Medical Oncology

·         Lead-time bias, length-time bias, selection bias, overdiagnosis bias, and avoidance bias can make a screening test appear to improve outcomes when it does not. When lead-time bias occurs, survival appears increased, but life is not truly prolonged. The test only lengthens the time that the patient, the physician, or the investigator is aware of the disease. When length-time bias occurs, aggressive cancers are not detected during screening, presumably due to the higher mortality from these cancers and the length of the screening interval. Selection bias can occur when the test population is either healthier or at higher risk for developing the condition than the general public. Overdiagnosis bias, such as with some indolent forms of prostate cancer, detects conditions that will never cause significant mortality or morbidity during a person’s lifetime. The goal of screening is to detect disease at an earlier and more curable stage.

·         Testing of the APC gene has been shown to be cost-effective when used to identify carriers of the disease-causing APC gene mutation among at-risk relatives of individuals with FAP. Early diagnosis via presymptomatic testing reduces morbidity and increases life expectancy through improved surveillance and timely prophylactic colectomy. FAP is an example of a condition in which presymptomatic testing may be lifesaving.

·         Long-term exposure to environmental tobacco smoke (passive smoking) has been associated with a 30% increase in the risk of lung cancer in nonsmokers. β-Carotene has been associated with an increase in the risk of lung cancer.

·         Hereditary prostate cancer, which accounts for 5% to 10% of all cases, is primarily associated with disease of early onset. Major susceptibility loci for hereditary prostate cancer were recently mapped to chromosome 1 and the X chromosome.

·         The Knudson model predicts that children with familial tumors have inherited an initial genetic hit (i.e., a distinct genetic alteration) and require only one additional, rate-limiting genetic hit to initiate tumorigenesis. In contrast, children with sporadic tumors need to acquire two independent genetic hits within the same cell, an unlikely event that explains the less frequent, unilateral presentation and later onset of sporadic cancers.

Knudson model also explains the paradox that tumor suppressor gene mutations are loss-of-function or recessive mutations, yet familial cancer presents as an autosomal dominant trait.

·         p53 functions as a transcription factor, directing expression of p21, an inhibitor of the cyclin-dependent kinases that regulate the cell cycle. Activation of p53 leads to arrest in the G1 phase of the cell cycle, enabling cells to repair DNA damage before proceeding into S phase and DNA replication. In other cells, activation of p53 causes activation of multiple effectors, leading to apoptosis—a suicide program in cells whose DNA may have been irreparably damaged.

·         SMAD genes, active in signaling by transforming growth factor–α (TGF-α), are mutated in pancreatic tumors.

·         P-glycoprotein is a member of the adenosine triphosphate (ATP)-binding cassette family. P-glycoprotein spans the plasma membrane and recognizes a broad spectrum of anticancer drugs. In the presence of ATP, P-glycoprotein pumps the drugs to the extracellular space, so that effective concentration at the intracellular target is never achieved.

·         The Goldie-Coldman model predicts drug resistance by use of cell number and the spontaneous cancer cell mutation rate. Even a tumor that is too small to be detected clinically has a significant chance of containing a cell with a resistance-conferring mutation. Although combination chemotherapy allows for reduction of the dosage of any one agent, it does not inherently reduce side effects or the risk of mutation-induced secondary malignancy or eliminate the need for radiation therapy (which reduces the risk of local recurrence). Finally, combination therapy does not allow for higher dosages. If anything, combination chemotherapy necessitates lower dosages of agents that have common toxicities. Combination chemotherapy attempts to address possible cross-resistance by employing different mechanisms, and nonoverlapping toxicities allow for effective dosing.

·         Coffee and alcohol consumption do not seem to increase the risk of pancreatic cancer.

·         Breast conservation therapy that involves lumpectomy with radiotherapy and modified radical mastectomy that involves removal of the breast and axillary nodes provide identical survival rates for women with stage I or II breast cancer.

·         Data from large cohort studies and case-control studies support the contentions that red meat, animal fat, and total fat consumption increase the risk of prostate cancer.

·         Both normal and malignant prostatic epithelial cells produce PSA; production may actually be higher in normal cells than in malignant cells. A problem with PSA-based screening is that an elevated PSA level lacks specificity. Despite the increased likelihood of prostate cancer in men with a moderately elevated serum PSA level (i.e., a level 4 to 10 ng/ml), biopsy usually reveals benign prostatic hyperplasia (BPH) rather than prostate cancer. Determination of the free PSA level (i.e., the percentage of PSA that is unbound to serum proteins) is also a potential means of distinguishing malignancy from benign hyperplasia. PSA derived from malignant epithelial cells tends to bind more avidly to serum proteins. Thus, in men with an elevated serum PSA level, cancer is more likely when the percentage of free PSA is low.

·         The mainstay of treatment for advanced-stage ovarian cancer is total abdominal hysterectomy with bilateral oophorectomy plus debulking and partial omentectomy, followed by a combination chemotherapy regimen containing a taxane and a platinum analogue.

·         Part of the success of Pap smear screening is due to the fact that this approach typically detects premalignant lesions, as opposed to invasive cancer. This unique feature makes it possible to eradicate precursor lesions before the development of frankly invasive cancers. In addition, the interval of time between the development of a precursor lesion and the occurrence of invasive disease may be several years, thus allowing many opportunities for the detection and eradication of premalignant disease.

·         Extracellular volume deficits exist in all patients with symptomatic hyercalcemia of malignancy. The single most important and urgent treatment is the infusion of normal saline to correct the extracellular volume deficit, increase the glomerular filtration rate, and, secondarily, increase renal calcium excretion.

Glucocorticoids may be useful in patients with lymphoid malignancies as the mechanism of hypercalcemia in those conditions is often related to excess hydroxylation of vitamin D. However, in HHM due to other causes, dexamethasone will have little effect on the calcium level and may exacerbate the altered mental status.

·         Epidural spinal cord compression should be suspected on the basis of the symptoms reported by the patient and the signs elicited by the physician on physical examination. The current recommendation for the radiographic evaluation of patients with suspected epidural compression is gadolinium-enhanced MRI of the entire spinal axis.

·         SVC syndrome is most commonly caused by extrinsic compression of the thin-walled, low-pressure SVC by a malignant mediastinal mass such as bronchogenic carcinoma (especially small cell lung cancer) and non-Hodgkin lymphoma. Before a histologic diagnosis is established, emergency treatment with mediastinal irradiation is only warranted in children and occasionally in adults who have mental status alteration, other life-threatening manifestations of increased intracranial pressure, cardiovascular collapse, or evidence of upper airway obstruction. In the absence of such conditions, as with this patient, the next step in the management of SVC syndrome should focus on efforts to obtain a histologic diagnosis of the underlying condition so that appropriate therapy may be initiated. Obtaining further radiologic studies will not assist in making a histologic diagnosis and are therefore not the most appropriate next step in the management of this patient. Recent experience in adults suggests that SVC syndrome is not a true emergency and that histologic diagnosis should be quickly established and treatment promptly initiated.

·         GISTs occur predominantly in middle-aged patients. Approximately 70% occur in the stomach, 20% occur in the small intestine, and less than 10% occur in the colon, esophagus, and rectum. Survival correlates with tumor location. The best prognoses are associated with tumors of the esophagus and stomach; the worst prognoses are associated with tumors occurring in the small intestine. GISTs frequently lack muscle and Schwann cell markers that are typical of leiomyosarcomas found in other anatomic sites. The protooncogene c-kit encodes a transmembrane tyrosine kinase receptor located on the long arm of chromosome 4. Mutations of c-kit cause the receptor to be activated constitutively without its ligand. Imatinib is an oral, relatively specific inhibitor of three tyrosine kinase receptors. It is used in the treatment of GISTs.

·         Side effects of intravesical BCG include dysuria, urinary frequency, hematuria, and a flulike syndrome. More significantly, because BCG is an attenuated mycobacterium, it can produce local, regional, and systemic infections. Granulomatous infections can occur at extravesical sites, including the prostate, epididymis, testes, kidney, liver, and lungs. BCG sepsis is the most serious complication and can be life-threatening. Systemic involvement is treated with triple-antibiotic antituberculous therapy for 6 months.

·         In some patients with CLL, the clinical course is complicated by progressive conditions, secondary malignancies, immune abnormalities, and infections. Progressive conditions include Richter syndrome, in which patients develop worsening lymphadenopathy, hepatosplenomegaly, fever, abdominal pain, weight loss, and anemia. Patients who develop Richter syndrome do not respond well to therapy, and survival is short. PLL is the second most common transformation in CLL; however, most cases of PLL arise de novo. Compared with patients with de novo disease, patients with PLL that arises through transformation tend to be younger, and they have less marked lymphocytosis. Other transformations in CLL include acute lymphoblastic leukemia, multiple myeloma, and Hodgkin lymphoma. CML is not a known complication of CLL.

·         The current treatment of choice for HCL is either cladribine or the purine analogue pentostatin; both of these agents have been shown to induce remission in 80% of patients, and the choice is based on physician preference.

·         Chemotherapy with melphalan and prednisone is a reasonable therapeutic option for MM because this combination has been shown to have a higher response rate than monotherapy with either drug. In patients who have bone disease, pamidronate is added to provide protection against skeletal complications; this approach appears to improve quality of life and possibly provides a survival advantage. Therefore, current recommendations are to add bisphosphonates such as pamidronate to the regimens for all patients with evidence of bone involvement.

·         Considerable data suggest that MDS results from combined defects of both stroma and hematopoietic stem cells. Several clinical syndromes that may have a more predictable natural history can now be defined. For example, a deletion of the long arm of chromosome 5 can be detected in some older patients, especially women, with a macrocytic, refractory anemia (RA). The platelet count is typically normal or elevated. The bone marrow picture in the RA with 5q– syndrome is characterized by the presence of monolobulated and bilobulated micromegakaryocytes. Two thirds of these patients have RA or RA with ringed sideroblasts (RARS), and the remainder have RAEB (RA with excess of blasts). In those patients who have a del(5q) as their sole cytogenetic abnormality, MDS tends to follow a more benign course, although progression to acute myeloid leukemia (AML) may occur.

·         The term complete remission is reserved for patients who have full recovery of normal peripheral blood counts and bone marrow cellularity with less than 5% residual blast cells.

·         The treatment for Ph+ ALL should include an intensive remission-induction chemotherapy program, followed by allogeneic stem cell transplantation in the first CR if a donor is available. Considerable interest exists in investigating new agents, especially the tyrosine kinase inhibitor imatinib mesylate, in this high-risk group of patients.

·         AML accounts for about 80% of acute leukemias in adults and is most likely to present with hemorrhage or infection. Standard induction therapy with cytarabine and daunorubicin (7 + 3 regimen) is followed by consolidation chemotherapy but generally no long-term maintenance regimen.

·         Up to 95% of patients with CML express Ph, which results from a reciprocal translocation between the long arms of chromosomes 9 and 22. Patients with CML who do not have Ph translocation have a significantly worse prognosis than do patients who test positive for the bcr-abl gene.

·         ET is diagnosed after secondary causes of elevated platelet counts (e.g., iron deficiency, malignancies, inflammatory conditions, and infections) have been excluded. Major thrombotic complications occur in 20% to 30% of patients. Thrombotic complications frequently manifest as DVT and pulmonary embolism. Thrombosis of hepatic veins leads to Budd-Chiari syndrome; thrombosis of renal veins can cause nephrotic syndrome. Erythromelalgia and digital ischemia constitute microvascular forms of arterial thrombosis in ET. Hemorrhagic events occur in up to 40% of patients, with the gastrointestinal tract, urinary tract, skin, eyes, and brain being possible bleeding sites. Individual patients can suffer from both thrombotic and hemorrhagic episodes. Unlike PV, ET rarely progresses, and leukemia develops in only 3% to 4% of patients.

·         Concomitant chemoradiotherapy involves sensitizing tumor cells to radiation by administering chemotherapy, usually cisplatin and fluorouracil, during radiation therapy. Use of concomitant chemoradiotherapy has led to improvements in the control of locoregional disease, & increased overall survival with concomitant chemoradiotherapy.

Induction chemotherapy leads to tumor shrinkage, laryngeal preservation, and decreased disease in areas other than the head and neck, presumably by eradicating micrometastases. However, survival is not improved with this modality because the locoregional control achieved is not better than that achieved with surgery and radiation therapy.

·         The half-lives of AFP and β-hCG are 6 days and 1 day, respectively. After treatment of NSGCT testicular tumor, unequal reduction of β-hCG and AFP may occur, suggesting that the two markers are synthesized by heterogeneous clones of cells within the tumor; thus, both markers should be followed. β-hCG is similar to luteinizing hormone except for its distinctive beta subunit.

·         Hyperleukocytosis is a potentially fatal complication of acute leukemia when the blast count is >100,000/µL. Complications of the syndrome are mediated by hyperviscosity, tumor aggregates causing slow blood flow, and invasion of the primitive leukemic cells, which cause hemorrhage. The brain and lungs are most commonly involved. The pulmonary syndrome may lead to respiratory distress and progressive respiratory failure. Chest radiographs may show either alveolar or interstitial infiltrates. A common finding in patients with markedly elevated immature white blood cell counts is low arterial oxygen tension on arterial blood gas with a normal pulse oximetry. This may actually be due to pseudohypoxemia, because white blood cells rapidly consume plasma oxygen during the delay between collecting arterial blood and measuring oxygen tension, causing a spuriously low measured oxygen tension. Placing the arterial blood gas immediately in ice will prevent the pseudohypoxemia.

·         Mutation control genes: Genes such as hMSH2 and hMLH1 are responsible for ensuring the fidelity of the DNA duplication process. Microsatellite instability results from the faulty DNA editing process. Subsequently, the mutation rate increases and cancers occur.