Breast Cancer Survivors

Chemo Secrets From a Breast Cancer Survivor

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

Chemo Secrets From a Breast Cancer Survivor Summary

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Emerging Microtubule Stabilizing Agents for Cancer Chemotherapy

Introduction - The discovery of the potent anti-cancer properties and subsequent elucidation of the mechanism of action of paclitaxel firmly established this compound as a leader in the treatment of difficult cancers. In addition, the unusual mechanism of action of paclitaxel, the stabilization of microtubules, distinguished it from other microtubule-binding agents, such as the vinca alkaloids, that act by destabilizing microtubules. In this paper, recent advances in the identification of non-taxane microtubule stabilizing agents for cancer chemotherapy will be discussed with an emphasis on work published in 2000-02.

Attachment Of Pc To Filarial Molecules As A Target For Chemotherapy

Targeting PC with respect to drug development - The immunomodulatory properties of PC appear to be important in allowing survival of filarial nematodes and for this reason the synthesis of PC-containing molecules might represent an important new target for chemotherapy. Certainly, new drugs are urgently required for treatment of filarial nematodes. With this in mind, it was decided to investigate the mode of attachment of PC to filarial nematode proteins. Can inhibitors of PC attachment be developed for chemotherapeutic use - The absence of PC-N-glycans from humans makes their biosynthesis an attractive option for chemotherapy. We have in fact shown that attachment of PC can be blocked by culturing filarial nematodes (A. viteae B. pahangi) with 1-deoxymannojirimycin (dMM) (41, 38). dMM is a mannose analogue which inhibits mannosidase I, an enzyme involved in N-type oligosaccharide processing, in the cis Golgi (36). Although it is unlikely that this reagent could be used in vivo for...

Chemotherapy Is the Mainstay in the Control of Trypanosomiasis

Chemotherapy is the use of chemicals (drugs) to rid infected host of parasites, while chemoprophylaxis refers to use of the same or other drugs to prevent transmission and limit the pathological effects of the disease. In the case of trypanosomiasis, such chemicals are called trypanocidal or trypanostatic depending on whether they kill or inhibit trypanosome multiplication, respectively. However, the term trypanocide is often used to embrace both classes of drugs. The success of trypanostatic drugs depends on the host immune system that has to eliminate the static population, if complete cure is to be achieved. Some trypanostatic drugs are said to inhibit multiplication by inducing the production of akinetoplastic trypanosomes that cannot undergo further multiplication (Chitambo et al. 1992). The major hindrance to chemotherapy is that there are few drugs on the market, most of which have been in use for over 50 years (Fig. 10.1). Because of economic reasons, the pharmaceutical...

Mammary Adipose Tissue and Breast Cancer

It is known that inflammation can promote tumorigenesis. There is compelling evidence indicating that both normal mammary gland development and breast cancer growth depend, in part, on microenvironment, of which adipose tissue is a key component (ref. 28 and references therein). Interestingly, the mammary gland microenvironment during postlactational involution shares similarities with inflammation, which may be promotional for breast cancer development associated with pregnancy (54). Recently, an elegant study by Celis et al. (28) provided the most extensive proteomic analysis of the mammary adipose secretome in high-risk breast cancer patients. Adipose fibroblasts are another important cellular component of breast cancer microenvironment. These cells, being bona fide steroidogenic cells, are one of the major extragonadal sources of estrogen secretion. Estrogen synthesis is mediated by the enzyme aromatase cytochrome P450 (P450arom), which converts androgens to estrogens (55). In...

Usefulness of Mammography for Breast Cancer Screening

An essential component in determining the efficacy of a screening program is an evaluation of benefits versus risk of harm. For mammography, the major risks to be addressed include radiation-induced breast cancer and the effects of false-positive and false-negative diagnoses. The balancing of potential benefit and harm has been, and continues to be, difficult because of the limited amount of available data. However, it is possible to estimate the recall rate and biopsy-requested rate of mammography screening and to estimate the breast cancer mortality reduction from screening. It is also possible to estimate the average radiation dose received per examination, and the level of risk of radiation-induced breast cancer. When these are considered in the context of the natural incidence of carcinoma of the breast, a benefit risk ratio can be

Breast Cancer

Despite early detection and improved treatments, many affected women will have breasts removed and about two-thirds will die within 10 years of diagnosis as a result of metastasis to the liver or other organs. Each year in the United States, about 180,000 new cases of breast cancer are diagnosed and 46,000 women die from the disease. The human female breast is an enlarged secretory gland (Figure 16.8). During lactation, grapelike clusters of lobes (mammary glands) produce milk that fills and enlarges the multibranched duct system. About 90 of all breast cancers originate from the epithelial cells of the secretory ducts. Initially, breast tumors form within the ducts, although some cancer cells later may leave the inside of a duct and form cell masses on the outside of the duct epithelium. After metastasis of breast tumors, secondary sites may include the chest wall, lung, liver, brain, bone, and other locations. Half of all breast cancers are detected in the...

Female Breast Cancer

Many epidemiological studies since the 1970s have assessed the association between anthropometric measures and female breast cancer occurrence and or prognosis (18,47). Early studies established that the association between body size and risk of breast cancer varied based on menopausal status that heavier women were at increased risk of postmenopausal, but not premenopausal, breast cancer (18). In fact, among pre-menopausal women, there is consistent evidence of a modest reduction in risk among women with high (> 28) BMI. This reduction in risk could be due to the increased tendency for young obese women to have anovulatory menstrual cycles and lower levels of circulating steroid hormones, notably progesterone and estradiol (17). Obesity has been shown consistently to increase rates of breast cancer in post-menopausal women by 30 to 50 (Table 3) (48-53). Some studies have found central adiposity to be an independent predictor of postmenopausal breast cancer risk beyond the risk...

Chemotherapy

In 1999 two large randomized prospective studies concluded that chemotherapy administered along with radiation significantly improved survival compared to radiation alone.16,20 As a result the standard of care has shifted to treatment involving concurrent chemotherapy with radiation therapy.15 Patients with poor performance status, co-morbid medical conditions or metastatic disease need to be evaluated on a case-by-case basis as to the additional benefits of radiation. Chemotherapy is indicated in the treatment of metastatic (stage IVB) and extra-pelvic recurrences of cervical cancer. Although multiple chemotherapeutic regimens have shown activity against cervical cancer with initial response rates as high as 80 , the response rates are generally in the order of 20 in previously treated patients.5

Aspects of Virulence Quorum Sensing

There is evidence for quorum-sensing systems in many other pathogens, including Escherichia coli, Enterococcus faecalis, Helicobacter pylori, Candida albicans, Vibrio spp., and Salmonella typhimurium (Donabedian 2003). Some utilize similar systems others actively metabolize signaling molecules from other species in order to disrupt the quorum-sensing process belonging to potential competitors. Inappropriate or insufficient antimicrobial chemotherapy, by removing susceptible commensals, encourages the growth of a pathogen and thereby accelerates the quorum-sensing process, turning a relatively benign visitor into a virulent invader. The system does, however, offer an additional target for potential therapy in the future, in that natural and artificial peptide inhibitors of the quorum sensing response have already been evaluated in vitro (Gorske and Blackwell 2006). Biostable peptide blockers might not eradicate the targeted pathogen but would allow more time for conventional...

Replication and Its Importance

A handful of susceptibility genes for common and complex diseases such as BRCA1 and BRCA2 in breast cancer (19,20), Calpain10 in NIDDM (21), NOD2 in Crohn's disease (22,23), Neuregulin 1 in schizophrenia (24), and ADAM33 in asthma (25) have been identified. Despite these successes, linkage studies of complex diseases have been difficult to replicate. A review of the linkage findings of 31 complex human diseases based on whole genome scan concluded

How Important A Problem Is Drug Resistance

It must be acknowledged that the high mutation rates of the classic RNA viruses such as influenza and HIV will always result in 'resistance' problems for antiviral drugs. With influenza A virus a single mutation in the target M2 gene allows the mutated virus to escape from the inhibitory effects of amantadine (Table 4.3). Similarly with HIV-1, amino acid changes in the target viral reverse transcriptase enzyme allow the virus to replicate in the presence of zidovudine and other dideoxynucleoside analogues. Recent studies have shown that drug-resistant HIV mutants emerge within days of initiation of treatment of an infected patient with certain dideoxynucleoside analogues. This has led to the use of combination chemotherapy (highly active antiretroviral therapy (HAART)) using three inhibitors, two against the RT enzyme and one against the protease enzyme. With a DNA virus such as herpes the drug resistance problem is correspondingly less acute because of the lower virus mutation rates....

How Are Antivirals Used In Clinical Practice

Most often antivirals are used therapeutically, being administered either after infection or even after the first clinical signs of the disease are noted. In this situation further progression of the disease may stop and or the virus infection may resolve more rapidly. Therapy is the favoured mode with HIV-1-infected patients, although the drug may be given before overt clinical signs of disease both to delay the time before early symptoms occur and also to lessen the chance of drug resistance occurring. There is still active debate about when to initiate chemotherapy, early in the disease or later. Aciclovir may be used to prevent recurrent herpes infections and this is a therapeutic use because the patient is already infected with the virus. The three anti-influenza drugs can all be used to ameliorate clinical symptoms and also to prevent secondary complications of influenza, but have to be given to the patient within 48 hours of onset of symptoms. It should be appreciated that even...

Which Are The Clinically Effective Antivirals

Aciclovir, enabling less frequent doses and higher plasma levels. Similar in concept is the clinical application of the prodrug famciclovir which is converted enzymatically in the patient to the active anti-herpes nucleoside analogue drug penciclovir (Figure 4.4). An expanding focus is with hepatitis B virus where an estimated 5 of the world are chronic carriers of the virus and combination chemotherapy with lamivudine, adefovir and famciclovir is being tested experimentally.

Zidovudine And Dideoxynucleoside Analogues As Antiretrovirus Drugs

Most importantly, combination chemotherapy with other dideoxynucleoside inhibitors (ddC, ddl, 3TC, D4T), or alternatively with non-nucleoside RT inhibitors such as nevirapine or viral protease inhibitors (saquinavir) is now widely used in AIDS patients to reduce the chance of drug resistance (HAART). Currently there is some conflicting evidence from clinical trials whether zidovudine and drug combination therapy should be used early in the disease in asymptomatic patients or whether it should be reserved until the patients begin to show early clinical signs of immunosuppression.

The Most Recent Past And The Future

Arguably the most important chemotherapeutic advances in the last years have been in the treatment of AIDS patients with drug combinations (HAART). Combination chemotherapy has now become the accepted clinical approach with HIV and will be rapidly extended to include new drugs and may be used in cases of chronic hepatitis B and C infection and influenza. Undoubtedly a clinical breakthrough has been the development of the two prodrugs, valaciclovir and famciclovir, to treat herpes infections. Fortunately drug resistance is not likely to be a major problem with herpesviruses. Two important antineuraminidase drugs against influenza have been licensed and a further two compounds are in development. These new possibilities in the clinical management of influenza have led to a renewed interest in the first antiviral, amantadine. There will be occasional major setbacks, but antiviral chemotherapy like other clinical-based sciences will continue to benefit from exciting scientific...

Therapy And Prophylaxis

Specific chemotherapy is not available, and treatment with immunoglobulin is without effect. Experiments in volunteers have found a- and b-interferon given intranasally to be effective in preventing rhinovirus infection, whereas studies using g-interferon have been unsuccessful. The suggestion that large quantities of vitamin C (ascorbic acid) taken prophylactically or during illness influences the course of the disease, has not been proven. Symptomatic treatment includes mild analgesics and nasal drops. Prophylactic use of antibiotics against bacterial superinfections is not recommended in otherwise healthy individuals.

General Guidelines for Use of Antimicrobial Agents

Drug-related immunosuppression (i.e., corticosteroids, immunosuppressants, cytotoxic agents, cancer chemotherapy) Other conditions that are associated with immunosuppression (i.e., Radiotherapy osteoradionecrosis of head and neck, transplant patients, neutropenia, granulocytopenia, patients with an indwelling intravascular catheter, those with immunocompromising procedures)

Antimicrobial management programmes

In the UK, under the supervision of the Effective Practice and Organisation of Care group of the Cochrane Collaboration, a review of international published studies of antimicrobial control programmes in the hospital setting has been conducted by a working party of the British Society of Antimicrobial Chemotherapy (BSAC) and the Hospital Infection Society (Davey et al., 2002). Preliminary results to date show that published studies concentrate primarily

Biological Functions of Intracellular Regulators of Apoptosis

The Bcl-2 family has been extensively investigated and has become the target of many approaches to modulate its expression and function. Bcl-2 antisense oligonucleotides are able to induce apoptosis in leukemia cell line and primary cells, and enhance chemotherapy-induced apoptosis (K4). This approach has already been implemented successfully in a phase I study in treating lymphoma patients (W7). The p53 protein is essential for the induction of apoptosis as a response to chromosomal damage (e.g., y-irradiation). It acts by blocking DNA replication of damaged cells. Cells deficient in p53 replicate in spite of the DNA damage to accumulate further mutations, thereby producing effects similar to overexpression of Bcl-2 to favor the accumulation of further mutations and reduce the efficiency of drugs for chemotherapy (E2).

Drug Resistance in African Trypanosomiasis

Abstract African trypanosomes include the causative agents of sleeping sickness in humans and those affecting live stock. Vaccination being jeopardized by the ever-changing surface coats of bloodstream-form trypanosomes, chemotherapy is the mainstay in the control of infections. However, the drugs in use are old, cause severe side effects, and their efficacy is undermined by the emergence of drug-resistant trypanosomes. Reliable supply of drugs for the human disease is difficult to maintain since patients are unable to meet treatment costs. Fortunately the prospects for the control of trypanosomiasis have improved recently by drug donations from Sanofi-Aventis to the WHO and through support from the Bill and Melinda Gates Foundation. Here we review the current drugs against African trypanosomes, discuss the mechanisms of drug resistance, and address key issues for the control of trypanosomiasis in face of the limited options for chemotherapy.

Campylobacter Species

The bacteria Campylobacter spp. are part of the normal intestinal flora of poultry, cattle and a number of other food-producing and domestic animals, and are predominantly spread to humans in contaminated food. Campylobacter jejuni and, to a lesser extent, C. coli are responsible for most cases of campylo-bacteriosis, which is increasingly one of the most commonly detected bacterial enteric infections in poor resource settings in most developing countries (Samie et al. 2007). The incidence of human Campylobacter infections has increased markedly in both developed and developing countries worldwide and, more significantly, so has the rapid emergence of antibiotic-resistant Campylobacter strains, with evidence suggesting that the use of antibiotics, in particular the fluoroquinolones, as growth promoters in food animals and the veterinary industry is accelerating this trend. Although most infections are self-limiting and do not require antimicrobial chemotherapy, in a small proportion...

Strategies and Considerations

Undetectable levels and are thus Ad-refractory 24-26 . An interesting finding in this regard was recently published by Okegawa et al., who demonstrated a striking inverse correlation between the level of CAR expression by prostate cancer cell lines and their tumorigenicity, thereby suggesting that in general the most aggressive tumors may be CAR-deficient and therefore refractory to therapeutic intervention utilizing unmodified Ad2- or Ad5-derived vectors 27 . The authors have also observed the same phenomenon on human breast cancer cells. If the results of this work are further corroborated by data from other laboratories, CAR deficiency in tumors may become a major obstacle in employing Ad vectors for cancer gene therapy, therefore necessitating the derivation of Ad vectors capable of infecting these tumors in a CAR-independent fashion. Another reason to develop tropism-modified Ad vectors is the fact that many normal human tissues express high levels of CAR 7 and may thus become...

Transductionally Targeted Ad Vectors for Clinical Gene Therapy Applications

As discussed above, the poor efficiency of Ad-mediated gene transfer in several human gene therapy trials has been correlated with a low level of expression of CAR by the target cells. Strategies to accomplish efficient cell-specific gene transfer by Ad vectors in vivo merely by exploiting physical methods to confine vector administration to isolated body compartments have proven inadequate. For example, locally administered Ad vectors carrying the herpes simplex virus thymidine kinase (HSV-TK) gene have been shown to disseminate, probably as a result of leakage into the bloodstream, resulting in a high level of liver-associated toxicity 119 . Substantial hepatic toxicity related to the absence of tumor cell-specific targeting has also been demonstrated in Ad-mediated transfer of the HSV-TK gene in an ascites model of human breast cancer 120 . Thus, targeted Ad vectors capable of efficient and cell-specific CAR-independent gene transfer are required for clinical gene therapy...

Role of Surveillance Through Commensal Bacteria

There is increasing agreement about the importance of extending the surveillance of resistance to the commensal bacteria of humans and animals. Commensal bacteria, although not being a specific target, are continuously exposed to the selective pressure generated by antibiotic chemotherapy and may become a potential reservoir of resistant strains that can cause infections, and of resistant determinants that can be transferred to pathogenic bacteria (Levy et al. 1988 Leverstein-van Hall et al. 2002 Alliance for the Prudent Use of Antibiotics-APUA). Therefore, some members of the commensal microbiota, such as the faecal E. coli, are considered as sensitive indicator bacteria for surveillance of antibiotic resistance, to measure the selective pressure generated by antibiotic usage, to evaluate the impact of modifications in antibiotic prescription policies and to predict the emergence of resistance in pathogens (Lester et al. 1990 Calva et al. 1996 Bartoloni et al. 1998, 2006a, 2008a...

Empirical antifungal therapy in neutropenic patients

By definition, empirical therapy does not fit the description of rational therapy (although it would be entirely irrational to exclude a persistently febrile neutropenic patient from antifungal treatment ). In clinical trials with antifungal agents, the usual criterion for treatment is fever in a neutropenic patient that persists for 5 days or more despite antibacterial chemotherapy. The clinical trials lean solely on fever as a primary criterion both for admission to the study and for efficacy. Though rigorously scientific, this approach fails to resemble the most common situation in febrile neutropenia where, by 5 days after onset of fever, the attending physicians usually have clues as to the nature of any possible fungal infection. This means that agents such as fluconazole can be avoided when the diagnostic evidence, albeit feeble, points to a possible invasive aspergillosis.

Clinical Trial Results with d1520 OnyxO15 Summary

Asthenia) were the most common toxicities and were increased in patients receiving intravascular treatment. Acute inflammatory cytokines (especially IL-1 and IL-6) increased within 3 h following intraarterial infusion, although these changes were extremely variable. Neutralizing antibodies increased in all patients, regardless of dose, route, or tumor type. Viral replication was documented directly (by biopsy) or indirectly (by delayed viral genome peaks in blood) in head and neck and colorectal tumors following intratumoral or intraarterial administration. Neutralizing antibodies did not block antitumoral activity in head and neck cancer trials of intratumoral injection. Single agent antitumoral activity was minimal ( 15 ) in head and neck cancers that could be repeatedly injected. No objective responses were documented with single agent therapy in phase I or I II trials in patients with pancreatic, colorectal, or ovarian carcinomas. A favorable and potentially synergistic...

Future Directions Why Has d1520 OnyxO15 Failed to Date as a Single Agent

Future improvements with this approach will be possible if the reasons for dl1520 failure as a single agent, and success in combination with chemotherapy, are elucidated. Factors that are specific to this particular adenoviral mutant, as well as factors that are generalizable to other adenoviruses, should be considered. Regarding this particular E1B 55-kDa gene mutant, it is important to remember that this virus is significantly attenuated relative to wild-type adenovirus in most tumor cell lines in vitro and in vivo, including even p53 mutant tumors 31, 39, 40, 43, 57 . This is an expected finding since this virus does not have critical E1B 55-kDa functions that are unrelated to p53, including viral mRNA transport and shut-off of host protein synthesis. This attenuated potency is not apparent with the adenovirus mutant if 922 947 31 .

Improving the Efficacy of Replication Selective Oncolytic Adenoviral Agents

Alterations within the adenoviral genome can be used to enhance selectivity and or potency. The promising adenoviral E1A CR-2 mutant dl922 947) has been described that demonstrates not only tumor selectivity (based on the Gl-S checkpoint status of the cell) but also significantly greater antitumoral efficacy in vivo compared to J 1520 (all models tested) and even wild-type adenovirus (in a breast cancer metastasis model) 26 . A very similar E1A CR-2 mutant adenovirus has demonstrated replication and cytopathic effects based on the pRB status of the target cell, in addition to encouraging in vivo antitumoral efficacy 32 . Deletion of the E1B 19-kDa gene (antiapoptotic bcl-2 homolog) is known to result in a large plaque phenotype due to enhanced speed of cell killing 60 . This observation has now been extended to multiple tumor cell lines and primary tumor cell cultures 61, 62 , A similar phenotype resulted from overexpression of the E3 11.6-kDa adenovirus death protein 63 . It remains...

Antifungal Prophylaxis

There is evidence supporting the use of antifungal prophylaxis in certain patient populations, including neutropenic patients and liver transplant recipients. Patients with prolonged neutropenia, including those undergoing intensive chemotherapy or bone marrow transplantation, are at higher risk for invasive candidiasis and mold infections. Antifungal therapy should be considered in high risk patients and, if given, should extend at least through the neutropenic period (23). In solid organ transplantation, liver transplant recipients, particularly those with identified risk factors (renal insufficiency, retransplantation, fungal colonization, choledochojejunostomy, and numerous intraoperative blood transfusions), are at higher risk for invasive candidiasis (23,54). A randomized, double-blinded, placebo-controlled study demonstrated that liver transplant recipients who received fluconazole prophylaxis have significantly decreased rates of superficial (4 vs. 28 p< .001) as well as...

Patterns of LOH in Cancers

In oligodendroglial tumors, LOH at 1p is associated with better prognosis.57 Further characterization of these tumors revealed that in cells with LOH at 1p, the expression of GLUT-1, a component of the glucose transport machinery, was reduced compared to cells that retained heterozygosity at 1p. Stockhammer et al57 speculated that the disappearance of GLUT-1 in cells might affect the tumor's sensitivity to chemotherapy drugs. Further study is needed to elucidate the details, but this research highlights how LOH detection can inform treatment planning. LOH on chromosome 8p21-23 is a frequent event in many cancers and is often associated with more aggressive disease. 1 01,102 Intense research has focused on 8p21 to identify tumor suppressor genes and look for connections between LOH and clinical characteristics. Shi et al103 investigated DBC2 (deleted in breast cancer 2) expression in bladder cancer. In these tumors, LOH was not frequent, but they discovered that promoter methylation...

PNS of the Peripheral Nervous System

Seronegative sensory-motor neuropathy with additional features such as involvement of the face and trunk, sensory ataxia, CNS signs, and inflammatory changes in the CSF have been reported among patients with breast cancer 116 . In such distinct patient populations, new target antigens will probably be identified in the future. Antibodies to gangliosides were described in patients with progressive neuropathy and malignant melanoma 117 and SCLC 118 . In the latter case, the SCLC expressed the ganglioside antigens, and there was a clonal expansion of VS 1 positive T cells in peripheral blood as well as in the tumor. In addition, the neurological symptoms stabilized after tumor therapy. Gangliosides are, however, not a frequent target in paraneoplastic neuropathy 119 .

Steroids Tetracyclines and Heparins

For tumor growth-delay studies, THC and 14-sulfated- -cyclodextrin 14(SO4)PCD were prepared in a 14-d osmotic pump, and implanted subcutaneously in the animals on d 4 posttumor cell implantation, by which time neovascularization of the tumors had begun (16,17). Administration of minocycline ip daily was also initiated on d 4 posttumor cell implantation, and continued until d 18. Neither the 14-d continuous infusion of THC-14(SO4)PCD nor daily im injection of minocycline for 2 wk altered the growth of the LLC (Table 1). The three modulators administered together (THC-14(SO4)PCD-minocycline) produced a modest tumor growth delay of 1.2 d in the LLC. Single-agent chemotherapy or radiation therapy was administered to the tumor-bearing animals beginning on d 7, when the tumors were about 100 mm3. Each treatment agent was administered at a standard dosage and schedule.

Antibacterial RD has taken a downturn

The pharmaceutical enterprise currently has fewer than 30 new antibacterial drugs in clinical development for various indications, with most being revised versions of old drugs 1,9 . This is in stark contrast to development efforts in other disease areas such as cancer chemotherapy with nearly 650 drug candidates in active development 10 . There are also more than 145 drug candidates in development for cardiovascular diseases and nearly 80 for HIV AIDS 8 . The low numbers of antibacterial drug candidates reflects patent expirations that have fueled the growth of generics in this market sector as many of the key players in the pharmaceutical industry have deemphasized or eliminated antibacterial R& D programs since 2000. There are approximately 25 publicly traded pharmaceutical companies worldwide with market caps ranging from < 10 million to 200 billion that have active antibacterial R& D programs 11,12 . Roughly 30 additional closely held companies also are working in this...

Functional Genomics Applications

An example of pathway cross-talk elucidated by the use of a 9984-element cDNA microarray is provided by a study of TRAIL-mediated gene expression in breast carcinoma cells (21). TRAIL is an apoptosis-inducing member of the tumour necrosis factor family, which was found to induce three sets of genes (early, middle and late) spanning a 24h period. The early set includes a wide range of proteins not previously known to be associated with TRAIL the middle set includes known members associated with the TNF pathway as well as novel observations, and the late set strongly correlates unexpectedly with induction of the interferon pathway. Subsequent combination of TRAIL and interferon-beta in vitro synergistically induced apoptosis and caspase activation in breast cancer cells. The authors concluded from this study that multiple levels of cross-talk exist between these two diverse cytokine pathways, which has implications for target discovery and combination therapy.

Have early menopause What does this mean for my bones and will I need treatment

Permanent menopause that is not natural can be caused as a result of surgical removal of the ovaries, chemotherapy, or radiation to the pelvis. Induced menopause can also be a result of chemotherapy and radiation used to treat cancers. While surgically induced menopause always causes an abrupt stopping of the production of estrogen by the ovary, chemotherapy and radiation to the pelvis stops ovarian secretion of estrogen but sometimes this occurs over a longer period of time. This often means that women undergoing radiation and chemotherapy will have more time to adjust to the loss of estrogen. But it also means that they will begin to lose bone once the ovaries have stopped making hormones. While women who have their ovaries removed for reasons unrelated to cancer could use MHT to treat their symptoms and to prevent osteoporosis, breast cancer survivors will have fewer options to treat their symptoms and to prevent bone loss. Few women who experience breast cancer can take estrogen...

Mass Treatment of Parasitic Disease

The past decade has seen a resurgence in interest in the implementation of chemotherapy-based control programs to reduce the morbidity associated with helminth infections in humans (table 1). These programs, targeting lymphatic filariasis (LF), onchocerciasis, schistosomiasis and intestinal helminthiasis, share a strategy based on MDA with relatively inexpensive drugs, but differ both in terms of their target populations and whether their ultimate objective is to control morbidity or to eliminate infection. These different goals represent distinct risks in terms of drug resistance and will be considered separately.

Therapy for Paraneoplastic Nervous System Syndromes

There are two approaches to treating PNS eradicating the source of the antigen, that is, the tumor, through surgery, radiotherapy, or chemotherapy and modulating the immune response such as by administering corticoster-oids, intravenous immunoglobuline or azathioprine, or depleting IgG (plasma exchange) 219, 220 . The single most important factor in managing patients with PNS is identifying and treating the associated tumor as early as possible, but even with complete tumor remission, the PNS respond to varying degrees 12, 221 . Nevertheless, case reports indicate neurological improvement following chemotherapy and radiotherapy, and complete regress of tumor is associated with a more favorable course of PEM 10 and longer survival in PCD 68 . Patients with syndromes affecting the CNS usually benefit less from oncological therapy than patients with peripheral nerve syndromes as SN, possibly due to the fact that the CNS syndromes evolve rapidly, and at the time the PNS is correctly...

Evaluation of epothilones as drug leads

Initial studies at BMS confirmed the potent cytotoxicity of the epothilone natural products. Therefore, there was considerable enthusiasm to assess the antitumor activity of these agents in preclinical models of cancer. In a xenograft model (Pat-7) derived from a breast cancer patient, epothilones A and B were not efficacious when dosed intravenously (iv) at their respective maximum tolerated doses (MTD) 6,20 . Similarly, iv bolus administration of epothilone B in a murine allograft model (M5076) was inactive. However, slow iv infusion of the compound was efficacious, suggesting that epothilone B was metabolically unstable in mice. This hypothesis was confirmed by in vitro studies in both murine plasma and liver microsomal fractions. Higher stability was observed in the corresponding human in vitro assays (vide infra). Additional in vitro and in vivo studies in the presence of a general esterase inhibitor, bis-dinitrophenyl phosphate, revealed that the macrolactone is susceptible to

Ist In A Number Of Experimental Settings

Most pertinent to readers of this book, IST has been used to study CTLs directed against cancer antigens. Using a mouse tumor model, Haanen et al. used IST to show that tumor rejection was associated with the infiltration of tumor specific T cells. In human melanoma, T cells specific for the tumor antigen survivin were readily detected in tissue sections from the primary tumor and a sentinel lymph node isolated from a melanoma patient (6). Similarly, in tissues from a breast cancer patient, survivin specific T cells were readily detectable in situ. Importantly, these cells were shown to have functional cytotoxic activity when assayed ex vivo (6).

Pi3kakt Kinase Pathway Inhibitors In Clinical Trials

Perifosine (27) is a synthetic, orally available alkylphospholipid, derived from alkylphosphocholine, which targets the PI3 AKT survival pathway. Although the molecular mechanism underlying the antineoplastic activity of 27 is not fully elucidated, studies suggest that 27 interferes with turnover and synthesis of natural phospholipids. This disrupts membrane signaling at several sites resulting in the inhibition of the PI3K AKT survival pathway 42,43 . Recent preclinical evaluation in cultured human Jurkat T-leukemia cells has shown that adding low concentrations of 27 (5 mM) after treatment with the commonly used chemotherapy drug etoposide, induced cell death in a synergistic fashion. The observed increase in cell death is attributed to an inactivation of the AKT survival pathway, as treated cells showed a complete dephosphorylation of AKT 44 . Compound 27 also inhibited baseline phosphorylation of AKT in multiple myeloma cells in a time- and dose-dependent fashion 45 . Reduced...

Myelodysplastic Syndromes and Aplastic Anemia Pathologic and Immunologic Implications

Approximately 50 of patients have acquired chromosomal aberrations. The most common include +8 del5q -7 and 20q- (5). The median survival is about 3 years but can range from less than 6 months to over 10 years. Thirty percentage will progress to Acute Myeloid Leukemia. This is much more common when the initial percentage of blasts exceeds 5 compared to less than 5 blasts. Therefore, close to 70 of patients will suffer from complications of cytopenias without disease progression to AML. For these latter patients effective treatment of the marrow failure without the use of cytotoxic drugs should offer a more desired form of treatment, without the complications of chemotherapy.

Ist To Monitor T Cell Directed Vaccine Trials In Cancer Patients

As discussed above, T cells specific for the tumor antigen survivin taken from melanoma and breast cancer tumors were shown to be cytolytic ex vivo (6). In contrast, recent studies of T cells specific for the MART tumor epitope showed that the tumor specific T cells had effector function in circulating blood but were functionally tolerant in tumor lesions (21). Findings such as these demonstrate that the functional status of T cells in blood does not always reflect the functional status in tissues and stresses the importance of in situ analysis of T cells in tissues.

Nuclear Transplantation into Immature Oocytes

In some cases of infertility, a limiting step for the assisted reproductive technologies (ARTs) is the availability of normal oocytes, and this has stimulated research into cryopreservation of oocytes at different maturational stages and freezing of the ovarian cortex for young women undergoing chemotherapy and or radiotherapy (85).

Prostate Specific Antigen

Has also been detected in the gastrointestinal tract 65 . PSA can occasionally be found in other cancers such as adrenal, kidney, lung, and colon cancers, and it has also been used as a prognostic marker for breast cancer 66-69 . With ultrasensitive immunoassays, PSA can be detected at very low concentrations in female serum and other body fluids, including amniotic fluid, breast fluid, cyst fluid, and nipple aspirate fluid 70-72 .

Molecular Classes Of Serms

Triphenylethylenes (TPE's) - Triphenylethylenes were among the first reported structural classes of SERM molecules and tamoxifen (1_) and clomiphene (7, shown as E-isomer) are probably the best known examples. Tamoxifen has been widely used for decades as a treatment for breast cancer and its indication was recently expanded for the prevention of breast cancer in women at risk (19). While long-term use of tamoxifen was associated with a 45 -50 decrease in breast cancer incidences in longterm studies of women at increased risk for the disease, there was a concomitant increased incidence in uterine cancer, deep vein thrombosis and hot flushes (20). The hyperplastic effect of tamoxifen on the uterus is of some concern and considerable efforts have been expended modifying the structure in order to decrease its trophic action on uterine tissue. Toremifene (8) is currently marketed for the treatment of breast cancer but apparently also suffers from similar uterine liability (21)....

Radiation Proctopathy

Treatment but usually resolves within 2-3 months. Chronic radiation injury is an ischemic process usually beginning 2-3 months after treatment has ended. Factors that may increase the likelihood of radiation injury include a history of lower abdominal surgery, concomitant medical illnesses predisposing to vascular disease such as diabetes or hypertension, and possibly chemotherapy (53). Total radiation dose delivered and volume of tissue exposed also play a major role in the severity and incidence of complications (54). Conformal radiotherapy techniques, which focus the high-dose volume of radiation to the affected tissue while sparing adjacent structures such as the rectum and bladder, produce fewer complications (55).

Immunomodulatory phosphorylcholinecontaining proteins secreted by filarial nematodes

What then is responsible for the induction and maintenance of this phenotype Although current chemotherapy for treatment of filarial nematodes is inadequate with respect to certain species, drug treatment where successful, has often been shown to reverse the observed defects in immune responsiveness (5). This suggests that the worms may release immunomodulatory products and indeed several such molecules have been described (6,7). All filarial nematodes examined to date have been found to actively secrete proteins which contain a phosphorylcholine (PC) moiety (reviewed in 8). These molecules can be found in the bloodstream of individuals infected with filarial nematodes and were potentially of interest as there is some evidence in the literature to PC possessing immunomodulatory properties such as interference with antibody responses and

Animal Models of Lung Cancer

Conventional multimodality therapy for lung cancer incorporates surgery, radiation, and chemotherapy using a variety of clinical protocols dictated by the subtype and extent of disease. Theoretically, gene therapies may play important synergistic roles in augmenting the effectiveness of conventional approaches. For many such strategies, there already exists a scientific rationale to test them in combination with conventional multimodality therapy. For example, one may enhance the radiation-sensitivity or chemosensitivity of tumor cells (e.g., p53 or kBa gene therapy) 127, 128 or modify normal tissue susceptibility to cytoablative therapy (e.g., mucosal tissue protection by virtue of MDR-1 or bFGF gene transfer). Examples of synergism with the suicide gene therapy approaches have also been studied. The HSV thymidine kinase gene ganciclovir system induces radiation sensitivity into transduced tumor cells 129 , suggesting that these two forms of therapy can be combined to potentiate...

Molecular and Parasitological Evidence Suggesting the Development of Resistance in Filarial Parasites

A single nucleotide polymorphism associated with anthelmintic resistance in veterinary helminths has been detected at high frequencies in populations of W. ban-crofti 22 . This phenylalanine to tyrosine substitution at position 200 on -tubulin was shown to be 26 higher in microfilariae sampled from parasite populations having received a single round of albendazole + ivermectin treatment than in populations naive to chemotherapy against W bancrofti. The difference in resistance allele frequency between these 2 parasite populations may have been caused by prior treatment of hosts with benzimidazole drugs for soil-transmitted helminthiases or through a combination of high parasite genetic heterogeneity between hosts and a low number of hosts being sampled 30 . The significance of the position 200 mutation in filariae also needs to be confirmed with functional studies, as the presence of this mutation is not always associated with resistance in benzimidazole resistant trichostrongyles or...

Phase IIIII registrational trials

Following on the promising phase I II studies in breast cancer, ixabepilone was studied in a phase II trial with patients referred to as triple-refractory 57 . These patients received prior treatment with an anthracycline, a taxane, and capecitabine (CAPE), and all experienced disease progression before entering the ixabepilone trial. Patients were dosed every 3 weeks with 40 mg m2 of ixabepilone (3-h iv infusion). In this highly drug-resistant population, the objective response rate as determined by independent radiological review was 12 , with an additional 50 of patients experiencing stable disease. Investigator-determined response rate was 18 with 44 of patients characterized as having stable disease (Table 1). A phase III trial enrolling > 750 metastatic breast cancer patients was conducted to compare the combination of ixabepilone and CAPE versus CAPE alone in a setting where patients had progressive disease following treatment with an anthracycline or a taxane 58 . The dose...

Keith Poole and Ramakrishnan Srikumar 1 Introduction

Resistance to antibiotics in target bacterial populations has long complicated antibacterial chemotherapy. First described in the early 1980s (1,2), efflux mechanism of resistance, whereby the antibiotic is actively (i.e., in an energy-dependent fashion) pumped from the bacterial cell, are being described with increasing frequency in recent years. Initial examples of bacterial antibiotic efflux systems were agent-specific, providing for export of and resistance to single agents (e.g., tetracyclines, chloramphenicol, macrolides) (3). More recently, bacterial drug efflux systems of broad substrate specificity have been described (4,5). These systems are able to accommodate a wide variety of structurally unrelated antibiotics, contributing to intrinsic and acquired multiple antibiotic (multidrug) resistance.

Tumor classification for tailored cancer therapy

Introduction - Cancer is an unmet clinical disease that remains the second largest killer in the Western world, with a steady rise in both the occurrence and death rates due to cancer throughout the last century. Cancer is a genetic disease which, together with its multi-stage nature and the realization that many environmental and dietary factors can influence the disease, has wide ranging implications for its treatment and prevention in the 21st century. Although chemotherapy is currently the most promising treatment in clinical use, its success is greatly limited by a severe lack of understanding of tumor biology. This leads to an inability to predict the response of a given tumor type to a particular treatment regime, and consequently a considerable failure rate in clinical oncology.

Immunodeficiency Disorders

Immunodeficiency can be an unwanted side effect of certain medications, such as those used to treat cancer. Anticancer drugs used during chemotherapy affect cells that divide rapidly, including the white blood cells (lymphocytes) that fight infection. Because of this, people undergoing chemotherapy may become more susceptible to opportunistic infections.

Benefits and Risks of Mammography

Screening is the periodic examination of a population to detect previously unrecognized disease. The major goal of breast cancer screening is to reduce breast cancer mortality through detection of earlier-stage disease. Earlier detection also provides a wider choice of therapeutic options. Mammography can frequently detect breast cancer at a relatively early stage when tumors are too small to be palpable. TABLE 7.1 Breast cancer detection by the BCDDP according to lesion size and modality findings.a Breast Cancer Sizeb TABLE 7.1 Breast cancer detection by the BCDDP according to lesion size and modality findings.a Breast Cancer Sizeb 7.1.3 Breast Cancer Survival Rates Survival rates among breast cancer patients depend in large part on two related factors tumor size and stage at time of diagnosis. Smaller cancers with no histologic evidence of spread to the regional lymph nodes have the best prognosis. The 20 y relative survival rates in the BCDDP were 80.5 percent (overall), 85.1...

Epidemiology of Multidrug Resistant TB

MDR-TB development not only hinders treatment but also increases the costs of treatment by 100-fold and lengthens the treatment time (WHO 74, 1997). The basic treatment of mycobacterial infection is chemotherapy. In TB treatment, because single drug therapy can cause an increase in drug resistance strains, a combined treatment should be applied. With a combined treatment, cure can be > 95 (Geo. F. Brooks, 2001). INH, RIF, pyrazinamide (PZA), ethambutol (EMB), and streptomycin (SM) are the first-line agents. These drugs are used for drug-susceptible TB infections. The most important risk factor for MDR-TB is failure to complete treatment for tuberculosis. Six months short-course therapy, starting with treatment with INH, RIF, ETH, and PZA for 2 months, followed by 4 months treatment with INH and RIF, is still being used. The American Thoracic Society, the Centers for Diseases Control and Prevention (CDC), the Infectious Diseases Society of

Histopathology immunophenotype and molecular genetics

The treatment of choice of intravascular large B-cell lymphoma is systemic chemotherapy. Autologous peripheral blood stem cell transplantation has been used in one patient achieving a complete remission with a 15-month disease-free survival 22 , but data on large numbers of patients are lacking. The prognosis of cases limited to the skin may be better than that of the generalized (multisystem) disease but only a very limited number of patients have been followed up to date.

Problemsspecial considerations

Many women who have had a successfully treated malignancy expect to have children. Many of them are unaware that their pulmonary function is not normal as they have no symptoms during ordinary activities, nor are all of them told that there has been any pulmonary damage as a result of treatment of their malignancy. Pulmonary function tests show a reduction in the vital capacity and forced expiratory volume. They show no evidence of restrictive lung disease unless they have other pathology. Most of these women tolerate the pregnancy with little or no problem, although they need a plan for their delivery. Patients who have had a treated malignancy have usually had chemotherapy and may have had drugs that cause myocardial damage, e.g. bleomycin. It is therefore important that these women have echocardiography to assess their cardiac function.

Evaluation by the International Agency for Research on Cancer

An International Agency for Research on Cancer (IARC) Working Group on the Evaluation of Cancer-Preventive Strategies published a comprehensive evaluation of the available literature on weight and cancer that considered epidemiological, clinical, and experimental data (18). Their 2002 report concluded that there is sufficient evidence in humans for a cancer-preventive effect of avoidance of weight gain for cancers of the endometrium, female breast (postmenopausal), colon, kidney (renal cell), and esophagus (adenocarcinoma) (18). Regarding premenopausal breast cancer, the report concluded that available evidence on the avoidance of weight gain suggests lack of a cancer-preventive effect. For all other sites, IARC characterized the evidence for a cancer-preventive effect of avoidance of weight as inadequate in humans. The conclusions regarding the evidence in humans are based on epidemiological studies of overweight and or obese individuals compared with leaner individuals, not on...

Gynecological Cancers

Three studies reported on the prognostic significance of angiogenesis in advanced stage ovarian carcinoma (123-125). All the series studied enrolled patients with FIGO stage III-IV disease, who treated with cisplatin-based combined chemotherapy. Both Hollingsworth et al. (123) and Gaparini et al. (124) reported that the patients with highly angiogenic tumors had poorer prognosis, compared to those with low-vascularized carcinomas. Gasparini et al. (125) also observed that mucinous carcinomas were more vascularized than the other tumor types, and that the degree of microvessel density and performance status were significant and independent predictors of pathologic response to therapy. Van Diest et al. (125) used a less sensitive marker to stain endothelium (ulex europeus I), and did not find microvessel count to be of prognostic value.

Contents of cellular origin

RNA polymerase II, EAP ribosome component, proliferating cell antigen, retinoblastoma protein, p53, DNA ligase 1, DNA polymerase a, promyelocytic leukemia (PML), DNA-PKcs, Ku86 nonhomologous end joining, Bloom syndrome gene product, breast cancer-associated gene 1 protein, MSH2, Rad50, WRN RecQ helicase family member, BRG1 or BRM-associated factor 155, brahma-related gene-1 protein, brahma protein, histone deacetylase 2, hSNF2H, mSin3a, TATA binding protein (TBP), TBP-associated factors.

Hematological Malignancies

The degree of angiogenesis was also evaluated in 22 of these patients after the completion of remission chemotherapy. The authors observed that the patients with ALL had a significantly higher angiogenesis than normal controls. No difference in microvessel density was observed by comparing bone marrow biopsies before and after chemotherapy. S imilarly, also, the urinary levels of bFGF were higher in ALL, compared with controls.

Conclusions 61 Prognosis

The data summarized in Table 3 suggest that the patients with high-risk, operable breast cancer, with highly vascularized tumors, do not benefit from conventional adjuvant hormone or chemotherapeutic treatments. However, a proper evaluation of the predictive capability of a marker needs a prospective controlled, randomized comparative study of therapy vs no therapy. Such a study design may also identify the subgroup of patients who do not benefit from conventional anticancer therapy, for whom novel therapeutic approaches, such as inhibition of angiogenesis, may be useful. The studies by Hollingsworth et al. (123) and Gasparini et al. (124), on vascularization of patients with advanced stages of ovarian cancer suggest that highly vascularized ovarian cancers are poorly responsive to platinum-based combined chemotherapy. Similar findings were reported also for patients with highly vascularized squamous cell carcinomas of the head and neck treated with concurrent chemoradiation therapy...

Radiation Risks of Mammography

The risks associated with routine mammographic screening which have received the most attention are those concerned with the possible induction of breast cancer by the low-energy radiation 7.2.1 Factors Defining Breast Cancer Risk The great majority of studies demonstrated increased incidence or mortality from breast cancer following irradiation. A linear dose-response function generally provides a reasonable fit to the data, though for some studies it is not possible to exclude the possibility of a linear-quadratic relationship. Using a linear model to fit the data from high dose studies to predict risk from the low doses employed in mammogra-phy is a conservative approach (if the quadratic term is positive) in that it predicts greater breast cancer risk than with the use of the linear-quadratic model. There appears to be a minimum latent period between exposure and the time at which risk increases, a period that appears to be at least 5 y. In addition, there appears to be no...

Laboratory Diagnosis

The PCR technique represents a major advance in the diagnosis of HIV infection. This powerful technique can amplify target DNA present in minute amounts. It is therefore useful for early detection of HIV in infants born to infected mothers, since the presence of maternal IgG antibodies excludes serological testing during the first months after birth. Quantitative determination of plasma viraemia (virion RNA) by reverse transcription PCR (RT-PCR) has become a major tool to follow the progression of HIV infection in untreated patients and to monitor the effects of antiviral chemotherapy in patients.

Phase I Trial Design Considerations For Inhibitors Of Angiogenesis

In the initial evaluation of a classic cytotoxic agent, phase I trials define the MTD, and characterize pharmacokinetics and pharmacodynamics. Generally, a dose-response relationship is observed in subsequent evaluation of the drug, so that dose levels significantly lower than the RPTD result in lower overall tumor-response rates. Tumor response rates have been the gold standard for judging the efficacy of cytotoxic drugs commonly used to treat solid tumors (18). A complete response (CR) is defined as complete resolution of all evidence of cancer on physical exam, and normalization of any abnormal radiology tests (i.e., CT scans, X-rays). A partial response (PR) is defined as greater than 50 reduction in the bidimensional tumor measurements, lasting for at least 4 wk. Stable disease (SD) is defined by no change in bidimensional tumor measurements or < 5 increase in bidimensional tumor measurements for at least 4 wk. The overall response rate (ORR) equals the addition of the CR and...

Optimal Biologic Dose

The experience with cytostatic hormonal agents in the treatment of metastatic breast cancer is particularly instructive in this respect. Tamoxifen is the endocrine therapy of choice for all stages of breast cancer, and the most prescribed cancer medication in the world (20). The antitumor effect of tamoxifen is mediated primarily through the estrogen receptor (ER). The tamoxifen-ER complex that is formed is incompletely converted to the activated form (e.g., estrogen-ER complex), and as a result the complex is only partially active in initiating the programmed series of events necessary to initiate gene activation required for cell growth and proliferation (20). Early clinical trials of tamoxifen demonstrated that, although higher daily doses than the standard of 20 mg d did not result in a significant increase in acute toxicity, there was no additional antitumor activity, defined as an increase in ORR (e.g., CR + PR + SD) (20). It is now appreciated that chronic administration of...

As2O3 as Single Treatment in Remission Induction

The application of arsenic compounds to APL treatment can be traced back to the early 1970s when white arsenic, containing essentially As2O3,was used by a group from Harbin Medical University in China, and its therapeutic effects were identified in some human cancers such as esophageal carcinoma, lymphoma, and leukemia. In 1992, the same group reported, for the first time, the administration of Ailin-1 (anticancer-1) solution, containing 1 As2O3 and a trace amount of mercury chloride by the intravenous route, for the treatment of APL. Of 32 cases treated, a complete remission (CR) rate of 65.6 was achieved, with the 5- and 10-year survival rates of 50.0 and 18.8 , respectively (Sun et al. 1992). In 1996, two groups in China, one from Harbin and the other from Shanghai Institute of Hematology, started to treat APL patients with pure 1 As2O3. Zhang et al. reported a CR rate of 73.3 in 30 primarily diagnosed patients, and 52.4 in 42 relapsed or refractory cases (Zhang et al. 1996),...

Circulating Angiogenic Factors

Angiogenic factors can be detected in the serum and urine of cancer patients, and may offer an indirect means to assess the efficacy of an AI. Fujimota et al. (36) was the first to report that elevated levels of basic fibroblast growth factor (bFGF) could be detected in the serum of patients with renal cell carcinoma. Nyugen et al. (37) reported that bFGF levels could be detected in the urine of many patients with a variety of malignancies, and that frequently, these levels, particularly in patients with metastatic disease, were markedly higher than in controls without cancer. More recently, elevated serum levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) have been detected in the serum of recurrent breast cancer patients, at concentrations believed to be high enough to elicit a biologic effect on the endothelium (38,39). Elevated serum VEGF levels have also been reported in patients with colorectal cancer (40), brain tumors (41), and other...

Phase Ii Trial Design

In phase II clinical trials of conventional cytotoxic chemotherapy drugs, the primary end points are ORR, survival, and further characterization of the toxicity profile associated with a new drug or combination of drugs. As already suggested, AIs may not produce tumor regression, so ORR may not be an appropriate end point for phase II trials. Rather, the fraction of patients attaining a stable disease status for a prolonged duration may be more appropriate to consider, and overall survival would remain important. Phase II trials would also be the appropriate setting to evaluate novel biological end points, and to attempt to correlate these findings with clinical outcome. Although these findings would not be definitive, they would provide hypotheses and questions that could be addressed in phase III randomized trials.

Phase Iii Trial Design

Phase III trials typically compare the standard therapy for a particular disease to a new treatment strategy that has shown promise in phase II, disease-directed clinical trials. The new treatment strategy may simply represent a novel way of administering the standard therapy. One example of the latter is evaluating the efficacy of different ways of sequencing two different chemotherapy drugs, A and B (i.e., AB, then AB, then AB vs AAA, then BBB). Alternatively, a standard therapy can be compared to standard therapy plus a new agent, or a standard therapy can be compared to a new drug or combination of drugs. These examples represent only some of the possible design considerations for phase III randomized trials (Table 2). The primary objective of phase III clinical trials is to define differences in clinical end points. For patients with metastatic disease, conventional chemotherapy trials typically focus on ORR, time to disease progression, and overall survival. More recently,...

Impact On Health Budgets Of Antibiotic

Stratchounski, Director of the Institute of Antimicrobial Chemotherapy Smolensk, Russia lead a study to inventory the content of antibiotics for systemic use (ASU) in home medicine cabinets (HMCs) of the non-medical population in Russian cities and to find out for which indications people report they would use ASU on their own (Stratchounski et al., 2002). One thousand two hundred families in twelve cities participated in the study. Two thousand five hundred forty five packages of antibiotics were identified.

Radiation Risk Versus Benefit of Mammographic Screening

In this Section, a comparison is presented between the risks of breast cancer induced by radiation exposure of the breast during mammography and the possible reduction in breast cancer mortality arising from mammographic screening. Risks are estimated in terms of the BEIR V models (NAS NRC, 1990), presented above, and benefits are considered in terms of various assumed reductions in breast cancer mortality rates as a consequence of mammo-graphic screening. The benefit risk model uses standard life table techniques to estimate the numbers of breast cancer cases and breast cancer deaths that will occur in a population of 100,000 women under various mammographic screening scenarios. The numbers of cases or deaths are those which will occur from the age at which a woman is first screened, under a particular scenario, to the end of life. Single-year age-specific breast cancer incidence, breast cancer mortality and all other cause mortality rates were estimated by linear interpolation from...

As2O3 as Combined Treatment with ATRA in Remission Induction

Nosis, offers a reliable tool for the detection of minimal residual disease. After CR, evaluation by quantitative real-time RT-PCR for PML-RARa transcripts confirmed that the combined therapy achieved a more profound molecular response than monotherapy, with the median fold reduction of PML-RARa fusion transcript copies as 118.9 (As2O3 and ATRA), 32.1 (As2O3), and 6.7 (ATRA), respectively. Further decrease of this fold reduction was found after consolidation chemotherapy, indicating that this beneficial effect in reducing tumor burden by combination therapy is persistent (Shen et al. 2004).

Crosstalk Between Retinoid And Interferon Signaling Pathways

Although not as common, there are examples of the upregulation of retinoid signaling proteins, namely the RARs, by IFN. In breast cancer cell lines IFN-y could upregulate RAR-y expression, and in the NB4 acute promyelocytic leukemia cell line IFN-a,p and y could upregulate RAR-a expression (75,76). Thus, the possibility of a mutual enhancement of signaling between retinoid and IFN pathways could be exploited therapeutically.

Retinoic Acidinterferona Combination Cancer Therapy

Combined 13cRA and IFN-a has achieved an overall major response rate of 45 in 55 patients with untreated locally advanced primary SCC of the cervix (114-116). Based on promising pilot data on 13cRA IFN-a integrated with radiotherapy (RT) (117), a phase III study of 13cRA plus IFN-a plus RT vs RT alone was launched. This trial has produced promising preliminary data, including significantly improved survival for patients with locally advanced cervical cancer receiving the combined regimen (118). Negative results with RA-IFN combinations have been reported by Hallum et al. (no response to 13cRA IFN-a among 13 patients with heavily RT-plus-chemotherapy-pretreated recurrent SCC of the cervix) (119) and by Wadler et al. (no response among 26 patients with chemotherapy-naive recurrent cervical cancer to ATRA plus IFN-a-2A) 120). Results have been recently reported from a Southwest Oncology Group (SWOG) NCI trial activated in 1992 (121). This randomized phase II trial evaluated ATRA plus...

Prodrugs Of Polar Compounds

The diacid 24 is poorly orally bioavailable and was derivatized to the corresponding diethyl ester 25, which showed high oral bioavailability (50 ) in rats 21 . In contrast, the diester prodrug ME3229 (27) afforded low oral bioavailability (10 ) of the parent diacid ME3277 (26) in rats due to an efflux transporter expressed on the apical membrane of enterocytes. Compound 27 crossed the apical membrane efficiently, but was metabolized to 26, 28, and 29 inside cells. These metabolites were then expelled back into the intestinal lumen by breast cancer resistant protein (BCRP) efflux transporters 22 . Various active transporters influencing pharmacokinetics of drugs were recently reviewed 23 . An opposite case was reported where an efflux transporter helps improve oral absorption. Experiments with Caco-2 cells indicated that pivampicillin (31) loaded into the apical chamber crosses the apical membrane and is converted to ampicillin (30), which is actively transported out to the...

Antiangiogenic Action Of Retinoids And Interferons

Early on in the use of retinoids for cancer chemotherapy it was hypothesized that they may be acting as antiangiogenic agents (123). This was first verified by experiments in which tumors were implanted into the corneas of rabbits receiving either vitamin A or control injections. Vitamin A-treated rabbits showed a reduced vascular response in the adj acent limbic vessels (host tissue) as well as greatly reduced tumor vascularization and tumor size compared to controls (123). Similar suppressive effects were observed for tumor-induced angiogenesis (TIA) of mouse tissue adjacent to the site of injection of transformed human keratinocyte cell lines (125). Also, using a cervical SCC tumor xenograft model in nude mice, systemic tRA treatment suppressed vascularization within the tumors (127).

Mycobacterium tuberculosis and the Global Impact of Tuberculosis

M. tuberculosis is a tenacious pathogen. Even when the primary infection is contained, the bacteria within the granuloma can survive for decades, persisting in a special dormant state (27,28). When the immune system is compromised, by such factors as malnutrition, HIV infection, diabetes, renal disease, chemotherapy, or extensive corticosteroid therapy, reactivation of the disease can occur (29). The protective granuloma disintegrates, and the long dormant M. tuberculosis revives and spreads unchecked.

Desa Mino 1epihydroxysisomicin

Weinstein, M.J., Luedemann, G.M., Oden, E.M. and Wagman, G.H., Antimicrobial Agents and Chemotherapy-1963, (1964), 1. 34. Mallams, A.K., Davies, D.H., Boxler, D.L., Vernay, H.F. and Reichert, P., Abstracts, 17th Interscience Conference on Antimicrobial Agents and Chemotherapy, New York, (1977), Abstract 251.

Postremission Treatment and Survival Time

For patients achieving CR and receiving As2O3, chemotherapy, or both as maintenance therapy in our previous study, 33 relapsed APL patients were followed for 8 to 48 months and the estimated DFS rates and OS rates at 2 years were 41.6 and 50.2 , respectively (Niu et al. 1999). Zhang et al. reported in 136 cases that the 5- and 7-year OS rates were 92.0 and 76.7 , respectively (Zhang et al. 2000). In the U.S. multicenter study, when As2O3 was used in relapsed cases, among 32 patients achieving CR, 18 received additional As2O3 treatment and 11 underwent allogeneic or autologous bone marrow transplantation. The estimated 18-month OS and relapse-free survival rates were 66 and 56 , respectively (Soignet et al. 2001). Mathews et al. reported that 10 of 11 newly diagnosed APL patients treated with As2 O3 and achieving CR remained in CR at a median follow-up of 15 months (Mathews et al. 2002). Therefore, it seems likely that As2O3 appropriately used in postremission therapy could prevent...

Problems during pregnancy

Malignancies may be affected by the different hormonal profile of pregnancy and its effects on the tissues this may make certain tumours more aggressive (e.g. breast cancer, melanoma). Some maternal malignancies may metastasise to the fetus or placenta (e.g. melanoma), although in general this is rare. A particular form of malignant disease affecting pregnancy is that arising from the placenta itself (gestational trophoblastic neoplasia), comprising hydatiform mole, invasive mole, choriocarcinoma and placental site trophopbastic tumour. It is more common at the extremes of reproductive age, in the Far East and Asia and if previous pregnancies have been affected. The pregnancy itself is non-viable and concerns about the fetus do not apply. These tumours generally respond well to chemotherapy, even if metastatic spread has occurred, with a mortality of < 1 . Molar pregnancy may be associated with hyperemesis, hypertensive disease, anaemia, ovarian cysts and rarely hyperthyroidism....

PolymerPEGlipid membrane artificial cells or PEGlipid vesicles

As a result of all these developments, and in particular the preparation of polymer(PEG)-lipid membrane artificial cells, there has been much recent progress. A number of drugs in PEG-lipid vesicles has already been approved for clinical use or use in clinical trials. The following are brief examples of some of the drugs and more details are available elsewhere (Torchilin, 2005) lipid vesicles containing daunorbicin for Kaposi's sarcoma doxurbicin as combination therapy for recurrent breast cancer doxorubicin for refractory Kaposi's sarcoma and ovarian cancer and breast cancer amphotericin B for fungal

Management options

In trophoblastic neoplastic disease, uterine evacuation may be adequate surgical management but hysterectomy may be required in more invasive disease, especially in older women. Surgery may also be required for torsion of, or haemorrhage into, ovarian cysts. Chemotherapy maybe required if human chorionic gonadotro-phin levels remain elevated or in metastatic disease. In terms of anaesthetic management, the above considerations should be taken into account and appropriate measures taken regarding investigation (including liver and thyroid function blood tests and chest radiography), monitoring and management. General anaesthesia is usually recommended since uterine bleeding may be rapid and severe, and blood should be cross-matched and ready before surgery.

Molecular Genetics of Cancer Syndromes

FEW diseases cause as MUCH DREAD and grief as cancer. Everyone knows someone who has died of cancer. A university professor at the prime of his career has blurred vision and headaches, goes to the doctor, is diagnosed with a brain cancer, glioblastoma, and despite therapy dies within two years. A tennis player is unusually fatigued, goes to the doctor, is diagnosed with chronic myeloid leukemia (CML), and although therapy prolongs his life, he dies nine years after onset of the cancer. A mother feels a continual soreness in the abdominal region, goes to the doctor, is diagnosed with liver cancer, which probably arose from a previous bout with breast cancer, and dies within a month. The most frightening aspect of cancer is that it begins suddenly and by chance in outwardly healthy individuals. Despite the pall that cancer spreads, many patients respond to treatment and have lifelong remissions.

The Problem Of Antibiotic Overuse And A Philosophy For Acne Treatment

Overuse of antibiotics has received increased attention from public health experts and the lay press for some time. The increase in resistant organisms is a real and a significant phenomenon that results in greater illness and expense in treatment of acne and other diseases as well. Moreover, chronic antibiotic use has been implicated in increasing the risk of breast cancer (37,38) and increasing the incidence of upper respiratory infections (39), all in single studies that have yet to be confirmed.

Is there treatment that stops MS

During the 7 years I went through as many changes as the corporations that owned the drug and then some. I had over 15 flare-ups, tried (without benefit) an interferon, volunteered for several drug trials that did not materialize, spent over a year at a 5.5 disability level, lost function in several areas, and considered chemotherapy. The day after FDA approval, our local pharmacist ordered a vial of Tysabri for me. On December 21, 2004, I took it to the doctor in our playmate cooler and had an infusion, one of the first in the world.

Role in Prevention and Clinical Trials

The National Institutes of Health (NIH)-sponsored Women's Health Initiative (WHI) was the first large, randomized trial of primary prevention of stroke and vascular disease (as well as numerous other endpoints) among healthy hormone users (29). Two parallel trials were originally designed. In one arm, women with a prior hysterectomy were randomized to receive either conjugated equine estrogen (0.625 mg day ERT) treatment or placebo. A second arm examined women with intact uteri, who were randomized to either combined estrogen plus progestin (HRT) or placebo, in acknowledgment of the increased risk of endometrial cancer with unopposed estrogen therapy. The primary outcome measure was the incidence of CHD, and the primary adverse outcome was invasive breast cancer. Secondary endpoints included the effect of HRT on stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death. The HRT arm of the trial, which was to have continued until 2005, was terminated in...

Immunocompromised Hosts

GI tract infections in individuals infected with human immunodeficiency virus (HIV) and other patients who are immunosuppressed, such as organ transplant recipients or individuals receiving chemotherapy, are a diagnostic challenge for the clinician and microbiologist. For example, cytotoxic chemotherapy and or antibiotic therapy may predispose patients to develop C. difficile colitis.

Literature Review 21 Direct Costof Illness

Scitovsky et al. (1986) calculated the average cost per AIDS-related hospital admission as US 9,024 ranging from US 7,026 to US 23,425. A more comprehensive picture is presented by Scitovsky and Rice (1987), who estimated provider cost of the AIDS epidemic in the United States in 1985, 1986, and 1991, based on prevalence estimates provided by the Center for Disease Control (CDC). They predicted that the core provider costs of AIDS would rise from US 630 million in 1985 to US 1.1 billion in 1986 and to US 8.5 billion in 1991. The authors compared their estimates of the cost of AIDS in the USA with the estimates for end-stage renal disease (US 2.2 billion), traffic accidents (US 5.6 billion), lung cancer (US 2.7 billion), and breast cancer (US 2.2 billion). They concluded that the core provider costs of AIDS were relatively low in comparison with the provider costs of all illness as well as the costs of these other diseases. However, they also assessed the non-care costs (e.g., for...

Palonosetron Antiemetic [7679

Palonosetron is a novel 5-HT3 receptor antagonist launched last year as an injectable agent for the prevention of acute and delayed nausea and vomiting associated with cancer chemotherapy. It has a much longer half-life ( 40 h) than the other currently available 5-HT3 antagonists, which provides efficacy advantages in the prevention of delayed nausea and vomiting that typically occurs after 24 h and up to six days post chemotherapy administration. Palonosetron was developed as a conformationally restricted analog of the previously known 5HT3 antagonists tropisetron and granisetron. It is synthesized in four steps starting with the condensation of 1,8-naphthalic anhydride and (S)-3-aminoquinuclidine to produce the corresponding imide. The subsequent steps include catalytic hydrogenation of one of the aromatic rings of the imide intermediate, selective reduction of one of the carbonyls to a hydroxyl group, dehydration to an olefin and catalytic hydrogenation. The recommended dosage of...

Strategies to Improve Rtpcr Monitoring and Quantitative Real Time RTPCR

Although the standard RT-PCR-based approach is regarded as clinically relevant for response assessment and prognosis, several issues have to be considered for improving standardization and reliability of results. To define molecular relapse (i.e., conversion from PCR-negative to PCR-positive) some investigators have recommended confirming positivity of the test in two successive marrow samples before initiating salvage therapy (Lo-Coco et al. 1999 Estey et al. 1999). Moreover, the frequency of PCR testing in clinical trials may be adapted to the relapse risk. According to most of the recent trials in which ATRA and chemotherapy have been used, the majority of relapses occur within the first 6-8 months after the end of consolidation therefore, a more stringent monitoring might be justified during this period. In addition, it seems reasonable to recommend more frequent sampling for monitoring studies in patients with hyperleukocytosis at presentation, as these patients have been shown...

Clofarabine Anticancer [1014

The higher potency of clofarabine relative to other purine nucleoside analogs is attributed to the higher efficiency of its phosphorylation by deoxycytidine kinase, and the longer intracellular half-life of the triphosphate metabolite (> 24h). The chemical synthesis of clofarabine involves the conversion of to the corresponding bromosugar with hydrogen bromide, subsequent coupling with 2-chloroadenine, and the removal of benzoyl protecting groups with catalytic sodium methoxide in methanol. The recommended pediatric dosage of clofarabine is 52mg m2 daily, administered by i.v. infusion over 2h, for 5 consecutive days. Treatment cycles are repeated following recovery or return to baseline organ function, approximately every 2-6 weeks. Clofarabine has a volume of distribution of 172 L m2, plasma protein binding of 47 , and a terminal half-life of about 5.2 h. It has a systemic clearance rate of 28.8 L h m2. Elimination is primarily via renal excretion, with 49-60 of the dose excreted...

CD8 cutaneous infiltrates in HIVinfected patients

Sidered as a bad prognostic sign for the underlying disease (the bad prognosis, however, may be linked to the very low CD4 count rather than to the skin lesions per se). PUVA, topical steroids and even chemotherapy have been used for the treatment of this uncommon condition 49 . Regression upon antiviral triple treatment has been observed 51 . A similar condition, but with monoclonal CD8+ T-lymphocytes, has been observed in common variable immunodeficiency.

Magnetic Resonance Imaging

Current clinical experience with breast MRI indicates its several strengths and weaknesses. Fatty and fibroglandular regions of the breast are clearly distinguished and areas of dense fibroglan-dular tissue are imaged with a greater range of contrast than with either mammography or CT scanning. Large and some small breast masses also are readily portrayed, especially, if surrounded by substantial amounts of fatty tissue with most cancers showing relatively irregular and ill-defined borders and benign lesions demonstrating more smooth and sharply-defined margins (El Yousef et al., 1984). However, even when using the best currently available surface coils, the spatial resolution of nonenhanced MRI is far inferior to that of mammography, so that the tiny clustered calcifications of DCIS and the fine spiculations characteristic of many invasive carcinomas are not imaged with MRI. The lack of inherent contrast difference between breast lesions and normal glandular tissue also makes it...

Infection Control chapter

Every year, between 1.75 and 3 million (5 to 10 ) of the 35 millioii patients admitted to acute-care hospitals in the United States acquire an infection that was neither present nor in the prodromal (incubation) stage when they entered the hospital. These infections are called nosocomial, or hospital-acquired, infections. Treatment of nosocomial infections is estimated to add between 4.5 and 15 billion annually to the cost of health care and represents an enormous economic problem in today's environment of cost containment. In addition, many of these infections lead to the death of hospitalized patients (patient mortality) or, at minimum, additional complications (patient morbidity) and antimicrobial chemotherapy.

Bloodstream Infections

The overall rate of nosocomial bloodstream infections increased in all NNIS hospitals between 1980 and 1989 when the inddence of infections with coagulase-negative staphylococci, enterococd, S. aureus, and Candida spp, increased. The risk factors that predispose patients to acquire a nosocomial bloodstream infection indude (1) age 1 year of age or younger or 60 years of age and older, (2) malnutrition, (3) immunosuppressive chemotherapy, (4) loss of skin integrity (e.g., bum or decubiti bedsore ), (5) severe underlying illness, (6) indwelling device (e.g catheter), (7) intensive care unit stay, and (8) prolonged hospital stay.

Magnetic Resonance Spectroscopy

Magnetic resonance spectroscopy (MRS) provides an indication of biochemical differences between tissues by its ability to measure specific metabolic products. Current experience with MRS of breast tissues principally involves pilot studies that characterize cancer-associated metabolites using 31P and 1H MR spectral profiles. While phosphate metabolites are virtually undetectable in breast fat and are identified in relatively low concentration in normal breast parenchyma, they appear to be considerably more abundant in many abnormal breast tissues, especially, in most breast cancers (Degani et al., 1986 Merchant et al., 1988 1991a 1991b Sijens et al., 1988 Twelves et al., 1994). The principal 31P MRS signals come from inorganic phosphate, phosphomonoesters, phosphocre-atine, nucleoside triphosphates (including ATP), phosphorylated glycans, and phosphodiesters. The biochemical data derived from In the earlier 31P spectroscopy studies, relatively large voxel sizes (6 to 8 cm3) were...

Bevacizumab Anticancer [1822

Bevacizumab, a humanized IgGl monoclonal antibody against vascular endothelial growth factor (VEGF), inhibits tumor angiogenesis and delays disease progression. It was launched in the US last year as an intravenous infusion for the treatment of metastatic colorectal cancer in combination with fluorouracil-based chemotherapy. Bevacizumab was developed by engineering the VEGF binding residues of the murine neutralizing antibody A.4.6.1 into the framework of the consensus human IgGl. Its amino acid sequence is approximately 93 human IgG and 7 murine antibody and is produced in a CHO cell expression system. Bevacizumab binds VEGF with high affinity (Kd 0.5 nM) and prevents its interaction with tyrosine kinase receptors VEGFR1 and VEGFR2 on the surface of endothelial cells, thereby inhibiting cell proliferation and microvascular growth. In mouse models, administration of bevacizumab blocked the growth of human tumor xenografts and reduced the size and number of metastases. The recommended...

Cell Therapy From The Laboratory To The Stroke Patient

The feasibility and safety of human BMSCs have been tested and confirmed in patients with degenerative arthritis for resurfacing of joint surfaces by direct injection into the joints (53). In breast-cancer patients infused intravenously with culture-expanded autologous BMSCs (54), and in patients with lysosomal and peroxisomal storage diseases treated with allogeneic BMSCs (55), no apparent adverse effects were evident. BMSC systemic injection has also been employed to treat patients with severe osteogenesis imperfecta to correct genetic defects (56). The robust therapeutic benefit of BMSCs in the treatment of experimental neural stroke and the apparent safe and broad application of BMSC therapy to the treatment of diseases provide a compelling reason to investigate the potential of MSC treatment of stroke. Moreover, the use of patients' own MSCs should circumvent any potential problems of host immunity and graft-versus-host disease. The easily accessible vascular route, as opposed to...

Gene Expression Assays in Cancer

Gene Expression Assays in Breast Cancer Some early studies demonstrated the potential of the new technology 39-41 to examine the differences between normal and malignant colonic tissue 39 and identifying potential subclassifications of breast cancer 41 . An interesting aside to these studies was the different analytical methods used by the authors to analyze and interpret the data. This variability of approach remains a feature of microarray studies and can hinder the comparison of data from different studies. However, there are now processes in place which attempt to standardize at least some of the analyses 42 . It is not possible to review all applications of gene expression arrays in the field of cancer and a number of excellent reviews are available to examine different aspects of the field, for example 43-48 . However, as an introduction to how the methodology has been applied, we will discuss breast cancer as an illustrative example. 4.1.1. Early Studies in Breast Cancer...

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