Certain malignancies have characteristic chromosome abnormalities. These can be chromosome deletions (the whole chromosome is absent or only a portion of a chromosome); additions (e.g., trisomy, when a third chromosome is present in a group that normally would consist of two); translocation, either single (where part of one chromosome breaks off and attaches to another) or reciprocal (where two chromosomes exchange a portion of each chromosome); or gene rearrangement (on the same chromosome). The most famous chromosome abnormality is the Philadelphia chromosome of chronic myelogenous leukemia (CML), present by standard chromosome analysis in about 85% of cases and by nucleic acid probe for gene rearrangement in about 95%–97% of cases (also present in about 25% of adult ALL, 5% of childhood ALL, and 1%–2% of adult acute myelogenous leukemia [AML]. This is a reciprocal translocation in which a portion of the long arm of chromosome 22 breaks off at an area known as the breakpoint cluster region (BCR or ph1 oncogene) and attaches to the long arm of chromosome 9, while the distal portion of the long arm of chromosome 9 (known as the abl oncogene) breaks off and replaces the missing part of chromosome 22. Chromosome 22 becomes shorter but finishes with part of the BCR oncogene still in place plus the addition of the ab1 oncogene, creating a very abnormal chromosome. In genetic terminology, the various changes involved in the Philadelphia chromosome abnormality are summarized by t(9;22) (q34;q11); t is the translocation; (9;22) are the chromosomes involved, with the lowest chromosome number placed first; (q34;q11) is the location of the changes on the chromosomes (q = long arm of the chromosome, p = short arm; the first number refers to a region; the second is a band within the region [chromosome quinocrine banding method]; a decimal followed by a number is a subband). Other symbols are del (deletion), inv (inversion), qh+ or – (long arm increased or shortened), ph+ or – (short arm increased or shortened), I (isochromosome [mirror-image chromosome composed of 2 long arms or 2 short arms]).
Tag: MALIGNANCY
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Hypercalcemia and Malignancy
In confirmed hypercalcemia, differential diagnosis is usually among PHPT, malignancy (metastatic to bone or the ectopic PTH syndrome), and all other etiologies. In most cases the differential eventually resolves into PHPT versus hypercalcemia of malignancy (HCM). There is no single laboratory test that can distinguish between PHPT and HCM every time with certainty. As noted previously, the better midmolecule PTH assays usually can differentiate normal from either PHPT or HCM and frequently can differentiate PHPT from HCM. If PHPT and HCM are not clearly separated, intact PTH assay might be obtained since it is generally better at separating PHPT and HCM. In any case a nomogram containing a scattergram of known cases is necessary. If the different PTH assays are not available, some other tests might indirectly provide evidence one way or the other. Hand x-rays are helpful if typical changes of PHPT are found (but this occurs in only a small percentage of cases). Renal stones are common in PHPT and uncommon in tumor. The quickest and easiest screening test for myeloma is serum protein electrophoresis, although serum and urine immunoelectrophoresis is more sensitive. A serum chloride value at the upper limit of the reference range or above is evidence against metastatic tumor. A bone scan and x-ray skeletal survey are useful to detect metastatic tumor. Some investigators advocate the assay of calcitonin, which is elevated with varying frequency in tumors associated with hypercalcemia and is usually not elevated in PHPT (some investigators report mild elevation in some patients). Unfortunately, regardless of the test results, PHPT may be present concurrently with malignancy in about 5% of patients with cancer.
Serum calcitonin assay. Calcitonin (thyrocalcitonin, TCT) is secreted by nonfollicular C cells of the thyroid. An increased serum calcium level induces thyroid C cells to produce more calcitonin as part of hypercalcemia compensatory mechanisms. A major exception is PHPT, where the TCT level is usually normal or low, for poorly understood reasons (one report indicates an elevation in 10% of cases). The TCT level may be elevated in a considerable percentage of certain tumors known to metastasize to bone, such as lung carcinoma (about 30%-50% of cases; literature range 21%-62%) and breast carcinoma (about 50%; range, 38%-75%). Medullary thyroid carcinoma (MTC) produces elevated basal TCT in about 75% of cases (range, 33%-100%). Total serum calcium in MTC is usually normal. MTC or C-cell hyperplasia is found in >95% of patients with multiple endocrine neoplasia (MEN) syndromes type 2A and 2B. Type 2A also includes pheochromocytoma (about 50% cases) and PHPT (10%-25% cases). PHPT also is part of MEN type 1, which does not include MTC. The TCT level may be increased in the Zollinger-Ellison syndrome, as well as in certain nonneoplastic conditions such as chronic renal failure or pernicious anemia, and values may overlap with MCT. In summary, an elevated TCT level in a patient with possible PHPT raises the question of medullary carcinoma of the thyroid or some other malignancy, if the patient is not in renal failure.
Ectopic parathyroid hormone syndrome.
Nonparathyroid tumors that secrete PTH or PTH-like hormones (ectopic PTH syndrome) can produce considerable diagnostic problems. In one study, 19% of patients with tumor-associated hypercalcemia had no evidence of bone metastases. On the average, PTH assay values in ectopic PTH syndrome are lower than PTH values in PHPT. Although there is some overlap, the degree of overlap depends on the individual antiserum. There is disagreement regarding the nature of the ectopically produced hormone; that is, whether it is true PTH or a nonidentical molecule with a similar structure and PTH-like action that cross-reacts with most current PTH antisera. To further confuse matters, it is estimated that 5%-10% of patients with malignancy and hypercalcemia also will have a coexisting parathyroid adenoma with PHPT. It has also been stated that 15% of patients with PHPT have some coexisting disorder that could produce hypercalcemia.
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Infective Endocarditis
Endocarditis is infection of one or more heart valves, although infection of mural thrombi is usually included. The disease used to be separated into two types, acute and subacute. The acute type was most often caused by S. aureus, usually affected a normal heart valve, and had a relatively short severe course. Other bacteria less frequently associated with acute endocarditis were Streptococcus pyogenes, Streptococcus pneumoniae, and Neisseria gonorrheae. The subacute type was most often caused by streptococci of the viridans group with the enterococci next in frequency, usually involved previously abnormal heart valves, and had a relatively protracted course of varying severity. However, there is considerable overlap of clinical symptoms and severity of disease between the acute and subacute groups, and infections that would fit into the acute group may occur on previously abnormal heart valves. Therefore, many experts now include both types of endocarditis within one term, infective endocarditis.
Predisposing conditions. Certain conditions predispose to infection of normal heart valves. Some examples are IV injection of drugs by drug abusers, indwelling vascular catheters or other devices, major surgical operations, and factors that decrease immunologic resistance. Conditions that create abnormal heart valves are congenital heart disease, rheumatic fever, atherosclerotic valve lesions, prosthetic heart valves, mitral valve prolapse, and nonbacterial valve thrombi. In addition to the same conditions that predispose to infection of normal valves, dental operations and urinary tract manipulation frequently precede development of infection on already abnormal valves.
Organisms associated with endocarditis. Almost every pathogenic (and many relatively non-pathogenic) bacterium has been reported to cause infective endocarditis. Streptococci are the most frequent organisms (about 60%, range 50%-83%), with viridans group streptococci accounting for about 35% of all cases (range, 30%-52%); group D streptococci about 20%, and enterococci about 12% (range, 5%-20%). Staphylococcus aureus is isolated in about 20%-25% (range, 9%-33%) of cases. Coagulaseegative staphylococci are seen more frequently in association with intravascular catheters. When the patient has decreased resistance to infection (refer to the box), fungi and bacteria that ordinarily are considered uncommonly pathogenic or nonpathogenic may become involved.
Clinical findings. Infective endocarditis falls about halfway between bacteremia and septicemia. Bacteria grow in localized areas on damaged heart valves and seed the peripheral blood; this may be infrequent, intermittent, or relatively continuous, with gradations between the two extremes. Classic signs and symptoms include fever, heart murmurs, petechial hemorrhages in the conjunctivae, small “splinter hemorrhages” in the fingernail beds, and splenomegaly. Hematuria is very frequent, and red blood cell (RBC) casts are a common and very suggestive finding. There often (but not always) is a normocytic and normochromic anemia. Leukocytosis is often present, but it too may be absent. Signs and symptoms are variable among individual patients, and the diagnostic problem is often that of a fever of unknown origin.
Conditions Associated with Increased Rate of Infection or Infection by Unusual or Resistant Organisms
GENERAL CONDITIONS
Human immunodeficiency virus infection (e.g., AIDS)
Diabetes mellitus (poorly controlled)
Uremia
Alcoholism
Trauma (severe)
Burns (extensive or severe)
Malnutrition
Very young or very old age
THERAPY ASSOCIATED
Adrenocorticosteroid therapy
Immunosuppressant therapy
Chemotherapy of tumors
Antibiotic therapy (inappropriate or broad-spectrum)
MALIGNANCY
Myeloma
Leukemia and lymphomas
Widespread nonhematologic malignancies
INSTRUMENTATION
Indwelling urinary catheters
Indwelling vascular cathetersDiagnosis of infective endocarditis and identification of the organism involved are made through blood cultures. The clinical picture, evidence of abnormal heart valves, and the organism that is isolated (e.g., S. viridans) are major considerations in differentiating endocarditis from bacteremia and septicemia. However, in spite of the fact that viridans and group D streptococci together cause about 50%-60% of infective endocarditis, a few investigators state that when these organisms are isolated from blood culture, they are actually contaminants (or are not responsible for clinically significant disease) in 75% or more of the isolates. Blood culture methods used for diagnosis of infective endocarditis are the same as those used for septicemia.
Blood cultures. Many physicians draw one specimen from each of two different sites (“one culture set”) to increase total sample volume and to help decide whether certain organisms are more likely contaminants (e.g., S. epidermidis in only 1 of 2 specimens). One must avoid contamination by skin bacteria by aseptic technique; that is, cleansing the skin with alcohol, then with iodine or an iodophore like Betadine, which has the most efficient bactericidal effect of the common antiseptics available. It is then removed by alcohol. Since alcohol inactivates iodophores, the iodophore must remain on the skin a minimum of 1 minute, then it is removed by alcohol. Some obtain the blood culture before removing the iodophore or iodine tincture preparation. Alcohol requires at least 2 minutes contact time to be effective. Several reports emphasize the need for adequate quantities of blood per bottle (at least 5 ml and preferably 10 ml) to maximize bacterial recovery rate. The optimum specimen quantity depends on the amount of diluting medium and the presence or absence of certain additives, such as sodium polyanetholsulfonate (Liquoid). Repeated blood cultures are even more necessary in possible endocarditis than in diagnosis of septicemia because of the often intermittent nature of the blood involvement; avoidance of culture contamination becomes even more important. About 15% of patients (literature range, 2.5%-64%) do not have positive blood cultures. Uremia is especially apt to be associated with negative cultures.
False negative blood cultures. Some possible reasons for false negative blood cultures include recent antibiotic therapy, insufficient blood obtained for the amount of culture media, use of culture media unsuitable for anaerobes or for bacteria with special growth requirements, slowly growing organisms not detected during usual examination periods, various technical laboratory problems (specimens not obtained at optimal times), and combinations of these factors. One of the most important problems is insufficient blood specimen, especially when the number of organisms is small. Most investigators consider a 1:10 ratio of blood to culture medium to be optimal, and some insist on a minimum of 10 ml of blood (in adults) instead of the usual 5 ml. As noted previously, the optimal amount of specimen depends on the amount of diluting medium and the type of culture medium and system. There have been many blood culture systems advocated: use of many different media, vented and unvented containers, different anticoagulants and additives, hypertonic glucose media, filter or radioisotope detection equipment, and so forth. Interestingly, no system has consistently detected all bacteria all of the time. When two or more culture systems are compared, each system almost invariably detects a certain percentage of organisms that the others miss although some systems provide overall better results than others.
Nutritionally deficient streptococci. Occasional patients are infected by streptococci that grow in blood culture media but not on media used to subculture and identify the organisms. This could lead to a false impression of a negative culture. These streptococci are nutritionally deficient (not all in the same nutrient) and will grow on subculture media that are supplemented with the nutrients (e.g., pyridoxine) that they need. They usually grow as satellites around colonies of staphylococci, much as H. influenzae does.