HPV and Abnormal Pap Smear Results

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Cervical Dysplasia Abnormal Pap Smear

If a Pap smear shows cervical dysplasia (pre-cancerous cells), effective intervention is needed to prevent development of cancer. Untreated cervical dysplasia (depending on its severity) will typically develop into cervical cancer over the next 2-8 years. Unlike many other cancers that appear at older ages, cervical cancer most often occurs in younger women (ages 30-45). A healthy diet can reduce risk of cervical dysplasia, and supplementation with micronutrients after an

Human Papillomaviruses

Papillomaviruses are an extensive family of small DNA viruses that have been detected in a variety of hosts from birds to humans. They are highly species specific and in each case exclusively infect epithelial cells. HPV infections generally give rise to benign hyperplasias commonly referred to as warts. Papillomaviruses possess a double-stranded circular DNA genome of approximately 8000 base pairs in size. The entire coding information is contained on a single DNA strand. Papillomavirus genomes can be divided into three portions the early coding region that encompasses approximately eight open reading frames (ORFs), the late coding region consisting of two ORFs, and a third long control region (LCR) that does not contain extensive coding information but harbors multiple cis elements that control the viral replication and transcription programs. Individual ORFs are designated E or L for early and late, respectively, followed by a numeral that denotes their relative sizes the higher...

Micronutrients Cervical Dysplasia

3000 ig for women who have an abnormal Pap smear showing cervical dysplasia 800 ig for prevention 5 mg for women who have an abnormal Pap smear 0.4 mg for prevention Should contain ample beta-carotene, vitamin E, and vitamin C, as well as selenium (see pp. 118 for recommended levels of antioxidants) May help reverse dysplasia.27,28 High doses of vitamin A should only be taken with the advice of a physician May reverse dysplasia.29-31 Should be taken as part of a vitamin B complex May help reverse cervical dysplasia. Low intake of antioxidants increases risk28,32,33 Fig. 5.29 Folic acid supplementation and cervical dysplasia. 47 women taking oral contraceptives with dysplasia of the uterine cervixwere given folic acid (10 g day) or placebo for 3 months. At the end of treatment cytology scores from the folate group were significantly better than for the placebo group. Cervical dysplasia asociated with oral contraceptive use may, in some cases, be arrested or reversed by folate...


Symbole Umschalter

Papillomaviruses have proven difficult to treat because of the paucity of targets in the latent phase. Thus, treatment regimens have focused on eliminating the infected cells rather than treating the virus directly. Methods for doing this have included surgery, cryotherapy or caustic agents applied to warts, and topical application of cytotoxins such as podo-phyllin (502,503).These approaches have low success rates because of a high recurrence rate of the warts. Whereas the bulk of the wart can be removed by this method, the infected basal cells that provide the reservoir for continued viral genome replication are difficult to remove. One approach to overcoming this barrier comes from the observation that the warts may clear without treatment, presumably because of an immune response (504). This assertion is bolstered by observations that HPV-associated warts in HIV-positive patients responded to antiretroviral treatment (505, 506). Attempts to bolster the immune response led to...

Conclusion and Future Directions

HPV causes the most common viral infection of the reproductive tract worldwide. However, the infection is often transient and self-limited. Several studies have suggested that HPV infection and cervical dysplasia can be prevented by HPV L1 VLP vaccines. The licensure of a vaccine against HPV represents a major public health advance against cervical cancer and other less common cancers including those of the anus, vagina, and vulva. Much still needs to be investigated regarding the local immune responses to the vaccine in the lower genital tract, longevity of immune responses, and alternative delivery routes such as intravaginal, intranasal, and oral administration.

HPV 1618 vaccine could prevent 70 of cervical cancers

It is now widely accepted that high-risk HPV infections are a necessary, but not sufficient, cause of virtually all cases of cervical cancer worldwide (Fig. 2) and are a likely cause of a substantial proportion of other anogenital neoplasms and oral squamous cell carcinomas. An estimated 85 of anal cancers 50 of the cancers of the vulva, vagina, and penis 20 of oropharyngeal cancers and 10 of laryngeal and esophageal cancers are attributable to HPV (CDC 2004). Infection with low oncogenic risk HPV types, such as HPV 6 and 11, can cause benign lesions of the anogenital areas known as condylomata acuminata (genital warts), as well as a large proportion of low-grade squamous intraepithelial lesions of the cervix. Low-risk HPV clinical infections are responsible for substantial morbidity and invoke high costs associated with the treatment of clinically relevant lesions.

The Role of Transcriptional Repression in G2 Arrest

The downregulation by p53 of Cdc2 and cyclin B1, two proteins essential for cells to enter mitosis, helps to explain the effects of caffeine on the cell cycle. Caffeine can abrogate cell cycle checkpoints, including the G2 arrest that occurs in response to DNA damage (145). However, p53 can block the effect of caffeine on G2 arrest. For example, a breast cancer cell line with wildtype p53 arrests in G2 in response to DNA damage, and this effect could not be overcome by caffeine (146). However, when p53 was inactivated by expressing the E6 protein of the human papilloma virus, caffeine could abrogate the G2 arrest (146). These results suggested that p53 has to be inactivated to unleash the effects of caffeine because it downregulates both Cdc2 and cyclin B1. We recently reinvestigated this phenomenon and found that the inactiva-tion of p53 allows caffeine to abrogate G2 arrest induced by etoposide in HT1080 fibrosarcoma cells, which have wild-type p53 (147). The stable arrest of the...

Neoplastic Enlargement Gingival Tumors

Periodontal Disease Radiograph

Neoplasms account lor a comparatively small proportion of gingival enlargements and make up a small percentage ol the total number of oral neoplasms. In a survey of 2.S7 oral tumors,81 approximately 8 occurred on the gingiva. In another study1, of 868 growths of the gingiva and palate, ol which 57 were neoplastic and the remainder inflammatory, the following incidence of tumors was noted carcinoma, 11.0 fibroma, 9 * giant cell tumor. 8.4 papilloma. 7.3 leukoplakia, 4.9 mixed tumor (salivary gland type), 2.5 angioma, 1.5 osteofibroma. 1.3 sarcoma, 0.5 melanoma, 0.5 myxoma, 0.45 fibropapilloma, 0.4 adenoma, 0.4 and lipoma, 0.3 . Fig. 18-22 Papilloma ol the gingiva in a 26-year-old man Fig. 18-22 Papilloma ol the gingiva in a 26-year-old man Papilloma. Papillomas are benign proliferations of surface epithelium associated with the human papillomavirus (HPV). Viral subtypes HPV-o and IIPV-ll have been found in most cases of oral papillomas, (iingival papillomas appear as solitary, wartlike...

Regulation Of Physiological Events By Proteolytic Function

The phosphoprotein p53 is intricately involved in the checkpoint control at the Gj-M as well as at the G2-M transition of cells. p53 has a short half-life. Its degradation has been attributed to ubiquitination as well as to proteolysis by calpain. The PEST (Pro, Asp Glu, Ser, and Thr) motif is generally regarded as a signal in the substrate that is required for its recognition by an intracellular protease. p53 contains the PEST sequence, which is required for proteolysis by calpain. Ubiquit-ination of certain substrates, e.g., STE3 receptor of yeast, has been attributed to a PEST-like sequence (Roth et al. 1998), although we do not know if this is the case with p53 ubiquitination. Mutated p53, which has an increased half-life, does not contain these sequences. However, in some instances, p53 may be degraded by calpain in the absence of the PEST sequences. Wild-type p53 is also stabilised when cells expressing it are treated with inhibitors of calpain. However, the presence of the PEST...

Nucleolin As A Protooncogene That Stimulates Cell Proliferation

Cell transformation induced by the Human Papillomavirus (HPV18) could also involve nucleolin (Grinstein et al., 2002). Nucleolin binds in a sequence-specific manner to the HPV18 enhancer. Antisense inactivation of nucleolin blocks E6 and E7 oncogene transcription and selectively decreases HPV18(+) cervical cancer cell growth. Nucleolin might be involved in opening the chromatin structure of the HPV18 enhancer suggesting that through this mechanism, nucleolin functions as a regulator of HPV18 oncogene transcription and HPV18-induced cervical carcinogenesis.

The Role Of Hpvs In The Development Of Cervical Cancer 21 Biologic Properties of HPVs

HPVs represent a group of small DNA tumor viruses that comprise, at present, 80 different genotypes (6,23) (for genome organization, see Fig. 1). Based on their presence in specific lesions, they were subdivided into low - and high -risk HPVs (23). Low-risk types (HPV-6 and HPV-11) regularly produce benign lesions of the genital tract such as the exophytic condylomata acuminata (6,23). Although more than 30 distinct HPV types have been isolated from anogenital precancerous and malignant biopsy specimens, only a restricted number, mainly HPV-16 but also HPV-18, -33, -45, -52, -58, and a few others, belong to the high-risk group (6,23). These specific types can be detected in approx 95 of cervical cancer biopsies (6). Cancer of the uterine cervix, which is the second leading cause of cancer incidence in women worldwide, can be considered as a sexually transmitted disease, with a relationship between the onset of sexual activity, the number of sexual partners, and the prevalence of...

Chemokines And Cervical Cancer

Although HeLa cells were normally refractory to certain cytokines such as TNF-a and IL-1 (13,58), invasion of activated mononuclear cells may create a microenviron-mental situation, in which the secretion of locally high doses of growth-inhibitory cytokines can temporarily block the proliferation of the surrounding tumorigenic cells. A macrophage-derived growth factor that obviously can efficiently interfere with HPV-18 mRNA transcription in HeLa cells by arresting them in G1 of the cell cycle is IFN-a (55). Which cytokines were actually involved in the in vivo growth control of HPV-positive cells is presently not known and awaits further elucidation. 3.2. Transcriptional Regulation of the MCP-1 Gene in HPV-Positive Cells Another area of interest concerns the influence of viral oncogenes on chemokine expression. Since MCP-1 transcription is readily inducible by cytokines in both HPV-negative primary human keratinocytes (75) and human fibroblasts (76), the question emerges, whether...

Iga And Cervical Cancer

Cervical carcinoma has been one of the most common causes of cancer related death in women for many years. Although the mortality rates have fallen by 50 in the last three decades in developed countries, it continues to be a major gynecologic cancer in the underdeveloped countries. There were 15,700 new cases of invasive cervical cancer and 4900 deaths in 1996 46 , Lower socioeconomic status, early age of sexual activity, multiple sexual partners and smoking are considered to be predisposing risk factors. Human papilloma virus has attracted interest as an etiological agent in precancerous lesions and invasive cancer of the cervix. More than 66 types of HPV have been isolated and many of them are associated with genital warts. Protein products of HPV-16 (E7 protein) and HPV-18 (E6 protein) have oncogenic potential and have been associated with cervical cancer 84, 85 , Mann et al. 86 examined the sera of 186 cases of invasive cervical cancer and 172 matched controls. They found a strong...

Iga And Head And Neck Cancer

The annual number of new cases diagnosed in the US is approximately 40,000, accounting for about 5 of the malignancies in the adult population 46 . There are geographic variations in the location of head and neck cancers. In the Far East and Mediterranean countries, nasopharyngeal carcinomas are more common, whereas oral, oropharyngeal and laryngeal carcinomas comprise most of the head and neck cancers in Europe and North Americas. Alcohol and tobacco are the most common and significant carcinogens associated with head and neck cancer and the combination of the two carcinogens poses the most potent risk. Other implicated etiological factors include nickel refining, textile fibers, wood working and possibly dietary factors such as lack of fiber and increased consumption of salted fish. A viral etiology has been extensively studied and seems to be important in nasopharyngeal, laryngeal and perhaps tonsillar carcinomas. High levels of the Epstein-Barr Virus antibodies are seen in...

Karl Munger and Stefan Duensing Genomic Instability and Malignant Progression

In contrast, cervical carcinogenesis is almost exclusively associated with infections by high-risk human papillomaviruses (HPVs). High-risk HPV infection is a prerequisite for the development of almost all the pre-malignant cervical lesions but carcinogenic progression occurs gradually and overall represents a relatively low frequency event. Accumulation of host cellular mutations may thus be rate limiting for malignant progression of high-risk HPV-positive lesions. Consistent with this model, hallmarks of genomic instability, in particular mitotic abnormalities, are evident even in early high-risk HPV-associated pre-malignant lesions (reviewed in 19 ). Since only two small HPV proteins, E6 and E7, are expressed in cervical tumors it has been feasible to investigate the molecular mechanisms that can lead to genomic destabilization in an emerging neoplasm. These studies strongly suggest that the HPV E7 oncoprotein may act as a mitotic mutator by inducing primary centrosome duplication...

Induction of Centrosome Abnormalities by HPV Oncoproteins Boveris Model Revisited

Since expression of individual high-risk HPV oncogenes in primary human cells causes genomic instability 59 this model system appeared particularly useful for studying the emergence of centrosome abnormalities and their relevance to genomic destabilization. These studies revealed that primary human foreskin keratinocytes engineered to ectopically express HPV-16 E6 or E7 each developed numerical centrosome abnormalities within a few passages in culture. Supernumerary centrosomes were detected both in interphase and metaphase cells, and were associated with the appearance of multipolar metaphases and anaphases. Interestingly, however, there was no evidence of the development of structural centrosome abnormalities as detected in vivo 58 . This finding suggests that structural centrosome abnormalities may not arise as a primary consequence of HPV oncogene expression. Importantly, primary human keratinocytes expressing E6 or E7 genes derived from low-risk genital wart-associated HPVs did...

Do HPV E7induced Centrosome Anomalies Contribute to Carcinogenic Progression

Centrosome abnormalities have also been noted in a transgenic mouse model of cervical carcinogenesis. These mice were engineered to express HPV-16 oncogenes in basal epithelial cells under the control of the human keratin K14 promoter and to develop cervical tumors when treated with low doses of estrogen (reviewed in 92 ). Similar to reports for HPV-associated human cervical lesions, supernumerary centrosomes were already apparent in cervical precursor lesions, and the degree of abnormalities in this model increased in parallel with the severity of the lesions. When mice were generated that expressed HPV-16 E6 or E7 separately, the HPV E7-expressing animals developed high-grade cervical dysplasia and invasive cervical carcinomas. Expression of the HPV E6 oncoprotein, however, only induced low-grade cervical dysplasia and neoplastic progression did not occur 93 . As expected from the results with HPV E6 or E7 oncogene-expressing human keratinocytes, hyperplastic lesions that developed...

Viral Disruption of the Centrosome Duplication Cycle and Spindle Checkpoints

Perhaps the best characterized host-pathogen interaction involving centrosome cycle regulation is that of papilloma virus. The role of papilloma viral genes E6 and E7 in promoting ectopic centrosome duplication is covered extensively elsewhere in this book (see Chapter 18), and so will not be described here. However, studies with many other viruses are now following in the wake of papilloma virus, and the variety of different ways in which cell-cycle disruption may occur is proving to be particularly informative.

Signal Transduction Mechanisms

The molecular circuitry of cancer. Although countless differences between normal cells and cancer cells have been documented, much progress in identifying and connecting the fundamental pathways responsible for programming malignant cell growth has been made. Most cancer-associated mutations disrupt essential homeostatic mechanisms that regulate cell proliferation and survival. In many cases, particular mutations have been linked to specific biological phenotypes shown by cancer cells (yellow boxes). The cellular machinery responsible for controlling mammalian cell physiology is largely shared between human and mouse cells (black lines). Comparisons of human and mouse experimental cancer models identify several pathways that seem to have more prominent roles in human-cell transformation (red lines), as well as other molecular pathways that serve in dominant positions in mouse cancer models (blue lines). Perturbation of these five pathways (RB, p53, telomere maintenance,...

Urological Procedures

Local bladder pathology commonly identified by cystoscopy includes filling defects, foreign bodies, cystitis (infectious or inflammatory), diverticuli, herniation, tumors (leiomyoma, hamartoma, nephrogenic adenoma, fibrous polyp, papilloma, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma), and bladder calculi.

Approach To Cervical Cancer Definitions

Human papilloma virus (HPV) Circular, double-stranded DNA virus that can become incorporated into cervical squamous epithelium, predisposing the cells to dysplasia and or cancer. When a woman presents with postcoital spotting or has an abnormal Pap smear, cervical dysplasia or cancer should be suspected. An abnormal Pap smear usually is evaluated by colposcopy with biopsies, in which the cervix is soaked with 3 or 5 acetic acid solution. The colposcope is a binocular magnifying device that allows visual examination of the cervix. The majority of cervical dysplasia and cancers arise near the squaniocolumnar junction of the cervix. Many times, cervical intraepithelial lesions turn white with the addition of acetic acid, the so-called acetowhite change. Along with the change in color, dysplastic lesions often have vascular changes, reflecting the more rapidly growing process. In fact, the vascular pattern usually characterizes the severity of the disease. An example of mild vascular...

Animal Studies On Pufas And Cancer Metastasis

In an animal model of the benz-a-pyrene (BP)-induced skin papilloma, it has been shown that mice fed on 10 corn oil had the longest latency period and among the lowest incidence of skin papillomas when compared to those receiving a lower percentages of this dietary oil (105,106). The study suggests that tumour promoting activity of dietary linoleic acid may have target tissue specificity . However, the animal studies are made complicated by the fact that in EFA deficient animals, there were less lung colonisation from melanoma than normal controls (107)

Prevention of Ovarian Cancer

A strategy for preventing the 90 of ovarian cancers that are sporadic is less clear. Given the incidence and prevalence of ovarian cancer, subpopulations must be identified who are at sufficiently high risk to justify intervention, but not at sufficient risk to warrant prophylactic oophorectomy. More subtle genetic markers such as single nucleotide polymorphisms (SNPs) are being sought to identify women at risk for ovarian cancer (Berchuck et al. 2004). In addition to determining genetic predisposition with greater precision, tests could be developed to detect somatic alterations of the ovarian surface epithelium. Dr. David Fishman has proposed sampling the ovarian surface epithelium at outpatient laparoscopy, providing an ovarian PAP smear . Cells from the ovarian surface could be examined for alterations in PI3K, RAS MAP, and

Pylori A Type I Carcinogen

Chemokines Cholangiocarcinoma

Several diverse malignancies are known to arise from a background of chronic inflammation. Cholangiocarcinoma and bladder cancer are strongly associated with infection with the Digeneans Opisthorchis sinensis and Schistosoma haematobium. The viral infections hepatitis B and C and human papillomavirus have been causally linked with hepatocellular carcinoma and cervical carcinoma. H. pylori is the first bacterium to be linked with the development of human neoplasia. Prospective epidemiologic stud-

Approach To Adolescent Health Maintenance

All teenagers should be screened for eating disorders by use of a body mass index table. They should be queried about laxative use and induction of emesis. Drug use and depression should be questioned in a nonjudgmental fashion. Cancer screening in this age group consists of annual Pap smears for those who have engaged in sexual activity for 3 yr or have reached age 21 years. Annual Pap smear is then recommended up to age 30 years. If the annual cytology has been negative, then at age 30 years the interval of screening can be extended to every 2 to 3 yr. Also, after age 30 years, if cervical cytology and human papilloma virus (HPV) subtype testing both are negative. Pap smear is not necessary any sooner than every 3 yr. Finally, routine cervical cytology is not recommended in women who have undergone total hysterectomy for benign indications and have no history of cervical dysplasia. HPV typing is helpful in triaging cytology showing atypical squamous cells of undetermined...

Carotenoids and the Insulin Like Growth Factor System

The reports connecting carotenoids with changes in the IGF-I system suggest that interference in IGF-I signaling may be an essential mechanism for the anticancer activity of carotenoids. In addition, other growth factor systems important in cancer development may be affected by carotenoids. For example, Muto et al. have found that b-carotene-induced growth retardation in cervical dysplasia cell lines is associated with rapid reduction in cell surface binding, as well as internalization of epidermal growth factor (EGF) due to a decrease in EGF receptor levels (113).

CyA in Systemic Lupus Erythematosus

However, as cancers with a possible virus-related etiology, such as cervical and vaginal ones, are very often observed in SLE patients 70, 76 , it is advisable that females who receive CyA should have cervical smears taken at regular interval in particular it could be useful the extensive search for human papilloma virus. Similarly, due to an increased incidence of breast cancers in women with SLE 66 , careful manual and instrumental examination is suggested periodically in those taking immunosuppressive therapy.

CMyc and Activated Ras During Skin Tumorigenesis Cooperation at the Cancer Stem Cell Level

A number of transgenic mouse models have been used to study the in vivo effects of c-Myc ectopic or overexpression in murine skin. For example, human c-Myc (Waikel et al. 1999) or 4-OH tamoxifen-inducible, human c-MycER (Pelengaris et al. 1999 Flores et al. 2004) were targeted to the postmitotic (endogenously c-Mycneg) suprabasal compartment of the skin with the loricrin or involucrin promoters, respectively. In both cases, the mice developed epidermal hyperplasia and papillo-mas as a result of differentiated keratinocytes re-entering the cell cycle while subsequent terminal differentiation was inhibited. Interestingly, Loricrin-Myc mice exhibit reduced sensitivity to UV-B-induced apoptosis, suggesting that Myc may possess unexpected antiapoptotic functions, at least in some cell types (Waikel et al. 1999). Similar tumors were obtained by overexpressing mouse c-Myc within the basal layer of the epidermis, hair follicle outer root sheath, sebaceous glands, and hair follicle bulge...

Bacterial And Virus Infection

The most well known link between virus and cancer is the link between human papillomavirus (HPV) and cervical cancer. DNA of specific HPV types has been found in almost all cervical cancer biopsies (9). Current screening protocols are based on the use of Pap smears. In fact, high-risk HPV genotypes are also found to be responsible for other anogenital cancers, and squamous-cell carcinoma of the head and neck (10). The screening of high-risk HPV can be performed by the detection of viral DNA and cellular proteins (viral onocoproteins) by cytological and coloscopic analysis. The identification of specific types of HPV as causative agents for cancer of the cervix and its precursor lesions led to the development of a new method for cancer screening and early diagnosis. HPV genomes and viral oncoproteins should present convenient markers for a transient of persistent infection. The detection of high-risk HPV markers should be followed by a careful clinical investigation and repeated...

Etiology and Pathogenesis 361 etiology

In carcinoma of the thyroid in young people has been discussed elsewhere 4 . The highest incidence rates for NPC are found in parts of the Far East where it occurs in association with EBV infection. The rare cases of NPC in young people in Western developed countries may also be associated with EBV, and this should be explored, but it is likely that other cofactors are involved 67 . Carcinoma of the cervix and uterus, although typical of older age groups, is relatively frequent in young adult females and appears to be closely linked with sexually transmitted infections including herpes simplex virus type 2 and human papilloma virus 65 . Other carcinomas seen in adolescents and young adults that occur typically in later life may be strongly associated with genetic predisposition at young ages, as will be discussed below.

Neuronal and Mixed Neuronal Glial Tumors

A nut-sized amount of soft, bluish tissue removed from the cerebellopontine angle consists of cuboidal epithelial cells resting on fibrovascular core (extra-cerebral portion of the plexus of the fourth ventricle) (HE). B. Macrosection of a large choroid plexus papilloma in the lateral ventricle (HE). Choroid plexus papilloma A. A nut-sized amount of soft, bluish tissue removed from the cerebellopontine angle consists of cuboidal epithelial cells resting on fibrovascular core (extra-cerebral portion of the plexus of the fourth ventricle) (HE). B. Macrosection of a large choroid plexus papilloma in the lateral ventricle (HE).

Other Intradural Tumors

Dissemination from primary intracranial tumors (medulloblastoma, glioblastoma, oligodendroglioma, germinoma, and choroid plexus papilloma) occurs via the CSF. The seeded tumor cells infiltrate the nerve roots and may extend into the spinal cord along the perivascular spaces (see Fig. 11.7).

Telomeres And Direct Proof Of Their

Many reports have appeared suggesting a telomere-independent mechanism of cellular senescence is present in epidermal keratinocytes (39,40) and in mammary (39), adenoid (41), thyroid (42), and prostate (43) epithelial cells. The investigators who reported these findings found that inactivation of the p16 pRB pathway (by methylation of the p16 gene or by expression of viral oncogenes such as the human papilloma virus protein E7) was required before telomerase could immortalize these epithelial cells. Many of these epithelial cells were grown in a chemically defined medium in which the proliferative life span of 10-20 doublings is much less than the approximately 50 doublings that are seen when keratinocytes are grown on feeder layers (44). We have shown that keratinocytes can be immortalized by telomerase alone without inactivating p16 when grown in the more hospitable environment provided by feeder layers (which produce additional growth factors, extracellular matrix and or epithelial...

Use in Prevention and Therapy

Folate, together with vitamin A, may reduce the risk of cervical dysplasia progressing to cervical cancer.11,12 Folate (along with vitamin B12) can reduce dysplasia in the lungs of smokers and reduce the risk of lung cancer.13 Folate supplements may also reduce the risk of colon cancer in people with inflammatory bowel diseases.14

Immunization CD137 Breaks Ignorance and Tolerance

Vaccination with tumor antigens would be capable of starting the immune response generating antigen-specific activated T cells that would start to express CD137. A compelling study addressed this concept using peptide vaccination plus agonistic anti-CD137 mAb treatment (Wilcox et al., 2002a). It was demonstrated that several poorly immunogenic tumors, including C3 sarcoma, TC-1 lung carcinoma, and B16-F10 melanoma, once established as solid tumors or metastases, were refractory to treatment by anti-CD137 mAb due to immunological ignorance, rather than anergy or clonal deletion of tumor antigen-specific CTLs. Breaking CTL ignorance by immunization with tumor antigen-derived peptides, although insufficient to stimulate a curative CTL response, was necessary for anti-CD137 mAb to induce a CTL response leading to the regression of established tumors (Wilcox et al., 2002a). In this case, a well described epitope of the E7 oncogene of human papillomavirus 16 (HPV-16) was used as a surrogate...

Experimental Models for the Study of Carcinogenesis

Initiation and promotion during mouse skin carcinogenesis produce multiple benign squamous papillomas. A few squamous cell carcinomas eventually arise from the papillomas over many months. However, malignant conversion can be speeded up by exposure of papilloma-bearing mice to mutagens, which activates oncogenes such as H-ra.s and causes loss of tumor suppressor genes such as p53, as noted above. The mouse skin carcinogenesis model is also a useful one in which to study the role of diet and chemopreventive agents in carcinogenesis (see also Chapter 9). For example, calorie-restricted diets have been shown to reduce the number and size of papillomas during and following promotion with TPA in DMBA-initiated SEN-CAR mice.85 Furthermore, the latency period for occurrence of carcinomas was increased and the total number of carcinomas was decreased. Application of apigenin, aplant alkaloid,86retinoic acid,87 and prostratin, a nonpromoting phorbol ester88 have been shown to inhibit the...

Physical Examination Midclavicular Line At Edge Pf Costal Angle

External genitalia without lesions. Mild cystocele at introitus on straining. Vaginal mucosa pink. Cervix pink, parous, and without discharge. Uterus anterior, midline, smooth, not enlarged. Adnexa not palpated due to obesity and poor relaxation. No cervical or adnexal tenderness. Pap smear taken. Rectovaginal wall intact.

Adaptive Antitumor Responses

In transgenic models of hepatitis B-induced liver cancer, smoldering CD4+ and CD8 + T cell responses are required for progression of hepatocellular carcinoma (Nakamoto et al., 1998). Similarly, CD4 + T cells activated by normal cutaneous bacterial flora promote the evolution of squamous cell carcinoma in a human papilloma virus transgenic model (Daniel et al., 2003).

Tumorassociated Antigens Selfaltered Selfparadigm

It is noteworthy, however, that there exists two categories of potential rejection antigens that could be considered absolutely tumor-restricted. The first category includes those antigens that are derived from oncogenic viruses. A number of viral antigens have been studied on virally-induced murine tumors and were shown to be relevant for tumor rejection 53-57 . In humans, the best example is the E7 oncoprotein of human papilloma virus (HPV) 16, which is expressed almost ubiquitously in cervical carcinomas. Tumor-specific CTLs have been elicited by in vitro sensitization with E7 peptides presented by HLA-A2

The Mechanism of cdc2 Repression by p53

Several groups have reported that the long-term maintenance of G2 arrest after DNA damage requires transcriptional repression mediated by Rb-family members. The E7 protein from types l6 and l8 human papilloma virus inactivates all three Rb proteins by binding to them and causing their degradation. Cells expressing E7 can still arrest in G2 in response to adriamycin. If adriamycin is removed, the parental cells do not enter mitosis, whereas cells with E7 do enter mitosis, suggesting that Rb is required to stabilize the G2 arrest (161). Also, expression of a mutant E2F that neither binds to Rb proteins nor activates transcription, but still binds DNA, can reduce G2 arrest after DNA damage (162). This result suggests that active repression is required for proper G2 arrest. Our early studies suggested that one of the targets of Rb during p53-dependent G2 arrest is cdc2, although our recent experiments suggest that the Rb family has wider effects on the expression of genes required for...

Preview Recording the Pelvic Examination Female Genitalia

Note that initially you may use sentences to describe your findings later you will use phrases. The style below contains phrases appropriate for most write-ups. Unfamiliar terms are explained in the next section, Techniques of Examination. J No inguinal adenopathy. External genitalia without erythema or le-J sions no lesions or masses. Vaginal mucosa pink. Cervix parous, pink, and without discharge. Uterus anterior, midline, smooth, and not enlarged. No adnexal tenderness. Pap smear obtained. Rectovaginal wall intact.

Clinical Features

Optic nerve chiasma astrocytoma Brainstem glioma Choroid plexus papilloma -Cerebellar astrocytoma Medulloblastoma Craniopharyngioma Ependymoma Cerebral atrocytoma Oligodendroglioma Pituitary adenoma Hemangioblastoma Meningioma Schwannoma Metastases Choroid plexus papilloma Choroid plexus papilloma Choroid plexus papilloma Choroid plexus papilloma

Effect Of Aging On The Susceptibility To Tumor Promoters In Vivo

There is evidence of age-related accumulation of cells that are in the late stage of multi-stage process of carcinogenesis. Numerous experiments support this model. Thus, single skin application with 7,13-dimethylbenz a anthracene (DMBA) in mice aged 8 and 48 weeks at doses ranging from 10 to 300 Xg caused increased skin papilloma incidence in older mice 38. Also, the average diameter of the tumors was larger in the older animals. Of particular interest are the experiments using skin transplants. TPA failed to induce tumors in the skin of 2-month-old mice grafted to animals of different ages, but caused the same tumor incidence in the skin of 1-year-old donors irrespective of the recipient's age 39,40. These results indicate that the age of the target tissue, more than the age of the host, determines susceptibility to late-stage agents. Delaying wounding 16 weeks after initiation with a carcinogen led to a more pronounced skin tumor response compared with delay of only 6 weeks in...

Epidemiology and Pathogenesis

There are an estimated 6.2 million new cases of oncogenic HPV infections occurring in the US each year, and approximately 20 million Americans are infected with HPV at any one time (CDC 2004). High-risk or oncogenic HPV infections can cause precancerous cervical lesions that are detected by routine cytological screening with the Papanicolaou (Pap) test. If these lesions are left undiagnosed they may progress to invasive cervical cancer within a few months to several years (depending on the precancerous lesion grade). Invasive cervical cancer is the second most common cancer in women worldwide. In the US, there are still more than 9,000 cases of cervical cancer and more than 3,000 deaths from the disease annually (Jemal et al. 2006). Risk determinants for HPV infection that have been identified in various cross-sectional and prospective cohort studies include the number of sexual partners (lifetime and recent), age at first intercourse, smoking, oral contraceptive (OC) use, other...

The Sarcoplasmic Endoplasmic Reticulum Ca2ATPase Pump

Because ATP2A2 controls calcium homeostasis in the cell, it is conceivable that its deregulation by mutation of the ATP2A2 gene might represent an early event in carcinogenesis. It was demonstrated many years ago that thapsigargin, an inhibitor of SERCA2, not only alters intracellular calcium levels, but also functions as a tumour promoter (Hakii, 1986 Thastrup et al. 1990). With the demonstration that ATP2A2 mutations are associated with the genesis of DD, there have also been several attempts to investigate the incidence of neoplasia in association with DD. Soroush and Gurevitch (1997) have pointed out that basal cell carcinomas and other skin neoplasms occur in patients with DD. Downs et al. (1997) described the occurrence of a subungual squamous cell carcinoma in a DD patient. However, in this case the human papilloma virus might have been the aetiological agent. In general, neoplasia may be associated only infrequently with DD.

T Cellmediated Antitumor Immunity

To algorythms which are based on consensus anchor motifs for frequent HLA molecules. They are loaded on APC for in vitro stimulation of T lymphocytes 40 . The tumor antigens described so far can be classified into six groups 41, 42 , The first group represents tumor antigens encoded by genes that are silent in most normal tissues, except testis and placenta, but are expressed in a variety of different tumor types. Examples are the genes encoding MAGE 43, 44 , BAGE 45 , GAGE 46 and RAGE 47 , These antigens are shared by different tumors and therefore represent promising targets for cancer immunotherapy. The second group comprises differentiation antigens, that are not only expressed in tumor cells but also in the corresponding normal cells. Examples are tyrosinase 48 , Melan-A 49 , gp 100 50 and CEA 51 . A third group contains antigens encoded by genes that are expressed ubiquitously but are mutated in tumor cells as e. g., CDK4 52 , 6-catenin 53 and bcr-abl 54, 55 , The fourth...

Immune Responses to HPV

Several studies have demonstrated that virus-neutralizing antibodies mediate protection of animals from experimental papillomavirus infection. For example, passive transfer of sera from virus-like particle (VLP)-vaccinated rabbits to naive rabbits is sufficient for protection (Bre-itburd et al. 1995). Similarly, vaccination with L2 peptides protects rabbits from papillomas resulting from viral but not from viral DNA challenge, consistent with the protection mediated by neutralizing antibodies (Embers et al. 2002). Most of those who develop benign HPV lesions eventually mount an effective cell-mediated immune response that results in lesion regression. Regression of anogenital warts is accompanied histologically by a CD4+ T cell-dominated Th1 response, and data from animal models suggest that the response is modulated by CD4+ T cell-dependent mechanisms. Failure to develop effective cell-mediated immunity to clear or control infection results in persistent infection and, in the case of...

Causes Of Cancers In

Human papillomavirus (HPV) has been associated with the development of premalignant and malignant tumors of the vagina and cervix 69 , Cohen et al. 70 described an SLE patient with cutaneous lesions who was treated with azathioprine and developed multiple lesions of SCC of the skin. HPV type 11 DNA and the oncogenes neu and ras were identified in the tissue of the SCC, suggesting a role for HPV in the development of SCC of the skin in SLE.


When the patient does not have any apparent disease or complaint, then the goal of medical intervention is disease prevention. One method for targeting diseases is using the patient's age. For example, the most common cause of death for a 16-year-old person is a motor vehicle accident hence, the teenage patient would be well served by the physician encouraging him or her to wear seat belts and to avoid alcohol intoxication when driving. In contrast, a 56-year-old woman most likely will die of cardiovascular disease, so the physician should focus on exercise, weight loss, and screening for hyperlipidemia. In a woman older than 65 years, cervical cancer screening if prior Pap smears have been normal is not cost-effective. Pap smear 2.2 A 46-year-old woman denies any health problems. Her last Pap smear was last year. Pap smear approximately 3 yr after onset of sexual activity Annual Pap smear after Pap smears Pap smear Age 50 stool for occult blood, barium enema with flexible...

Clinical Pearl

Normal Size Endometrial Stripe

Pap smear To assess for cervical dysplasia or cervical cancer involves both ectocervical component and endocervical sampling (Figure 1-2). Many clinicians prefer the liquid-based media because it may provide better cellular sampling and allows for HPV subtyping. Figure 1-2. Pap smear with ectocervical and endocervical components. The Figure 1-2. Pap smear with ectocervical and endocervical components. The ii. Menorrhagia due to uterine fibroids CBC, endometrial biopsy, and Pap smear. Endometrial biopsy is performed to assess for endometrial cancer and the Pap smear for cervical dysplasia or cancer.

The Viruses

There are seven families of DNA viruses that are pathogenic for humans. These pathogens come from the Adenoviridae, Hepadnaviridae, Herpesviridae, Polyomaviridae, Papilloma-viridae, Parvoviridae, and Poxviridae families. Herpesviruses, hepadnaviruses, and papillo-maviruses are well established as human health problems and as targets for antiviral chemotherapy. The biology of adenoviruses, parvoviruses, polyomaviruses, and poxviruses has been intensively studied, but these viruses have not been pursued as drug targets to the extent of the other viral families. DNA viruses have assumed more importance as pathogens as the prevalence of patients with suppressed immune function has increased. This increased prevalence comes in turn from two sources greater use of organ transplantation and the AIDS epidemic. Most of the DNA viruses are ubiquitous in the human population, but several become a serious health threat in the absence of a fully functional immune system. The lack of. immune...


Here that an association between infection with Epstein-Barr virus and Burkitt's lymphoma, hepatitis B and C viruses and liver cancer, human T-cell lymphotropic virus (HTLV) and leukemia, and human papilloma virus and cervical cancer are examples of this linkage. A number of neoplasms have also been associated with HIV infection in patients with AIDS. These include Kaposi's sarcoma and non-Hodgkin's lymphoma primarily, but central nervous system tumors and Hodgkin's disease are also seen in patients with AIDS.132

Enrolling the Public

Of course, convincing health-care professionals to prescribe its new genetic test would not be enough. In order to ensure the financial success of its laboratory technology, Myriad had to encourage public demand as well. While media coverage of the BRCA gene discoveries had created early excitement about the promise of testing, Myriad faced the possibility that criticism from patient advocacy groups and a short public memory would quickly depress the use of its technology. In order to encourage demand for BRCA testing, Myriad used what Bruno Latour has called an I want what you want strategy.29 Appropriating the slogan Knowledge is power from the women's health movement, Myriad lobbied the skeptical patient-advocacy community first. At a 1996 conference attended by both scientists and activists, Myriad's Chief Scientific Officer Mark Skolnick emphasized that the company was providing an important technology that could help women make medical decisions, noting that BRCA testing should...

Spin 10789389

That would be required to study progression to more advanced precursor lesions (and, indeed, regression to earlier stages), although in some cases, alternative sampling techniques (e.g., Pap smears) might provide the possibility of doing so without encountering such problems however, cytopathological and even histologi-cal examinations are prone to errors due to inadequate sampling of the affected tissue and or to incorrect microscopic interpretation. Nevertheless, study of cancer precursors is important for several reasons. Firstly, elucidation of the etiology of precursors will provide insight into the etiology of the corresponding cancer, since if the precursor represents an intermediate stage in the causal pathway between exposure and the occurrence of invasive cancer, then etiological factors for the former must be a subset of those for the latter. Secondly, cancer precursors, if clearly defined, can provide targets for screening and hence early detection of those at increased...

Ependymal Tumors

Choroid Plexus Papilloma (Grade 1) This benign tumor derives from the epithelial cells of the choroid plexus, and accounts for 0.5 of all intracranial tumors. It is more common in infants and children, and seldom is congenital. In children and adolescents, it has a predilection for the lateral ventricles in adults, the fourth ventricle. Seldom, it occurs in the cerebellopontine angle. The detection of elements of the oncogenic papovavirus SV40 in some choroid plexus papillomas and carcinomas raises the possibility of the role of the virus in tumor pathogenesis.


Cervical dysplasia or carcinoma in situ Screening for other sexually transmitted diseases (syphilis, hepatitis B and C, gonorrhea, chlamydia) should be performed initially and repeated, if needed, because of any ongoing risks identified. Hepatitis B and A vaccination should be offered to those who lack immunity. A purified protein derivative (PPD) test should be done, and if initially negative, repeated annually. Women should have regular Papanicolaou (Pap) smears to evaluate for cervical dysplasia or cancer.

Changes in menopause

Widespread testing by Papanicolaou (Pap) smear has contributed to a significant drop in the incidence of invasive cervical cancer. Careful technique to ensure sampling of endocervical cells at the squamocolumnar junction and use of accredited laboratories to interpret smears improve accuracy of the test. Screening should begin at age 18 or with onset of sexual activity. Recommendations about frequency of testing are undergoing revision. Annual testing until age 65 has been common, but does not appear to improve detection compared to longer intervals. A number of professional organizations recommend annual Pap smears for 3 years and then, if these are normal, less frequent testing based on clinician discretion. The U.S. Preventive Health Services Task Force recommends a 3-year interval beginning with onset of sexual activity. More frequent testing is warranted for women at increased risk those with early onset of sexual activity, multiple partners, infection with human...


As suggested by Ziegler et al. (23), circulating homocysteine may be an especially accurate indicator of inadequate folate, an integratory measurement of insufficient folate in tissues, or a biomarker of disruption of one carbon metabolism. Higher levels of plasma homocysteine were also detected in head and neck squamous cell carcinoma (24). There was also a report concerning the association of methylenetetrahydrofolate reductase polymorphism C677T and dietary folate both have an impact on homocystene level, with the risk of cervical dysplasia. A polymorphic variant (TT) has been linked to reduced levels of plasma folate, aberrant DNA methylation in leucocytes, and increased risk of colorectal cancer (CRC) under conditions of low folate intake. Serum homocysteine has been strongly and significantly predictive of invasive cervical cancer risk (25). As a result, maintaining adequate folate and pyridoxine status and lower levels of homocysteine will reduce the risk of pancreatic cancer.


Genital Warts Caused by the human papilloma virus (HPV) Genital warts usually result from sexual contact (intercourse or oral-genital contact) with an infected partner. Genital warts appear as growths or bumps on the pubic area, penis, vulva, or vagina. Only some types of HPV cause genital warts. Other types of HPV can cause abnormal cell changes on a woman's cervix, which can result in cervical


A 50-year old Caucasian female, new to your practice, presents for an annual physical examination. She reports that she is generally very healthy, feels well and has no specific complaints. She has a history of having had a partial hysterectomy, by which she means that her uterus and cervix were removed but her ovaries were left in place. The surgery was performed because of fibroids. She has had a pap smear every year since the age of 18. all of which have been normal. She has had annual mammograms since the age of 40. all of which have been normal. She has no other significant medical or surgical history. She takes a multivitamin pill daily but no other medications. Her family history is significant for breast cancer that was diagnosed in her maternal grandmother at the age of 72. The patient is married, monogamous, does not smoke cigarettes or drink alcohol. She tries to avoid dairy products because of lactose intolerance. She walks 3 miles 4-times a week for exercise. Her physical...

Cervical Cancer

This is almost two different diseases one in the developing world and a different one in the developed world, although the etiology is similar. For example, in the United States and other developed nations, routine PAP smears and gynecologic examinations detect the majority of cases early and the cure rate is close to 100 for patients with pre-invasive lesions (cervical intraepithelial neoplasia, CIN). The cure rate is 92 for localized carcinomas that are minimally


A Pap smear should be initiated at age 21 years or approximately 3 yr after onset of sexually activity, whichever occurs first. 2.2 I. A Pap smear for cancer screening is recommended every 2 to 3 yr after age 30 years if three prior Pap smears have been normal. Fasting blood sugar level and fasting lipid panel testing are indicated after age 45 years.


Both basal cell and squamous cell carcinomas arise from the epidermal layer of the skin. The primary risk for these types of skin cancers is exposure to ultraviolet radiation, especially sun exposure but also tanning bed use. A history of actinic keratoses and human papillomavirus infection of the skin also raises the risk of squamous cell carcinomas.

Vaccine Efficacy

Dysplasia and cancer, it might be a useful surrogate in future vaccine efficacy studies. Indeed, if vaccines prove to be effective against transient or especially persistent HPV infections, it is likely that they will protect women against cervical cancers as well. Given the mode of transmission of HPV, vaccination of males needs to be considered. Males and females pass this virus back and forth, and logically one would anticipate more effective prevention of transmission if both genders were vaccinated. Because there is little detectable pathology associated with high-risk HPV in males, recommendations for male vaccination may require data from studies of prevention of infection. A vaccine against the nononcogenic HPV types 6 and 11 could be considered in the prophylaxis of genital warts in males to prevent the morbidity associated with this common infection (Shaw 2005).


Among environmental factors, irradiation to the head has been established as a potential risk for tumor development. An association between head trauma and brain tumor, particularly meningioma, has been suggested. Epstein-Barr virus has oncogenic potentials and is associated with primary central nervous system (CNS) lymphomas in HIV-infected patients. The papovavirus SV40 is implicated in the pathogenesis of choroids plexus papilloma and choroid plexus carcinomas. An association between brain tumors in human and various chemicals has been suggested but not proven.

Astrocytic Tumors

Choroid plexus papilloma (grade 1), a rare tumor, has a good prognosis when totally resected. Prognosis is better with diploid papilloma than it is with aneu-ploid, which is aggressive. The prognosis for its malignant variant, the choroid plexus carcinoma, is poor. Both tumors have a tendency to disseminate via CSF.

Prophylactic Vaccine

In general, prophylactic vaccines induce the generation of neutralizing antibody to the pathogen and thus prevent disease on subsequent exposure. Studies exploiting natural papillomavirus infections in the dog, rabbit, and cow, together with HPV1 and HPV11 infections in humans (all situations in which adequate amounts of virus could be obtained), showed clearly that there were serum responses to viral capsid proteins in individuals who were or had been infected (Stanley 1997). In the animal models, seropositive individuals were resistant to subsequent viral challenge. Neutralizing antibody, directed to determinants on the viral capsid L1 protein, was generated in these individuals (Stanley 2006a). none of the 755 vaccinated women developed CIN2 3 caused by HPV-16 during 48 months of follow-up. After immunization, HPV16 serum antibody titers peaked at month 7, declined through month 18, and remained relatively stable between months 30 and 48. Overall, the observed efficacy for...