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A. Peptide antigens associated with major histocompatibility complex (MHC) molecules.
B. Membrane-bound antigens.
C. Cytoplasmic antigens.
D. Nuclear antigens.
E. All of the above.
DISCUSSION: It was long thought that CTL recognize antigen expressed on the surface of the target cell destined to be killed, similar to the recognition of an antigen by an antibody; however, it was found that the mechanism of CTL recognition of antigens was fundamentally different from the mechanism of antibody recognition. CTL can detect antigens derived from cell surface–associated proteins, but in addition can recognize proteins that are normally in the cytoplasm or in the nucleus. In fact, the normal location of the protein can be anywhere within the cell.
To understand how a CTL can distinguish an antigen from a protein that is normally located within the cytoplasm or nucleus of the cell, investigators had to determine exactly what was being recognized by the CTL. T cells were found to recognize short linear fragments of processed or even denatured protein. It was found that proteins that were synthesized endogenously were degraded within the cytoplasm into 9– or 10–amino acid long peptides. These peptides were then transported to the endocytoplasmic reticulum and associated with newly synthesized MHC class I molecules. Certain peptides could fit within the MHC class I molecule and were then transported to the cell surface as a complex. It was this complex, consisting of a 9– to 10–amino acid peptide within a MHC class I molecule that was presented to, and recognized by, CD8+ CTL.
A. Nonspecific stimulation of effector cells.
B. Expansion ex vivo of large numbers of lymphocytes.
C. Infusion with interleukin 2 (IL-2).
D. Significant toxicity at high doses.
E. All of the above.
DISCUSSION: LAK cells, generated by short-term culture of peripheral blood lymphocytes in the presence of high concentrations of IL-2, lyse transformed target cells, and have minimal lytic activity for most normal tissues. Up to 10 11 in vitro generated LAK cells have been administered in a single intravenous infusion to cancer patients. Therapeutic trials have also combined short courses of high-dose systemic IL-2 administration with LAK cell transfer to promote LAK function and viability, with apparently enhanced efficacy. The shortcomings of LAK and IL-2 therapy included a larger degree of toxicity (including pulmonary, renal, and hepatobiliary) with a significant proportion of patients requiring intensive care unit admissions and 2% to 5% treatment-related mortality. Despite this, response rate remained relatively low.
Another therapy using in vitro expanded lymphocytes derived from a TIL has been evaluated in clinical trials. In humans, TIL cell lines have been generated by mincing tumor specimens and culturing eluted lymphocytes with high concentrations of IL-2. TIL lines can be expanded to 10 8 to 10 11 cells over 3 to 8 weeks in culture, and some lines appear to function as T cells with lytic specificity for autologous—but not allogeneic—tumor targets, whereas others function as LAK cells and lyse both autologous and allogeneic tumor targets. Adoptive transfer of 5 × 10 10 TIL alone has not been associated with significant toxicity, and administration of 5 × 10 10 TIL cells with concurrent systemic IL-2 has caused toxicities that are attributable to the IL-2.
A. Clearly demonstrated induction of tumor-specific immune response.
B. Repeatedly demonstrated clinical response to large tumor burden.
C. Not clearly demonstrated induction of tumor-specific immune response.
D. Not been performed to date.
DISCUSSION: Several different approaches in experimental animal studies in the 1970s formed the basis for human clinical trials of SAI against human cancers. Although several thousand patients have been injected with a variety of tumor cell preparations in this country and elsewhere during the past 25 years, the complexity of the studies has made it difficult to definitively assess the value of this approach to cancer therapy. Nonetheless, a number of clinical trials have suggested a therapeutic benefit of SAI. Most of these trials have two features in common: (1) a therapeutic effect was not seen or, if seen, has not been confirmed independently; and (2) no acceptable information was provided on the presence of tumor antigens in the vaccines and the immune response of patients to these antigens.
A. Most patients are diagnosed after age 60 years.
B. Skin color has no association with risk of melanoma.
C. Sun exposure is the only risk factor for melanoma.
D. The per capita incidence of melanoma is highest in Australia.
DISCUSSION: The median age at diagnosis is in the late forties; so, a minority of patients are diagnosed after age 60. The risk of melanoma is closely tied to skin color: Caucasians are at highest risk, and those with a Celtic complexion at even higher risk. Australia has a large Celtic population living near the equator, and it has the highest per capita incidence of melanoma in the world. Sun exposure is believed to be an important cause of melanoma, but the data remain incomplete. Some melanomas arise in sites not exposed to the sun (e.g., mucous membranes), so sun exposure is not the only risk factor.
A. Breslow thickness.
B. Clark's level.
E. Celtic complexion.
DISCUSSION: The prognosis for melanoma is best predicted by the thickness, measured in millimeters (Breslow thickness). Clark's level and ulceration are also predictive, but less so. Gender is a secondary prognostic factor. Skin color may have a mild impact on outcome, but it is primarily a risk factor for developing melanoma.
A. In the absence of systemic disease, the primary melanoma of the right calf should be excised with at least a 2-cm. margin.
B. Complete right inguinal node dissection should be performed if there is no evidence of systemic metastasis.
C. If further work-up reveals multiple lung metastases of melanoma, they should be excised as soon as possible.
D. Chemotherapy for melanoma is primarily palliative; so surgical therapy is preferred if there is no evidence of metastatic disease beyond the inguinal region.
E. If the nodes do not contain metastatic disease but are simply reactive, the chance of 5-year survival is 50% or less.
DISCUSSION: This patient should be evaluated with computed tomography in addition to a careful history, review of systems, and physical examination. If there is no evidence of metastatic disease beyond the inguinal region, therapy should focus on the local and regional disease. The primary lesion should be excised with a 2- to 3-cm. margin. The enlarged nodes can be evaluated by fine-needle aspiration (FNA) or node excision. If the FNA or excisional biopsy does show metastatic melanoma, then complete inguinal node dissection should be performed. Alternatively, complete node dissection can be justified simply on the basis of clinical findings. Chemotherapy does not provide any significant chance of cure, whereas a significant proportion of patients with isolated nodal metastases will live long. The depth of the primary lesion would predict chances of 5-year survival at less than 50%, even if the nodes are not metastatic. If work-up does reveal multiple pulmonary nodules, chemotherapy or experimental systemic therapies should be considered. Surgery has no role in the therapy of multiple lung metastases of melanoma.
A. High thigh amputation.
B. Extracompartment excision with negative margins.
C. Complete excision with negative margins.
D. Adjuvant radiation therapy.
E. Adjuvant chemotherapy.
DISCUSSION: This is a common presentation of soft tissue sarcoma. Surgery remains the principal modality for curative therapy for all soft tissue sarcomas. Provided the entire tumor is removed, less radical procedures have not been demonstrated to adversely affect local recurrence or outcome. The surgical objective is complete removal of the tumor with negative margins and maximal preservation of function. Adjuvant radiation improves local control. Adjuvant chemotherapy has not proven to be efficacious.
A. Mutations of p53 in metastatic liposarcoma.
B. A low (less than 1%) risk of metastasis for small, low-grade lesions.
C. Recurrent disease in at least 33% of patients.
D. Lymph node metastasis in less than 3% of patients.
E. Mutations of p53 in Li-Fraumeni syndrome.
DISCUSSION: Inactivation of the p53 tumor suppressor gene is involved in tumorigenesis of several sarcomas, but not specifically liposarcoma. The relevance of this gene is underscored by the frequent occurrence of soft tissue sarcomas in the Li-Fraumeni syndrome, where all families studied have p53 germ line mutations. Low-grade lesions have a low (less than 1%) risk of subsequent metastasis, whereas high-grade lesions have a high (greater than 50%) risk of subsequent metastasis. Despite optimal multimodality treatment, at least 33% of patients develop recurrent disease (median disease-free interval 18 months). Lymph node metastasis occur in fewer than 3% of adult soft tissue sarcomas.
A. The ideal tumor marker should be tumor specific; that is, in the normal population or patients with benign diseases, false-positive test results are rare.
B. The ideal marker must have a low false-negative rate; that means that all patients with a particular type of cancer should test positive.
C. The circulating level of an ideal tumor marker should correlate directly with the amount of viable tumor and be a measure of the response to therapy.
D. The ideal tumor marker should act as a prognostic indicator.
E. All of the above.
DISCUSSION: Each of the above is a criterion for an ideal tumor marker.
A. CA 15-3.
B. CA 19-9.
C. Alphafetoprotein (AFP).
D. Carcinoembryonic antigen (CEA).
E. CYFRA 21-1.
DISCUSSION: CA 15-3 is a marker for breast cancer. AFP is a marker for hepatocellular and testicular cancer. CEA is a marker for colon cancer. CYFRA 21-1 is a marker for non–small-cell lung cancer. CA 19-9 is a marker for pancreatic cancer.
A. Breast cancer.
B. Colorectal cancer.
C. Gastric cancer.
D. Lung cancer.
E. All of the above.
DISCUSSION: CEA is relatively nonspecific, and each of the listed cancers can cause elevated levels of CEA.
B. C-erb B-2.
D. Human chorionic gonadotropin (hCG).
DISCUSSION: Some 20% to 30% of breast cancers have C-erb B-2 gene expression. Studies have demonstrated that it is an independent prognostic tumor marker. Tumors that express C-erb B-2 have a poorer prognosis.
A. CA 50.
B. Levels of vitamin B 12.
DISCUSSION: Eighty percent of patients with hepatocellular carcinoma have elevated serum levels of AFP.
B. Detection of recurrence.
C. Guiding second-look operations.
D. Following treatment response.
E. Early diagnosis.
DISCUSSION: CEA levels may be used for each of the indications except early diagnosis.
C. CA 15-3.
D. Two of the above.
E. None of the above.
DISCUSSION: AFP and hCG are useful in managing testicular cancer. Approximately 90% of patients with testicular cancer have elevated levels of one or both of these markers.
A. CA 125.
C. CA 19-9.
D. CA 15-3.
DISCUSSION: CA 15-3 is the only useful marker for patients with breast cancer. Approximately 73% of patients with breast cancer have elevated levels.
B. Neuron-specific enolase.
C. CYFRA 21-1.
E. Chromogranin A.
DISCUSSION: CYFRA 21-1 is a new marker for non–small-cell lung cancer (NSCLC). Approximately 40% to 50% of patients with NSCLC will have elevated levels.
A. Chromogranin A.
B. Neuron-specific enolase.
D. Two of the above.
E. None of the above.
DISCUSSION: Although most endocrine tumors have a specific marker hormone that is the mainstay of diagnosis, both chromogranin A and neuron-specific enolase may be useful as serum markers in patients with all types of neuroendocrine tumors.
Surgeons have a definite role in excising isolated metastatic lesions, especially those in the brain, lung, liver, and soft tissues. Patient selection is critical and such operations should be performed only when the potential benefits clearly outweigh the risks. The best results are obtained when surgical excision of metastatic lesions can be combined with effective chemotherapy. Several institutions have demonstrated a 20% to 30% five-year survival rate in selected patients whose pulmonary metastases from sarcomas, melanomas, colon cancers, and testicular carcinomas have been resected. In a recent national survey of patients undergoing liver resection for colorectal metastases, the overall five-year survival rate was 33%. Excision of metastatic tumors to the brain is also indicated in selected patients, especially when combined with irradiation.
a. Pulmonary fibrosis
b. Cataract formation
d. Aplastic anemia
While any chemotherapeutic drug may exhibit a diverse array of toxicities, most classes of drugs are known for particular adverse effects. These are often graded by their severity from 0 (no toxicity) through 4 (life-threatening toxicity); grade 5 toxicity is equivalent to death. Most therapies allow for dosage reductions for toxicities greater than grade 2 or 3; one exception is the therapy of acute leukemia, where a grade 4 hematologic toxicity is expected. Some toxicities are only observed with prolonged drug administration, such as anthracycline-induced cardiotoxicity, bleomycin-and nitrosourea-related pulmonary fibrosis, or secondary leukemias associated with the nitrosoureas, etoposide, or mechlorethamine (nitrogen mustard), or when drugs are given at very high doses (nitrosourea-related hepatic veno-occlusive disease), or are given regionally (chemical peritonitis, arteritis, or biliary sclerosis).
a. Breast carcinoma
b. Gastric carcinoma
c. Endometrial carcinoma
d. Prostate cancer
e. Carcinoma of the uterine cervix
Answer: b, c, e
Estimates of cancer incidence in the United States reveal that in men, lung, prostate, and colorectal carcinomas have the highest incidence. Breast carcinoma accounts for 29% of all cancer in women, followed by colorectal, lung, and uterine carcinomas. From 1973 to 1987, there was a 15% increase in incidence for all cancer sites. Cutaneous melanoma showed the greatest increase at 83%, and non-Hodgkin’s lymphoma and prostate carcinoma followed with increases of about 50%. Only a few cancers declined in incidence over the same interval. Carcinoma of the cervix showed the greatest reduction at 36%, followed by endometrial carcinoma and gastric carcinoma. The reduction in carcinoma of the cervix is likely due to the early detection and treatment of cervical dysplasia resulting from the widespread use of routine cervical cytological screening.
a. Chromosome translocation
b. DNA point mutation
d. Gene deletion
Answer: a, b, c
Cellular proto-oncogenes are key regulatory components in cell growth, and many proto-oncogenes are expressed during periods of proliferation, development, and differentiation. Abnormal proto-oncogene function or activation may, therefore, result in the deregulated proliferation and dedifferentiation characteristic of the neoplastic state. Various activation mechanisms can change a normal gene into an oncogene. Point mutations (single nucleotide changes in DNA) are one such mechanism. For example, members of the ras gene family are some of the most frequently activated oncogenes in solid human tumors. The ras gene products are plasma membrane proteins capable of binding guanosine triphosphate (GTP). These proteins, called G proteins, are involved in intracellular signal transduction. In tumors with ras activation, the difference in the oncogene compared to the normal gene is a single nucleotide change. Point mutations resulting in single amino acid substitutions in the ras protein change a normal protein into one with transforming activity.
Another important mechanism of oncogene activation is chromosomal translocation, the shifting of a segment of one chromosome to another chromosome. One of the most well-known examples is the formation of the Philadelphia chromosome in chronic myelogenous leukemia. The proto-oncogene c-abl is translocated from chromosome 9 to the bcr locus on chromosome 22. Transcription of the new bcr/abl locus results in the formation of a fusion protein. This new protein has enhanced tyrosine kinase activity and transforming capabilities. In other tumors, an oncogene may be found in an increased number of gene copies per cell, termed amplification. DNA amplification results in an increased level of gene expression. Amplification of N-myc has been found to correlate with prognosis in patients with neuroblastoma.
a. The cells have a DNA content 1 times the baseline content
b. The cells have hyperchromatic nuclei
c. The cells have a DNA content 2 times the baseline content
d. The cells have squamous morphology
e. The cells have a DNA content not an even multiple of baseline content
The development of flow cytometry (FCM) has enabled analysis and sorting of individual cells. FCM is now widely used clinically to rapidly measure the DNA content and estimate the proliferative rate of normal cells and populations of cells comprising malignancies. Normal human resting somatic cells contain 46 chromosomes and a baseline diploid DNA content of 1; cells in mitosis are tetraploid, with a DNA content of 2; and cells undergoing DNA synthesis have a DNA content between 1 and 2. Tumor cells often exhibit gross chromosomal karyotypic changes in both structure and number, which is frequently reflected in a DNA content other than 1 or an even multiple of 1, known as aneuploidy.
The clinical application of FCM attempts to identify aggressive populations or subpopulations of tumor cells within a localized primary lesion that may predict early-stage patients at risk for micrometastatic disease. For most solid tumors, it has been difficult to demonstrate the presence of aneuploidy as negative prognostic variables independent from other negative prognostic variables, such as high nuclear grade, vascular or lymphatic invasion, or the presence of regionally involved lymph nodes. There does seem to be a subpopulation of node-negative breast cancer tumors with aneuploidy that are more biologically aggressive other node-negative breast cancers.
a. Cellular hyperplasia
b. Cellular hypertrophy
d. Carcinoma in situ
Hyperplasia is an increase in cell number. For example, an increase in growth rate over baseline is a normal response in wound healing. Liver regeneration after hepatic injury or hepatectomy results in both a dramatic hyperplastic response with an increase in cell number and a hypertrophic response with an increase in cell size. Metaplasia is a reversible transformation of one mature cell type to another in a given tissue. Epithelial metaplasia secondary to chronic inflammation has been extensively investigated. In cases of chronic gastroesophageal reflux, the normal distal esophageal squamous cell mucosa may undergo metaplasia to a “gastric-type” columnar epithelium. In the respiratory tract, the normal pseudostratified columnar epithelium may be replaced by squamous cells. Dysplasia is a term usually applied to epithelial tissues, characterized by altered cell size, shape, and organization. Dysplasia is classified as mild, moderate, or severe, depending on the degree of cellular dedifferentiation. The gastrointestinal tract, respiratory tree, urinary bladder, cervix, vagina, breast, and the skin all may exhibit foci of dysplasia. Nuclear polymorphism and hyperchromatism are present and often accompanied by total loss of cellular and epithelial polarity. Mitoses are more frequently seen in the afflicted areas than in the surrounding normal epithelium. Although disordered growth of superficial tissue is present, there is no penetration of abnormal cells through the epithelial basement membrane. Carcinoma in situ demonstrates all of the above changes, with an increased number of mitoses, but it is still confined by the basement membrane and may be considered the most disordered extreme of dysplasia.
a. Retinoblastoma results from amplification of the H-ras oncogene
b. Clinical disease results after chromosomal loss in a retinal cell after birth
c. Retinoblastoma results from the loss of a tumor suppressor gene
d. Clinical disease results from chromosomal translocation
Answer: b, c
Genetic events leading to oncogene activation result in either increased gene expression or increased activity of the oncoprotein. Another distinct class of genes has been described as negative regulators of cell proliferation. These genes have been referred to as tumor-suppressor genes. The loss of these genes allow tumor development by the loss of normal growth-inhibitory signals.
Genetic analysis of families with hereditary and sporadic retinoblastomas (Rb) has provided evidence for the role of tumor-suppressor genes in human tumors. In inherited retinoblastomas, an abnormal Rb gene is transmitted to half the offspring. As long as a normal allele is present, the tumor does not develop, and the abnormal germ-line mutation behaves in a recessive fashion; however, a second mutation of the normal allele (somatic cell mutation) may occur in a retinal cell, leading to the development of the tumor. In sporadic retinoblastomas, development of a tumor requires two somatic mutations. The genetic loss in retinoblastomas involves deletion of DNA from chromosome 13q14.
Using the technique of restriction-fragment-length polymorphism (RFLP), tumor suppressor genes may be identified through the loss of heterozygosity of the allele in question or a specific marker associated with that allele. Heterozygosity refers to the presence of two different alleles for a given gene. In the Rb gene example, presence of heterozygosity at the Rb locus prevents tumor development because of the influence of the normal wild-type allele. Loss of this wild-type allele in a second genetic event results in the absence of a normal tumor suppressor gene product and subsequent tumor formation.
b. Plasminogen activator
c. Fibroblast growth factor
Answer: a, b
Evidence for the involvement of tissue-degradative enzymes in neoplastic invasion is convincing. The production and activation of specific tissue-destructive enzymes such as lysosomal hydrolases and collagenases has been documented in tumor invasion. Destruction of host tissue by hydrolytic enzymes, aided by pressure atrophy and the occlusion of blood and lymph vessels by an expanding tumor mass, facilitates infiltration of neoplastic tissue. Histologic examination of tissues obtained from sites of tumor invasion displays considerable variation in the degree of tissue damage, and many human and animal malignant neoplasms express higher levels of lytic enzymes than benign tumors or corresponding normal tissues. Lysosomal catheptic activities are elevated within some tumor tissues, and increased production of cathepsin B in breast carcinomas has been observed compared with that in normal or benign tissue. Enhanced production and secretion of the serine protease plasminogen activator has been associated with the neoplastic transformation of a variety of cell types.
Both intravasation and extravasion are pivotal in hematogenous, systemic metastasis. In either instance, the tumor cells are confronted with a barrier significantly comprised of type IV collagen. Type IV collagen is a major structural protein of basement membranes between parenchymal cells and the connective tissue on which cells rest. A strong correlation exists between the ability of murine tumor cells to produce spontaneous metastases and their ability to produce increased levels of collagenase IV. Tumor cells that invade blood vessels or leave capillaries of distant organs in which they have lodged must penetrate the basement membrane. Dissolution of the basement membrane, suggestive of enzymatic action, has been observed in areas adjacent to arrested tumor cells.
a. Pulmonary fibrosis
b. Gastrointestinal ulceration
c. Hematologic suppression
In chemotherapy regimens, it is important not only to deliver adequate doses with each treatment cycle but also to deliver them in a timely fashion. The interval between each treatment cycle is determined by the toxic effects experienced by normal tissues and the amount of time required for resolution of the effects. The scheduling of treatment courses is crucial. If a course follows too closely upon the preceding one, additive toxicities are noted, much to the detriment of the patient, and often the ability to deliver further therapy is at least temporarily compromised. For most agents, the dose-limiting toxicity is myelosuppression, usually leukopenia and/or thrombocytopenia. Nadir blood counts are reached approximately 14 days after the initiation of each cycle and begin to improve 3 to 5 days later, often with complete resolution by day 28. The resiliency of the bone marrow reserve is dependent upon prior chemotherapy and radiotherapy. Agents such as busulfan, mitomycin C, procarbazine, and the nitrosoureas display delayed myelosuppression, often up to four weeks after the initiation of therapy and lasting several weeks. Therapy with these drugs may be delivered only every 6–8 weeks; in addition, therapy with these agents may lead to chronic cumulative myelosuppression and, in some cases, marrow failure.
a. As a transmembrane efflux pump for chemotherapeutic agents
b. As a DNA repair molecule
c. As an isoform of superoxide dismutase
d. As a membrane stabilizer
Resistance to chemotherapeutic agents may become manifest during the administration of drugs of very different classes, with a variety of presumed intracellular targets. Such resistance, a function separate from the state of proliferation of the malignant cells, has been termed multidrug resistance. This form of resistance is mediated by the cell surface protein, P-glycoprotein, a product of the MDR-1 gene. A magnesium-dependent ATPase, P-glycoprotein acts as a transmembrane efflux pump and appears to serve as a cellular detoxifier and possibly as a chloride pump. P-glycoprotein causes the extrusion of diverse agents such as anthracyclines, epipodophyllotoxins, Vinca alkaloids, and actinomycins out of the cell before they are able to reach their intracellular targets. The protein is normally found on the luminal surface of such organs as the colon and rectum, small intestine, proximal tubules of the kidney, and gravid uterus; the acinar and bile canalicular surfaces of pancreatic and hepatic parenchymal cells, respectively; and in cells of the adrenal cortex, where there is no polarity to the cell surface location. P-glycoprotein has likewise been found in tumors derived from these organs.
P-glycoprotein can be induced in vitro by exposing cell lines to increasing concentrations of various agents, a phenomenon which also extends to tissues and cell lines not known to normally express significant amounts of P-glycoprotein, such as melanoma, ovarian carcinoma, small cell carcinoma of the lung, and adenocarcinoma of the breast.
a. Hepatocellular carcinoma
b. Esophageal cancer
c. Burkitt’s lymphoma
d. Gastric carcinoma
Although a genetic predisposition exists for some cancers, most available information favors environmental variation as the major contributor to the disparate geographic incidence of different cancer types. In many cases, the high incidence of a specific cancer in a particular region or country is linked to a specific causative agent. The chewing of a betel nut, tobacco, and lime mixture in regions of India has resulted in a high incidence of oropharyngeal tumors. The high incidence of gastric carcinoma in Japan is linked to a diet of smoked and highly salted foods, and food contaminated with aflatoxin. The high incidence of hepatitis B infections in parts of Africa and China is thought responsible for the high incidence of hepatocellular carcinoma in these regions. Geographic differences in several other common solid tumors are less clearly explained. Breast and colon carcinomas are common in North America, but rare in Africa and Asia. Carcinomas of the stomach, esophagus, and cervix are more common in developed countries.
a. Thoracic mesothelioma
b. Bladder carcinoma
c. Laryngeal carcinoma
d. Testicular carcinoma
e. Non-Hodgkin’s lymphoma
Answer: a, b, c
Exposure to asbestos fibers or dust markedly increases the risk for neoplastic disease. Among the inorganic carcinogens, asbestos is unusual in its induction of otherwise rare mesotheliomas. In addition to the mesothelioma, workers exposed to asbestos show increased incidence of bladder carcinoma, gastrointestinal tract neoplasms, and laryngeal and esophageal tumors. Clinical and experimental model investigations reveal that asbestos may act as a primary carcinogen or as a cocarcinogen. Thus, individuals who smoke tobacco and are exposed to asbestos fibers increase their risk beyond that associated with the individual susceptibilities.
a. Left sided colon cancers
b. Autosomal dominant inheritance
c. Multiple polyps beginning in adolescence
d. Multiple cutaneous nevi
The most widely investigated familial cancer of the colon is the heredity non-polyposis colorectal cancer (HNPCC). HNPCC syndrome is divided into two main categories: (1) hereditary site-specific colon cancer, or Lynch Syndrome I, and (2) colorectal cancer in association with other forms of cancer or Lynch Syndrome II. The main features of Lynch Syndrome I are an autosomal dominant model of heredity, no associated polyposis, right-sided colon cancers, multiple colon cancers, and long survival. In Lynch Syndrome II, many of the characteristics are the same as Syndrome I, with the added burden of increased risk for endometrial, ovarian, stomach, and urinary tract tumors. The HNPCC group comprises nearly 5% of all colorectal cancers, and in some centers, this figure approaches 15 to 20%. The potential for control of this form of colorectal cancer lies in use of computer registries and clinical surveillance of the high risk group. The molecular basis of HNPCC has been identified as defective DNA mismatch repair gene(s).
a. Increased tissue vascularity
b. High tumor mitotic rate
c. Tissue hypoxia
d. Subcutaneous tumor location
The radiosensitivity of cells depends on their position within the cell cycle. Cells in the M phase (mitotic phase) are most sensitive. At the time of any given dose, only a fraction of cells will be in a vulnerable position within the cell cycle. Subsequently, the sensitivity of the tumor versus normal tissue depends on the ability of cells to redistribute and repopulate within the radiated volume. In tumors that are particularly radiosensitive, this balance between cell killing and repopulation favors the normal tissues over the tumor. The ability to recruit cells from adjacent undamaged areas should also favor normal tissues.
The presence or absence of molecular oxygen greatly influences the proportion of cells killed by a given dose of radiation. The availability of oxygen is clearly the most important factor for enhancing the formation and prolonging the survival of free radicals. Therefore, radiosensitivity of cells within a given tumor varies based on their location relative to oxygen-carrying capillaries. Cells in hypoxic regions of a tumor may escape the effects of radiation. As conditions change with progressive cell killing, fewer cells theoretically exist in hypoxic regions, and oxygen may become more evenly distributed within the tumor volume.
Brachytherapy is a technique in which the source of the radiation is adjacent to or within the targeted tissue. In this method, isotopes such as 198Au and 125I are placed in special catheters, the positioning of which is based on precise geometric considerations. The placement of the radiation source is critical because, in principle, a high dose of energy is delivered to the immediate vicinity of the target and then decreases rapidly with distance. The advantage of this technique is the ability to deliver high, concentrated doses to the target while limiting damage to nearby normal tissue. Clinical applicability is somewhat limited, but there is considerable experience with brachytherapy in the treatment of some oral tumors, gynecologic malignancies, and soft tissue tumors of the extremities.
a. Colorectal cancer
c. Kaposi’s sarcoma
d. Hepatocellular carcinoma
e. Esophageal carcinoma
The role of the immune system in the development of neoplastic disease has been the subject of extensive debate. Clinical observations and the results from experimental animal models are not completely congruent. For example, patients with immune deficiency or immunosuppressed transplant recipients are at greater risk for neoplastic disease. Frequently these are tumors of the lymphoreticular system, and only selected nonlymphoid tissues exhibit increased incidence of neoplasia. Patients with acquired immunodeficiency syndrome and some transplant patients are at an increased risk for Kaposi’s sarcoma.
a. Burkitt’s lymphoma
b. Testicular carcinoma
c. Cervical carcinoma
d. Osteogenci sarcoma
e. Esophageal carcinoma
Answer: a, c
Three groups of DNA viruses have oncogenic strains. The papovaviruses include the papilloma, polyoma, and simian viruses, which induce tumors in animals. The second group is made up of adenoviruses, and the third group comprises the herpesviruses. Adenoviruses have been isolated from a variety of animal tumors; most of these are tumorigenic in newborn animals. An example of the herpesvirus group is the Epstein-Barr virus (EBV), which has been implicated in the etiologies of Burkitt lymphoma and nasopharyngeal carcinoma. The World Health Organization has indicated that previous and continued exposure to EBV results in high titers of antibody to the virus capsid antigen and a 30-fold increase in risk compared with control populations.
Herpes simplex virus type 2 (HSV-2) is the etiologic agent of genital herpes. Infected women with early sexual activity and a large number of sexual partners have significantly increased risk for cervical carcinoma. Women with invasive carcinoma have antibodies to HSV-2, and about 40% of cervical biopsies with severe dysplasia or carcinoma display HSV-2-specific DNA-binding protein. A similar relation has been established for human papovavirus.
A partial response is regarded as a 50%–99% reduction in all bidimensionally measurable disease, lasting at least four weeks or one treatment cycle. A complete response is defined as a total disappearance of all signs and symptoms associated with all malignant lesions, and complete resolution of all laboratory parameters associated with the disease, lasting at least four weeks or one treatment cycle. A minor response is a reduction of less than 50% of all bidimensionally measurable disease, or a reduction of 50% or greater which does not last at least four weeks or a treatment cycle. A minor response is not considered significant, though it may indicate potential biologic activity. Neither a minor nor a partial response is curative, though they may be associated with palliation of symptoms. The presence of a residual mass does not always indicate viable disease, as it may be composed of necrotic or fibrotic tissues.
a. Viral receptors may not be present on target cell membranes
b. For integration, the host cell must undergo mitosis
c. Virus particles are labile
d. Viral purification is difficult
Answer: a, b, c, d
There are several limitations of recombinant retroviruses which make them unsuitable for some gene transfer protocols. First, retrovirus entry requires that target cells contain the appropriate viral receptor. In many cases, these receptors are not known. Difficulties in efficiently transducing certain target cell populations may be due to low levels or absence of appropriate virus receptors. A second requirement for efficient retroviral gene integration is the process of cell proliferation. The dependence of integration on mitosis is thought to be due to the need for nuclear membrane breakdown to enable the viral integration complex to enter the nucleus. Production is another problem, as retrovirus particles are relatively labile when compared to other viruses. In general, retroviruses cannot be purified without significant loss of infectivity.
a. Alpha-1-antitrypsin is a plasma elastase inhibitor
b. Most homozygous patients develop chronic obstructive pulmonary disease
c. The spleen is the primary site of alpha-1-antitrypsin synthesis
d. Intracellular accumulation of abnormal protein occurs in hepatocytes
Answer: a, b, d
Alpha 1-antitrypsin (a-1-AT) is a plasma protease inhibitor with elastase as a major physiological substrate. Synthesis, post-translational modification, and secretion occur primarily in the hepatocyte. Disease-causing alleles are inherited in an autosomal recessive manner. Homozygotes have only 15 to 20% of the normal plasma levels of a-1-AT. Defects in normal a-1-antitrypsin expression and processing, brought about as a result of mutation, can lead to pathology in the lung and liver. Diminished levels of a-1-AT in the blood result in an imbalance between proteases and protease inhibitors, allowing destruction of lung parenchyma. Chronic obstructive pulmonary disease is the most common clinical manifestation of a-1-AT deficiency, with basal lung parenchyma most severely affected.
The liver is the primary site of a-1-AT biosynthesis. In some cases, alteration in the protein sequence of a-1-AT prevents normal post-translational processing and results in the intracellular accumulation of large quantities of abnormal protein, detectable as intracytoplasmic inclusions. One pathologic consequence of abnormal protein accumulation is the development of liver injury.
a. The genetic material contained within a retrovirus is RNA
b. Inside the host cell the viral RNA is converted to single-stranded DNA
c. Proviral DNA is integrated into the host chromosome
d. Retroviruses can be used to transfect both replicating and non-replicating cells
Answer: a, c
Retrovirus particles are composed of a ribonucleic acid (RNA) genome encapsidated into a complex virus particle structure containing both viral and cellular components The virus enters cells primarily on the basis of interactions between viral coat proteins and complementary proteins on the host cell membrane. Once internalized, the viral RNA is converted to a double stranded DNA sequence, the provirus. The proviral DNA is integrated into the host chromosome by means of an integrase protein utilizing proviral DNA sequences known as long terminal repeats. An important point is the need for host cell replication for successful proviral DNA integration.
a. Adenoviral infection is a common cause of upper respiratory tract infection
b. Adenoviral genetic material consists of double-stranded DNA
c. Adenovirus can be produced in large quantity and easily purified
d. Adenoviral infection requires host cell mitosis
Answer: a, b, c
There are over 40 human adenovirus serotypes, many of which are pathogenic in humans. Diseases caused by adenoviruses include hepatitis, conjunctivitis, upper respiratory tract infection, and diarrhea. Multiple exposures to adenoviruses throughout life result in the development of humoral immunity.
Human adenovirus contains 36 kilobases (kb) of double stranded DNA. Adenoviruses are internalized by receptor-mediated endocytosis and transported to the nucleus where the immediate early genes are expressed. Unlike retroviruses, adenoviral infection does not require host cell division. Early gene units express a variety of proteins involved in the regulation and control of the viral life cycle. The concerted activities of the early genes contribute to initiation of the late phase of viral replication whose hallmark is the onset of DNA replication. Adenoviral mRNA undergoes extensive post-transcriptional processing, leading to expression of five sets of late proteins comprising structural components of the virion. Production of the virus, which can be grown in large quantities and highly purified, is relatively easy.
a. Cystic fibrosis is inherited as an X chromosome-linked recessive trait
b. Cystic fibrosis is caused by a defective chloride channel
c. Cystic fibrosis is caused by defective acetylcholine receptors
d. Cystic fibrosis is inherited as an autosomal recessive trait
Answer: b, d
Cystic fibrosis is a lethal autosomal recessive disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene encodes a 170 kDa protein that functions as a cAMP-regulated chloride-channel on the apical surface of epithelial cells.
a. Factor II
b. Factor VII
c. Factor IX
d. Factor X
Hemophilia B is a chromosome X-linked blood clotting disorder which results when the gene encoding Factor IX is deficient or functionally defective. The enzyme is synthesized in the liver, and the existence of animal models for this genetic disease have permitted the development of somatic gene therapy protocols aimed at transfer of functional copies of the factor IX gene into the liver. A recombinant retroviral vector was used for the transfer of human factor IX cDNA in rabbit hepatocytes. The infected rabbit hepatocytes produced human factor IX that was indistinguishable from functional protein derived from human plasma.
Factor IX hepatic gene transfer has also been accomplished in vivo by the direct infusion of recombinant retroviral vectors into the portal vasculature. Canine factor IX cDNA was transduced directly into the hepatocytes of affected dogs in vivo. The dogs transduced with canine factor IX recombinant retrovirus constitutively expressed canine factor IX for 5 months after the procedure at a high enough concentration to improve the whole blood clotting time and partial thromboplastin time.
a. Absence of hepatic low density lipoprotein receptors
b. Overproduction of high density lipoprotein
c. Absence of lipoprotein lipase
d. Overproduction of hepatic ornithine transcarbamylase
The molecular basis of familial hypercholesterolemia is a mutation in the gene that encodes the low density lipoprotein (LDL) receptor. Patients who inherit one abnormal allele have moderate elevations in plasma LDL and suffer premature coronary heart disease. The prevalence of heterozygotes in most populations is 1 in 500, representing approximately 5% of patients under 45 who suffer myocardial infarction. Patients with two abnormal LDL receptor alleles have severe hypercholesterolemia and life-threatening coronary artery disease. Characterization of mutant alleles has revealed a variety of mutations including deletions, insertions, missense mutations, and nonsense mutations. Class 1 mutations are associated with no detectable protein and are often caused by gene deletions. Class 2 mutations lead to abnormalities in intracellular processing of the protein. Class 3 mutations specifically affect binding of the ligand LDL, and class 4 mutations encode receptor proteins that do not internalize within hepatocytes.
c. Post-translational processing
Many strategies for oncogene-directed cancer gene therapy involve the use of antisense oligodeoxynucleotides. Instead of engineering a virus or other gene delivery vehicle, a piece of DNA is inserted which is complementary to messenger RNA molecules. The antisense molecules bind to the sense mRNAs so that mRNA translation cannot occur. Should the bound mRNA subsequently escape its antisense partner, translation could proceed. Antisense molecules are essentially drugs which do not require virus-mediated gene transfer. The oligonucleotides can be made resistant to nuclease degradation.
b. Herpes simplex virus
d. Adeno-associated virus
The ability to manipulate the expression of genes in the mammalian brain leads to opportunities to treat neurologic disorders. DNA viruses have been used for most attempts at gene therapy of non-malignant CNS disease. The herpes simplex type I (HSV I) has been used extensively because of its neurotropic host cell range. Recombinant HSV vectors retain functional viral genes which may be cytotoxic or may reactivate preexisting latent virus in recipient cells. To circumvent these problems, defective HSV viruses have been engineered to eliminate viral genes while retaining certain recognition sequences.