Diagnosis & management of pituitary tumors

Pharmacologic agents are useful in the management of some patients with pituitary tumors. The diagnosis and management of pituitary adenomas are discussed.     

The role of chemotherapy in the management of nasopharyngeal carcinoma

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a radiosensitive tumor for which there is a high local control rate after radical radiotherapy (RT). However, for patients with locoregionally advanced disease, the rate of distant metastasis is high and the 5-year overall survival rate is poor. METHODS: A review of retrospective and prospective clinical studies was performed to assess the role of chemotherapy in three settings: metastatic disease; neoadjuvant and/or adjuvant; and concurrent chemotherapy with radiotherapy. RESULTS: Cisplatin-based combination chemotherapy results in a high response rate in patients with metastatic NPC, and a subgroup may achieve long term disease free survival. The use of neoadjuvant and adjuvant chemotherapy to treat locoregionally advanced disease has resulted in consistently high response rates, but no randomized trial to date has demonstrated an improvement in overall survival. A recent Head and Neck Intergroup study randomized patients in the United States to receive concurrent chemotherapy (cisplatin) and radiotherapy or radiotherapy only. Although this approach demonstrated significant benefit in overall survival favoring the use of concurrent chemotherapy and radiotherapy, its applicability in geographic areas of high NPC incidence remains to be proven. CONCLUSIONS: NPC is a chemosensitive tumor, and patients with metastatic disease have a high response rate. Further prospective studies will define the standard approach to treating locoregionally advanced NPC, which is likely to incorporate into the primary treatment some form of systemic chemotherapy.     

Late toxicity after chemotherapy of malignant testicular tumors

Improved survival in testicular cancer has been accompanied by concern about long-term side effects of chemotherapy or radiotherapy. Secondary malignant neoplasia represents one of the worst possible long-term complications, leading to death in patients cured of their primary malignancy. Patients with testicular germ cell tumors appear to have a 2-fold increased risk of developing any second cancer 25-30 years after the diagnosis, resulting in a cumulative incidence of 16-23% at that time. The risk for secondary solid tumors can be mainly attributed to radiotherapy. There is strong evidence of an increasing risk for secondary solid tumors with time since treatment. Tumor-specific analysis of the risk for second cancers revealed statistically significant excesses for stomach, pancreas, bladder, rectum, prostate, and kidney cancer, as well as for cancer of the thyroid, melanoma, sarcomas, and non-Hodgkin's lymphoma. No significantly elevated risk for secondary solid tumors was observed after treatment with chemotherapy alone. The risk of secondary leukemia was associated with both radiotherapy and in particular with chemotherapy. In recent clinical surveys of patients with testicular cancer, estimates of the risk of leukemia after chemotherapy have ranged from 10- to 300-fold. An elevated risk was observed within the first two decades after diagnosis, later the risk was as expected in the normal population. Etoposide seems to be leukemogenic, especially at cumulative doses higher than 2 g/m2, although the effects of dose and schedule as well as the effects of other cytotoxic agents and radiotherapy remain to be finally clarified. Based on currently available data in patients with testicular cancer, it can be concluded that a significant elevated risk for the development of secondary leukemia exits after chemotherapy. However this risk does by far not outweigh the therapeutic benefit of etoposid-based therapy in patients with germ cell tumors. Secondary Raynaud's phenomenon is the main late vascular toxicity affecting about one third of patients after curative chemotherapy for testicular cancer. Hypertension will occur in one fifths of the patients. The incidence of vascular toxicity appears to be lower following PEB-therapy compared to PVB-therapy and major vascular events seem to be rare. Other frequent symptomatic toxicities are ototoxicity and peripheral neuropathy. A major risk factor for the development of toxicity is the cumulative dose of cisplatin given. Alterations of gonadotropin levels and Leydig cell insufficiency persist in more than half of young patients cured from testicular cancer by cisplatin-based combination chemotherapy. Approximately one fourth of patients have low serum magnesium or phosphat levels, or elevated creatinine levels. These toxicities seldomly result in clinical symptoms. We conclude that 3-4 courses with bleomycin, cisplatin and etoposide in testicular cancer patients will only rarely lead to symptomatic impairment of organ functions and a decrease of quality of life. Germ cell cancers have served as a valuable model for the development of new treatment strategies contributing largely to defining the role of cisplatinum, etoposide and recently ifosfamide in medical oncology. However, germ cell cancer may also be a useful model for investigating the long term side effects of the oncological therapies. Thus, germ cell cancer is not only a "model for a curable neoplasm" (L.H. Einhorn) but can also be seen as a "model for the study of late sequelae of modern oncological therapies".     

The role of stereotactic radiosurgery in the treatment of malignant skull base tumors

PURPOSE: To determine the efficacy and toxicity of stereotactic radiosurgery in the treatment of malignant skull base tumors. METHODS AND MATERIALS: Thirty-two patients with 35 newly diagnosed or recurrent malignant skull base tumors < or = 33.5 cm3 were treated using the Leksell Gamma unit. Tumor histologies included: adenoid cystic carcinoma [12], basal cell carcinoma [1], chondrosarcoma [1], chordoma [8], nasopharyngeal carcinoma [3], osteogenic sarcoma [2], and squamous cell carcinoma [8]. RESULTS: After a median follow-up of 2.3 years, 83% +/- 15% (+/-95% confidence interval) of patients experienced a symptomatic response to treatment. Local control at the skull base was 95 +/- 9% at 2 years and 78 +/- 23% at 3 years. Local-regional control above the clavicles was 75 +/- 15% at 1 year and 51 +/- 20% at 2 years. Overall and cause specific survival were identical, 82 +/- 13% at 1 year, 76 +/- 14% at 2 years, and 72 +/- 16% at 3 years. One patient developed a radiation-induced optic neuropathy 12 months after radiosurgery. CONCLUSION: Stereotactic radiosurgery using the Leksell Gamma Unit can provide durable tumor control and symptomatic relief with acceptable toxicity in the majority of patients with malignant tumors 4 cm or less in size involving the skull base. Further evaluation of more patients with longer follow-up is warranted.     

Acute suppurative thyroiditis and aggressive malignant thyroid tumors: differences in clinical presentation

The FDA has issued proposed regulations to require that manufacturer's evaluate the "steam sterilizability" of parenteral products. There are many different ways to assess sterilizability. Within a company, it is helpful to standardize the methodology used to determine whether the product should be terminally sterilized. The following is one approach to determining product sterilizability. This approach is also depicted in a flow chart (Figure 4).     

The evolution of the role of radiation therapy in the management of mucocutaneous malignant melanoma

The role of radiation therapy in the treatment of malignant melanoma has evolved substantially over time. Years ago, malignant melanomas were generally considered radioresistant. Over time, the palliative value of radiation therapy was established. Most recently it also has become clear that judiciously applied therapy may be curative in either an adjuvant setting or for small-volume disease.     

MIB-1 labeling indices in benign, aggressive, and malignant meningiomas: a study of 90 tumors

Predicting tumor behavior in meningiomas based on histology alone has been problematic. This study retrospectively compares histology and MIB-1 (cell proliferation marker) labeling indices (LI) in benign, aggressive, and malignant meningiomas. Six histological features, including mitoses, necrosis, loss of pattern, hypervascularity/hemosiderin deposition, prominent nucleoli, and nuclear pleomorphism, were compared in 90 meningiomas (Fisher's exact test). Tumors with two or more of the above features were designated as aggressive meningiomas. Malignant meningiomas were characterized by brain invasion or metastasis. The MIB-1 LIs (% positive tumor cell nuclei) were compared between the three groups (Kruskal-Wallis test, Wilcoxon two-sample test). Of the benign meningiomas (n=37; mean age, 54 years), 41% had one of the six histological features, with nuclear pleomorphism (n=10) being the most frequent. The aggressive tumors (n=29; mean age, 61 years) were characterized by nuclear pleomorphism (n=28), mitoses (n=20), necrosis (n=16), loss of pattern (n=16), prominent nucleoli (n=6), and hypervascularity/hemosiderin deposition (n=5). Malignant tumors (n=24; mean age, 59 years) were characterized by nuclear pleomorphism (n=22), mitoses (n=21), loss of pattern (n=21), necrosis (n=21), nucleoli (n=17), and hypervascularity/hemosiderin deposition (n=3). Significant differences were found between the aggressive and malignant groups with regard to loss of pattern, necrosis, and nucleoli (P=.0043, .011, and .00029, respectively). Mean MIB-1 LIs for the benign, aggressive, and malignant groups were 1.0% (range, 0 to 5.5%),5.5% (range, 0.1 to 32.5%), and 12.0% (range, 0.3 to 32.5%), respectively. Differences in the mean MIB-1 LI between groups were statistically significant, with P values of <.0001 (benign v aggressive) and .0012 (aggressive v malignant). Mean MIB-1 LIs for recurrent versus nonrecurrent tumors were 7.1% (range, 0 to 32.5%) versus 3.8% (range, 0 to 20.9%) (P=.32). The mean MIB-1 LI for patients who were alive with or without tumor was 6.2% (range, 0 to 32.5%) versus a mean MIB-1 LI of 14.2% (range, 2.8% to 32.5%) for patients who died of or with tumor (P=.0013). In conclusion, (1) There is a statistically significant difference in the increasing MIB-1 LI means between benign, aggressive, and malignant meningiomas and between patients who were alive versus those who died; (2) there is some overlap in MIB-1 LI ranges between groups, which warrants caution in interpreting an individual MIB-1 LI in a given tumor.     

The role of chemotherapy and radiation in the management of biliary cancer: a review of the literature

Carcinoma of the biliary tract is a rare tumour. To date, there is no therapeutic measure with curative potential apart from surgical intervention. Thus, patients with advanced, i.e. unresectable or metastatic disease, face a dismal prognosis. They present a difficult problem to clinicians as to whether to choose a strictly supportive approach or to expose patients to the side-effects of a potentially ineffective treatment. The objective of this article is to review briefly the clinical trials available in the current literature utilising non-surgical oncological treatment (radiotherapy and chemotherapy) either in patients with advanced, i.e. locally inoperable or metastatic cancer of the biliary tract or as an adjunct to surgery. From 65 studies identified, there seems to be no standard therapy for advanced biliary cancer. Despite anecdotal reports of symptomatic palliation and survival advantages, most studies involved only a small number of patients and were performed in a phase II approach. In addition, the benefit of adjuvant treatment remains largely unproven. No clear trend in favour of radiation therapy could be seen when the studies included a control group. In addition, the only randomised chemotherapeutic series seemed to suggest a benefit of treatment in advanced disease, but due to the small number of patients included, definitive evidence from large, randomised series concerning the benefit of non-surgical oncological intervention as compared with supportive care is still lacking. Patients with advanced biliary tract cancer should be offered the opportunity to participate in clinical trials.     

High plasma proopiomelanocortin in aggressive adrenocorticotropin-secreting tumors

A specific propiomelanocortin (POMC) immunoradiometric assay was developed using antibodies directed against ACTH and beta-endorphin (beta end). Partially purified standard POMC was prepared from the human small cell lung carcinoma cell line DMS-79 culture medium. Ten units (U) POMC had the same displacement ability as one pg beta end in a C-terminal beta end radioimmunoassay and thus were close if not equal to 10 pg POMC. This POMC assay was used to investigate patients with ACTH-dependent Cushing's syndrome. Plasma POMC was undetectable (< 60 U/mL) in 17 normal controls and in 4 patients with Addison's disease (concomitant ACTH plasma levels between 362 and 1058 pg/mL). Forty-two patients with Cushing's disease were studied, either before (n = 25) or after (n = 17) bilateral adrenalectomy: 7 patients with highly invasive macroadenomas had high POMC plasma levels, between 240 and 4200 U/ml (concomitant ACTH plasma levels between 77 and 5730 pg/mL); 35 patients, including one with an invasive macroadenoma, had undetectable POMC plasma levels (concomitant ACTH plasma levels between 31 and 2820 pg/mL). Among 20 patients with histologically proven ectopic ACTH syndrome, 16 had high POMC plasma levels, between 80 and 8000 U/mL (concomitant ACTH plasma levels between 45 and 9265 pg/mL); all those tumors were malignant, and the highest POMC/ACTH plasma levels ratios (taken as an index of altered POMC processing) were observed in the 3 patients with small cell carcinomas of the lung; in one of these patients, ACTH and POMC plasma levels both decreased during the course of chemotherapy, in parallel with the reduction of the tumoral mass. Four patients with ectopic ACTH syndrome had undetectable POMC plasma levels (concomitant ACTH plasma levels between 78 and 335 pg/mL): they were all typical bronchial carcinoids. These data show that high POMC plasma level is neither specific for nor constant in ectopic ACTH syndrome. Rather it should be considered as a marker of tumor aggressivity, in pituitary- and non-pituitary tumors. Its diagnostic help appears limited for the most frequent cause of occult ectopic ACTH syndrome, the typical bronchial carcinoids.     

The chemotherapy of adult primary brain tumors

Adult patients with primary malignant brain tumors are a heterogeneous group. Most patients will have high-grade astrocytomas and can be expected to obtain minimal benefit from current standard chemotherapy regimens. Intra-arterial chemotherapy, high-dose chemotherapy with autologous bone marrow rescue, and new chemotherapeutic agents designed to penetrate the blood-brain barrier have not resulted in significant advances to date. However, there are exciting new directions in the chemotherapy of high-grade astrocytomas which are entering clinical trials. Two potentially promising approaches include interstitial chemotherapy using surgically implanted polymers and the continuous infusion of combinations of active chemotherapeutic agents. Other therapeutic modalities such as radioactive seed implants, stereotactic radiosurgery, and gene therapy are also being evaluated. Hopefully, this intense activity by subspecialists with a wide range of interests and expertise will produce novel and effective treatments for the large number of patients with malignant astrocytomas. In contrast, patients with many of the less common neoplasms of the central nervous system may benefit from the addition of chemotherapy to their treatment. Primary germ cell tumors or lymphomas of the central nervous system are very sensitive to chemotherapy. The germ cell tumors respond to the cisplatin-containing regimens developed for testicular malignancies. The optimal chemotherapy for CNS lymphoma is not clear but exciting results have been reported with a combination of radiation, systemic and intrathecal methotrexate, and systemic cytosine arabinoside. Although limited, the available literature suggests that patients with anaplastic oligodendrogliomas may also benefit from chemotherapy at diagnosis or at relapse. Studies in children suggest a benefit for adjuvant chemotherapy and radiation therapy in poor risk patients with medulloblastomas although these findings have not been confirmed in adults. Finally, anecdotal reports suggest that chemotherapy may be useful in the very rare patient who presents with a pineal tumor or an ependymoma.     

The effect of docetaxel on malignant tumors

In recent years numerous molecular biological discoveries enlightened the various steps of the neoplastic transformation. Based on new targets, this development made it possible to synthetize new tumour inhibitory substances. Among them taxanes capable to block depolymerization of tubulin--which is an essential molecule in cell division--play an important role. Docetaxel (Taxotere) belongs to this group and is an active drug in the treatment of breast cancer. Moreover, platinum-resistant tumours may also respond to the therapy. It is important to note that even visceral (hepatic) metastases may express chemosensitivity. Results of combination chemotherapy seem to be also promising. The antitumour effect of Taxotere in NSCLC and other malignant neoplasms in under investigation. The toxicity of Taxotere may be successfully reduced by premedication of steroids. The necessary protective measures render the Taxotere therapy safe and of being perspectivistic.     

Dose-effects and chemotherapy dose intensity of aggressive non-Hodgkin''s lymphomas in the adult

Papillary fibroelastoma is a rare, benign cardiac tumor. Before echocardiogram came into existence, it was diagnosed only by necropsy or incidentally at surgery. This kind of tumor may appear on the endocardial surface or in any of the valves. Although it is usually small in size, it is associated to embolic phenomena, thoracic pain and sudden death. This report presents the first case of papillary fibroelastoma in the presence of a mechanical valvular prosthesis in mitral position. In a patient 55 years old, presenting inactive rheumatic heart disease. The tumor was detected by means of transthoracic and transesophageal echocardiogram.     

The role of ceramide in the cellular response to cytotoxic agents

STUDY AIM: The aim of this study was to report the results of pharyngoesophageal reconstruction in extensive corrosive strictures and to describe an original conception concerning extensive chemical burns of the pharynx with involvement of the epiglottis, oro-hypopharyngeal junction and cricopharyngeal pinchcock. PATIENTS AND METHODS: A personal series of 253 esophageal reconstructions using the colon and ileum is reported. In 124 patients, the cervical anastomosis of the graft was performed at the level of the pharynx, and these cases with extensive pharyngeal lesions were the basis of this study. The anastomosis was performed with the hypopharynx in 27 patients, with the oropharynx in nine and a total reconstruction of the pharynx or "pharyngoplasty" was carried out in 69 patients. The pharyngoplasty was classified according to the approach, in anterior, posterior, lateral, superior (transmandibular) and inferior. In high strictures with epiglottic injury, epiglottectomy was necessary in order to prevent recurrence. A visceral pharyngoplasty was performed in 61 patients, using the colon in 42 and the ileum in 19, a skin reconstruction in six patients and a myocutaneous flap in two. RESULTS: The global postoperative mortality rate was 4.7%. Stenosis of the cervical anastomosis occurred in 4.9% of the whole series. With a follow-up from 6 months to 10 years, 70% of the patients resumed a normal oral diet, 21% had mild symptoms and 7% had poor results (patients with tracheostomy and gastrostomy). CONCLUSION: Extensive chemical burns of the pharynx are very severe and their treatment very difficult. For the author, total visceral pharyngeal reconstruction is considered to be the procedure of choice, using ileopharyngoplasty with realization of an ileal pouch. Good results were obtained in 70% of the patients with extensive corrosive strictures.     

The management of malignant hypercalcaemia

Malignant hypercalcaemia is a common problem for cancer clinicians. However, the management of this condition has altered substantially over the last 10 years and the condition is usually amenable to modern treatment. A number of effective pharmacological agents are available in current practice. Bisphosphonate drugs, particularly clodronate and pamidronate, are confirmed as the mainstay of modern management. Bisphosphonates are effective and well tolerated when given intravenously. Many aspects of the actions of bisphosphonates are not well understood, and knowledge of their pharmacokinetics is limited.