"Generic 100 mg amantadine otc, hiv infection after 1 year".

I. Roy, M.B. B.CH. B.A.O., Ph.D.

Clinical Director, Midwestern University Arizona College of Osteopathic Medicine

This syndrome is caused by decreased glucocorticoids and may be seen with malignant replacement of the adrenal gland. Hirsutism is associated with virilism and is caused by increased glucocorticoids and testosterone, typically from adrenal and ovarian tumors. Internal organ involvement is common and respiratory failure causes death in 30% of patients with this disorder. Corticosteroids and cyclosporin have been advocated and high-dose cyclophosphamide without stem cell rescue has been successful in one patient. Bullous and Urticarial Lesions Bullous pemphigoid is characterized by large tense bullae. Muir-Torre syndrome is a sebaceous gland neoplasm that may precede, follow, or coexist with visceral cancers. Micellaneous Lesions Dermatomyositis is a rare severe inflammatory myelopathy with erythema or telangiectasias of the knuckles, upper chest, or periorbital regions. Frequency of cancer in adults is reported to vary from 10% to 50%, increasing with age. Malignancy can precede, follow, or occur with dermatomyositis; the most frequent pattern is onset of cancer within 1 year of the diagnosis of dermatomyositis. Pachydermoperiostosis is characterized by thickening of the skin and creation of new folds; thickened lips, ears, and lids; macroglossia; clubbing; thickening of the forehead and scalp; and excessive sweating. Hypertrichosis lanuginosa (malignant down) is the development of long, silky hair on the ears, forehead, and possibly the entire body, associated with lung, colon, bladder, and a variety of other cancers. They may also be associated with benign disorders such as primary systemic amyloid. There is an increased prevalence of malignancy, most often in women, typically breast and thyroid cancer. The syndrome includes multiple osteomas, fibromas, lipomas, desmoid tumors, fibrosarcomas, epidermoid cysts, and leiomyoma, as well as dental abnormalities. If untreated, death occurs before the age of 50; therefore, total colectomy is recommended for prevention. Keratosis palmaris et plantaris or tylosis is an autosomal dominant disease associated with esophageal carcinoma. Malignancies develop in a minority of patients and are most often pheochromocytoma. There are numerous additional hereditary disorders associated with malignancy described in Table 47-8. However, both phrases (neurologic paraneoplastic syndromes and remote effects of cancer on the nervous system) are often used interchangeably in the more restrictive sense and are used that way in this review. The neurologic paraneoplastic disorders can logically be separated into anatomic categories, although there is often overlap. This is particularly true of the dementias, which are often lumped together with brain stem, cerebellar, and spinal cord lesions under the rubric of carcinomatous encephalomyelitis. The older term carcinomatous neuromyopathy has been used to describe all the remote effects of cancer on the nervous system as well as the disorders of peripheral nerves and muscle associated with cancer. Recognized neurologic paraneoplastic syndromes occur in less than 1% of patients with cancer. In approximately 50% of patients with known cancer, the nervous system symptoms precede the discovery of the underlying malignancy. However, a variety of causative mechanisms have been proposed to explain the individual syndromes. Opportunistic infections have also been invoked as a possible cause of paraneoplastic syndromes. Although this etiologic link to slow viruses is intriguing, it is not clear how the 14-3-3 protein is involved in the development of paraneoplastic syndromes, 286 and further research in this area is warranted. Another possible mechanism involves competition by the tumor for a biochemical nutrient or substrate. In this way, large metastatic carcinoid tumors produce an encephalopathy by depletion of tryptophan and niacin. Furthermore, it is unlikely that the small tumors frequently associated with paraneoplastic syndromes could consume enough of any substrate to produce a deficiency syndrome, and paraneoplastic syndromes usually run a course independent of that of the tumor.

Their grading system assigned a point system to nuclear atypia, mitoses, endothelial proliferation, and necrosis. An assiduous resection can remove 90% of a typical astrocytoma (1-log cell-kill) and thereby decompress the brain as well as substantially reducing the tumor cell burden. In addition, a large tumor mass left in the brain can serve as a nidus for cerebral edema after radiation therapy because of the indolent removal of dead cells from the brain. Tumors are approached through an incision in the crest of an overlying gyrus or through a sulcus. The selection of the entry site is aided by intraoperative ultrasound images and the frameless image-guided stereotactic system. Self-retaining retractors are placed to retract gently both sides of the cortical incision (generally approximately 3 cm in length), and then the operating microscope is brought in for the approach through the subcortical white matter to the tumor. Hemispheric tumor cysts can be drained and, when possible, fenestrated into an adjacent ventricle to prevent reaccumulation. Tumors not amenable to resection because of their location or their diffuseness should be biopsied stereotactically. Again, there is no indication for a craniotomy when the purpose is merely to biopsy (and not resect) a tumor. The introduction of cortical mapping procedures into brain tumor surgery has made feasible the extensive resection of tumors in functionally critical areas. By use of intraoperative cortical stimulation, motor- and speech-associated cortex can be mapped, and safe routes to deep-lying tumors and safe resection limits determined. Because their data suggest that reoperation can significantly enhance the effects of chemotherapy on recurrent brain tumors, Harsh and associates would not suggest confining reoperation to young patients in excellent condition, but would suggest instead simply using these factors as guidelines in the broader therapeutic picture. Fortunately, randomized trials are being performed to clarify many of the issues surrounding the treatment of these tumors. Approximately 10% to 35% of astrocytomas are amenable to total surgical resection. Shaw and associates found that patients with supratentorial pilocytic astrocytomas who underwent subtotal resection or biopsy and irradiation survived longer than nonirradiated patients. Based on these data, postoperative irradiation is not indicated for pilocytic astrocytomas when a complete or near complete resection has been performed. After subtotal resection, either immediate irradiation or close follow-up, reserving treatment for those patients with symptomatic, progressive, nonresectable tumors may be recommended. Because recurrences are infrequent in children with completely resected astrocytomas, postoperative irradiation is generally not recommended. The outcome of adult patients after total or radical subtotal resection, has been found in some series to be similar to that of patients undergoing less extensive surgery. For irradiated patients, 5-year survival rates varied from 36% and 55%, and 10-year rates ranged from 26% to 43%. In contrast, 5-year survival rates for subtotally resected, nonirradiated tumors varied from 19% to 32% and 10-year rates were approximately 10%. Further, marked changes in the quality of surgery, radiation therapy, and patient management occurred over the long time intervals spanned by these studies. Indeed, survival rates in these reports increase directly as a function of the time period in which the patients were treated. The improved outcome appears to be related to the earlier diagnosis of tumors in neurologically intact patients who exhibit only seizures at the time of diagnosis. Recht and colleagues 96 reported 26 patients with suspected low-grade supratentorial gliomas (based on clinical and radiologic features only) who were monitored without other treatment except anticonvulsants. Of these patients, 58% subsequently required intervention (surgery alone or with radiotherapy) within a median of 29 months (range, 4 to 123 months) because of increased size of the radiographic abnormality, refractory seizures, new symptoms, or malignant transformation. When compared with 20 patients who had similar characteristics but in whom the decision was made for immediate intervention, there was no difference in the outcome of patients who received immediate or deferred treatment and no difference in the time to neoplastic transformation. Arguments for performing an immediate biopsy are to confirm the diagnosis and to identify patients with nonenhancing anaplastic tumors. Further, complete surgical resection may improve survival, obviate the need for irradiation, and decrease the risk of malignant transformation, the most common cause of death in low-grade astrocytoma patients, 95,96 and 97 by reducing the tumor burden. Although it is generally agreed that patients with unfavorable astrocytomas with radiographic evidence of tumor growth, intractable seizures, progressive neurologic impairment, or malignant transformation of the tumor should undergo radiotherapy, this treatment is commonly deferred in patients with well-controlled seizures who present with asymptomatic, indolent tumors. Among those in the control arm, 65% of patients received subsequent radiotherapy, 19% underwent surgery, chemotherapy, or both, and the remainder received only supportive care. A preliminary analysis of the study demonstrated that although immediate irradiation improved the 5-year progression-free survival (44% vs.

Again, the skeletal event curves of the pamidronate and placebo groups diverged, in this instance from the initiation of the study. Although bisphosphonates have not been proven to be efficacious in managing bone metastasis due to other tumors, theoretically these compounds should be of value in all cancers causing lytic bone lesions. There is also evidence that bisphosphonates may actually prevent the development of bony metastases. In several animal models, injected tumor cells failed to establish colonies in bone that had been pretreated with bisphosphonate. When a more rapid response is needed, radiation therapy or surgery (or both) still are required. Chemotherapy and Hormone Therapy Because of the significant percentage of patients with breast cancer who develop metastatic bone lesions, the effects of chemotherapy and hormone therapy on these lesions have been investigated. The goals of chemotherapy and hormone therapy in patients with metastatic disease involving bone are pain control, disease stabilization, and reduction of the risk of morbid skeletal events. Anderson Cancer Center who were treated with 5-fluorouracil, doxorubicin, and cyclophosphamide, bone lesions showed an 18% complete and a 65% partial response to the regimen. Hormone-sensitive breast carcinoma has a predilection to metastasize to bone; therefore, hormone therapy can be effective in these cases. As with other therapies, a peritreatment lesion "flare" may occur that makes the evaluation of overall response difficult. The indications for radiation therapy are pain relief and suppression of local tumor growth. Suppression of local tumor growth is important in the treatment of impending fractures, after surgical fixation of metastatic lesions, and in the treatment of neural compression. Tumor reduction and pain relief can begin immediately, particularly for very radiosensitive round cell tumors. Thoughtfully planned treatment with high-energy radiation causes minimal morbidity, and the benefits far exceed the risks in most situations. Radiation is of therapeutic value in patients with localized symptomatic lesions and should be considered in all but the few cases in whihc either the disease is very responsive to systemic treatment. The radiation oncologist must collaborate with the medical oncologist and surgical personnel to optimize treatment. This interdisciplinary cooperation is critical in the management of an impending fracture. Occasionally, a lesion will heal with radiation therapy, especially if it is mechanically protected. However, fracture and subsequent intramedullary fixation necessitate treatment of the entire bone, which can be difficult to implement if a radiation treatment protocol has already been applied within the new field. More than 80% of patients with a limited number of well-localized bony metastases can be treated effectively by external-beam irradiation. Radiation may render the patient asymptomatic and control the disease for an extended period. If symptoms persist over the course of several months, alternative management for localized disease should be considered. External-beam irradiation to the most symptomatic or potentially troublesome areas should be used to supplement systemic therapy. Hemibody radiation or systemic radionuclide therapy should be considered for widely disseminated bone disease. Irradiation of a weight-bearing bone such as the femur should be undertaken only after careful evaluation of the potential fracture risk produced by the underlying lesion (as discussed later in Impending Fractures: Prophylactic Fixation). There is an increased risk of pathologic fracture in the peri-irradiation period due to an induced hyperemic response at the periphery of the tumor. Identification of disease progression and management of associated morbidity by the treatment team is very important during the course of irradiation, because other treatments often are suspended during this time. The interdisciplinary communication essential for high-quality treatment often is best provided through a medical practice environment in which all the specialists are in geographic proximity. This minimizes the need for excessive travel by the patient who is experiencing a limitation in mobility and is at risk for fracture.

Ecthyma gangrenosum is the most characteristic skin lesion associated with systemic P aeruginosa infection, but it is not pathognomonic. Ecthyma gangrenosum begins as a raised erythematous papule or nodule that progresses to a bluish-black necrotic lesion within 12 to 24 hours. Pathologically, ecthyma gangrenosum is a necrotizing process in which masses of bacteria are often observed within the vessel wall. Local soft tissue infection by P aeruginosa in the neutropenic patient can rapidly spread through fascial planes, causing extensive necrosis and fulminant sepsis. A needle aspiration of the lesion showing gram-negative bacilli establishes the diagnosis of invasive infection; however, a negative aspiration does not rule out the diagnosis. Stenotrophomonas maltophilia can cause a variety of dermatologic infections, including mucocutaneous ulcerations, primary cellulitis, a metastatic nodular cellulitis, and ecthyma gangrenosum [see Stenotrophomonas (Xanthomonas) maltophilia, earlier in this chapter]. Aeromonas hydrophilia is a gram-negative rod that grows in fresh and brackish waters and can be acquired by nosocomial transmission. Immunocompromised persons are more susceptible to extensive soft tissue infections from direct penetration through the skin, leading to sepsis. In a patient exposed to fresh or brackish water preceding an episode of cellulitis, an antibiotic regimen with activity against A hydrophilia should be initiated. The organism is usually susceptible to fluoroquinolones, trimethoprim-sulfamethoxazole, third-generation cephalosporins, and imipenem. Septicemia by viridans streptococci is associated with facial flushing and a rash in 60% of cases in a series from the M. Skin exfoliation occurred on the palms and soles in 25% of patients 2 weeks after the onset of the rash. These manifestations are likely the result of acquisition of a plasmid producing a toxin associated with a toxic shock syndrome. Bacteremia caused by C jeikeium is associated with skin lesions in 30% to 50% of neutropenic patients. The skin lesions often occur at catheter sites and at sites of trauma, such as bone marrow aspiration, and may only become apparent after resolution of neutropenia. If diphtheroids are isolated from a skin lesion, the microbiology laboratory should be asked specifically to evaluate for C jeikeium. Bacillus species are rare causes of skin infection, but can be associated with impetiginous, ulcerative, and necrotic skin lesions. Clostridium species are gram-positive anaerobes that cause deep soft tissue infection involving the fascia and muscle (see Clostridium Species, earlier in this chapter). Typically, a small dusky or purplish lesion on the leg or abdominal wall rapidly expands, and as infection progresses, the lesions become necrotic, bullous, and hemorrhagic. Systemic toxicity, including fever, malaise, and mental status changes occur early. Because the infection occurs in the deep soft tissue, tenderness and evidence of vascular compromise typically precede the development of cellulitis. A rapidly progressive deep soft tissue infection with gas formation suggests clostridial myonecrosis (or polymicrobial necrotizing fascitis). Needle aspiration characteristically shows the organism in the setting of a mild or absent inflammatory response. Biopsy and fungal staining of cutaneous lesions can provide an immediate clue to the diagnosis, prompting the early addition of antifungal therapy. Trichosporon beigelii is a yeast that causes sepsis and disseminated infection in neutropenic patients. Histologically, budding yeast are present in the dermis, as distinguished from Candida species, which produce pseudohyphae. Cutaneous infection by filamentous fungi may be primary or may represent systemic infection. Primary cutaneous infection with molds can occur in immunocompetent patients by traumatic inoculation.

The combination of drugs might be tolerated if the toxicities were nonoverlapping. Initial attempts with two-drug combinations revealed the potential of this approach. Further information on chemotherapy is provided in Advanced-Stage Disease later in this chapter. Combined Modality Chemotherapy In addition to the many factors that affect either chemotherapy or radiotherapy when used alone, there are several issues that arise specifically because of potential interaction and summing of effects when they are combined. Failure-free survival was the same in all groups, strongly implying that after optimal chemotherapy, irradiation dose, at least to nonbulky sites, can be reduced without sacrificing efficiency. The risk of two important late complications of irradiation may be reduced by lowering the dose. Stanford University investigators found that a higher dose of irradiation to the mediastinum was associated with increased mortality from cardiac disease. The same theoretic considerations that apply to irradiation are relevant when one considers reduction of the dose of chemotherapy used in combined modality treatment. In theory, either the chemotherapy or the radiotherapy could come first in the sequence of combined modality treatment. In practice, it is almost always desirable for chemotherapy to precede radiotherapy. The reason for this includes early effective treatment of disseminated disease, delay in induction of irreversible loss of bone marrow function, and the opportunity to use smaller, potentially less toxic radiation treatment fields after chemotherapy has induced tumor regression. Implicit in the rationale for this approach is the assumption of a steep dose-response relation for lymphoma patients subjected to chemoradiotherapy. Although care must be exercised in interpreting clinical results, both animal models and clinical studies support the existence of such a relationship. Mucositis and enterocolitis represent the most significant nonhematologic toxicities associated with high-dose melphalan. This information will generally be phrased in terms of probabilities-for instance, the probability of cure for various values of a prognostic factor. It may be used for informing the patient or, in the context of clinical trials, for defining or describing the study population or adjusting the data analysis; however, for the clinician, the most important role of the prognostic factor is to help in selecting an appropriate treatment strategy. Among the remaining patients with early-stage disease who had previously continued to receive radiotherapy alone, an "unfavorable" subgroup often was defined to select patients for combined modality therapy. Each group has thus been associated with a typical standard treatment strategy: Early stages, favorable: radiation alone (extended field) Early stages, unfavorable: moderate amount of chemotherapy (typically four cycles) plus radiation Advanced stages: extensive chemotherapy (typically eight cycles) with or without consolidating (usually local) radiation these "typical" strategies are not uniformly applied, and the investigation of alternatives. In the scheme just listed, two divisions between the three prognostic groups must be noted, each division possibly being defined by a different set of factors. Furthermore, the attempt has been made to identify advanced-stage patients with a particularly high risk of failure for intensified therapy. Prognostic factors are rarely the subject of specific clinical studies but are discovered and evaluated using data from large cohorts of uniformly treated, well-documented, and reliably followed-up patients, usually from large clinical trials. In the following few sections, recognized prognostic factors are described for early stages treated with radiotherapy alone, for early stages treated with chemotherapy, and for advanced stages (treated with chemotherapy), respectively. Such factors are required to show independent prognostic value in multivariate analyses of large numbers of patients. This account refers in general to clinically staged patients, because laparotomy is now rarely performed. The use of these factors to define prognostic groups for treatment purposes, as practiced by various institutions and study groups, are described. These factors are relevant to the decision as to which early-stage patients should be classed as unfavorable and receive combined modality therapy because their prognosis with radiotherapy alone is relatively poor. Favorable patients were generally given radiation only, although the additional application of mild chemotherapy has increased. A 30% long-term failure rate was observed, however, and this policy was not continued. All the factors listed for radiation-treated patients have also been reliably confirmed in cohorts who also received chemotherapy,161,162 either in early or in advanced stages. This similarity of prognostic effects is supported by the observation from a metaanalysis of radiotherapy versus combined modality treatment in early stages that the size of the difference in failure-free survival between these two treatment strategies was essentially constant over different prognostic groups. This gradual shift to use of more intensive therapy was based on prognostic factor analyses.