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...

Chemo Secrets From a Breast Cancer Survivor Summary


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Highly Recommended

The writer presents a well detailed summery of the major headings. As a professional in this field, I must say that the points shared in this manual are precise.

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Breast Cancer Cell Proliferation

Considerable evidence from our and other laboratories has shown that polyamines are critically involved in breast cancer cell proliferation (21). In hormone-responsive tumors, ODC activity is stimulated by estrogen leading to an increased cellular polyamine content (22). Administration of DFMO has been shown to consistently inhibit estradiol-stimulated ODC activity and estrogen-stimulated growth in numerous experimental systems (23-25). It is important to emphasize, however, that polyamines are selectively involved in hormone action because other estrogen-regulated events (assessed concomitantly with tumor growth) have not been found to be affected by DFMO administration (25). Polyamines are likely to influence hormone action in breast cancer cells at multiple steps. They include the association kinetics of the estrogen receptor with specific DNA sequences (26), the synthesis of estradiol-regulated, cell-cycle specific genes (27) and the synthesis or action of hormonally regulated...

Polyamines and Breast Cancer Progression and Metastasis

The natural history of human breast cancer is characterized by an inevitable transition from a relatively indolent hormone-dependent phenotype to a more aggressive typically hormone-independent status that is ultimately responsible for the patient's demise. Evidence indicates that activation of the polyamine pathway may be one of the contributing factors to breast cancer progression. Using an experimental system of mammary tumor progression, we found that an increase in cellular ODC activity was associated with transition to hormone independence and to a less differentiated and more metastatic phenotype (40). With respect to human breast cancer, increased ODC In a pilot study involving a cohort of 50 primary human breast cancers, we have observed that ODC activity was a strong negative, independent prognostic factor of overall survival 42). Figure 2 illustrates the effect of a 10-fold difference in ODC activity on overall survival after adjustment for other prognostic factors. This...

Present Chemotherapies for HRPC

The NCCN recommends combination chemotherapies as a treatment option in the management of patients with HRPC.6 It is understood that these regimens are solely palliative and yield no definitive survival benefit. Nonetheless, their inclusion in these guidelines illustrates the diminished pessimism associated with chemotherapy for HRPC. These regimens include ketoconazole doxorubicin, mitoxantrone prednisone, and various estramustine-based combinations that include etoposide, vin-blastine, paclitaxel and docetaxel. Among these combinations are two

Adjuvant Radiochemotherapy

The efficacy of post-operative radiation and 5-fluo-rouracil (5-FU)-based chemotherapy for stage II and III rectal cancer was established by a series of prospective, randomised clinical trials (GITSG, NCCTG, NSABP) (Table 2) 22-25 . These studies demonstrated an increase in both disease-free interval and overall survival when radiation therapy is combined with chemotherapy following surgical resection. Following the publication of these trials, the National Cancer Institute (NCI) concluded at a Consensus Development Conference in 1990 that post-operative combined modality treatment is recommended for patients with stage II and III rectal carcinoma 26 . Subsequent studies have attempted to increase the survival benefit by improving radiation sensitisation, and by identifying the optimal chemotherapeutic agents and delivery systems. The chemotherapy associated with the first successful combined modality New effective drugs including capecitabine, raltitrexed, irinotecan and oxaliplatin...

Pre Operative Radiochemotherapy

The principles of the neoadjuvant scheme are higher efficacy of radiation and chemotherapy agents Because surgery is performed only one week after the completion of radiation therapy, as in Swedish trials, significant tumour shrinkage is very unlikely and one of the major goals of pre-operative treatment, the preservation of sphincter, is more likely to be achieved. Prolonging the interval between RT and surgery has been studied. The longer interval (6 weeks against 2 weeks) between radiation in long course and surgery was associated with a significantly better clinical tumour response (71 vs. 53 , p 0.007) and pathological downstaging (26 vs. 10 , p 0.005), and sphincter-preserving operations (76 vs. 68 ,p 0.27) 40 . Due to the short overall treatment time, such as 25 Gy in a week, radiation therapy cannot be combined with an adequate dose of systemic chemotherapy. Thus the potential effect of radiosensitising of the chemotherapy drug to enhance local tumour response and...

Optimization of Breast Cancer Screening Modalities

Mathematical models and decision analyses based on microsimulations have been shown to be useful in evaluating relative merits of various screening strategies in terms of cost and mortality reduction. Most investigations regarding the balance between mortality reduction and costs have focused on a single modality, mammography. A systematic evaluation of the relative expenses and projected benefit of combining clinical breast examination and mammograpphy is not at present available. The purpose of this report is to provide method-ologic details including assumptions and data used in the process of modeling for complex decision analyses, when searching for optimal breast cancer screening strategies with the multiple screening modalities. To systematic evaluate the relative expenses and projected benefit of screening programmes that combine the two modalities, we build a simulation model incorporating age-specific incidence of the disease, age-specific pre-clinical duration of the...

Pathologic Evaluation of Sentinel Lymph Nodes in Breast Cancer

Lymphatic mapping utilizing technetium labeled sulfur colloid and isosulfan blue dye injections has successfully identified the sentinel lymph nodes (SLNs) and allowed accurate staging.1,2 This minimally invasive technique may lead to more conservative lymph node dissection for stages I and II breast cancer patients with decreased morbidity and cost savings for the health care system. For most cancers, the nodal status is the single most important prognostic indicator and determines the need in many cases for adjuvant chemotherapy.3 Micrometastases in the axillary lymph nodes has been reported to be associated with poorer survival.4 Currently, there is a failure rate of 15 to 20 at five years in node-negative patients which may be attributed to the low detection rate of micrometastases using the routine hematoxylin and eosin (H&E) stain.5 With the advent of lymphatic mapping, these SLNs may be carefully and thoroughly evaluated for successful identification of micrometastases as SLN...

Pgp Inhibition as an Adjunct to Treating Chemotherapy Resistant Cancers

An extensive survey of MDR-1 mRNA expression levels in cancer patient tissue samples and normal controls suggested that three types of MDR-1 behavior may be distinguished in different cancer cells (121, 122) (1) MDR-1 is normally expressed in transporting epithelium, liver, colon, kidney, pancreas, and adrenal gland. Expression of MDR-1 remains high in cancers derived from these tissues. (2) Cancer cells derived from other tissues that normally do not express MDR-1 may be induced to express it when selected by drug treatment, and promoter analysis has shown that P-gp expression is induced by a variety of xenobiotics. This appears to result from clonal selection for resistant cells during the initial phase of drug treatment and leads to patient relapse following an initially successful response to therapy. Such relapses are commonly seen in leukemias, lymphomas, breast, and ovarian cancers. (3) Cancer cells that normally do not express MDR-1 may acquire expression in the absence of...


The use of chemotherapy in AIPC has undergone a revolution in the past decade. Once labeled 'chemotherapy resistant', new agents have shown great promise in both palliative and response endpoints. While the new agents have been tested extensively in phase II trials, only a few phase III trials have been conducted using chemotherapy in AIPC in the last decade. A summary of these trials is shown in Table 46.1. Table 46.1. Phase III trials using chemotherapy in the treatment of AIPC. Table 46.1. Phase III trials using chemotherapy in the treatment of AIPC.

Cancer Chemotherapy

Except for heart and coronary disease, cancer is now the principal cause of death in the Western world. Despite extensive cancer research to find improved drugs and treatments, the average chance of being cured of cancer is augmented every year by only 0.5 percent. Cancer comprises a broad group of diseases characterized by uncontrolled and independent proliferative growth of tumor cells (Alberts et al., 1994). In cancer, malignant tumors invade surrounding tissue and give rise to formation of secondary tumors (metastases). The ability to metastasize is largely responsible for the lethality of malignant tumors. Surgery and radiotherapy are mostly used for treatment when a tumor is localized to a certain tissue. When metastasis has occurred, chemotherapy becomes an important weapon against cancer. Cancer chemotherapy, first experimented with in 1943 by employing mustard gas alkylating agents (DeVita et al., 1997), is typically associated with severe side effects because highly toxic...

Oral Chemotherapy

A protracted continuous infusion of FU has the advantages of a different and milder toxicity, but there is the drawback of the need of a central venous system for infusion and the discomfort of carrying an infusion pump. Oral regimens using prodrugs of FU pharmacologically simulate continuous infusion and are under clinical evaluation. Furthermore, patients receiving therapy for late-stage disease prefer oral rather than IV chemotherapy (IVC) but are unwilling to accept a lower response rate or a shorter duration of response to their preferred choice of oral chemotherapy.

George M Lazarus Md Faap

How will it help us to better understand gender differences Consider the example of teenagers with Hodgkin's disease. Boys are more susceptible to infertility from chemotherapy, while girls are at great risk of developing breast cancer after radiation treatment. Pediatric oncologists, therefore, can tailor the treatment of this disease according to the sex of the patient.

Cancer Treatment and Research

Gradishar, W.J., Wood, W.C. (eds) Advances in Breast Cancer Management. 2000. ISBN 0-7923-7890-3. Sparano, Joseph, A. (ed.) HIV & HTLV-I Associated Malignancies. 2001. ISBN 0-7923-7220-4. Ettinger, David, S. (ed.) Thoracic Oncology. 2001. ISBN 0-7923-7248-4. Bergan, Raymond, C. (ed.) Cancer Chemoprevention. 2001. ISBN 0-7923-7259-X. Raza, A., Mundle, S.D. (eds) Myelodysplastic Syndromes & Secondary Acute Myelogenous Leukemia 2001. ISBN 0-7923-7396. ISBN 0-7923-7523-8. Stack, M.S., Fishman, D.A. (eds) Ovarian Cancer. 2001. ISBN 0-7923-7530-0. Bashey, A., Ball, E.D. (eds) Non-Myeloablative Allogeneic Transplantation. 2002. ISBN 0-7923-7646-3. Leong, Stanley, P.L. (ed.) Atlas of Selective Sentinel Lymphadenectomy for Melanoma, Breast Cancer and Colon Cancer. 2002. ISBN 1-4020-7013-6. Andersson, B., Murray, D. (eds) Clinically Relevant Resistance in Cancer Chemotherapy. 2002. ISBN 1-4020-7200-7.

Stem cell trafficking

The ability of stem cells to traffic around the body and to search out sites suitable for haemopoiesis is well demonstrated by (a) the 'homing' of transplanted stem cells to the bone marrow and (b) the chemotherapy and cytokine-induced 'mobilization' of stem cells into the circulation. Homing involves transendothelial migration from the bloodstream into the marrow microenvironment, whereas mobilization involves detachment from the microenvironment and transendothelial migration in the reverse direction. Together, these processes may provide a paradigm for stem cell trafficking in general (Figure 1.2). They are likely to involve multifactorial processes involving chemokines, cytokines, adhesion molecules and matrix-degrading enzymes.

Global Burden And Significance Of Infectious Diseases

In industrialised countries, many infectious diseases were controlled successfully during the twentieth century by improvements in hygiene and nutrition as well as by the availability of anti-infective chemotherapy and preventive measures (e.g. vaccines). As a consequence, the importance of infectious diseases has been regarded as becoming very small, and probably vanishing completely, at least in the developed world. However, during the last two decades infectious diseases have regained considerable significance and interest even in high-income countries. The reasons for this are varied

Fdgpet Cost Effectiveness Studies

The economic modelling has been performed in different health care settings and suggests that PET is cost-effective, or even cost-saving, based on the assumptions made. Whether PET affects long term outcome remains to be fully tested in malignant conditions, but what is clear is that it can affect the short term management of patients with cancer (Table 1.4). Outcome effects may take up to 20 years to evaluate, for example, whether changes in chemotherapy or radiotherapy regimens early in the course of disease treatment will reduce second cancers. If an imaging modality is superior to another imaging modality and provides different information allowing management changes we should not wait a further 5 to 10 years to show long term outcome effects - these changes have been modelled and prospective studies are showing these models to be true. Furthermore the human costs of delay in the introduction of this modality may be large, since the management changes demonstrated suggest that...

Patient Features Affecting Prognosis

This syndrome can be clinically divided into two groups. In one, NMTC is a relatively infrequent component of a familial tumor syndrome (familial adenomatous polyposis 84 and Cowden syndrome with multiple hamartomas and breast cancer). The PTC is found in younger patients but not in infants, and is characterized by multicentric and often microscopic tumor that usually has an excellent prognosis 84 .

Mechanism Of The Development Of Osteoblastic Metastases

Although prostate cancer is characterized by osteoblastic metastasis, several investigators have suggested that both bone formation and resorption are accelerated at bone metastatic sites.71'72 Usually, bone scintigrams used for detection of metastatic bone disease are incapable of disclosing bone degradation. Biochemical markers of bone metabolism, such as urinary calcium, urinary hydroxyproline and serum alkaline phosphatase, studied as indicators of bone response, may be influenced by the rate of bone resorption and are a non-specific reflection of bone function. Recently developed osteolytic markers, such as pyridinoline and deoxypyridinoline in urine, reflect an increased rate of bone resorption and are sensitive and specific indexes of the rate of cartilage and bone break-down.73 In breast cancer patients with osteolytic bone metastasis, the serum levels of these markers are significantly higher than those in patients without bone metastasis. Also in patients with prostate...

Clinical Trials Of Treatment With Curative Intent

Assessment was by Coates et al. (1987) who reported that, contrary to their initial expectations, continuous as opposed to intermittent chemotherapy for advanced breast cancer not only prolonged survival but most importantly resulted in superior QoL. Similarly, other RCTs recognised that QoL may be the principal outcome of interest. For example, an RCT comparing three anti-hypertensive therapies conducted by Croog et al. (1986) demonstrated major differences in QoL, and the cancer chemotherapy trial of Buccheri et al. (1989) suggested that small treatment benefits may be more than outweighed by the poorer QoL and cost of therapy. In extreme cases, the cure might be worse than the disease.

Genetic Considerations

Clearly, the pathogenesis of prostate cancer reflects complex interactions among both environmental and genetic factors. There are few areas of research in prostate cancer that have increased as quickly as the area of susceptibility gene research, nor have the results been as promising, especially in this new era of the human genome project. A recent Scandinavian study of twins has attempted to elucidate the relative contributions of these two factors. This study definitely increases our prior estimation of the genetic factor in the development of prostate cancer, as 42 of the risk of prostate cancer was attributed to the genetic factors. Interestingly, this significant genetic predisposition was greater than both colorectal carcinoma (35 ) and breast cancer (27 ), within this same cohort.31 This value is much higher than previously thought, as recent as the last decade. Monozygotic twins have a four fold increase in likelihood of developing prostate cancer when compared with...

Example from the literature

Slevin et al. (1990) asked 106 consecutive patients with solid tumours to complete questionnaires about their willingness to receive chemotherapy. They were told that the more-intensive regimen was likely to have considerable side-effects and drawbacks, such as severe nausea and vomiting, hair loss, frequent tiredness and weakness, frequent use of drips and needles, admission to hospital, decreased sexual interest, and possible infertility. They were given different scenarios, such as (a) small (1 ) chance of cure, (b) no cure, but chance of prolonging life by three months, and (c) 1 chance of symptom relief only. All patients knew they were about to commence chemotherapy, and thus considered the questions seriously. Cancer nurses, general practitioners, radiotherapists, oncologists and sociodemographicallv matched controls were asked the same questions. Table 1.2 shows the percentage of respondents that would accept chemotherapy under each scenario. There are major and consistent...

Vinblastine and Vincristine

Vinblastine and vincristine are binary indole alkaloids isolated from the aerial parts of the Madagascan periwinkle (Catharanthus roseus G. Don syn. Vinca rosea L.). The plant contains 0.2-1 alkaloids, which form a very complex mixture in which about 95 components have been identified. Vincristine is found at a level of 0.0003 , and vinblastine is a little more abundant. In spite of the low concentration, both alkaloids are extracted from plant material. Many efforts have been made to produce these substances by cell culture, but so far no cost-effective method has been found. Both substances are antimitotic agents. Vincristine is used for the treatment of acute leukemia and in combination chemotherapy, and vinblastine is indicated in the treatment of Hodgkin's disease (2).

Pathways Leading To Apoptosis

Caspases cleave both structural proteins involved in cell architecture and functional proteins and those involved in cell-cycle regulation and DNA repair.78 The inactivation of DNA repair enzymes, such as poly (ADP-ribose) polymerase (PARP) and activation of a caspase-activated DNase (CAD), serve as crucial events in the commitment of the cell to undergo apoptosis.79 Likewise, caspase-3-mediated cleavage of p21 Waf1 has been shown to convert cancer cells from growth arrest to apoptosis, leading to the acceleration of chemotherapy-induced apoptotic process in these cancer cells.80 In many instances caspase cleavage generates a constitutive kinase activity responsible for transduction of the apoptotic signal.81 Identification of these kinases, in particular their deregulation, allows for novel targets for gene therapy in prostate cancer.82 Certain antiapoptotic proteins of the Bcl-2 family, when cleaved by the caspases,

Breast carcinoma continued

Reconstruction May be performed concurrently with surgical excision. Latissi-mus dorsi or transverse rectus abdominis myocutaneous flap are used. Systemic therapy Chemotherapy Used in premenopausal women, rapidly progressive disease, visceral involvement, oestrogen receptor negative tumours and where hormonal treatment has failed. Many regimen options (e.g. 5-fluorouracil, cyclophosphamide, methotrexate, adriamycin) with response rates in 50 using a combination of drugs. A promising new agent is herceptin, a monoclonal antibody against HER-2 protein (tumour cell growth promoter).

Management of Malaria in Pregnancy

The management of pregnant women with malaria is essentially the same as for other patients, although frequent blood glucose and foetal monitoring is recommended. The choice of chemotherapy will depend on the factors outlined above but will also be influenced by the known safety profile of the drugs in pregnancy. For instance, doxycycline and primaquine are contra-indicated and pyrimethamine sulfa combinations should be used with caution. There is little information about the use of halofantrine or artemesinin and its derivatives. Quinine and chloroquine have been used extensively in pregnancy with no specific adverse findings. Mefloquine appears safe when given in the second or third trimester of pregnancy, although there has been a trend towards increased rates of spontaneous abortion in some studies (Smoak et al., 1997 Phillips-Howard et al., 1998).

Genotyping Single Nucleotide Polymorphisms

More than 99 of the genome sequence is identical across the human population. SNPs reflect the small sequence variations (often a single base change) that can occur within an individual gene. It is important to note that SNPs do not change much from generation to generation. Human genome sequencing projects have identified more than 2 million SNPs as genetic markers. Most SNPs are found outside of coding sequences, but some SNPs found within a coding sequence are of particular interest to researchers, because the change may alter the biological function of a protein. Because of the enormous potential to associate SNP maps with the development of complex diseases such as cancer, Alzheimer's, diabetes, and hypertension, researchers are feverishly working to identify thousands of useful SNP markers. For example, SNPs in the breast cancer genes 1 and 2 are associated with the development of breast cancers (Freedman et al., 2005). SNPs in the apolipoprotein E gene have been linked to a...

Twodimensional Polyacrylamide Gel Electrophoresis Protein Databases

Our laboratory has established several comprehensive 2D gel protein databases that focus on skin biology (human keratinocyte databases), bladder cancer (TCCs and SCCs) and breast cancer (tumor interstitial fluid and adipose tissue) (http Figure 2.9). With the integrated approach offered by these databases, it will be possible to reveal and identify phenotype-specific proteins and to study regulatory properties and function of groups of proteins that are co-coordinately expressed in both health and disease.

Double Helix Stabilization Dnadna Dnarna and RNARNA

Venkiteswaran et al. (12) recently studied the effects of natural and synthetic polyamines on the thermal stability of DNA-DNA, DNA-RNA, and RNA-RNA duplexes comprising a therapeutic antisense oligonucleotide targeted toward the initiation codon of the human epidermal growth factor-2 (HER-2) mRNA. The antisense oligonucleotide had the following sequence 5'-CTCCATGGTGCTCAC-3'. A major goal of this study was to examine how polyamines interacted with DNA-RNA hybrids during the use of antisense oligonucleotides for therapeutic purposes. The HER-2 gene is overexpressed in several cancers, and breast cancer patients with HER-2 overexpression have poor prognosis. Efficiency of antisense technology (i.e., the ability of a small oligonucleotide to block the translation of targeted genes) depends to a large extent on the stability of DNA-RNA hybrid formed in vivo. In addition, the antisense oligo-nucleotides have to be stable against nuclease digestion. A commonly used technique to impart...

Localized Prostate Cancer

Therefore, both radiation dose escalation and randomized series show a more pronounced effect of dose escalation in patients with intermediate risk prostate cancer. Patients with more favorable disease may not benefit from higher doses because conventional doses are adequate to eradicate these tumors. Patients with high risk disease may have a local control benefit from high dose RT however, due to the high likelihood of occult metastases, long term biochemical no evidence of disease (NED) and DFS may not be affected. For this high-risk group of patients, adjuvant hormonal therapy and possibly chemotherapy may be necessary in addition to dose escalation. It is also not clear that dose escalation is without potential toxicity with longer follow-up15 and particularly when higher doses are used, although studies in general report an improvement in late sequelae of 3D-CRT and IMRT dose escalation.17-19

Additional Types Of Tissue Microarrays

The advent of improved radiologic imaging has allowed for extremely accurate image guided needle biopsies of suspicious lesions. In prostate cancer, small prostate needle biopsies may represent the only material available from a patient as they continue with definitive radiation or chemotherapy. Ongoing prostate cancer clinical trials to test chemopreventive nutrients or drugs or to evaluate tumor progression are based around the collection of prostate needle biopsies. We have developed a method whereby these specimens can be used in the production of tissue microarrays (45). Although technically challenging, these microarrays can maximize the very limited material present in a prostate needle biopsy, such that multiple studies can be performed from the limited material.

Protein Expression Mapping

Protein expression mapping by 2D gels and mass spectrometry has also been used to identify markers specific for breast cancer (Page et al., 1999). In this study, the protein expression profiles of normal adult human luminal and myoepithelial breast cells were compared. The cell types were purified from breast tissue in sufficient quantities for proteomic studies by using an immunoaffinity cell sorting technique (Page et al., 1999). After cell lysis and protein separation by 2D electrophoresis, the proteins were detected using a fluorescent dye that binds noncovalently to the SDS moiety that attaches to proteins during SDS-PAGE. The stained gels were scanned and a computer program was used to analyze each spot between the sets of luminal or myoepithelial protein expression profiles (Page et al., 1999). A total of 170 proteins that exhibited at least two-fold changes in expression between the cell types were identified. Fifty-one of these proteins were identified by tandem mass...

Tumour Regression Assessment After Pre Operative Therapy

A 1 to 5 grading system has been proposed 84 to evaluate tumour regression. This system is based on residual disease and fibrosis, as proposed by Man-dard et al. for tumours of the oesophagus treated by neoadjuvant radio- and chemotherapy 89 . Disease downstaging is related to a much better prognosis for disease-free patients the presence of a stromal response in terms of fibrosis with scant inflammatory infiltrate and the absence of ulceration are related to a reduced disease-free survival 90 .

Clinical Management

Erythrocyte exchange transfusions are useful in severely ill patients with high levels of parasitemia and hemolysis (Jacoby et al., 1980 Cahill et al., 1981 Machtinger et al., 1993). When used in conjunction with chemotherapy, the level of parasitemia is reduced. In addition, toxic factors produced by the parasites or of host origin might be removed.

Inherited Versus Environmental Factors Twin Studies

Epidemiology studies have shown that the risk of prostate cancer among Asian men increases within two generations after immigration to North America, presumably due to adoption of a 'Western' diet and lifestyle. However, the definitive quantification of genetic versus environmental factors in prostate cancer has been provided by studies of cancer in twins. Monozygotic (MZ) twins have 100 of their genes in common. Dizygotic (DZ) twins share an average of 50 common genes. As the contribution of heritable factors increases, the observed concordance of MZ twins increases relative to DZ twins. In fact, every reported study of cancer in MZ and DZ twins reveals a higher concordance rate for prostate cancer among MZ twins, than for DZ twins. When 1649 MZ and 2983DZ unselected Swedish male twin pairs were studied, 19 versus 4 of the twin pairs were concordant for prostate cancer, respectively.1 Another large twin study followed over 31 000 US veteran twins, and found 27 concordance among MZ...

Recognizing And Quantifying The Risk Family Studies

Family studies began to provide more thorough quantification of these familial risks in the 1980s. Foreshadowing the more definitive studies with MZ and DZ twins, a study of the Utah Mormon population in 1982 by Cannon etal. reported that prostate cancer shows stronger familial clustering than both breast cancer and colon cancer.6 Using the same Utah Mormon population, Meikle and Stanish observed a fourfold increased risk of prostate cancer among the brothers of

Prevention and Control

Lymphatic filariasis is prevented by avoiding mosquito bites and mosquito control measures. It has recently been identified as a potentially eradicable disease and WHO is coordinating efforts towards this end. These efforts entail both environmental vector control (e.g. adequate maintenance of open drains and septic tanks, spraying a film of oil over water surfaces, the addition of larvivorous fish to ponds and the use of larval insecticides) and mass chemotherapy. It has recently been shown that single annual doses of diethylcarbamazine and or ivermectin have potent, sustained activity in reducing microfilaraemia and that additional treatment with albendazole has macro-filaricidal activity (WHO, 1992 Ottesen and Ramachan-dran, 1995). These findings lay the foundations for a successful international eradication campaign.

Current Clinical Application And The Potential For So Much More

When major susceptibility genes, and or specific combinations of minor effect genes, are in fact identified and characterized, it will be possible to offer gene testing to high-risk individuals among HPC families, in addition to risk assessment and genetic counseling. This will also allow for an individualized measure of prostate cancer risk, following a model of genetic assessment similar to that currently used in hereditary breast cancer care. Such a measure will allow individuals at highest risk to pursue more frequent screening and more aggressive preventative measures, while also helping to ease the concerns of individuals who are at low risk and do not carry an HPC gene. This means the ultimate in patient specific preventative medicine for prostate cancer is on the near horizon, while the more distant horizon may hold dramatic changes in the way we treat prostate cancer by including molecular medicine and pharmacogenetics.

Screening And Prevention

Survival rates for breast cancer and prostate cancer are significantly improved when the disease is discovered in an early, localized stage, and this has prompted screening efforts for both of these cancers. For breast cancer, recent data suggest that screening should begin early, at age 40, with a yearly mammogram and physical examination.17 In addition, women are encouraged to begin monthly self-examination at age 20 and a clinical breast examination is recommended every 3 years between the ages of 20 and 39. Women with a strong family history of breast cancer, particularly early onset or bilateral disease, should begin formal screening with mammography and physical examination earlier in life, although the exact age for this has been controversial. Policy for screening for prostate cancer remains a topic of debate, but most urologists have followed the recommendations of the American Urologic Association, screening with digital rectal examination (DRE) and serum PSA beginning at...

Metastatic Profile Osseous Metastases

It has long been recognized that both prostate and breast cancer belong to a well-defined group of tumors that readily metastasize to bone. One autopsy series reported that 64 and 66 of patients with metastatic breast and prostate cancer, respectively, had metastases to the bone.44 There are important differences, however, most notably being the pattern of bone metastasis seen in each of these cancers, i.e. typically osteoclastic in breast cancer and osteoblastic in prostate cancer. In an effort to further characterize this phenomenon, researchers have identified several osteoblast-stimulating factors produced by prostate cancer cells, such as bone mor-phogenic proteins, osteoblast mitogenic factor, prostatic osteo-blastic factor and bone phosphatase-elevating factor. Other studies have suggested that insulin-like growth factor binding proteins sequestered in the bone matrix, which normally inhibit the osteoblastic activity of insulin-like growth factors, may undergo PSA-dependent...

Support of Patients During Treatment and Followup

One challenge for all practitioners dealing with cancer patients is that of offering shared decision-making capacity. With thyroid cancer, the treatment protocols for most will be relatively inflexible, and patient choice will be limited to whether to agree to treatment or not. However, studies in breast cancer patients indicate some women want an active role in decision-making. Degner et al. showed that women with higher levels of education and who were younger wanted to be more actively involved in decision-making. However only 30-40 of patients achieved the role they preferred for themselves 20 . These findings may not be transferable to other cancer patients it has been shown that patients with colorectal cancer had a lower proportion of patients wanting to have an active decision-making role than was the case with breast cancer patients 21 .

Lowfat diets and dietary factors

Increased consumption of dietary fiber is considered to have salutory effects, particularly with respect to preventing colon cancer and possibly breast cancer.70 Interestingly, some foods behave differently depending on subtle differences in preparation. For example, if potatoes are eaten hot the starch is totally digested in the small bowel, but behaves as fiber if the potatoes are eaten cold.70,71 However, there is no evidence for a protective effect of dietary fiber on urological malignancies.

QoL Research or Clinical Instrument

Nowadays, evidence is accumulating to suggest that QoL per se plays a role as a prognostic factor. Baseline QoL predicts survival in different types of cancer, such as myeloma 28 , head and neck cancer 29 , breast cancer 30 and oesophageal carcinoma 31 . Also, two large cohort studies 32, 33 reached the same results by analysing different malignancies. The first studies on rectal cancer obtained the same results. Earlam 34 demonstrated that a better QoL (measured by the Rotterdam Symptom Checklist Score) was associated with improved survival in patients with colorectal liver metastasis. Maisey et al. 35 retrospectively analysed patients with advanced colorectal cancer enrolled in 4 different clinical trials for testing different chemotherapy regimens. They found that baseline QoL was an independent prognostic indicator in all the patients involved in these four phase III clinical trials. Both previous studies take account of patients with advanced stage disease (inoperable cancer) and...

Potential Side Effects of Statins

Fatal heart attack and breast cancer rates in the CARE trial (Pravastatin) Death from heart attack Case of breast cancer Evaluation by Ravnskov 2000 The merits (a marginal reduction of death from coronary heart disease) and demerits (increased incidence of breast cancer) by statin treatment as shown in this table need to be critically evaluated.

Data Acquisition Storage And Analysis

Success Rate The ability to locate SLN in all basins identified by preoperative lymphoscintigraphy. Note that in the literature, this is not the biopsy of all nodes identified on nuclear scans it is the biopsy of at least one node from each basin found to contain at least one SLN by lymphoscintigraphy. The expected rate for melanoma should approach 100 . The rate for breast cancer, with its documented longer learning curve, should be above 90 within the first 20-30 cases. Yield Number of sentinel nodes biopsied per patient (sometimes broken down per basin). Generally, for both melanoma and breast cancer, a mean of 1.5-2.0 SLN are biopsied per patient, with an upper range of 5-6 nodes. Positivity Percentage of patients who will have lymph node metastases identified by SLN pathologic examination. This number varies with patient diagnosis and known primary lesion prognostic factors, principally tumor size for breast cancer and Breslow thickness and ulceration for melanoma. This rate will...

P53 Tumour Suppressor Gene Mutations

In the other couple, the 39-year-old mother with LFS was a carrier of 902insC mutation of the p53 tumour-suppressor gene, representing an insertion of C in exon 8. She was diagnosed with breast cancer at the age of 30, followed by bilateral mastectomy. She also had thyroid cystocarci-noma, which was also removed. Her mother died from stomach cancer at age 51. One of her sisters, diagnosed with breast cancer at age 48 followed by mastectomy, also died at age 51. Two of her four brothers were diagnosed with bone or brain tumours at their teens (Figure 3.19).

Maternal and Child Risks

The use of ARTs and ovulation promotion has raised concern about potential risks to the women who undergo these procedures and the children who are conceived as a result. Some investigators have speculated about the effects of fertility drugs on the risk of breast cancer and cancers of the reproductive system. A study by Klip and colleagues (2000), in which a cohort of women in The Netherlands was monitored for 5 to 8 years, found no increase in the risk of breast cancer or ovarian cancer in women who underwent IVF compared with that in subfertile women who had not undergone IVF. The study also found that both women who had undergone IVF and subfertile women did not have an increased risk for endometrial cancer. The authors suggest a potential link between endometrial cancer and subfertility.

Pre Operative Local Staging Assessment

An accurate pre-operative staging of rectal cancer is of dramatic importance for successful local treatment. Digital examination, endorectal ultrasonography (EUS), magnetic resonance imaging (MRI) and computed tomographic scanning (CT) are all valuable tools that play an important role in the staging process of rectal malignancies, and basically help identifying those patients who should be treated by radical resection, those amenable to LE, and those in whom neoadjuvant radiation and chemotherapy should be recommended first.

Management Plan for Recurrent or Metastatic Thyroid Cancer

Once recurrent or metastatic cancer has been diagnosed, consultations within the multidis-ciplinary team should lead to the most appropriate management plan. For recurrence in the thyroid bed or cervical lymph nodes, surgical re-exploration usually followed by 131I therapy is mostly preferred. Bone metastases can be treated with 131I, external radiotherapy, embo-lization, or orthopedic intervention. Metastases in the lungs and elsewhere not amenable to surgery can be treated with 131I. In otherwise uncontrolled end-stage disease chemotherapy with doxorubicin and cisplatinum has been tried, with limited success.

Ursula A Germann 1 Introduction

The simultaneous resistance of cells to multiple structurally and functionally unrelated cytotoxic agents is known as multidrug resistance (MDR). The phenomenon of MDR was first observed in the clinic in tumors of patients undergoing chemotherapy. Multidrug resistance was recognized as a major factor contributing to the failure of chemotherapeutic treatment of cancer (1) Multidrug resistance also occurs in cultured cells selected for resistance to anticancer drugs (2,3). Exposure of cultured cells to a single cytotoxic agent, e.g., Adriamycin (or doxorubicin) will enhance their resistance to anthracychns and related agents (daunorubicm, idarubicin, mitoxantrone), as well as to Vinca alkaloids (e.g., vincristine, vinblastine), epipodophyllotoxins (VP-16 etoposide and VM-26 teniposide ), and other anticancer drugs (e.g., actmomycm D, mitomycin C, and topotecan) (4,5). Numerous cell lines have been established as in vitro model systems to demonstrate the clinical relevance of MDR, to...

Advances and Insights from Pharmacological Studies

Ondansetron, an anti-nausea drug best known for its use in cancer chemotherapy, has been reported to be effective in reducing drinking, especially in patients with early-onset alcoholism (before age 25) 81 . In their discussion, the authors speculate that ondansetron changes the balance of activity among the neurotransmitters dopamine and serotonin. In particular, it reduces the activity at one of the serotonin receptors, 5-HT3 in previous animal studies, blocking this receptor had been found to reduce the consumption of alcohol. It is hypothesized that early-onset alcoholics may carry a genetic variant of the receptor that makes them more vulnerable to the addictive effects of alcohol. Interestingly, the blood test used to measure alcohol use in this study is a new one it measures carbohydrate-deficient transferrin (CDT), which accumulates in the blood with sustained heavy drinking, as haemoglobin Aic does in diabetes, and persists at elevated levels for weeks after drinking stops....

Dominance and Recessiveness of Mutations in Tumors

Such second hits, the disease can affect multiple generations in a typical autosomal dominant pattern. Other familial cancer syndromes such as breast cancer associated with BRCA mutations show a similar pattern of dominance within families but recessiveness at a molecular level.

Differential Item Functioning

Groenvold et al. (1995) tested the EORTC QLQ-C30 for item bias, using data from 1189 surgically treated breast cancer patients with primary histologically proven breast cancer. They examined each of the 30 items, using age and treatment (whether they received adjuvant chemotherapy or not) as the two external variables for forming patient subgroups. Groenvold et al. note that the bias seen here may reflect an effect of chemotherapy (mainly given to patients below 50 years of age) some patients may have been in bed owing to nausea, not to a bad overall physical function. Groenvold et al. also found that the pain item Did pain interfere with your daily activities and the cognitive function item Have you had difficulty remembering things were biased in relation to treatment.

Questionnaire Development and Scoring

Before considering the issues to be addressed by the instrument, it is essential to establish the specification of the target population. What is the range of diseases to be investigated, and are the symptomatology and QoL issues the same for all disease subgroups What is the range of treatments for which the questionnaire should be applicable For example, in cancer there can be a wide range of completely different treatment modalities, from hormonal treatment to surgery. Even within a class of treatments, there may be considerable variability the drugs used in cancer chemotherapy include many with completely different characteristics and toxic side-effects. A QoL instrument that will be used for more than the immediate study should ensure that it is appropriate for the full range of intended treatments. Similarly, patient characteristics should be considered. For example, what is the age range of the patients, and might it include young children who have very different priorities and...

ATPBinding Cassette Superfamily

The most extensively studied drug transporter, and the paradigm for the ABC transport superfamily, is P-glycoprotein (P-gp), the product of the mdrl (multidrug resistance) gene (69-71). This transporter was discovered during the 1970s through studies of chemotherapy-resistant tumors in cancer patients. Multidrug resistance can be acquired both by patients receiving chemotherapy and by cultured cells exposed to chemotherapeutic agents in vitro. Cells, which

Representative Sample

Whom the QoL issues might vary, it is important to ensure that there is adequate representation of all these types of patients, and the sample size may have to be increased accordingly. Thus if a QoL questionnaire is intended to address issues associated with different modalities of treatment, it should be tested separately with patients receiving each of these forms of therapy. For example, an instrument for cancer patients could be tested in those receiving surgery, chemotherapy or radiotherapy. It is crucial to ensure that patients with each of these cancers are able to complete the questionnaire without difficulty, distress or embarrassment, and that all patients feel the relevant issues have been covered.

Reducing the risk of infection

The most logical approach to the control of the infection is to reduce transmission whilst providing humane care for patients. The role of chemotherapy in the control of the disease is expanding but it is limited in developing countries because of the high cost of the drugs and the complexity of the schedules as well as the demanding close monitoring of the patients. The most important tool is modification of human behaviour through education directed at each of the four modes of transmission

B Late Toxicity B2 Breast Appearance

The main goals of breast conservation therapy in early stage breast cancer are to provide primary tumor control comparable to mastectomy and to preserve an acceptable cosmetic appearance of the breast. An unsatisfactory cosmetic outcome should be considered as a potential late toxicity. The rate of poor or fair cosmetic outcome in most series is 15 20 or less.42-46'48-50 It has been demonstrated in many studies that surgical factors including the extent or volume of surgical resection45'46 and scar orientation,45 have the largest impact on breast appearance and the cosmetic outcome.42-47 The use of chemotherapy and patient factors such as breast size, older age, and race have also been associated with more frequent cosmetic failures.42-47 However, several radiation treatment factors are associated with poorer cosmetic outcomes as well. It is important to consider these factors when planning radiation treatment to minimize the late toxicity rate. Table 7 lists the cosmetic outcomes...

Medical Condition Category

Current breast cancer 4 H o breast cancer 3 Similar to progestin only pills, Depo-Provera has only one true contraindication, that of current breast cancer. There are several other conditions for which it may not be the most appropriate method (Table 7.6). In general, Depo-Provera is safe and well tolerated and should remain a powerful component of one's contraceptive armamentarium.

Hepatocellular carcinoma 103

M Medical Chemotherapy and radiotherapy have limited role as adjuvant therapy to surgery, but may be used to control unresectable disease temporarily. Examples of chemotherapeutic agents include doxorubicin and carboplatin. Surgical Liver resection is indicated if localised to a single lobe. Liver transplantation can be considered if the tumour is small and the liver cirrhotic. Embolisation Useful for single solitary lesions in cirrhosis. Ablation Useful to shrink tumours not amenable to resection. Radiofrequency, cryoablation, or percutaneous ethanol injection are used.

Bayesian Trial Designs

Bayesian approaches currently find little understanding on the part of regulatory authorities, and thus are, probably unduly, little utilized by generalist pharmaceutical physicians. However, Baye-sian methods are finding increased uses in specialized areas, e.g. trials of cancer chemotherapy, and studies in rare diseases. The potential benefits of Bayesian methods include the use of fewer patients to demonstrate efficacy, as well as potential seamlessness of Phase II and Phase III development when the number of drugs or dose sizes of interest has been reduced during the trial from several to one or two patients recruited after this transition may be regarded as patients in a pivotal trial by an enlightened regulatory authority.

Toxic Clinical Effect

In the near future, it is likely that genomics and proteomics will expand the current repertoire of bio-markers. Pharmacogenomics already has played an important role in the mechanism-driven development of trastuzumab and several other oncology drugs (59). The observation that the HER2 gene, which encodes the HER2 epidermal growth factor receptor, is overex-pressed in 25-30 of breast cancer patients and is correlated with increased tumor aggressiveness, led to the successful development of traztuzumab, a humanized monoclonal antibody directed against the extracellular domain of this receptor (60). HER2 overexpression not only served as a useful biomarker during many phases of traztuzumab development (59), but now provides the labeled indication for prescribing the drug (61).

Coping and adjustment

Skin disease however, is not only an individual's problem. It is an interpersonal issue that has psychological consequences for both partners. Most couples share responsibility in solving difficulties (Skerrett, 1998), thus when one partner has a skin disease, it is important to know what kind of support is helpful An interesting study of breast cancer patients and their partners revealed that following diagnosis, husbands provided greater support as their wives' physical impairment increased, but less support as wives' emotional distress increased (Bolger et al., 1996). This confirms the tendency among wives to engage in interpersonal and emotion-focused coping and a propensity among husbands to prefer interpersonal distance during periods of stress (Gottlieb & Wagner, 1991). Similar gender effects could operate in couples with skin disease, which suggests that emotional reactions to disfigurement, may at times, reduce chances of receiving empathic support when it is needed most.

Primary and secondary control

While other approaches to schistosome control merely reduce transmission without any direct effects on human worm load, chemotherapy reduces the output of live eggs from the patient's body and, in doing so, diminishes transmission. Moreover, killing worms in the treated individual not only reduces the risk of morbidity and mortality due to the disease, but also enables the patient to recover from reversible lesions. It is important to distinguish between these two beneficial effects. The second, a fall in disease risk, benefits only those who are treated, while the first, a reduction in transmission, helps the whole community. Even when the reduction in transmission is incomplete, the fall in disease risk may still be considerable. Chemotherapy is thus a tool for both primary and secondary control of schistosomiasis. The choice between mass chemotherapy, selective chemotherapy and targeted chemotherapy depends upon balancing maximum control with safety and economic consideration. The...

Therapy Of Cancerassociated Osteolysis

Bone metastases are associated with several clinical sequelae, including bone pain, neuralgia, pathologic bone fracture, and myelophthisis. Thus, targeting these lesions has received much research effort. Bisphosphonates are a group of chemicals that inhibit osteoclast activity, resulting in decreased bone resorption and, thus, have received much attention as inhibitors of clinical complications of bone metastases (178-180). Bisphosphonates work directly on osteoclasts to induce their apoptosis (181,182). Animal studies have demonstrated that bisphosphonates can diminish tumor-induced osteoclastogenesis and osteolysis (183-187). In some instances, they seem to only reduce tumor-induced lysis, but not tumor burden (188). Studies in breast cancer and myeloma patients have shown that these agents markedly inhibit the progression of bone disease, resulting in improved survival and decreased morbidity from bone pain and fracture (189,190). These results have led to their incorporation into...

C Infrared or Near Infrared Light

Studies on diabetic rats indicated significant increases in the amount of collagen and in tensile strength of light-treated wounds over controls (Stadler et al., 2001 Reddy et al., 2001). In combination with hyperbaric oxygen, light-treated skin wounds in rats closed faster (Yu et al., 1997), an effect that was associated with a more uniform rise and fall in VEGF and FGF-2 instead of the sharp peaks at day four and subsequent rapid drop-off observed in control wounds (Whelan et al., 2001). In vitro, proliferation of mouse fibroblasts was increased by over 150 and that of human epithelial cells by 155 -171 (Whelan et al., 2001). Whelan et al. (2001) also reported that wound-healing time was decreased by 50 aboard a submarine, where the atmosphere is lower in oxygen and higher in carbon dioxide, and that children suffering from oral mucositis as a result of chemotherapy experienced a 47 reduction in pain.

The Systematics Of Image Interpretation

Knowledge of the consequence of a particular decision. Consider, for example, the hypothetical situations of a clinician using an ultrasound scanner, first of all to screen a population of predominantly healthy women for possible signs of breast cancer, and, secondly, to examine a woman with a previously detected breast lump in support of a decision on whether major surgery should be undertaken. In the first case, the statistical expectation of an abnormality will be very low, but the consequence of a high false-positive rate will be the relatively mild one of an excessive number of patients undergoing further examinations. Thus there could be a valid bias towards achieving high sensitivity at the cost of decreased specificity. In the second case the expectation of a serious abnormality will be much higher, but the investigator will need to be able to convey to the referring surgeon the degree of confidence that can be attached to the eventual assessment.

Johanna C Bendell Md Christopher Willett Md

The upper gastrointestinal tract lies within the radiation field for most thoracic and abdominal cancers. Toxicity to the upper gastrointestinal tract often limits the radiation doses that can be given. Radiation therapy causes both acute and late effects. The acute effects of radiation include mucosal denudation, while late effects consist of fibrotic changes leading to decreased mobility and ischemia. Multifield and conformal radiation therapy, as well as patient positioning techniques, reduce the volume of normal tissue exposed to radiation and can decrease the potential toxicity. However, the treatment of radiation toxicity is mainly supportive. The increasing use of concurrent chemotherapy and radiation therapy has required enhanced awareness of potential effects and better methods to decrease toxicity, as this combination oftreatments is associated with a higher rate of gastrointestinal toxicity. The first part of this chapter will review the pathologic changes of acute and...

Types Of Missing Data

Curran et al. (1998b) give the Kaplan-Meier plot (Figure 11.1) of time on protocol treatment for breast cancer patients with newly diagnosed bone metastases. The median time on treatment was 6.4 months. The patients were requested to complete a QoL questionnaire pre-treatment, monthly for the first seven months and three-monthly thereafter until progression.

Apoptotic Pathways in Tumor Progression and Therapy

Abstract Apoptosis is a cell suicide program that plays a critical role in development and tissue homeostasis. The ability of cancer cells to evade this programmed cell death (PCD) is a major characteristic that enables their uncontrolled growth. The efficiency of chemotherapy in killing such cells depends on the successful induction of apoptosis, since defects in apoptosis signaling are a major cause of drug resistance. Over the past decades, much progress has been made in our understanding of apoptotic signaling pathways and their dysregulation in cancer progression and therapy. These advances have provided new molecular targets for proapoptotic cancer therapies that have recently been used in drug development. While most of those therapies are still at the preclinical stage, some of them have shown much promise in the clinic. Here, we review our current knowledge of apop-tosis regulation in cancer progression and therapy, as well as the new molecular targeted molecules that are...

Selective estrogen receptor modulators SERMs

Tamoxifen 1 risk of contralateral breast cancer in adjuvant setting risk-benefit unclear when given as 1 prevention in Pts at T risk I invasive breast cancer, butr DVT & uterine CA risk, and t in all-cause mortality (lancet 2002J60.817) Raloxifene i risk of invasive breast cancer & vertebral fx. 1 risk of stroke & DVT PE (rutrnqai 2006 355 125) - tamoxifen in prevention of breast cancer w 1 risk of DVT PE & cataracts, trend towards 1 uterine cancer (star.jama 2006 295 2727) Prophylactic bilateral mastectomy (NEJM 2001 345 159) and bilateral sal pi ngo-oophorectomy (i risk of ovarian and breast cancer, nejm 2002 346 160*jama 2006 296.185) are effective.

Development of New Vitamin D Analogs and Their Use in Combination Therapy for Prostate Cancer

Agents that either promote vitamin D responsiveness or reduce the hyper-calcemia are used. The regimens used for vitamin D combination therapy include the chemotherapy drug (Paclitaxel, Taxotere),42'43 anti-mitotic agents (Genistein),44 differentiation agents (retinoic acid),45'46 and the agents that modulate vitamin D VDR action (Dexamethasone).47 All regimens were shown to potentiate the anti-tumor effects of vitamin D and reduce vitamin-D associated hypercalcemia in prostate cancer cells and animal models, yet detailed mechanisms are not yet known and more clinical trials need to be done.

United States Preventive Services Task Force Recommendations

Recommendations for population-based screening that earned grade A (strongly recommended) or grade B (recommended) in a 2006 review for adult men and women are the following obesity, depression, and high blood pressure screening for persons of all ages, syphilis screening for persons at increased risk, colorectal cancer screening at age 50, diabetes type 2 screening for adults with hypertension or hyperlipidemia, and lipid disorder screening per age and gender (men, age 35 women, age 45) ( Guide to Clinical Preventive Services, 2006). Additional procedures are recommended for women breast cancer screening (mammography) at age 40, cervical cancer screening if sexually active, chlamydial infection screening women 25 and younger or at increased risk, and osteoporosis screening for women 65 or older, postmenopausal, or at increased risk for osteoporotic fractures. Men age 65-75 with a history of ever smoking should be screened for abdominal aortic aneurysm via...

Vitamin DBased Clinical Trials

Evidence accumulated from both experimental and epidemiological studies supports the idea that vitamin D could be used as a therapeutic drug to control prostate cancer, and several vitamin D-based clinical trials have been conducted, mainly enlisting patients with advanced androgen-independent prostate cancer (AIPC). Pilot studies from small numbers of patients that took daily orally doses of calcitriol found that the PSA levels in those patients were significantly lower before calcitriol therapy. However, there is incidence of hypercalciuria or hypercalcemia, and the development of renal stones in some patients, which limits its clinical usefulness.35 One Phase I clinical trial was conducted by injection of calcitriol subcutaneously every other day in the advanced malignancy patients and tested the tolerable toxicity via this route.48 Then, different calcitriol-based clinical trials, with either modifications in the schedules and route of administration, or combinations with...

Future Perspectives

Qi X, Pramanik R, Wang J, et al. (2002) The p38 and JNK pathways cooperate to trans-activate vitamin D receptor via c-Jun AP-1 and sensitize human breast cancer cells to vitamin D(3)-induced growth inhibition. J Biol Chem 277 25884-25892. 32. Weitsman GE, Ravid A, Liberman UA, Koren R (2003) Vitamin D enhances caspase-dependent and -independent TNFalpha-induced breast cancer cell death The role of reactive oxygen species and mitochondria. Int J Cancer 106 178-186. 36. Trump D, Lau YK (2003) Chemotherapy of prostate cancer present and future. Curr Urol Rep 4 229-232.

Choice Of Health States

Suppose a patient with operable lung cancer has the tumour surgically removed, so that in practical terms the patient is (almost) free of disease and hence symptom-free. However, post-operative chemotherapy of three cycles is given to sterilize any potential metastases. During the course of chemotherapy the patient experiences severe toxicity for 5, 3 and 7 days respectively following each cycle of chemotherapy. Thereafter the patient remains without either symptoms or toxicity until the disease recurs at 250 days after surgery when symptoms also reoccur and he dies 50 days later. Here TOX 5 + 3 + 7 15, TWiST 235, REL 50 and OS 15 + 250 + 650 300 days.

Timing of the Perineal Colostomy and Electrostimulated Graciloplasty

The perineal colostomy could be performed at the time of the Miles' operation but this is not recommended because of the risk of local recurrence. A minimum period of 2 years of oncological follow-up should be long enough to exclude patients at risk for local recurrences and to overcome the effects of adjuvant chemotherapy. Failure to follow this obvious rule can lead to a high failure rate, as recently reported by Ho and Seow-Choen 17 .

Predicting Recurrence From Expression Signatures

As an alternative to studies profiling aggressive and metastatic samples in an attempt to understand CaP progression, several groups have attempted to use expression patterns to predict which patients will demonstrate biochemical or clinical recurrence after treatment. These studies have been encouraged by demonstrations that microarray profiling can stratify patients into good prognosis vs bad prognosis groups in other cancers, including diffuse large B-cell lymphoma (55,56), acute lymphoblastic leukemia (57), acute myeloid leukemia (58,59), and breast cancer (60). In addition to providing valuable diagnostic markers, functional examination of implicated genes should aid in understanding the molecular alterations that drive CaP progression.

Orphan Receptors that Bind as Monomers

Of normal development of midbrain dopaminergic neurons and die soon after birth. These findings implicate the NGFI-B family members as critical players in neuronal differentiation and function however, the exact roles need to be elucidated. NGFI-B and Nurr1 play a role in regulation of the hypothalamic-pituitary-adrenal (HPA) axis through the regulation of corticotropin releasing factor (CRF) and POMC (proopiomelanocorticotropin), a precursor for several neuropeptides including adrenocorticotropic hormone (ACTH). NGFI-B also regulates CYP21, a steroid hydroxylase gene encoding an enzyme involved in glucocorticoid and mineralocorticoid biosynthesis. In addition, NGFI-B plays a role in programmed cell or apoptosis of T cells following T-cell antigen receptor (TCR) stimulation. However, NGFI-B knock-out mice do not exhibit grossly abnormal functions of the HPA axis or TCR-mediated apoptosis, suggesting a possible redundancy among NGFI-B family members. These receptors may play a role in...

New Prognostic And Riskstratification Factors

Although the median duration of survival in men with AIPC is approximately 12 months, the heterogeneity of response to chemotherapy suggests the existence of subgroups of responsive and non-responsive disease. Therefore, prediction of response for the individual patient is impossible. Most of the risk stratification or prognostic factors in AIPC are associated with tumor burden (high PSA, alkaline phosphatase) and patient status (performance scores, weight loss). New methods of disease evaluation may be useful in tailoring therapy to both risk and response. If the significant survival benefit associated with a negative RT-PCR reflects properties of the tumor cell itself, molecular characterization of the differences between circulating and non-circulating cells could provide further therapeutic targets. In the future, technologies such as RT-PCR could assist with stratification of risk-benefit ratios for all interventions, from prostatectomy to salvage chemotherapy.

Decreasing Estramustine Toxicity

Given these confusing results, the necessity of determining the appropriate dose and schedule of estramustine remains paramount. Two small studies reported in abstract form attempt to address this question.29,30 In the first cohort, consisting of an 8-week cycle, estramustine is dosed at 420 mg three times per day (TID) on days 1-4, with docetaxel administered on day 3 weekly for 6 weeks (5040 mg of estramustine 8 weeks). In the second cohort, consisting of a 6-week cycle, estramustine is dosed at 420 mg X4 on days 1 and 2, and 280 mg X5 on day 3, with docetaxel administered on day 2 weekly X2 (4700 mg estramustine 6 weeks). Eighteen patients were enrolled, 12 of whom had received prior chemotherapy. Fourteen patients (78 ) had a PSA response. Four patients with measurable disease had objective responses. Twelve patients had symptomatic improvement or an increase in performance status. Although only 18 patients were studied, the comparable results in terms of PSA and measurable...

Assessment During Therapy

Frequently, for administrative convenience, assessment times during treatment will be chosen to coincide with patient visits to the clinic. For diseases such as long-term treatment for hypertension, patients' condition may be expected to be relatively stable and so the precise time point may not be critical. In this situation, timing of QoL assessment becomes relatively easy. For other diseases, such as cancer, patients commonly attend at the start of each course or cycle of chemotherapy treatment, with the patient completing the QoL questionnaire whilst waiting to be reassessed by the clinician. However, some QoL instruments specify a time frame of during the last week . . . , and will therefore collect information about how the patient recalls feeling only during the week preceding the next course of therapy. If treatment courses are for example pulsed at intervals of three to four weeks, this may or may not be what is ideally wanted, as the impact of transient toxicity might remain...

Introduction and notations

It is often of high interest to study simultaneously the times to several events for example, in breast cancer, one can be interested in studying the time until a tumor appears for both breasts, and in this case, the times to failure for a female patient are correlated. Suppose that the sample of size n is composed of two groups, A and B, with respective sizes ha and hb , and that each subject may experience K 1 events, possibly censored. For an easier understanding, let K 2, but generalization to K 2 is immediate. For k 1, 2 and j A, B, let A3k be the cumulative hazard function for event k in group j. The null hypothesis AA AB can be tested with rank tests when there is no censoring, or with weighted logrank statistics in the censored case ( GEH65 MAN66 COX72 PETO72 PRE78 HF82 ). But these test statistics can not be used if we are interested in testing H0 AA AB, AA AB because of the dependence between the failure times. In 1984 Wei, L. J. and Lachin, J. M. WL84 proposed a test...

Orphan Receptors That Have Set a Precedent for Drug Discovery

During the past few years, the identification of therapeutic agents acting through two different orphan receptors, RXRs and PPARs, has provided an important proof-of-principle for orphan receptors as targets for future drug discovery efforts. Research on both receptors has led to the development of new drugs that are currently being used to treat diseases such as lymphomas, leukemias, breast cancer, HIV-related Kaposi's sarcoma, and type II diabetes. These two receptors provide examples illustrating the potential for orphan receptors as bona fide molecular targets for drug discovery.

Antiangiogenesis agents

This study, while appearing to provide only a minor role for thalidomide in AIPC, must be viewed in the appropriate context. First, the mechanism of antiangiogenic agents could be to reduce the potential for metastatic growth. In comparison to chemotherapy, their role may be considered cytostatic as opposed to cytotoxic. Thalidomide and other antiangiogenesis agents may be best suited for patients with a low disease burden. In this study, however, patients had markedly advanced disease and were heavily pre-treated. Additionally, in vitro data have suggested that thalidomide may up-regulate the secretion of PSA in certain prostate cancer cell lines.48 If this holds true in vivo, even small declines in PSA may correlate to a significant amount of tumoricidal activity. Further studies in this area are eagerly awaited.

Non Surgical Treatment of Local Recurrence

Although surgery plays the major role in therapy for recurrent local disease, other modalities of therapy should be considered. Maintenance of chemotherapy as a component of an aggressive treatment approach is recommended, because a local relapse is a prelude of distant metastases in about 50 of cases 54 .

Mechanisms of Uptake of 18Ffluorodeoxyglucose

In addition to malignant tissue, 18FDG uptake may be seen in activated inflammatory cells 7,8 , and its use has even been advocated in the detection of inflammation 9 . An area where benign inflammatory uptake of 18FDG may limit specificity is in the assessment of response to radiotherapy 10 . Here uptake of 18FDG has been reported in rectal tumours and in the brain in relation to macrophage and inflammatory cell activity 11-13 . This may make it difficult to differentiate persistent tumour from inflammatory activity for a number of months following radiotherapy in some tumors. Non-specific, inflammatory and reactive uptake has also been recorded following chemotherapy in some tumours 14,15 , and there is no clear consensus on the optimum time to study patients following this form of therapy.

Weaknesses of Current Cancer Biomarkers

Seven percent of ovarian tumors are metastases originating from primary lesions in the gastrointestinal tract (Wauters et al., 1995). This makes primary ovarian and metastatic colon carcinomas difficult to diagnose. Because ovarian and colon cancer chemotherapies differ dramatically, misdiagnosis can result in inappropriate drug therapy and thereby delay effective treatment of both the primary and meta-static tumor (Lagendijk et al., 1998). Epithelial tissues differ in their pattern of keratin expression and this pattern is often maintained in carcinomas and their metastases therefore, keratin subtypes have been used to determine the site of origin of the metastatic tumor. Two such keratins are currently in use for this purpose. CK7 is ubiquitously present on ovarian carcinomas, but not on colon carcinomas. CK20 shows the opposite pattern of expression. These biomarkers appear promising at first glance, but in fact predict the primary site in metastatic carcinomas only 60-80 of the...

Anaplastic Thyroid Carcinoma

ATC typically presents clinically as a rapidly enlarging neck mass in the thyroid area. This is usually associated with compression signs, such as dyspnea and dysphagia. The duration of the disease is short, ranging from a few weeks to a few months. At the time of diagnosis, at least 50 of patients harbor metastases in the lung, bone, or brain 44 these sites of potential disease spread should be carefully screened at the time of initial diagnosis. Surgical excision is the first line of therapy, although in most cases the tumor is so widespread or invasive that total removal is impossible. Nevertheless, surgery may be necessary to relieve compression symptoms. 131I and THST are completely ineffective for ATC therapy, while multidrug chemotherapy (doxorubicin- or paclitaxel-based) has very minimal or no impact in prolonging survival

Benign Causes of 18FDG Uptake

Cumulation in macrophages and other activated inflammatory cells 7, 8 . In oncological imaging, this inflammatory uptake may lead to decrease in specificity. For example, it may be difficult to differentiate benign postradiotherapy changes from recurrent tumour in the brain, unless the study is optimally timed or unless alternative tracers such as 11C methio-nine are used. Apical lung activity may be seen following radiotherapy for breast cancer, and moderate uptake may follow radiotherapy for lung cancer 36 . It may also be difficult to differentiate radiation changes from recurrent tumour in patients who have undergone radiotherapy for rectal cancer within six months of the study 12 .

Coactivators in Disease States

Since their initial characterization, several nuclear receptor coactivators have been implicated in disease states. AIB-1 hSRC-3 is consistently overexpressed in a high percentage of primary breast tumors and cultured breast cancer cell lines, often against a background of relatively low expression levels of SRC-1 and SRC-2 TIF2. These results indicate that AIB-1 hSRC-3 is involved in breast tumorigenesis, and that the selective advantage that this overexpression evidently affords is not constrained by the comparatively low levels in these tumors of SRC-1 and TIF2. There are also instances where levels of coactivator are normal, but their affinity for a specific receptor is reduced, as is the case with the TR in patients with generalized resistance to thyroid hormone (GRTH). A variety of TR mutations in GRTH patients are now known to affect the interaction of these TR mutants with coacti-vators such as SRC-1. A TR AF-2 mutant, E457D, which bound hormone normally and recruited NCoR in...

Planning the PET Service

When setting up a clinical PET service it is important to consider the types of scans that will be offered. When deciding which protocols are going to be used, the most important thing to consider is what question is being asked of PET. This may not always be clear in the initial referral, and it is important that this is established prior to the study so that PET is not used inappropriately. Other things to consider are whether quantification (for example, a semi-quantitative standardized uptake value (SUV) 1,2 ) of the data will be required as this can only be performed on attenuation corrected studies. It is also important to know whether the patient is a new patient or is attending for a PET study as part of their follow-up. If they are for a follow-up scan it is essential to know what treatment they have had and, critically, when this treatment finished or was last given. Following the completion of chemotherapy, approximately 4-6 weeks should elapse before the patient is...

Chimeric haemopoietic growth factors

Hochaus S, Wassmann B, Egerer G (1998) Recombinant human granulocyte and granulocyte-macrophage colony-stimulating factor (G-CSF and GM-CSF) administered following cytotoxic chemotherapy have a similar ability to mobilize peripheral blood stem cells. Bone Marrow Transplantation 22 625-30. Lee S, Radford J, Dobson L (1998) Recombinant human granulocyte colony stimulating factor (filgrastim) following high dose chemotherapy and peripheral blood progenitor cell rescue in high grade non-Hodgkin's lymphoma clinical benefits at no extra cost. British Journal of Cancer 77 1294-9. Sheridan WP, Begley CG, Juttner CA etal. (1992) Effect of peripheral-blood progenitor cells mobilized by filgrastim (G-CSF) on platelet recovery after high dose chemotherapy. Lancet 339 640-4.

Microtubule Inhibitors and Induction of Apoptosis

Like DNA-damaging agents, microtubule inhibitors also lead to the phosphorylation and stabilization of p53 as a mechanism for drug-induced apoptosis (Blagosklonny, 2002 Wang et al., 1999). However, in MCF-7 breast cancer cells, inactivation of p53 does not affect cellular sensitivity to paclitaxel killing. In those cells, p53 may act as a survival factor by blocking them in the G2 M phase, rather than serving as an apoptotic inducer. By contrast, the transcription factor FOXO3a has been shown to upregulate the proapoptotic Bcl-2 family member, Bim, and contribute to paclitaxel-induced cell death in MCF7 cells (Sunters et al., 2003). Similarly, another FOXO family member, FOXO1, has been implicated in drug-induced apoptosis through the transcriptional activation of the TNF-R1-associated protein TRADD (Rokudai et al., 2002).

Toxicity Side Effects

Morbidity after neoadjuvant radiochemotherapy is difficult to assess and depends on a lot of variables, i.e., abdominoperineal resection vs. sphincter-saving surgery, type of anastomoses, presence of a diverting stoma, the schedule of RT (dose, fractions), the kind of chemotherapy, the interval between the end of systemic pre-operative therapy and surgery, timing of follow-up, etc. It is reported in literature between 9 and 61 . Comparison of different studies is inconclusive 59 .

What is a clinically meaningful difference and how is it determined

As with clinical trials assessing survival end-points, QOL instruments need guidelines as to how much of a difference in scores is clinically meaningful. In clinical trials, this is often a judgment, i.e. a 10 advantage in 5-year survival with adjuvant chemotherapy may or may not be clinically meaningful depending upon the toxicity. In QOL instruments, the commonly used SF-36 assessment of general QOL has a recommendation of 6-8 points being clinically significant.22'23'35 For the UCLA PCI and EPIC, a ten-point difference is recommended by the authors36 (both the SF-36 and UCLA PCI contain several domains scored on a 100-point scale). Guyatt etal.37 have suggested a 0.3-0.5 standard deviation as representing a clinically meaningful change. Litwin36 has used this concept in a longitudinal study to determine what level of return of a QOL function represents a fair 'return to baseline'. For many instruments, however, this concept has not been addressed.

Metastatic and Recurrent Rectal Cancer

Chemotherapy in metastatic disease 5-FU with or without leucovorin was the standard treatment for a long time. This regimen with continuous infusion of 5-FU, modulated with leucovorin or methotrexate, induces remission or shrinkage of the cancer in 10-44 of patients and the average patient survives approximately one year from treatment 74-76 . Patients with non-surgical liver disease may benefit from other procedures such as hepatic artery infusion (HAI) of a chemotherapeutic drug. This procedure has the potential advantage of delivering a higher dose of a chemotherapeutic drug directly to liver metastasis while avoiding the side effects of a systemic delivered chemotherapy. A trial of hepatic arterial floxuridine plus systemic 5-FU plus leucov-orin was shown to result in improved 2-year disease- RT, radiotherapy CHT, chemotherapy 5-FU, 5-fluoruracil LV, leucovorin RT, radiotherapy CHT, chemotherapy 5-FU, 5-fluoruracil LV, leucovorin free and overall survival (86 vs. 72 , p 0.03) but...

Transcript Profiling and Predicting Cancer Outcomes

A major objective in the field of oncology centers on accurate prediction of outcome and patient stratification for planned interventions such as surgery, radiation treatment and chemotherapy. Clues to tumor behavior may be found in the molecular heterogeneity within individual cancer diagnostic categories such as chromosomal translocations, deletions of tumor suppressor genes, amplifications or mutations of oncogenes, and numerous chromosomal abnormalities. Ultimately, the majority of these molecular alterations will produce changes in gene expression that manifest in phenotypic behaviors of invasion, metastasis and drug resistance. A landmark study involving the molecular analysis of Non-Hodgkins Lymphoma (NHL) proved the hypothesis that gene expression profiles could be used to stratify cancers into clinically relevant categories. This study compared the variability in the natural history of a NHL subtype with analyses of molecular heterogeneity in the tumors as assessed by cDNA...

Prosurvival Signaling Mitogenic Kinases and NF kB

Mitogenic protein tyrosine kinases play a major role in drug resistance through their regulation of antiapoptotic signaling pathways (Blume-Jensen and Hunter, 2001). These include, for instance, members of the EGFR and Ras families, Bcr-Abl, and Akt. Overexpression of EGFR and Her-2 has been reported to increase resistance to chemotherapeutic drugs (Chevallier et al., 2004 Knuefermann et al., 2003 Mendelsohn and Fan, 1997 Nagane et al., 1998 Pegram et al., 1997). Activated Ras family members have also been shown to decrease cells' sensitivity to cytotoxic agents (Fan et al., 1997 Jansen et al., 1997). For example, several reports suggest that expression of Ras oncoproteins can contribute to cisplatin resistance by reducing drug uptake and increasing the degree of DNA repair (Dempke et al., 2000 Levy et al., 1994). Similarly, Bcr-Abl-expressing hematopoietic cell lines and various patient-derived CML cell lines are highly resistant to apoptotic induction by chemotherapy (Aichberger et...

Pre Operative Radiotherapy

In our department pre-operative radiotherapy is the standard treatment for stage 2-3 rectal RC and, as reported before, an increasing body of data suggests the superiority of pre-operative radiotherapy combined with chemotherapy in terms of local control, disease-free survival and reduction of bowel toxicities. There are two types of pre-operative radiotherapy fractionated radiotherapy and short course. Short-course pre-operative radiotherapy is delivered one week before surgery in 5 daily fractions of 5 Gy without any chemotherapy. Pre-operative frac-tioned radiotherapy is delivered in a period longer than 5 weeks (daily doses of 1.8-2 Gy for total doses of 45-50 Gy), usually with a 5-FU schedule, and is followed by surgery which is performed 4-6 weeks after in order to restore the acute damage and as well as to reduce tumour volume. Probably the most important argument in favour of pre-operative radiation therapy is tumour regression, which may improve the likelihood of a successful...

Treatment of Local Recurrences

Local recurrent RC represents a major problem to the surgical oncologist, occurs in 4-5 of patients after apparently curative resection and is resectable in only 15-20 of cases. This type of pelvic tumour causes significant morbidity and accounts for 90 of disease-related deaths within five years. Surgical resection is the initial choice of treatment. The objective, if feasible, is removal of both the tumour and primary nodal drainage with as wide a margin around them as possible. If recurrence occurs in patients not previously treated with radiation therapy, pre-operative radiochemotherapy is highly recommended and it is possible to complete the radiation treatment in case of suboptimal resection of the tumour with intraoperative radiation therapy boost (IORT). Patients who achieve a gross total resection at the time of IORT have a markedly better prognosis than those with residual gross disease. The major IORT-related post-operative complications are leakage from anastomoses, deep...

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