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 Overview

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My Chemo Secrets From a Breast Cancer Survivor Review

Highly Recommended

The author 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.

Purchasing this book was one of the best decisions I have made, since it is worth every penny I invested on it. I highly recommend this to everyone out there.

What Is Hereditary Breast Cancer

It is worth stating at the outset that the term hereditary breast cancer, while in widespread usage, is somewhat problematic. Hereditary implies that the propensity to disease in that individual has been inherited. Thus, the implication is that breast cancer can be dichotomized into those cases where susceptibility is inherited and those where it is not. This concept arose from consideration of cancers with a simpler genetic basis such as retinoblastoma and Wilm's tumor, which can be usefully categorized in this way (2,3). As we shall see, the situation is much more complex for breast cancer. There are many different susceptibility genes for breast cancer, and a substantial fraction (in fact the majority) of breast cancer cases occur in women who are predisposed in some way. It is also worth emphasizing here that there is no known pathologically distinct type of breast cancer that is hereditary (although certain pathological features are more common in BRCA1 carriers), so it is not...

Epidemiological Studies Of Familial Breast Cancer

Much of the impetus for breast cancer genetics has come from observations of families with extraordinary numbers of cases of the disease (5). These families have often been critical to the identification of the high-risk susceptibility genes. They are, however, less useful for evaluating the risks associated with a family history of breast cancer or with any particular gene, because they are not collected in a systematic fashion. To provide useful information for genetic counseling, risk estimates from epidemiological studies are required. Fortunately, many such studies have been conducted. Most are case-control studies that compare the family history of breast cancer in cases with the family history in controls. Other studies are cohort studies of relatives of breast cancer patients. These latter studies include those based on record linkage with national records, notably those done in Sweden, Iceland, and Utah, and they provide estimates that are free from any potential recall bias...

Twin Studies and Bilateral Breast Cancer

In principle, the familial aggregation of breast cancer may be due either to genetic factors or to lifestyle or environmental factors that are shared among relatives. The latter possibility is unlikely in that no lifestyle risk factors that are sufficiently strong to materially affect familial aggregation of the disease have been identified. More formal evidence that familial aggregation has a genetic basis comes from twin studies. Based on an analysis of population-based twin registers from the Nordic studies, Lichtenstein et al. (23) found that the risk of breast cancer in the monozygotic (MZ) twins of cases was about twice as great as the risk in the dizygotic (DZ) twins. Using a particular multifactorial model, this study estimated that about 27 of the variation in breast cancer risk was genetic. This particular estimate should be viewed cautiously since it does depend on the model used and on how one defines the variation in breast cancer risk, but it does point to a substantial...

Breast Cancer Susceptibility And Other Risk Factors

An important and largely unresolved question is the relationship between genetic and lifestyle risk factors for breast cancer. The combined analysis by the Collaborative Group examined the effect of several important risk factors on the familial risk of breast cancer, including parity, age at first full-term pregnancy, and ages at menarche and menopause. In each case, they found that the relative risks conferred by these risk factors were similar in women with and without a family history (1). These results imply that such risk factors can be assumed to multiply the familial risks of breast cancer (an assumption made in the Tyrer et al. and Gail models). It also suggests that such risk factors are largely independent of genotype. Whether this is true for specific susceptibility genes, in particular BRCA1 and BRCA2, is less clear however. Several studies have examined the effects of these risk factors in BRCA1 2 carriers but many of the results are contradictory, perhaps reflecting...

Models Of Breast Cancer Susceptibility

Several models have been developed to derive estimates of risk to women with a family history of breast cancer or to estimate the probability of carrying a mutation in the BRCA1 or BRCA2 gene. These models can be broadly categorized as empirical models and genetic models. Empirical models are based summarily on measures of family history, such as the number of affected relatives and other risk factors. Perhaps the most widely used model of this kind is the Gail model, which incorporates a variety of breast cancer risk factors in addition to the number of affected relatives (31). Such a model is useful in the general population context, for example, in selecting women for prevention trials but is less useful in high-risk families where the nuances of the family history cannot be captured well. Genetic models seek to model the familial aggregation of the disease in terms of the effects of specific genes or other familial risk factors. These models are developed from population-based...

Association of 16aHydroxylated Estrogens with Breast Cancer Risk

Mation of 16a-hydroxylated estrogen metabolites might be associated with increased risk of developing breast cancer. Their initial studies showed that 2- and 16-hydroxylation of estradiol was minimally affected by age and did not differ between premenopausal and post-menopausal women.129 However, when these enzymatic activities were compared between breast cancer patients (n 33) and matched controls (n 10), 16-hydroxylation was associated with increased risk of breast cancer, whereas the competing 2-hydroxylation pathway was either neutral or associated with decreased risk.135 The investigators suggested that the breast cancer patients had an increased extent of 16a-hydroxylation prior to the onset of the disease, unless the increase was a consequence of the cancer itself. In a subsequent study, using a murine mammary tumor model, Bradlow and associates136 reported a close correlation between the extent of tumor incidence and 16a-hydroxylation, but not 2-hydroxylation, of estra-diol....

The 216aHydroxylated Estrogen Breast Cancer Risk Hypothesis

On the basis of the studies described above, which showed that increased formation of 16a-hydroxylated metabolites relative to 2-hydroxy-lated estrogen metabolites may be associated with an elevated risk of breast cancer, it was hypothesized that a low urinary 2-hydroxyestrone to 16a-hydroxyestrone ratio should be inversely associated with breast cancer risk.144 Development of a competitive-type enzyme immunoas-say (EIA) method for quantifying these metabolites in urine145 allowed the hypothesis to be tested rapidly and relatively inexpensively in a large number of samples. This assay was used in the study by Kabat and associates,144 who measured the metabolites in spot urine from breast cancer cases (n 42) and controls (n 64), including both premenopausal and postmeno-pausal women. Although the 2-hydroxyestrone to 16a-hydroxyestrone ratio was not associated with breast cancer overall, the ratio in the post-menopausal group was significantly lower in the cases (n 23) compared to the...

Other Breast Cancer Genes High Risk Breast Cancer Genes

Breast cancer is involved in two other hereditary syndromes, for which causative genes have been identified. The Li-Fraumeni syndrome is characterized by childhood sarcoma and early-onset breast cancer, brain tumors, and a variety of other cancers. Most families with Li-Fraumeni syndrome appear to be due to germline mutations in the TP53 gene. TP53 mutations confer a very high risk of breast cancer (approaching 100 by age 50) but are much rarer than BRCA1 or BRCA2 mutations (45,46). Cowden's syndrome is a rare syndrome characterized by hamartomas, multiple hamartomas, thyroid cancer, and mucocutaneous lesions and is due to germline mutations in PTEN (61). The risk of breast cancer associated with Cowden's syndrome has not been well estimated, but it is of the order of 30 to 50 lifetime (47).

Low Risk Breast Cancer Genes

A growing list of genes is associated with more moderate risks of breast cancer. The first such gene to be identified was ATM. Mutations in this gene cause the recessive condition Ataxia-Telangiectasia (A-T) (62). Studies dating back over 30 years have suggested that relatives of A-T patients were at increased risk of breast (and perhaps other) cancer (63). This was long regarded as controversial because the studies were small. However, more recent national cohort studies, and direct studies of ATM mutations in breast cancer families and controls, have confirmed that ATM mutations confer an approximately twofold risk of breast cancer (with perhaps a higher relative risk at young ages) (64-67). Another important low-risk susceptibility gene is CHEK2, another DNA repair gene that acts downstream of ATM. Mutations in this gene were first identified in patients with a family history reminiscent of Li-Fraumeni syndrome, and it was therefore suspected that this was another high-risk...

Contribution Of Known Genes To Breast Cancer Incidence

The frequency of BRCA1 and BRCA2 mutations in breast cancer cases has been estimated by a number of studies. By pooling data from a number of population-based studies, Thompson and Easton (78) estimated that the prevalences of BRCA1 and BRCA2 mutations among breast cancer patients diagnosed below their mid-30s were approximately 4.6 and 3.5 , respectively. In contrast, the Anglian Breast Cancer Study (the largest population-based study to date) found the prevalences among cases diagnosed between 45 and 54 years of age to be just 0.3 and 1.0 , respectively (79). These studies underestimate the true prevalence of mutations because studies use methods that are not fully sensitive. Indeed, the fraction of mutations that are detected by such studies is somewhat uncertain because some variants in BRCA1 and BRCA2 are of uncertain significance and may or may not be associated with risk. Nevertheless, overall fraction of breast cancer patients in outbred populations carrying BRCA1 and BRCA2...

Contribution Of Known Genes To Familial Breast Cancer

An important question is the extent to which the known susceptibility genes can explain the familial aggregation of breast cancer. The simplest assessment of this is the proportion of the familial risk to first-degree relatives of cases that is explicable by each gene. We might term this the familial attributable fraction of each gene. These estimates can then be added over genes, on the assumption that the genes interact either additively or combined on a log scale, if the genes interact multiplicatively. Unlike the population-attributable fraction, the contribution of known genes to the familial risk cannot exceed 100 , so that it provides an assessment of how much genetic variation remains to be explained and is a much more useful concept. Note, however, that this does not reflect the In the case of BRCA1 and BRCA2, the familial attributable fraction can be estimated using data from population-based studies that have performed mutation screening, based on the proportion of cases...

Tyrercuzick International Breast Cancer Intervention Study

This is the most recently developed of the breast cancer risk assessment models (32). It was developed using published data regarding BRCA1 and BRCA2 mutation carrier frequencies from a study of mother-daughter pairs (33) and penetrance estimates from the Breast Cancer Linkage Consortium (34) rather than one specific dataset. There are two parts to the model's calculations a genetic part and a personal risk factors part. Like the BRCAPRO model, International Breast Cancer Intervention Study (IBIS) uses Bayesian calculations as a basis for the genetic part of the model. The Bayesian variables used are BRCA1 mutation, BRCA2 mutation, and other genetic risk factor, an as yet unknown low-penetrance gene that is assumed to follow an autosomal-dominant inheritance pattern. Like BOADICEA, IBIS can incorporate exact family relationships and is not restricted to a certain number of first- and second-degree relatives in order to make its assessment. It is also capable of dealing with bilateral...

Prognostication After Chemotherapy

Much experience has been gained in predicting outcomes of patients who complete chemotherapy and in regard to adjunctive therapies following chemotherapy. In particular, post-chemotherapy surgical findings have been analyzed in efforts to identify those who are at high risk for additional events. Foster and colleagues recently reported the role of retroperitoneal lymph node dissection (RPLND) in patients with persistently elevated markers after the completion of standard chemotherapy for disseminated disease. Of those patients with persistently elevated markers and residual radiographic abnormalities, all were able to undergo complete resection. Approximately one-third of the patients were disease free with either surgery alone or surgery plus post-surgery chemotherapy, with a minimum follow-up of 24 months.18 Patients who have an incomplete radiographic response to chemotherapy but a normalization of elevated serum biomarkers frequently undergo post-chemotherapy resection of residual...

Molecular Chemotherapy With rAAV

Although a majority of both preclinical and clinical gene therapy studies using molecular chemotherapy approaches have been conducted with recombinant adenoviral Consideration of molecular chemotherapy strategies for selective killing of tumor cells suggests that long-term expression of transgenes is not an imminent requirement hence, AAV-based vectors are less preferred over adenoviral vectors. Further, the efficacy of adenoviral infection in different tumor cells has been reported to be significantly higher than many other available gene therapy vectors. However, it has recently been reported that the efficiency of rAAV transduction of primary tumor material, derived from malignant melanoma and ovarian carcinoma, is significantly higher (> 90 ) than that seen in established tumor cells of the same derivation in culture (86). This observation suggests that it is possible to utilize rAAV in direct targeting of tumor cells for an effective killing by approaches such as molecular...

Estrogens Aromatase and Risk of Breast Cancer

These observations provide the rationale for the use of endocrine therapy as preventative measures against BC in women with high risk ofthe disease. Four trials using tamoxifen have been published (55-57), as has a fifth trial using raloxifene (58). Although there are differences among studies, a recent metaanalysis of the tamoxifen trials indicated that results were compatible with a 42 reduction in short term incidence of breast cancer with tamoxifen use (59).

Modifications Of Technique For Postchemotherapy Dissection

The technique for RPLND for postchemotherapy tumor is an extension of the same techniques used for primary RPLND (see also Chapter 11). The subtraction concept holds in postchemotherapy disease, and the operation remains essentially a vascular procedure. The great vessels are mobilized from the tumor and posterior body wall by dividing lumbar arteries and veins. The ureters and renal vascular structures are similarly dissected away from the retroperitoneal lymphatics. After chemotherapy, residual tumor is frequently adherent to retroperi-toneal structures such as the aorta and the vena cava. Hence, surgeons embarking upon postchemotherapy RPLND should have at their disposal a full array of vascular techniques and capabilities (Figure 10-21). It is interesting that the therapeutic capability of RPLND is retained in cases of disease after chemotherapy. The surgical removal of tumor after chemotherapy is curative in 30 to 80 of cases, depending on the clinical situation and the pathology...

Postchemotherapy Histology

The histology of a residual mass after initial chemotherapy varies substantially in different series. Steyerberg and colleagues5 reviewed 996 postchemo-therapy resections from 19 studies published between 1983 and 1990. Residual cancer was present in an average of 16 of cases, mature teratoma was in 36 of cases, and fibrotic and or necrotic tissue was in 48 . In resected lung lesions, necrosis was found more often (57 of cases) and teratoma was found less frequently (27 of cases). The same author6 reviewed six studies published between 1986 and 1993 that included a total of 556 patients undergoing postchemotherapy retroperitoneal lymph node dissection (RPLND) 13 of patients had residual cancer, 42 had mature teratoma, and 45 had fibrosis-necrosis. Steyerberg and colleagues7 also found a higher frequency of residual necrosis in patients treated with regimens containing etoposide (as I and my colleagues had predicted in 1985).8 Last, but not least, about 50 of patients undergoing...

Extent Of Postchemotherapy Surgery

Early in his very large experience, Donohue24 found residual tumor in the para-aortic and right and left suprahilar nodes in patients with a right-sided primary tumor and in the right and left suprahilar, right iliac, and interiliac nodes in patients with left-sided primaries (15 cases). Therefore, due to an obvious risk for the presence of residual tumor in lymph node groups located outside the boundaries of a limited template dissection, a modified retroperitoneal lym-phadenectomy was considered an unacceptable compromise for patients with advanced-stage disease after chemotherapy. On the other hand, a significant number of intra- and postoperative complications have been reported in patients undergoing extended postchemotherapy RPLND.17-19,25 Therefore, several investigators have tried to identify the optimal extent of limited postchemotherapy RPLND. Hendry and colleagues26 evaluated the outcome of the excision of para-aortic tumor masses alone (lumpectomy) in 231 patients after...

Further Chemotherapy For Radically Resected Residual Cancer

The presence of viable cancer cells in completely resected residual masses carries the worst prognosis when compared with the presence of mature teratoma or necrosis alone (see also Chapter 16).26,33 Since the study by Einhorn and colleagues,37 which reported a dismal outcome for all 18 patients with residual cancer at postchemotherapy surgery who received no further therapy, many investigators have opted for the routine use of postoperative adjuvant chemotherapy.2,5,9,11,12,24,26,33 No compelling evidence has existed to confirm whether adjuvant chemotherapy for consolidation is justified in this setting. Thus, my colleagues and I recently challenged this approach as we found no difference in the 5-year survival in a retrospective study of 49 evaluable patients who were treated (24 patients) or not treated (25 patients) with adjuvant chemotherapy following complete resection of residual cancer after first-line (30 patients) or salvage (19 patients) chemotherapy.38,39 An international...

Breast Cancer Risk In Males

Familial clustering of female breast cancer was demonstrated as early as 1926 (81), and epidemiological studies have shown that although both men and women with breast cancer are more likely to have family histories in first-degree relatives than unaffected individuals, men with breast cancer were even more likely to have a first-degree relative with ovarian cancer than affected women (82,83). It is noteworthy that initial linkage studies of BRCA1 did not reveal an association with male breast cancer (14,84). Linkage studies for BRCA2, on the other hand, did contain male breast cancer cases (16). Germline analyses of 50 men affected with breast cancer unselected for family history revealed that 14 of these men carried a BRCA2 mutation (85). Easton et al. (52), in a study of two large kindreds linked to BRCA2, estimated the cumulative risk of breast cancer in male carriers to be 6.3 by the age of 70 years. In an analysis of 164 BRCA2 kindreds, a similar estimate for cumulative risk...

Recommendations For Chemotherapy

The chemotherapy regimen developed at Indiana University should be considered the standard of care for patients with good-prognosis NSGCT. This recommendation is based on successful results with this program in a number of randomized clinical trials comparing it to other treatment programs.7,64,66,70,77,81 The regimen has been used successfully in centers Table 13-4. PATIENT GROUPS WITH NONSEMINOMA ELIGIBLE FOR GOOD-PROGNOSIS CHEMOTHERAPY REGIMENS 2. Patients with low-bulk stage II disease managed in centers (generally outside North America) that select primary chemotherapy rather than retroperitoneal lymph node dissection for this group. These patients should also fulfill the IGCCC criteria for good prognosis. The recent MRC EORTC trial demonstrated that the same doses of chemotherapy could be delivered over 3 days without compromising efficacy.66 Toxicity and quality-of-life data indicate little difference between the 3- and 5-day schedule, with increased nausea and vomiting...

Management of Nonseminomatous Testicular Cancer Chemotherapy for Poor Risk Patients Standard Dose Therapy

And actinomycin D, cyclophosphamide, and etopo-side (ACE) was devised in 1977.4 The concept behind this essentially alternating schedule of chemotherapy was to alternate the POMB schedule, which was less myelosuppressive than the ACE schedule, and to increase the dose intensity by having a schedule of every two weeks rather than the more commonly used schedule of every three weeks of chemotherapy. Although the POMB ACE schedule contains seven drugs, the total cumulative dose of each individual drug is less than that in schedules such as PVB and such as bleomycin, etoposide, and cisplatin (BEP)5 because the component schedules essentially alternate. The experience of the past 25 years of treating these patients is that durable remissions are maximized if the chemotherapy contains a minimum of 300 mg m2 of cisplatin and that the proportion of remissions probably increases with the total dose of etoposide administered.*

Commonly Used Chemotherapy Regimens For Metastatic Germ Cell Tumor

We try for normalization of the main two serum tumor markers hCG and AFP and continue alternating POMB and ACE until the patient has been in tumor marker remission for approximately 4 weeks (Figure 14-1). In common with other centers, as confidence in the stability of the complete remissions obtained with chemotherapy has increased, we have shortened the total duration of treatment. It should be noted that we have modified our current approach to this regimen, shortening the duration of treatment by omitting the second 24-hour infusion of bleomycin. two courses usually are sufficient to reduce the organ failure so that the full POMB ACE schedule can be started as described above. This approach allows chemotherapy to be delivered to patients who would otherwise get major toxicity if they received either BEP in full dose or POMB in full dose. In our last analysis of the patients treated with POMB ACE chemotherapy for metastatic NSGCT between 1977 and 1995,16...

PTEN and Cowden Syndrome Prevention Of Breast Cancer In Cs

Some women with CS consider prophylactic mastectomy, especially if breast tissue is dense, making surveillance difficult, or if repeated breast biopsies have been necessary. Prophylactic mastectomy reduces the risk of breast cancer by 90 in women at high risk (63), although no studies have specifically addressed this intervention in patients with CS. There is no direct evidence to support the routine use of agents such as tamoxifen or raloxifene in individuals with CS to reduce the risk of developing breast cancer. Physicians should discuss the limitations of the evidence and the risks and benefits of chemoprophylaxis with each individual. In addition, the clinician must discuss the increased risk of endometrial cancer associated with tamoxifen use in this population that is already at increased risk for this malignancy.

Evidence For Inherited Predisposition To Breast Cancer

Mutations in BRCA1 or BRCA2 account for the majority of families with multiple cases of either breast cancer alone or breast and ovarian Figure 7.1 Familial breast cancer. Individuals were diagnosed with primary breast cancer at the ages shown. A familial pattern such as this is strongly suggestive of autosomal dominant predisposition by a single predisposing gene. These cases proved to be due to mutation in BRCA1. Figure 7.1 Familial breast cancer. Individuals were diagnosed with primary breast cancer at the ages shown. A familial pattern such as this is strongly suggestive of autosomal dominant predisposition by a single predisposing gene. These cases proved to be due to mutation in BRCA1. cancer. It is perhaps surprising that they account for only a small part of the excess familial clustering of these cancers in the population as a whole. The overall extent of familial clustering can be measured by ascertaining a large series of breast cancer cases from the population and...

Genetic models of breast cancer susceptibility

It is likely that the inheritance of most common cancers is polygenic. Breast cancer, like other common cancers, exhibits some degree of familial clustering, with disease being approximately twice as common in first-degree relatives of cases (Amundadottir et al., 2004 Collaborative Group on Hormonal Factors in Breast Cancer, 2001). The higher rate of most cancers in the monozygotic twins of cases than in dizygotic twins or siblings suggests that most of the familial clustering is the result of genetic variation rather than lifestyle or environmental factors (Lichtenstein et al., 2000 Peto and Mack, 2000). Further evidence for the relative importance of genetic factors comes from the observation that more distant relatives of a case (i.e. those beyond the nuclear family) are also at increased risk of disease even though they would be expected to share environmental or lifestyle factors to a lesser degree (Amundadottir et al., 2004). Furthermore, the magnitude of the risks in distant...

Use in Increasing Chemotherapy Dose Intensity

The guidelines note that there is an apparent steep dose-response curve in preclinical studies but that retrospective analyses of dose-delivered intensity in the clinic suggest that bias may have been introduced. Some of the randomized trials compared lower than standard-dose chemotherapy with standard-dose chemotherapy. In the late 1990s, trials increasing dose intensity above standard levels were not shown to improve survival. The recommendation was that outside the setting of clinical trials, the use of CSFs to increase dose intensity was not justified.

Principles Of Chemotherapy For Central Nervous System Malignancies

Treatment of high-grade gliomas (HGG) with systemic chemotherapy poses challenges unique to brain tumors. Foremost is the blood-brain barrier (BBB) which impairs delivery of adequate concentrations of most chemotherapeutic agents to the tumor. The BBB is maintained by interaction between astrocytes and endothelial cells that protect the brain from the foreign and undesirable molecules. This membrane lacks intercellular fenestrations, has high-electrical resistance and low-ionic permeability rendering it relatively impermeable to many water-soluble compounds (1). Most cytotoxic drugs traverse the BBB by passive diffusion while some use specific endothelial cell transport mechanisms to gain access to the central nervous system (CNS). Gadolinium enhancement, however, most likely signifies disruption of the BBB that may allow access of chemotherapeutic agents although the degree of penetration is unknown. To cross the BBB, chemotherapy agents administered systemically must be less than...

Finding lowpenetrance breast cancer alleles

And gene-environment interactions in the etiology of cancer with more than 20 cohorts participating (www.epi.grants.cancer.gov Consortia cohort.html). Advances in our understanding of the nature of human genetic variation coupled to new genotyping technologies raise the hope that empirical whole-genome approaches will bring similar successes to those achieved by empirical family-based linkage studies. Empirical association studies to scan 60 of the genome for breast cancer susceptibility genes are currently in progress, and similar studies of other cancers are likely in the near future. The association studies design relies on the ''common disease common variant'' hypothesis. It is, however, equally possible that much of the variation in cancer risk is due to rarer alleles. Indeed, virtually all susceptibility alleles identified to date have frequencies of less than 1 . These include both high-penetrance mutations, but also low-penetrance variants in ATM and CHEK2 that predispose to...

Frequency Of Germ Line P53 Mutations In Breast Cancer

The earliest publications on LFS focused on childhood soft tissue sarcoma and breast cancer (1,2), with most ascertainment through the less common childhood sarcomas. However, with the opportunity to test for a specific gene, focus shifted to the far more common, and often familial, breast cancer. The question was, what fraction of breast cancer, young, familial, bilateral, or associated with other cancers, might be attributable to germ line p53 mutations A flurry of papers appeared in the literature from the early 1990s, studying different clinical groups of breast cancer and using various techniques to identify mutations. However, few p53 germ line mutations were observed using criteria of familial breast cancer (40-46), bilateral breast cancer (47), age at breast cancer diagnosis less than 31, 35, or 40 years (48-50), breast cancer associated with a personal or family history of multiple primary tumors (51), or breast cancer associated with no more than one sarcoma in the index...

Penetrance For Breast Cancer In P53 Mutation Carriers

Overall data from the IARC TP53 Database (14) confirm findings of smaller series that breast cancer is the most common cancer in LFS, accounting for about 25 to 30 of all cancers. For p53 mutation carriers the median age of breast cancer onset is 33 years, significantly earlier than for non-p53 LFS at 42.5 years. To date no genotype-phenotype correlation, that is, no association of specific p53 mutations by structural or functional domain, or by mutation type, has been observed for breast cancer overall however, breast cancer median age of onset was significantly younger in those with mutations in the DNA-binding domain (average age 32 years) as compared with missense mutations not in the DNA-binding domain (average age 42 years) age of onset for those with inactivating or likely null mutations was similar to that for mutations in the DNA-binding domain (median age 33 years) (14). This is in contrast to previous findings (57) of a higher incidence and earlier onset of breast cancer in...

Risk Factors for Chemotherapy Induced Febrile Neutropenia

Cytokines reset the thermoregulatory center in the hypothalamus to retain heat and allow the core temperature of the body to increase. Mononuclear phagocytes are the principle producers of the endogenous cytokines that cause fever and are much less affected by chemotherapy than neutrophils. Therefore, fever is reliable as a marker of infection in patients receiving chemotherapy, including neutropenic patients. In a review of the risk of FN among patients with intermediate-grade NHL receiving cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy, Lyman and coworkers (5,6) identified several factors associated with an increased risk of neu-tropenia-related complications. Data for this study came from 577 patients and 224 occurrences of FN in 12 community and academic oncology practices. Age > 65 yr (p 0.001), significant cardiovascular or renal disease (p 0.02), baseline hemoglobin concentration < 12 g dL (p 0.018), and administration of > 80 planned dose...

Treatment Of Chemotherapyinduced Febrile Neutropenia

The treatment of patients with chemotherapy-induced FN is multifactorial and includes not only antibiotic and CSF therapy but also supportive measures. Observational vigilance is an important aspect in the care of patients with chemotherapy-induced neutropenia there is no substitute for frequent observation and examination, particularly of the oropharynx, chest, and abdominal and perirectal areas. Frequent blood cell counts, blood cultures, and culture and examination of exudates and other bodily fluids in patients with fever remain the mainstay of good medical care. In addition to good skin care and oral hygiene, every effort should be made to maintain good functional status through nutritional support and exercise. Patients with cancer should be encouraged to decrease or eliminate smoking and maintain their immunization status, including influenza immunizations. Education of the patient and family, as observers of health status, is also important, particularly to recognize the...

Standard Dose Salvage Chemotherapy Summary

Approximately 50 of recurrent testicular cancer patients will achieve a disease-free status when VeIP is administered as second-line therapy.72,73 Half of the patients who achieve complete remission on VeIP eventually relapse therefore, approximately 25 of patients with recurrent germ cell tumors can have the expectation of long-term disease-free survival with standard salvage chemotherapy. The substitution of paclitaxel for vinblastine has yielded impressive results in a patient population with favorable prognostic features. However, a direct comparison to VeIP is needed to determine its true worth in this setting.

Breast Cancer As A First Or Subsequent Cancer In

Not only is breast cancer the most common cancer observed in LFS, it plays a major role in subsequent cancers. In the Hisada et al. (71) series, 200 LFS patients had at least one cancer, including 104 females and 96 males among 30 patients who developed one or more additional cancers, 19 (63 ) were in females. The 19 females who had multiple primary tumors experienced a total of 46 cancers (original plus subsequent), with breast cancer accounting for 26. Forty-five of the original tumors were female breast, and 10 of those patients developed at least one additional tumor, including eight with an additional breast cancer. Breast cancer also accounted for 5 6 (83 ) of second cancers in those with an initial sarcoma (the other common original tumor). These data overall suggest an extremely high probability of breast cancer in LFS females, most of which occur before age 45, with a remarkably high probability of a second breast cancer. In Hwang et al. (58), the cumulative risk of female...

Radiation And Chemotherapy Risks

Most series of LFS families, as well as case reports, have noted not only the high risk of multiple primary tumors but the frequent occurrence of new cancers in radiation-treated sites (48,53,58,60,71-73). Hisada et al. (71) observed only one of 14 subsequent breast cancers arising in a previously irradiated area however most of the subsequent sarcomas arose in previously irradiated areas, and studies of childhood cancer survivors, especially young soft tissue patients (67,74), have noted a significant excess of female breast cancer, both within and in the absence of radiation therapy. It seems clear that there is an extremely high risk of multiple primary tumors in LFS patients, occurring both spontaneously and in irradiated sites. This is consistent with observations in heterozygous p53 knockout mice in which radiation significantly accelerates tumor development (75). Many authors have suggested that radiation not be used for cancer treatment in p53 mutation carriers if feasible,...

Highdose Chemotherapy At First Relapse

High-dose chemotherapy as the first salvage treatment of relapsed germ cell tumors has been less extensively investigated.115 Unlike patients with multiply recurrent germ cell cancer, patients in first relapse can expect a 50 likelihood of complete remission and a 25 chance of long-term freedom from disease with conventional-dose salvage chemotherapy. The goal, therefore, is not the salvage of otherwise doomed patients but improvement in the efficacy of salvage therapy. Demonstrating efficacy in this setting is thus more challenging. The typical approach employed to date has included one or two cycles of conventional-dose chemotherapy followed by one or two courses of high-dose chemotherapy with carboplatin etoposide, with or without an alkylating agent.116119 Less commonly, high-dose therapy has been administered alone, without a prior conventional-dose salvage regimen.120,121 Investigators at Indiana University Table 16-2. PROGNOSTIC SCORING FOR OVERALL SURVIVAL AND FAILURE-FREE...

Breast Cancer Prognosis In

Many studies have indicated that a p53 somatic mutation is an independent poor prognostic indicator for breast cancer (86), with some data suggesting that the prognosis may be influenced by the nature of the mutation (87). Miller et al. (30) have shown that an expression signature for p53 functional status in breast cancer is more predictive of outcome than p53 sequence analysis, and suggest that p53 may be functionally attenuated in the absence of DNA sequence variants. From those data one might assume that the breast cancer in germ line p53 mutation carriers would also carry a poor prognosis surprisingly little data are available to support that expectation, and the absence of data perhaps speaks loudly. Given that there are no published survival data for breast cancer in p53 mutation carriers, the frequent reports of multiple primary tumors occurring over 10 to 30 years (71) suggest that many of these patients do not succumb to their breast cancer. Unlike BRCA1,2 mutation carriers...

More intensive chemotherapy as standard CHOP

After earlier studies showed that intensive chemotherapy led to a disproportionately high risk of infection and toxic complications (Kaplan 1997), the tendency for a long time was to withhold HIV infected patients from therapy and often to treat them with reduced-dose regimens. This seems to be changing in the age of HAART. Prospective studies have shown that the tolerability of chemotherapy is improved through HAART (Powles 2002, Sparano 2004). In the past few years, small pilot studies have been repeatedly published in which HIV infected patients have been treated with CHOP regimens. There are also studies in which doxorubicin has been given as liposomal Caelyx (Levine 2004) or where the dose of cyclophosphamide was increased (Costello 2004). In addition, CDE, a regimen which, when given for several days as infusions is supposed to overcome the potential chemotherapy resistance of lymphoma cells, is propagated again and again (Sparano 2004). The CR rates in these studies were...

Gene transfer and its implications for chemotherapy

Traditionally, drug and vaccine design often targets parasite-specific pathways or structures that are essential for the survival and growth of the parasites (Fairlamb 2002 Agbo et al. 2003). The fact that apicoplasts provide essential functions (e.g. fatty acid and isoprenoid synthesis) and the fact that humans and other mammals to do not have apicoplasts, makes this organelle and its associated biochemical processes excellent antiapicomplexan drug targets (McFadden and Roos 1999 Ralph et al. 2004). Additionally, many of the laterally transferred genes also bear implications for chemotherapy. For example nucleotide biosynthesis is essential to parasite growth. Because Cryptospor-idium lost both de novo purine and pyrimidine biosynthetic abilities, their dependence entirely on salvage pathways that assembled with several prokaryotic genes can be explored for antic-ryptosporidial drugs. Antagonists of IMPDH have already proven to affect C. parvum viability

QOL in Long Term Survivors of Breast Cancer

In total, 16 studies met our search criteria for breast cancer, all published after 1998. The studies are described in Table 1 and include our study,32 which will be discussed in greater detail following the general review. Quality of life was a primary outcome in all studies. Of the 16, five studies compared the QOL between breast cancer survivors and healthy or normal controls.4,41-44 Two of five also compared QOL outcomes between survivors who have experienced a cancer recurrence to those who have not.4,43 Three of the 16 studies compared QOL between breast cancer survivors receiving different types of treatment.2,45,46 Two of the 16 investigated the QOL between breast cancer survivors diagnosed at different ages47,48 another two studies compared QOL at time of diagnosis and follow-up32,49 and two more examined the impact of treatment on QOL.50,51 One study looked specifically at the role of ethnicity in QOL outcomes,52 while the final study examined the...

Adjuvant Chemotherapy

The use of one or two courses of adjuvant carbo-platin for patients with stage I seminoma has been reported by a number of investigators over the past decade (see Chapter 19).61243-45 Oliver and colleagues, who treated stage I seminoma with one to two courses of adjuvant carboplatin chemotherapy, pioneered this approach. Dieckmann and colleagues, with a median follow-up of 48 months, reported no relapses among 32 patients treated with two courses of carboplatin and reported 8 relapses in 93 patients given only one course. Steiner and colleagues reported their institutional experience over 10 years using two courses of car-boplatin in 99 patients.45 With a median follow-up of 60 months, 2 patients (1.85) developed recurrence both relapses occurred within the first year and were successfully salvaged with cisplatin-based regimens. Reiter and colleagues reported on their 12-year experience with 107 patients treated with two courses of carboplatin. No recurrences or deaths from seminoma...

Noninvasive breast cancer

Was evidence of microinvasion, with 4 having lymph node metastases. In addition, there is also a risk of patients with DCIS subsequently developing invasive cancer. Although different estimates of this risk have been reported, approximately 2 of these patients are likely to develop invasive breast cancer each year.

Dose Intensity in Breast Cancer Preclinical and Retrospective Clinical Data

Preclinical in vivo and in vitro data suggest that increasing the dose of chemotherapy increases tumor cell kill, but with significant myelosuppression (4). Hryniuk and Bush (5), in a literature review of regimens for metastatic breast cancer, calculated the dose of CMF chemotherapy given over a unit of time and concluded that a relationship was apparent with dose intensity and response rate in the setting of metastatic breast cancer. For the adjuvant setting, Hryniuk and Levine (6) evaluated chemotherapy trials for women with stage II breast cancer treated with CMF-like regimens. In this retrospective study, the authors concluded in both univariate and multivariate analyses that dose intensity was a significant predictor of relapse-free survival (6). These initial observations of dose intensity, although suggestive, were retrospective.

Prospective Dose Intensity Trials for Breast Cancer

Tannock et al. (7) evaluated the dose-intensity concept in a prospective setting for patients with metastatic breast cancer. Patients were randomly assigned to receive two dose levels of CMF chemotherapy every 3 wk standard (cyclophosphamide 600 At the M.D. Anderson Cancer Center, Hortobagyi and colleagues (8) evaluated the impact of higher dose anthracycline therapy in metastatic breast cancer. Patients were randomly assigned to receive either standard 5-fluorouracil (F), doxorubicin (A), and cyclophosphamide (C) or 260 higher FAC. The median response durations and overall survival rates were not significantly different. Furthermore, hematologic, infection-related, and gastrointestinal complications were increased in the high-dose FAC group (8). The studies by Tannock et al. (7) and Hortobagyi et al. (8) seemed to indicate that a threshold dose existed for the treatment of breast cancer, but a large confirmatory trial was needed.

Threshold Dose in the Treatment of Breast Cancer

The Cancer and Leukemia Group B (CALGB) did a randomized trial evaluating different doses and dose intensities of adjuvant chemotherapy in patients with node-positive breast cancer 1572 patients were randomized to receive CAF at three dose levels low-dose (5-flurouracil 300 mg mL, doxorubicin 30 mg mL, cyclophosphamide 300 mg mL), moderate dose (5-fluorouracil 400 mg mL, doxorubicin 40 mg mL, cyclophosphamide 400 mg mL), and high dose (5-fluorouracil 600 mg mL, doxorubicin 60 mg mL, cyclophosphamide 600 mg mL). Women treated in the moderate- and high-dose-intensity groups had significantly longer disease-free and overall survival than those in the low-dose group. Survival was not different between the moderate- and high-dose groups (9). This study validated the idea of a threshold dose in the treatment of breast cancer.

Biological Basis For Tamoxifen As A Breast Cancer Preventive

Tamoxifen was selected for testing as a preventive based on (1) animal studies that demonstrated it could prevent carcinogenesis,49-52,103 (2) extensive clinical experience that showed few serious side effects, and (3) a beneficial profile of estrogen-like action in maintaining bone density and reducing circulating cholesterol. Ta-moxifen was already known to reduce the incidence of contralateral breast cancer47 and to have a favorable toxicity profile, making the drug the primary agent to test in high-risk women. Sporadic reports19,104 and placebo-controlled randomized trials20,105 demonstrated that ta-moxifen can increase bone density in the lumbar spine, forearm, and neck of the femur by 1 -2 . Although the increases are modest compared to the results obtained with estrogen or biphosphonates (5 increase in bone density), tamoxifen produced a marginal decrease in hip and wrist fractures as a secondary end point in the breast cancer prevention trial.106 Tamoxifen reduces circulating...

Risk Factors For Breast Cancer

Identification of women at risk for definitive clinical trials. Family history is probably the best-recognized risk factor for breast cancer. An inherited gene mutation is thought to account for 5 -10 of breast cancer cases.116,117 Although infrequent, these mutations are significant since they are associated with a lifetime risk of breast cancer of 50 -80 ,118,119 beginning at a young age. At present, two predisposition genes, BRCA1, located on chromosome 17q21,120 and BRCA2, located on chromosome 13q12-13,121 have been identified, both of which are inherited in an autosomal dominant pattern. Most women with a family history of breast cancer do not have the genetically transmitted form of the disease, and their risk is much less than that seen in women who have inherited a predisposing gene. The cumulative probability that a 30-year-old woman with a mother and sister with breast cancer will develop breast cancer by the age of 70 is between 7 and 18 .122,123 While this risk increases...

Metastatic breast cancer

Patients with metastatic disease may present because of symptoms caused by the metastatic deposits. However, up to one-half of patients who present with a loco-regional recurrence of disease either have demonstrable metastatic disease at the time of presentation or shortly thereafter. Once metastatic breast cancer has been diagnosed the mean survival of these patients is approximately 18-24 months. Thus, the primary aim of any treatment is to palliate and improve the quality of life. supportive care relief of debilitating, disabling and distressing symptoms management of pathological fractures correction of disorders of body functions, etc.) and (ii) treatment to retard the growth of the tumour. These latter treatments are either chemotherapy or hormonal therapy.

Breast cancer in the elderly

The incidence of breast cancer continues to rise through life with 40 of all cases occurring in patients older than 70 years. A small number of these patients, because of concurrent disease, will be unfit for any form of loco-regional therapy other than tamoxifen (20-40 mg day). With tamoxifen as the sole therapy it has been shown that approximately one-half of the tumours will show a reduction in size and of these, up to 50 will be complete responses (6-12 months of treatment may be required). However, approximately 50 of those tumours which initially responded to tamoxifen will relapse within 2 years, with tumour growth then occurring. It should also be noted that if the tumours are OR negative they are unlikely to respond to tamoxifen and OR status should be established before commencing therapy. In general, therefore, it is recommended that older patients should be treated along the same principles as outlined previously. Stage for stage the results of therapy in women over 65...

Bilateral breast cancers

A second primary cancer in the opposite breast may be found either at the time of the initial presentation (synchronous tumour, 0.5-2 ) or more commonly at a subsequent date (metachronous cancer, 3-9 ). A woman who has a primary breast cancer has a four- to sixfold risk of developing a cancer in the opposite breast. Other risk factors for the The prognosis for patients with bilateral breast cancers depends on the staging of the tumours and treatment should be appropriate for the disease stage. Patients who have a genetic predisposition (mutations of the putative breast cancer gene(s) and associated genomic abnormalities (e.g. loss of heterozygosity of the p53-suppressor gene)) are at very high risk of developing bilateral breast cancers. In these patients, consideration may be given as to whether prophylactic mastectomy (with or without reconstruction) should be undertaken.

Breast cancer during pregnancy and lactation

Breast cancer presenting during pregnancy or lactation occurs in up to 3 in 10 000 pregnancies, and comprises less than 2 of all breast cancer cases. The median age of these patients is 34 years or less, depending on the series. Earlier studies had suggested that the prognosis was worse in pregnant women with breast cancer, when compared with those who were not pregnant. This is partly due to the fact that presentation tends to be delayed and up to 70 of pregnant women with operable breast cancer have involved axillary nodes. When compared stage for stage with non-pregnant women there appears to be no difference in prognosis. However, in general young women with breast cancer, aged 30 years or less, tend to have a worse prognosis than those aged 35 years or more. The treatment of the breast cancer should be as for the general population. For example, mastectomy can be safely undertaken. Lumpectomy and axillary surgery, if deemed appropriate, may be carried out in the third trimester....

Breast cancer in the male

Cancer of the male breast accounts for 0.5-1 of all breast cancers and less than 1 of all male malignancies. Only 5 of male breast cancers occur before the age of 40 years and the median age of presentation is 68 years (older than that of the female population who develop breast cancer). The aetiology of male breast cancer has not been elucidated but there are risk factors which may predispose to the development of breast cancer. These include increased levels of oestrogens either in the circulation or in the breast tissue (Kleinfelters syndrome, treatment with oestrogens for prostatic cancer), increased prolactin levels, exposure to ionising radiation, genetic predisposition and occupational risk factors (steel and news printing workers). The clinical presentation is usually a lump, most commonly centrally placed or in the upper outer quadrant. Up to 20 of patients may have nipple discharge which can be either serous or sero-sanguineous. Histologically, invasive ductal carcinomas of...

Granulocyte Colonystimulating Factor And Granulocytemacrophage Colonystimulating Factor For Chemotherapyinduced

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are endogenous glycoproteins that participate in the differentiation and proliferation of granulocytes, monocyte-macrophages, and other cells for hematopoeisis (17). Myelosuppresion is the major toxicity of chemotherapy for solid organ tumors, and prolonged myelosuppression and neutropenia lead to a reduction in chemotherapy dose intensity. Therefore, with the discovery, cloning, and production of recombinant human forms of G-CSF and GM-CSF (rHuG-CSF and Fig. 1. The relationship between absolute neutrophil count (ANC) and neutropenic fever after salvage chemotherapy is shown for patients with metastatic breast carcinoma. When the ANC decreases to a level below the threshold of 500 mL, the incidence of neutropenic fever increases in a linear trend (p < 0.01). *, Number of courses with fever number of courses with nadir ANC in the same range. Fig. 1. The relationship between...

Screening for breast cancer

Clinical studies have demonstrated that mammographic screening of women can reduce the number of deaths from breast cancer. In particular, studies (USA, Europe) have demonstrated that if women aged 40-74 years of age underwent regular screening there was a decrease in mortality from breast cancer of approximately 25 over 15 years, with the most benefit being found in those women over 50 years of age. In 1988 a UK National Health Service Breast Screening Programme was introduced. The aim of this programme was to reduce deaths from breast cancer by approximately 25 by the year 2000, provided that at least 70 of women in the population being screened attend for mammography. Women aged 50-64 years were invited to attend a screening centre for a single, high-quality mediolateral oblique view mammogram, every 3 years. However, there was concern that a single view mammogram could miss abnormalities that would have been detected if two mammographic views had been taken. Therefore, two views...

Prevention Of Breast Cancer With Tamoxifen

In 1986, Cuzick et al.156 outlined a prevention trial with tamoxifen in women at high risk of breast cancer. The previous year, Cuzick and Baum157 documented a marginally significant reduction in the risk of a second primary cancer in the contralateral breast of breast cancer patients after 2 years of tamoxifen. This initial observation was confirmed in larger randomized clinical trials. Fornander et al.158 recruited 1846 postmenopausal patients for the Stockholm Adjuvant Tamoxifen Trial and randomized them to a trial of adjuvant tamoxifen or nothing for early breast cancers. In the tamoxifen patients, new primary breast cancers occurred less often (RR 0.55). Similar results were obtained by the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14.159 These results led to the obvious interest in tamoxifen as a possible preventive for primary disease. Carefully controlled clinical chemoprevention trials continue to establish the activity and toxicity of specific agents and...

Regional Intraarterial Chemotherapy

In patients with HCC, uncontrolled tumor in the liver is the most significant cause of morbidity and mortality, although extrahepatic metastases are apparent in up to 25 of patients at the time of diagnosis and up to 90 on autopsy. Thus, effective local chemotherapy would have a significant clinical effect. Administration of the drug into the hepatic artery could theoretically increase local drug delivery to the tumor tissue and possibly lower systemic toxicity. An ideal pharmacologic profile would be a high degree of hepatic extraction, high systemic clearance, rapid biotransformation to less toxic metabolites, and a steep dose-response relationship with respect to tumor cell kill.

Filgrastim In The Treatment Of Breast Cancer

Although filgrastim was known to have an effect on hematopoetic cell lines, it was not clear whether it stimulated nonhematopoetic cells or tumor cells. Several studies were done to elucidate the effect, if any, on human breast cancer cells. Emerman and Eaves (22) evaluated human breast epithelial cells from normal and malignant tissues and evaluated the effects of eight cytokines G-CSF, GM-CSF, Steel factor, interleukin (IL)-2, IL-3, IL-6, transforming growth factor-P (TGF-P), and macrophage inflammatory protein 1-a. The authors found no effect of the cytokines on the growth of normal or malignant breast epithelial cells. Filgrastim appears to be safe in the treatment of breast cancer, but when in the course of chemotherapy is the best time for it to be given

Indications For Chemotherapy

It is now generally accepted that patients with bulky abdominal nodal metastases from testicular semi-noma, patients with supradiaphragmatic metastases, and patients with extranodal metastases should be treated with chemotherapy. There is some controversy over the treatment of patients with small-volume retroperitoneal node metastases since in the past, these patients have been treated with radiotherapy, reserving chemotherapy for those 10 to 20 who experience recurrence. However, with abdominal node metastases that are greater than about 5 cm in diameter (see Figure 20-1), there is a risk of renal damage from the radiation fields, and the risk of recurrence after radiotherapy becomes higher.6 Also, in most centers, abdominal node metastases > 5 cm in cross-sectional diameter would provide an indication for chemotherapy rather than radiotherapy. The efficacy of chemotherapy is such that many centers would administer chemotherapy for abdominal node metastases of smaller volume. There...

Biological Basis For Raloxifene As A Breast Cancer Preventive

Raloxifene, originally named keoxifene or LY156758,170 was discovered in the breast cancer program at the laboratories of Eli Lilly (Indianapolis, IN). The drug has a high binding affinity for the ER,171,172 primarily because it has strategically located phenolic groups (Fig. 12.1). Raloxifene and an analogue, LY117018,59,173-175 are short-acting compounds with poor bioavail-ability due to rapid phase II metabolism.176 Indeed, a concern in the early clinical trials was an inability to monitor blood levels. Although numerous assays are available to monitor ta-moxifen and its metabolites,177 the structure of raloxifene does not permit the use of similar chemical methods of detection. The analytical technique used to monitor raloxifene has not been published therefore, there has been limited clinical experience for the treatment of breast cancer. The initial study, conducted at the M.D. Anderson Cancer Center in Houston, showed no responses in heavily pretreated patients with stage IV...

Comparisons Of Longterm Effects Of Diagnosis And Treatment By Cancer Site Breast Cancer And Hodgkins Disease

Was expected that type and frequency of the physical dimension of QOL would be explained by type of treatment, age at the time of treatment and time since diagnosis. It was also expected that social and psychological dimensions of QOL would be explained by differences in educational attainment. The sample was composed of 141 individuals (55 male) who participated in two different surveys conducted at Stanford University Medical Center. The initial interviews were conducted in-person while the 12-year follow-up interviews were self-administered both surveys were conducted when the individual came to the clinic for a routine check-up. The second study was a 5-year follow-up of a population-based cohort of 185 women who were younger 50 years of age at diagnosis of breast cancer and were cancer-free 5 years later. The initial survey was in-person, often in the women's home, and the 5-year follow-up was a telephone survey.32 Comparative findings are organized according to Ferrell and...

Combination Chemotherapy

There are relatively few prospective randomized trials of different chemotherapy regimens for advanced seminoma. When interpreting reports of uncontrolled trials, it should be remembered that over the last two decades there have been considerable changes in staging classifications, in the use of radiotherapy for metastatic seminoma, and in the definition of response. The modern era of successful chemotherapy for seminoma was heralded by the introduction of cisplatin. As early as 1974, there was a reported case of a complete response of stage C seminoma to cisplatin despite relapse after previous treatment with radiotherapy and with actinomycin D.12 At the same time, at the M. D. Anderson Hospital, less aggressive chemotherapy that also appeared to be effective had been evaluated. This treatment was based on sequential weekly pulse cisplatin combined (in most patients) with cyclophosphamide. The report on 52 patients included 8 patients treated only with cisplatin 85 of patients...

Residual Masses And Postchemotherapy Radiation

Especially with cases of large-volume seminoma, it is common to find a residual mass on scanning the patient after a course of chemotherapy. However, approximately 90 of these masses do not contain residual malignancies and appear to be fibrotic remnants (Figure 20-3).30,31 Attempted resection can be hazardous because of extensive dense scar tissue involving the great vessels and retroperitoneal tissues. The analysis from the Memorial Sloan-Ketter-ing Cancer Center suggested that there was a higher risk of residual malignancy if the residual mass was > 3 cm in diameter.32 This suggestion has led, at some centers, to a policy of particularly close surveillance or adjuvant radiotherapy for this subset of patients.33 However, other investigators have not found that recurrence was more likely when the residual mass was 3 cm in diameter.34 Furthermore, retrospective data from 302 patients treated in 10 European centers with chemotherapy for metastatic seminoma indicated that 174 of those...

Concurrent Use With Chemotherapy

In 1994, Livingston et al. (43) began a series of studies exploring the concept of dose density, namely, multifractioned doses of chemotherapy given at shorter intervals than standard regimens. To prevent dose-limiting myelosuppression, they began intermittent and then continuous neutrophil support with daily filgrastim. In the first study, vinorelbine 35 mg m2 was given weekly with continuous filgrastim 5 mg kg to 40 patients previously treated with anthracyclines and resistant to paclitaxel. They observed that continuous filgrastim allowed a nearly twofold increase in the delivered dose intensity, from 46 to 73 , compared with similar historical series without fil-grastim. The increase in delivered dose intensity was suggested as the basis for the observed 25 objective response rate. Use of continuous filgrastim with an alkylating agent, cyclophosphamide 60 mg m2 d, continously with doxorubicin 24 mg m2 wk was tested preoperatively in 122 patients with locally advanced breast cancer...

Expression and amplification oerbB2 in breast cancer

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

Breast Cancer Risk Modifiers

The incomplete penetrance associated with mutations in BRCA1 and BRCA2 suggests that environmental or genetic risk-modifying factors may exist that affect the phenotype of BRCA1 and BRCA2 mutation carriers. Initial estimates from clinic-based data indicated that around 80 of carriers of mutations in BRCA1 and BRCA2 from multiple-case families would develop breast cancer (1,2), whereas a later pooled analysis from population-based studies has suggested that for the great majority of mutation carriers, their average lifetime risk is closer to 45 to 66 (3). This pooled-analysis of BRCA1 and BRCA2 carriers also showed that in BRCA1 mutation carriers, the breast cancer penetrance for relatives ascertained through a breast cancer case was significantly higher than for those ascertained through an ovarian cancer case, and even higher if the index case was diagnosed before the age of 35 (3). Conversely, the ovarian cancer risk was higher in families ascertained through an ovarian cancer index...

Tumor Suppressor Activity of E1A in Breast Cancer Experimental Models

The initial link between E1A and tumor suppression in breast cancer was based on the observations that E1A could suppress the transformation phenotype of the neu-transformed NIH mouse 3T3 cells (10-12) by transcriptionally repressing the promoter of rat neu oncogene (9). HER-2 is amplified and overexpressed in approximately 30 human breast cancer patients with poor prognosis (29-31). Because the neu gene is a murine counterpart of the human HER-2 proto-oncogene, it was hypothesized that E1A could also repress HER-2 expression in human breast cancer. Indeed, both HER-2 protein and mRNA levels were reduced in HER-2-overexpressing breast cancer cell lines infected with an E1A-expressing adenovirus (Ad.E1A(+)) but not a mutant adenovirus (Ad.E1A(-)) in which E1A is deleted (13). To test whether the E1A-mediated HER-2 repression affects the cell growth in cell model systems, both the high-HER-2 (e.g., MDA-MB-361 and SKBR3) and the low-HER-2-expressing (e.g., MDA-MB-435 and MDA-MB-231)...

Some Basic and Applied Principles of Cancer Chemotherapy

Although our understanding of the basic molecular nature of the neoplastic transformation is still relatively primitive, significant advances have been made during the past three decades in the successful treatment of neoplasms that were not curable by surgery and or radiation alone prior to 1970. The principal modality (used alone or in combination) that has resulted in significant improvement in treating a number of neoplasms, many of which are in persons less than 30 years of age (Chapter 1), is chemotherapy, by use of an increased spectrum of drugs, hormones, and other natural products. Chemotherapy may be defined as the treatment of disease through the use of chemicals. This includes infectious as well as neoplastic disease. Cancer chemotherapy specifically is the treatment of cancer by chemicals that maximize the killing of neoplastic cells while minimizing the killing of most or all other cells of the host. With most malignant neoplasms, the greatest danger to the host results...

Variables In The Chemotherapy Of Cancer

Although a variety of specific drugs are used in the chemotherapy of cancer, their effects can be quite variable from patient to patient and even within the same patient at different periods of the treatment regimen. Such variability involves different factors, some of which we have discussed above and others of which are noted in Figure 20.6. In this figure, the overall pharmacological-therapeutic process from a drug dose to its therapeutic effect is depicted. However, since neopla-sia is a somewhat specific situation involving cell growth as well as specific humoral effects of the neoplasm on the host (Chapters 17 and 18), other variable factors come into play, some of which are considered here. It is already obvious that drugs used in the chemotherapy of cancer have a variety of toxic effects in the host that may or may not be directly related to its effect on the neoplasm. Thus, in any such situation, the toxicity to normal tissues and the organism as a whole becomes a limiting...

Bik Induces Apoptosis in Breast Cancer Cells

In vitro, we showed that transfection of a bik expression vector and SN2 complex (SN-bik) into breast cancer cell lines such as MDA-MB-231, MDA-MB-468, and MCF-7 resulted in a drastic increase of apoptosis as measured by sub-G1 cell population (47). As expected, the SN-bik transfected breast cancer cells exhibited drastic reduction of the number of colony in soft agar. These results suggest that bik is a potent proapoptotic agent and may be suitable for further development as a potential therapeutic gene in vivo.

Chemotherapy Regimens For The Treatment Of Leukemias And Solid Neoplasms

With the expansion of the knowledge base for modern chemotherapy of cancer, the efficacy as well as the rationale of the use of combinations of drugs for the therapy of neoplasia became of paramount importance. The ideal situation in which application of the basic knowledge developed to the present time is seen with rapidly growing neoplasms, particularly leukemias, in which neoplastic cells occur systemically but with easy access to the therapeutic agents through the vascular circulation. Here are considered examples of this more idealized treatment as well as the therapy of solid neoplasms, where delivery of the drug to the neoplastic cell becomes a major therapeutic hurdle.

Mutant bik DD Enhances Apoptosis in Breast Cancer Cells

Objective, we attempted to modify the bik gene to make it more potent than the wild type bik. It has been implicated that phosphorylation of threonine 33 (T33) and serine 35 (S35) of bik protein are required for its maximum apoptotic activity (96). We hypothesized that T33 and S35 substitutions with the negatively charged aspartic acids (D33 and D35) (i.e., bik DD) would be constitutively active and, thus, more potent. Indeed, we found that bik DD has higher binding affinity with the antiapoptotic molecules, Bcl-2 and Bcl-XL, than does the wild-type bik. Subsequently, transfection of bik DD led to higher apoptosis in breast cancer cells such as MCF-7 than did wild type bik (97). These results suggest that bik DD is a more potent apoptotic agent than the wild type bik.

Recent Modalities In And Potential For Cancer Chemotherapy

Until recent years, the principal direction of cancer chemotherapy has been toward newer and better drugs aimed at affecting cell replication as well as by endocrine-active drugs. A very significant portion of the drugs presently in use were discovered as a result of serendipity or their efficacy is directly related to serendipitous findings. With the dramatic increase in our knowledge of the cellular and molecular biology of living tissues, both normal and neoplastic, it is now reasonable to devise chemotherapeutic agents on the basis of several rationales. Several of these are discussed below. Signal Transduction Pathways as Targets for Chemotherapy With a dramatic increase in our knowledge of molecular mechanisms involved in signal trans-duction and its aberrations in neoplasia, components of this pathway have been suggested as possible targets for chemotherapy (Powis, 1994). Although there are many possibilities, certain specific sites have been targeted by agents developed...

Enhancement of Radiation Therapy or Chemotherapy

Chemotherapy and radiation therapy induce tumor cell death in large part by causing DNA damage that leads to apoptosis (programmed cell death). Toxicity to normal cells at higher doses with conventional agents often leads to the inability to completely eradicate tumor with conventional agents. Gene therapy strategies may therefore include transduction of genes that synergize with conventional agents without increasing toxic-ity to normal cells. One example of such a gene is wt-p53 which is involved in monitoring DNA damage. Following DNA damage cellular p53 expression increases with tranduction of other genes such as p21 that induce G1 cell arrest and allow the cell to repair the damage. If the damage is not repaired, apoptosis may be induced. Cells with mutated p53 are more resistant to radiation therapy induced cell death than cells with wild type p53 leading to tumor resistance with conventional therapies (23). In the laboratory, the administration of adenoviral p53 before...

Amplified in Breast Cancer

BRCA1 is a coactivator of AR, and this activation is mediated in part through an estrogen-receptor coactivator, amplified in breast cancer 1 (AIB1) (73). Rebbeck et al. studied the effect of a glutamine repeat polymorphism at the AIB1 locus, whose functional effect is unknown, using a matched case-control sample of 448 women with germline BRCA1 (n 370) or BRCA2 (n 78) mutations (29). These women were at a significantly higher breast cancer risk if they carried alleles with at least 28 or 29 polyglutamine repeats in AIB1, compared with women who carried alleles with fewer repeats (OR 1.59 95 CI 1.03-2.47 or OR 2.85 95 CI 1.64-4.96, respectively). This effect was also seen when analysis was restricted to only BRCA1 mutation carriers. Women were at an even higher risk if they had AIB1 alleles with at least 28 polyglutamine repeats and were either nulliparous or had had a late age at first live birth (OR 4.62 95 CI 2.02-10.56) compared to women with none of these risk factors. The...

Strategies Incorporating Hormonal Therapy and Cytotoxic Chemotherapy

The benefit of cytotoxic chemotherapy for patients with hormone-refractory prostate cancer is now firmly established.171,172 Several attempts have been made to determine whether response to and duration of clinical remission from hormonal therapy can be improved by the early addition of cytotoxic chemotherapy. Generally, with the notable exception of a combination of estramustine with selected cy-totoxic drugs (see below, Estramustine in Combination with Cytotoxic Drugs), these attempts have met with limited success. The Southwest Oncology Group studied the combination of endocrine therapy (estrogens or or-chiectomy) with doxorubicin and cyclophos-phamide randomized against endocrine therapy alone with addition of the same chemotherapy regimen at progression.173 This trial accrued between September 1982 and October 1986. Patients on the combined chemo-endocrine therapy arm had a slightly higher response rate (63 ) compared to those on endocrine therapy alone (48 ), but this was not...

Modifiers Of Penetrance And Breast Cancer Genes Other Than Brca

Several studies have noted an increased penetrance for BRCA1 2 in more recent birth cohorts. The NYBCS (9) confirmed Narod's earlier observation of a significant increase in breast cancer risk by the age of 50 years in birth cohorts after 1940 (67 after 1940, 24 before 1940) (39). Ovarian cancer risk did not differ by birth cohort. This increase in incidence for BRCA1 2 mutation carriers parallels an increase in breast cancer in the general U.S. population over that period (37). Antoniou et al. (61) analyzed the results of 22 studies in which cases were unselected for family history. The RR for breast cancer among BRCA1 2 mutation carriers in the post-1960 birth cohorts was two to three times the RR in the preceding four decades. A study of Austrian BRCA1 mutation-positive women found that those from birth cohorts after 1958 had a significantly higher incidence of breast cancer by 40 years of age than those from earlier birth cohorts 46 versus 27 , respectively (89). Finally,...

Prognosis After Chemotherapy

In a prognostic factor analysis of chemotherapy results in germ cell tumors, the International Germ Cell Cancer Collaborative Group (IGCCCG) reviewed 637 patients treated for advanced seminoma. The 3-year survival rate was 82 .9 However, the majority of patients were in a good prognostic subgroup, with metastasis confined to either lymph nodes or lung fields, and in this group, the 5-year survival rate was 86 . Those with nonpulmonary visceral metastases had a 5-year survival rate of 72 . In an analysis of a subset of 236 of these patients treated with cisplatin-based chemotherapy at 1 of 10 European oncology units, a very-good-prognosis group was identified this group comprised patients who had not had previous radiotherapy and who either had abdominal node metastases with any level of serum lactate dehydrogenase (LDH) or were stage C patients without nonpulmonary visceral metastases and whose serum LDH was less than twice the upper limit of normal. These patients had a 94 3-year...

Expression in Breast Cancer

Situation analogous to the regulation of promoter II by FSH in the ovary. Indeed, it appears that in breast cancer cell lines an additional CRE, located within promoter 1.3 ( 66 59), contributes to cAMP-induced transcription from promoters II and I.3.59 This CRE-like sequence overlaps a binding site for the zinc-finger tran-scriptional factor Snail (SnaH), which was identified by yeast one-hybrid screen using the CRE as a probe.60 SnaH acts as a repressor of promoter 1.3 activity and was expressed at higher levels in normal breast epithelial cell and stro-mal fibroblast cell lines than in breast cancer cell lines.60 Thus, downregulation of SnaH in stro-mal cells adjacent to malignant breast epithelial cells might contribute to induction of aromatase through promoter I.3. Figure 8.5 Proposed regulation of aromatase gene expression in breast adipose tissue from cancer-free individuals and from those with breast cancer. In the former case, expression is stimulated primarily by class I...

Cell Molecular Biology Breast Cancer

Bi-directional Regulation of Human Progesterone Receptors and the Mitogen Activated Protein Kinase Pathway in Breast Cancer Cell Models Abnormal Properties of Mutants in the Hinge Region of ErV Implications in Breast Cancer Microarray Analysis of Estrogen-Induced Protection Against Breast Cancer

Preirradiation Or Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy refers to treatment given at diagnosis before other modalities such as radiation. It has several potential advantages. First, neoadjuvant chemotherapy allows early treatment of the infiltrating tumor cells that may be at or beyond the border of the radiation field. Second, neoadjuvant chemotherapy allows true assessment of the efficacy of the chemotherapy. Such information is important at the time of tumor progression in deciding whether treatment with the same regimen might be helpful. Finally, new agents are most effectively screened for activity in this setting (51). If a given agent has no efficacy in newly diagnosed patients, it will not help patients with recurrent tumors, and further testing in these patients can be avoided. The risk of tumor progression during chemotherapy, however, is significant, particularly for patients with GBM. The neoadjuvant trial design for patients with HGG requires very close monitoring. Most such trials appropriately...

Breast Cancer

Breast cancer incidence and mortality rates are strongly influenced by changing reproductive patterns, diagnostic screening practices, and treatment options. The introduction of mam-mography across the United States in the 1980s was followed by a rapid rise in breast cancer incidence (Fig. 1.4). Incidence rates increased among African-American and white women of all ages from 1973 through 1991 (37.4 and 33.1 , respectively). From 1991 through 1998, breast cancer incidence continued to increase at a slower rate among African-American (5.7 ) and white (6.5 ) women aged 50 and older, while decreasing in women under the age of 50 (African American, 10.8 white, 3.0 ). The initial rise in cases in the 1980s was limited to early-stage breast cancer and in situ disease however, more cases of stage II lymph node-positive breast cancer among white women 50-64 years old have been reported in recent years (1994-1998).29,32 The reason for the change in incidence may be explained by the impact of...

Role ofChemotherapy

As with adults, there are hundreds of studies reporting the efficacy (and lack of efficacy) of many different chemotherapeutic agents in treating this disease. Conventional dose studies have been performed with the nitorsoureas (BCNU and CCNU), the platinum agents (cisplatin and carboplatin), vincrisitine, etoposide (VP-16), cyclophosphamide and ifosfamide, procarbazine, topotecan, and others. High-dose chemotherapy using combination chemotherapy with BCNU, carboplatin, etoposide, thiotepa and others followed by either autologous bone marrow rescue and more recently autologous stem cell rescue has been used to treat highgrade glioma as well. The role of chemotherapy was first explored (and established) in a randomized trial of 58 children conducted by the Children's Cancer Group. Patients were randomized and treated with maximal surgical resection and involved-field radiotherapy with or without eight cycles of chemotherapy (CCNU, vincristine and prednisone). The 5-yr PFS was 18 in the...

Chemotherapy

Numerous trials of chemotherapy, used either in an adjuvant or neo-adjuvant setting have not demonstrated benefit. Most of the earlier trials involved single or multiple agents in a phase II setting. More recent studies have involved the use of neo-adjuvant chemotherapy or concurrent chemotherapy and or radiation sensitizers with irradiation. Although results from some of these trials were initially encouraging, the final results have been uniformly disappointing as well (44,45,47-50). The Children's Cancer Group conducted a randomized trial of two different arms of intensive pre-irradiation chemotherapy followed by hyperfactionated radiotherapy. Children were randomly assigned to receive three courses of carboplatin, etoposide, and vincristine (arm A, n 32), or cisplatin, etoposide, cyclophosphamide, and vincristine (arm B, n 31). Granulocyte colony-stimulating factor was used in both arms. Following chemotherapy, both groups received 7200 cGy of radiation in 100 cGy bid fractions....

Chemotherapy Effects

The skin and mucous membranes form the primary barriers to invasion of the body by micro-organisms. The skin is normally quite impervious, and infection is almost always caused by a mechanical break or injury, including medical procedures such as intravenous catheter insertion. The oropharynx is normally coated by bacteria, most of which are regarded as of low pathogenicity. Normally, these areas are kept free of overt infection by the constant exudates of neutrophils around the teeth and at breaks in the surface integrity. In healthy persons, large numbers of neutrophils are constantly exuding to these surfaces. Interruption of the neutrophil supply, as occurs with myelo-toxic chemotherapy, is often first manifest by oral pain, mouth ulcers, and inflammation of the gingivae. Further along the gastrointestinal tract, the epithelium on the surface of the large and small intestine is constantly being renewed. The toxic effects of chemotherapy disrupt this fragile barrier bacterial...

Before Chemotherapy

When administered before chemotherapy as a daily subcutaneous injection, PEG-rHuMGDF produced a dose-dependent increase in peripheral blood platelet counts and a modest increase in megakaryocyte, erythroid, and myeloid progenitor cell counts in patients with advanced cancer (106-110). No evidence of platelet activation or altered platelet function was observed with PEG-rHuMGDF administration (111). rHuTPO has produced a dose-dependent increase in platelet counts in patients with sarcomas and gynecologic malignancies (112-116). A phase 1-2 study examined the effect of rHuTPO on megakaryocyte and platelet production before chemotherapy with doxorubicin and ifosfamide in patients with sarcomas who were at high risk of developing chemotherapy-induced thrombocytopenia. When given intravenously before chemotherapy, a single dose of rHuTPO was associated with a dose-dependent increase in peripheral platelets that began on d 4 and peaked on d 12 in most patients (113). This...

CURRENT cLinical oNCOLOGY

Colorectal Cancer Evidence-Based Chemotherapy Strategies, edited by Laughlin and Hillard M. L z run, 2003 Chronic Leukemias and Lymphomas Biology, Pathophysiology, and Clinical Management, edited by Gary J. Schiller, 2003 Colorectal Cancer Multimodality Management, edited by Leonard Saltz, 2002 Breast Cancer A Guide to Detection andMultidisciplinary Therapy, edited by Michael H. Torosian, 2002 Regional Chemotherapy Clinical Research and Practice, edited by Maurie Markman, 2000

Cancer Drug Discovery and Development

Soprano, 2003 Chemoradiation in Cancer Therapy, edited by Hak Choy, 2003 Fluoropyrimidines in Cancer Therapy, edited by Youcef M. Rustum, 2003 Targets for Cancer Chemotherapy Transcription Factors and Other Nuclear Proteins, Apoptosis and Cancer Chemotherapy, edited by John A. Hickman and Caroline Dive, 1999 Signaling Networks and Cell Cycle Control The Molecular Basis of Cancer and Other

Hormonal Carcinogenesis

During the early 1970s, MacMahon and col-leagues10 published a series of papers suggesting that estrogens, generally, and estradiol, specifically, could be involved in human breast cancer carcinogenesis. At the same time, there was widespread scientific interest in the publication of data from Spiegelman's laboratory11 demonstrating a microscopically, and immuno- logically, identifiable murine mammary tumor virus or type B virus in human breast milk. We undertook our first epidemiological study of breast cancer in young women to address the possibility that a transmissible agent causing breast cancer might also exist in human breast milk. We were unable to substantiate this hypothesis as there was no evidence of excess risk associated with breast-feeding, and the excess familial risk of breast cancer was seen in both the paternal and the maternal family trees.12 However, we were very impressed with the evidence supporting a role for endogenous estrogen and the key importance of age at...

Biology of Germ Cell Tumors

Germ cell tumors, which constitute one of the most fascinating groups of malignancies, represent a curious interface between cancer and differentiation. Their embryologic complexity and structural diversity have made these tumors the focus of intense clinicopathologic and molecular scrutiny.1 Just a quarter of a century ago, metastatic testicular cancer caused death in the vast majority of patients. With the evolution of effective chemotherapy and the development of a more rational approach to surgery, as well as an improved understanding of the clinical biology of the disease, this pattern has changed to one in which more than 80 of patients with advanced disease should expect to be cured. Nevertheless, one of the most curious aspects of this disease is that despite the success in achieving cure, clinicians and scientists do not really understand the basis of these results at a biologic level, and the basis of the delicate balance between differentiation and dedifferentiation remains...

Replicationdefective Adenovectors

Additional strategies for improving adenoviral vector-based gene delivery systems have also been explored. For example, chemically or genetically modified capsid proteins to enhance the transduction efficiency in CAR-defective cells or to redirect vector tropisms have been rigorously tested and it has been reported that the formulation of an adenovector in protamine or other pharmaceutical excipients enhance in vivo transduc-tion in the lung after systemic administration, intratracheal instillation, or aerosolized vector delivery (59,60). Furthermore, several small molecules, such as Syn3 and some anticancer agents (61,62), have been reported to dramatically enhance adenovector-mediated gene delivery. Treating animals with low-dose etopside can suppress the formation of neutralizing antibodies and thus enhance intratumoral transgene expression in immunized animals (63). Moreover, the modification of adenovectors with polyethylene glycol (64-68) and formulations of adenoviral vectors...

Classification And Functional Pathology

Ogy large centrally located spherical hyperchromatic nuclei with irregular outlines and one or more basophilic nucleoli and intense histochemical staining for alkaline phosphatase. Thus, this cell type closely resembles the normal or primordial germ cell, and this has led to the concept that the primordial germ cell gives rise to seminoma. Seminoma is characterized by occurrence in patients of a somewhat older age and by an exquisite responsiveness to radiotherapy and chemotherapy. A well-characterized variant is anaplastic seminoma, which is less differentiated and to which a worse prognosis has been attributed in some series (see below and Chapters 18 and 19).

Oligodendroglioma And Mixed Glioma

High-grade tumors are generally more cellular than low-grade tumors (Fig. 20). Nuclear pleomorphism is more prominent and in some tumors may approach the variation in nuclear size and shape that marks high-grade astrocytomas. Mitotic activity is more prevalent and often approaches and exceeds five mitotic figures ten high power fields. Vascular proliferation and foci of necrosis may be present (Fig. 21). Some tumors resemble GBM with palisaded necrosis (Fig. 22). These tumors should not, however, be referred to as GBM tumors of oligodendroglial lineage generally have a better prognosis and are more likely to respond to chemotherapy. Assessing the behavior of these tumors has been difficult. More recently, the molecular evaluation of mixed gliomas (oligoastrocytomas) for loss on chromosomes 1p and 19q has helped to clarify this issue. Mixed gliomas which are 1p 19q deleted appear to act more like oligodendrogliomas (i.e., more likely to benefit from a course of chemotherapy and have a...

Molecular Correlates Of Germ Cell Tumor Development And Function In Humans

Summersgill and colleagues, in a study of a series of eight seminomas, fourteen NSGCTs, two combined tumors, and two cell lines, confirmed the abnormalities of chromosome 12p but also identified gains in chromosomes 1, 2, 7, and 8, as well as loss of material from chromosomes 1, 4, 5, 9, 11, 16, and 18.65 Loss of material from chromosomes 19 and 22 and gain of regions on chromosomes 5, 6, and 13 were found less frequently in seminomas than in NSGCTs, suggesting that these regions may contain genes involved in the separate development of these tumor types. A broad range of chromosomal abnormalities have been identified in different studies, many of which reflect potential abnormalities in the function of tumor suppressor genes, including RB, DCC, and NME. Curiously, one important tumor suppressor gene that appears to be mutated only rarely in GCTs is the P53 gene, and it has been suggested that this may partly explain these tumors' exquisite sensitivity to radiation therapy and...

Chromosomal Instability A New Paradigm for Estrogeninduced Oncogenesis

Human sporadic breast cancer (BC) comprises > 90 of all BC cases whereas familial BC is less than 10 (1). Despite its likely multifactorial origin, there is now pervasive evidence from epidemiological and animal studies, developed over the past several decades, that the causation of human sporadic BC primarily involves female sex hormones, particularly estrogens (Es) (1-8). This view is consistent with long standing epidemiological data relating extended exposure to Es and elevated BC risk, such as early first menarche, late age at menopause, nulliparity, late age at full-term pregnancy, and absence of lactation (5, 6). These BC risk factors are all related to pre-menopausal women. Moreover, all ofthe well-established BC risk factors are associated with elevated circulating E levels. Even lesser risk factors such as obesity and alcohol ingestion are known to significantly increase serum E concentrations in women (9, 10). These earlier studies are buttressed by results of the recent...

Chromosomal abnormalities in cancer

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

Hepatobiliary Malignancies

Physicians and physician assistants in the GI Tumor Center at M. D. Anderson evaluated more than 900 new patients with primary or metastatic hepatobiliary tumors in 2002. Patients with primary liver cancer include those with hepatocellular carcinoma (HCC), gallbladder cancer, and intrahepatic or extrahepatic cholangiocarcinoma. Patients with liver metastases from other organ sites, most commonly colorectal adenocarci-noma, and with disease confined to the liver may be considered for surgery, tumor ablation, regional chemotherapy, or systemic chemotherapy. The initial screening evaluation of new patients includes a thorough review of outside medical records, pathologic assessment of any surgical or needle-biopsy specimens, and review of prior diagnostic CT scans and plain radiographs. Once again, a thorough history and physical examination are mandatory. In patients with liver metastases, recent assessment of the primary site of disease, such as colonoscopy for colorectal cancer, is...

Historical Perspective

Finally, from a historical perspective, it is personally very moving to me to realize that so much has been accomplished since Paul Broca, the eminent French surgeon, published a description of his wife's family in 1866 (6). This family certainly qualified as the first hereditary breast-cancer-prone family to be documented in the medical literature. Then, a century later, Lynch and colleagues (7-9) described for the first time the HBOC syndrome. This hereditary disorder posed an exceedingly difficult sell job to the breast ovarian cancer research community. However, thanks to the discovery of BRCA1 and BRCA2 mutations, its existence has been confirmed beyond doubt.

The Relationship Between HRT and Risk of Lobular Carcinoma

As a result ofthe observations described above, attention has been paid to potential risk factors that may be more strongly related to ILC risk than to IDC risk. In particular, there is a growing interest in the relationship between combined E and P HRT (CHRT) and ILC risk. Two main observations have driven this research. First, CHRT use in the USA increased over the same time period that ILC rates increased and IDC rates remained constant. From 1982-1992 the number E and P prescriptions increased 2.3-fold and 4.9-fold, respectively (24). Among controls from a recent USA multi-center case-control study of postmenopausal women spanning 1994-1998, 45 were current HRT users (25). Second, CHRT use has been shown to be associated with an elevated BC risk in numerous studies, and more recently in the Women's Health Initiative (WHI), a randomized controlled trial. The pooled analysis conducted by the Collaborative Group on Hormonal Factors in Breast Cancer of 51 observational studies found...

Granulocyte Colony Stimulating Factor

Many studies focus primarily on hematopoietic parameters after chemotherapy. For example, HuG-CSF accelerated granulopoietic recovery after cyclophosphamide in mice (120) and rats (121), after etoposide in mice (122), and after mitoxantrone and cyclophosphamide combination therapy in dogs (123). Animal models can allow evaluation of novel approaches to scheduling and drug delivery. The effectiveness of rectal administration of G-CSF by suppositories has been shown in cyclophosphamide-treated rabbits (124). Scheduling issues can be more readily evaluated in animal models than in patients, particularly when theoretical risks exist. The risks and benefits of different schedules of exogenous G-CSF administration before and after a cyclophosphamide dose have been studied in mice (125). Exogenous G-CSF administration immediately before chemotherapy and continued after chemotherapy accelerated neutrophil recovery, although neutrophil nadirs were lower than with other schedules. Exogenous...

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