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David S. Baskin and Charles B. Wilson

✓ Thirty-eight patients underwent transsphenoidal microsurgical treatment of non-neoplastic intrasellar cysts: 36 had cyst drainage and biopsy of the cyst wall, and in two the cyst was totally removed. Surgical morbidity was 8%. The mean follow-up time was 46.3 months; 100% patient follow-up evaluation was achieved. Sixteen female patients (mean age 24.6 years) had pars intermedia cysts: 88% had menstrual irregularities, 63% had galactorrhea, 31% had headache, and 56% had hyperprolactinemia. Within these groups, menstrual cycles returned in 86%, galactorrhea ceased in 90%, headaches resolved in 80%, and serum prolactin levels were restored to normal in 66%. Eight females and three males had Rathke's cleft cysts (mean age 34.0 years): of these 11 patients, 91% had headaches and 18% had hyperprolactinemia; of the eight females, 63% had amenorrhea and 63% had galactorrhea. Within these groups, serum prolactin levels normalized in 50%, and 80% noted reduced headache. Of the females, 80% had return of menses and 50% noted cessation of galactorrhea. Six males and two females had arachnoid cysts (mean age 42.2 years): 50% had headaches; 50% were asymptomatic. Preoperatively, 50% of these patients had hypothyroidism and 25% had adrenal hypofunction. Postoperatively, 75% of patients with headache noted improvement, and 33% of patients with abnormal thyroid function had normal function. Adrenal function did not improve. Three patients had an intrasellar cysticercosis cyst, epidermoid cyst, and postoperative cyst, respectively. All had evidence of partial hypopituitarism; none improved postoperatively. The results indicate that different types of pituitary cysts produce different clinical syndromes, and suggest that simple transsphenoidal drainage and partial removal of the cyst wall can provide safe and effective therapy.

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David S. Baskin and Charles B. Wilson

✓ Two patients with diabetes insipidus, hypopituitarism, and an enlarged sella turcica underwent a transsphenoidal operation for the treatment of intrasellar germinomas. Successful transsphenoidal treatment of such neoplasms has not been reported previously. The cases indicate that the diagnostic possibility of intrasellar germinoma should be considered in young patients with combined diabetes insipidus and hypopituitarism, even when the sella is markedly expanded.

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Primary cerebral neuroblastoma

Long-term follow-up review and therapeutic guidelines

Mitchel S. Berger, Michael S. B. Edwards, William M. Wara, Victor A. Levin, and Charles B. Wilson

✓ Primary cerebral neuroblastoma is a distinct pathological and clinical entity that differs from other primitive neuroectodermal tumors. To characterize the clinical course of this lesion, the authors performed a retrospective analysis in 11 patients who ranged in age from 17 months to 26 years. The tumor had no predilection for either sex. Signs and symptoms were mostly those associated with increased intracranial pressure. The lesions commonly involved the parietal and occipital lobes. Computerized tomography scans of nine patients showed five solid and four cystic lesions; calcifications were found more commonly in the solid lesions. Contrast enhancement was seen in all tumors, yet angiograms typically showed an avascular mass. Total removal of tumor was possible in only two patients, both with cystic tumors. The remaining nine underwent subtotal resection of a solid lesion (in five) or a cystic lesion (in four). All 11 patients underwent postoperative irradiation that included the spinal axis in two cases; only one received adjuvant chemotherapy (solid tumor). Four patients, all with solid tumors that initially were subtotally resected, had evidence of tumor recurrence. The only patient with a subtotally resected solid lesion who did not have recurrence received adjuvant chemotherapy. The six patients who had cystic lesions are free of recurrent tumor at 26 to 109 months after surgery. Based on follow-up analysis of the 11 patients, recommendations are proposed for the treatment of primary cerebral neuroblastomas.

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James E. Boggan, J. Blake Tyrrell, and Charles B. Wilson

✓ The development of transsphenoidal microsurgery and the refinement of endocrinological and radiological diagnostic procedures have afforded therapeutic options appropriate to the individual case in patients with hypercortisolism. The present series of 100 cases is derived from 104 patients with the diagnosis of Cushing's disease who underwent transsphenoidal pituitary exploration between 1974 and 1981. Excluding four patients in whom the pituitary gland was not exposed because of intraoperative technical difficulties, an overall cure rate of 78% was achieved. Among 71 patients with tumors confined to the sella turcica, 87% had correction of their hypercortisolism, 11% represented therapeutic failures, and one patient had tumor recurrence. In contrast, among 25 patients with extrasellar extension, correction of hypercortisolism was achieved in only 48%, 40% failed to respond, and 12% of the patients had recurrence. Four patients who failed to respond to total hypophysectomy have ectopic sources of adenocorticotropic hormone.

The results indicate that transsphenoidal microsurgical exploration for a basophilic adenoma is the procedure of choice in adults and children with Cushing's disease. The diagnostic and surgical approach to these tumors, as well as pitfalls in the transsphenoidal treatment of Cushing's disease, are discussed.

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Improved treatment of a brain-tumor model

Part 2: Sequential therapy with BCNU and 5-fluorouracil

Massimo A. Gerosa, Dolores V. Dougherty, Charles B. Wilson, and Mark L. Rosenblum

✓ A combination chemotherapy regimen for brain tumors was developed, based on investigations of the survival of animals harboring the intracerebral 9L rat brain-tumor model and on analyses of their clonogenic tumor cells. Fischer 344 rats harboring 9L brain tumors were treated with 2-day courses of 5-fluorouracil (5-FU), in order to expose all cycling tumor cells to the drug during DNA synthesis and achieve maximum anti-tumor activity for this cell-cycle-specific anti-metabolite. Although a 74% cell kill was obtained for a total dose of 45 mg/kg or greater, animal life span was not increased over that of untreated tumor-bearing controls. However, when 5-FU (48 to 96 mg/kg total dose over 2 days) was administered after a single LD10 dose of BCNU (13.3 mg/kg), additive cell kill was suggested. In three large series, long-term animal survivors and occasional tumor cures were observed with this drug combination, a result never observed following BCNU alone. Schedule dependency was not apparent. A previously published protocol for treating recurrent malignant gliomas with sequential courses of BCNU and 5-FU was partially planned based upon these initial observations. Anti-tumor activity with the combination of drugs was superior to therapy with BCNU alone. Both animal and human studies confirm that, contrary to presently accepted oncological tenets, a chemotherapeutic agent that kills significant numbers of tumor cells but is clinically ineffective when given alone might, nevertheless, be useful in combination therapy regimens.

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James E. Boggan, Richard L. Davis, Greg Zorman, and Charles B. Wilson

✓ The authors report the uncomplicated removal of an intrasellar epidermoid cyst that on presentation mimicked a pituitary adenoma. Current controversies regarding the differentiation of this cyst from other cystic lesions of the sellar region are reviewed.

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Improved treatment of a brain-tumor model

Part 1: Advantages of single- over multiple-dose BCNU schedules

Mark L. Rosenblum, Massimo A. Gerosa, Dolores V. Dougherty, and Charles B. Wilson

✓ Clonogenic cell and animal survival studies were used to determine the most effective BCNU therapy schedule in the 9L rat brain-tumor model. Survival of tumor cells following a single LD10 dose of BCNU (13.3 mg/kg intraperitoneally) was compared to cell survival after one to four daily 0.5 × LD10 doses. The posttreatment kinetics of surviving clonogenic cells were investigated at various times after BCNU was given in single doses of 0.25 to 1 × LD10 and in two daily doses of 0.5 × LD10. The cell kill was greater, time to reinitiation of cell growth was later, posttreatment rate of clonogenic cell proliferation was slower, and the interval to total repopulation of the clonogenic cell pool was longer with a single LD10 dose as compared to the multiple-dose schedules. Animal survival studies confirmed that a single LD10 dose of BCNU was at least as effective as a cumulative level of up to 1½ times that amount when treatment was administered in smaller doses, regardless of the fractionation schedule.

Clinical experience with patients harboring malignant brain tumors has shown that a single BCNU dose of 185 to 200 mg/sq m is tolerated well. Results of these animal experiments suggest that this therapy should have anti-tumor activity at least equivalent to the more commonly employed schedule of 80 mg/sq m/day given for 3 days. Although direct comparison of treatment efficacy using the two schedules is not possible, no adverse clinical effects have been observed with the recently adopted single-dose schedule. Furthermore, the duration of patient hospitalization for chemotherapy has decreased.

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Stem cell studies of human malignant brain tumors

Part 1: Development of the stem cell assay and its potential

Mark L. Rosenblum, Massimo A. Gerosa, Charles B. Wilson, Geoffrey R. Barger, Bertran F. Pertuiset, Nicolas de Tribolet, and Dolores V. Dougherty

✓ A stem cell assay for human malignant gliomas has been developed. Cells obtained from tumor biopsies grew into colonies composed of malignant glial cells, as documented by histochemical, immunohistochemical, and immunobiological techniques. Studies suggest that the disaggregated cells are representative of the cells within the solid tumor.

Clonogenic cells were obtained from 48 tumors and analyzed for their in vitro sensitivity to graded doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The in vitro anti-tumor activity of BCNU at clinically achievable doses was compared to clinical response to the agent based on changes in computerized tomographic scan, radionuclide brain scan, and neurological examinations. Twenty-two patients received nitrosoureas before or after tumor specimen analysis, and were eligible for in vitro-in situ correlations. Clinical tumor sensitivity to nitrosoureas was predicted by culture results in 42% of all evaluable patients, and clinical resistance was predicted in 100%. The capability of the assay can be appreciated best for the 13 patients not treated with BCNU prior to culture; the in vitro prediction of clinical sensitivity and resistance was 71% and 100%, respectively.

Preliminary findings show that clinical tumor resistance to BCNU may result from “intrinsic” cell resistance in some patients and from inadequate delivery of drug to tumor cells in other cases. The potential utility of this method to study the reason(s) for tumor cell resistance to drugs, to screen new chemotherapeutic agents, to individualize patient treatment, and to investigate tumor biology is discussed.

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Charles E. Alpers, Richard L. Davis, and Charles B. Wilson

✓ A 5-year-old girl with juvenile pilocytic astrocytoma subsequently had multiple episodes of symptomatic recurrence over the course of 21 years of follow-up review. This lesion underwent histological transformation to an anaplastic small-cell neoplasm 21 years after the initial resection and diagnosis. Late transformation of benign childhood cerebellar astrocytomas to malignant astrocytic tumors is very rare; transformation to an anaplastic small-cell neoplasm has not been reported previously. This case and other reported cases in which juvenile pilocytic astrocytoma recurred after a long interval indicate the requirement of long-term follow-up review of these patients before assuming either a cure or arrest of the tumor's growth.

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Stephen A. Hill, James M. Falko, Charles B. Wilson, and William E. Hunt

✓ Hyperthyroidism due to thyrotrophin (TSH)-secreting pituitary tumors is rare. Four cases are described, with the features that allow preoperative diagnosis. In all the patients, thyroid hormone production was consistently elevated despite antithyroid therapy, and TSH levels were inappropriately elevated. All patients were treated with both surgery and irradiation. Each patient had recurrent tumor with suprasellar, intrasphenoidal, or intraorbital spread. The combination of a recurrent, aggressive tumor complicated by thyrotoxicosis makes this a complex and difficult surgical problem.