a spectrum of studies supports the view that HSP28 is associated with inhibition of cell proliferation.

HSPs in cancer and their possible relevance to prognosis

Complex formation between p53 and HSPs has also been shown to occur in several human tumours. Davidoff et al. (1992) demonstrated p53 HSP70 complexes in breast cancer. The tumours investigated in this series have been described as primary invasive breast carcinomas. Unfortunately, no information is available from this study by Davidoff et al. (1992) about the relationship between the detection of these complexes and the invasive nature of the carcinomas. Perhaps the value of this approach may be diminished because Iwaya et al. (1995) state that only a part of the p53 pool may enter into complex formation with HSPs. Nevertheless, it is noteworthy that the expression of HSP correlated positively with oestrogen receptor expression and inversely with epidermal growth factor receptor expression (Takahashi et al., 1994). This suggests that changes in HSP expression could be one of the events associated with the progression of breast cancer. Elledge et al. (1994)...

What Is Adrenocortical Carcinoma34

The most common sites of metastases are the peritoneum, lung, liver, and bone. Palliation of metastatic functioning tumors may be achieved by resection of both the primary tumor and metastatic lesions. Unresectable or widely disseminated tumors may be palliated by antihormonal therapy with mitotane, systemic chemotherapy, or (for localized lesions) radiation therapy. However, survival for patients with stage IV tumors is usually less than 9 months unless a complete remission is achieved.40 To date, there is no convincing evidence that systemic therapy will improve the survival duration of patients with adrenal cancer.

Mucins In Diagnosis And Therapy

Human T-lymphocytes that recognize epitopes on the MUC1 core protein have been produced by in vitro stimulation with MUC1 from patients with breast, pancreatic, and ovarian carcinomas.140,141 These in vitro stimulated T-lymphocytes are unusual in that they show some cytotoxic activity against human tumor cells but they are not MHC-restricted in their specificity. The fact that they are derived from patients with progressive disease suggests that some mechanism prevents these cells from eradicating tumors in situ. There is an anecdotal report, however, of a case in which a long-term breast cancer survivor has relatively high levels of CTL precursors with MHC restricted specificity for MUC1 and a clinical history that is consistent with the development of anti-MUC1 responses in situ. A Phase I trial was conducted by Finn and collaborators142 in which 3 doses of 100 mg of 105 amino acid peptide corresponding to 5 tandem repeat units of MUC1 mixed with BCG were administered over a 9-week...

Invasive Vulvar Neoplasm

Alternatives to surgery include radiotherapy and or chemotherapy. Chemotherapy alone is of limited efficacy in vulvar cancer, but the combination of chemotherapy and radiotherapy appears effective (147). Radiation (142) and chemoradiation (146) can also be adjuvants to surgery. For patients with any stage of vulvar carcinoma who are unable to undergo surgery, radical radiation (147) alone may enhance survival. Surgical management of Stage IV vulvar cancer is radical or en block vulvectomy and lymphadenectomy and removal of metastases (139). With two or more positive nodes, surgery followed by radiation has better survival than postoperative pelvic node dissection (134). Preoperative radiation (147) or chemoradiation (146) may decrease the tumor size and the extent of surgery required. Chemoradiation (145) alone is an acceptable alternative to surgery. For those intolerable of or unsuitable for surgery or chemotherapy, radical radiation therapy alone may increase survival (147). There...

Granulocyte colony stimulating factor GCSF

Granulocyte-macrophage colony stimulating factor (GM-CSF) A naturally occurring cytokine glycoprotein that stimulates production of neutrophils, monocytes, and macrophages. Synthetically produced GM-CSF is effective in treating bone marrow deficiency after chemotherapy, bone marrow transplantation, or use of some certain drugs. It is synthetically produced but exactly the same as cytokines produced in every human's body. GM-CSF's generic name is sargvamostim. Side effects can include bone pain, edema, and eosinophilia. (Trade names are Leukine and Prokine.)

Learning from Patients Experiences

Consciously or not, patients apply their philosophy of life to the medical situation at hand. Common sense is often at the foundation. An 80-year-old man reflected on his illness, unstable angina, which was improving with medication. I know it's better, but I'm 75 years old It's like, 'We've got a good car, but it's twelve years old, so shall we drive from St. Paul to Los Angeles ' I don't need to take unnecessary chances. Our philosophy of life affects difficult decisions about tests and treatments including transfusions, surgery, chemotherapy, and end-of-life care. Part of the physician's task is to discover each patient's philosophy and needs. Sometimes the doctor has to read between the lines.

The Asymptomatic Iron

A 65-year-old Caucasian male presented to his primary care physician for a routine physical exam prior to retiring. He had enjoyed excellent health throughout his life, and did not report any new symptoms at the time. His past medical history included elevated prostate-specific antigens that had been evaluated with multiple negative prostate needle biopsies, and hypercholesterolemia treated with diet and medication. Family history was notable for cardiovascular disease, hypertension, and breast cancer. He did not smoke, and consumed less than one beer or glass of wine per week. On direct questioning, he did not acknowledge chest pain, shortness of breath, arthralgias, fatigue, cold intolerance, or decreased libido.

Basic Data for Comparison with Results of Future Sentinel Node Detection Programs

Five-year survival rates of patients with different subtypes of NSCLC (different types of lymph node involvement). Preoperative chemotherapy was associated with a better prognosis for cases LI one level involved, L2 multiple levels involved, c clinical involvement, m minimal involvement with cN2 (P< 0.0001) Table 8. Five-year survival rates of patients with different subtypes of NSCLC (different types of lymph node involvement). Preoperative chemotherapy was associated with a better prognosis for cases LI one level involved, L2 multiple levels involved, c clinical involvement, m minimal involvement with cN2 (P< 0.0001)

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