Somatostatin receptor (SSTR) subtype-selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas. Novel potential therapy for functional pituitary tumors.

Previously, we have shown somatostatin receptor (SSTR) subtype-specific regulation of growth hormone (GH), thyroid-stimulating hormone, and prolactin (PRL) secretion in human fetal pituitary cultures, where GH and thyroid-stimulating hormone are mediated by both SSTR2 and SSTR5, whereas SSTR2 preferentially mediates PRL secretion. We now tested SSTR subtype-selective analogues in primary human GH- and PRL-secreting pituitary adenoma cultures. Analogue affinities determined by membrane radioligand binding in cells stably expressing human SSTR forms were either SSTR2 or SSTR5-selective. Analogues preferential either for SSTR2, including octreotide, lanreotide, and novel compounds with improved affinity for SSTR2, or new SSTR5-selective compounds suppressed GH in tumor cell cultures (up to 44% of control; P < 0.0005). However, novel analogues from both groups were 30-40% more potent than octreotide and lanreotide in suppressing GH (P < 0.05). Heterologous analogue combinations containing both SSTR2- and SSTR5-selective compounds were more potent in decreasing GH than analogues used alone (P < 0.05), or than combinations of compounds specific for the same receptor subtype (P < 0.005). In contrast, SSTR2-selective analogues did not suppress PRL release from six cultured prolactinomas studied. However, new SSTR5-selective analogues suppressed in vitro PRL secretion (30-40%; P < 0.05) in four of six prolactinomas. These results suggest that both SSTR2 and SSTR5 are involved in GH regulation in somatotroph adenoma cells, whereas SSTR5 exclusively regulates PRL secretion from prolactinoma cells. Thus, somatostatin analogues with improved selective binding affinity for these receptor subtypes may be effective in the treatment of either GH- or PRL-secreting adenomas.

Specific cellular immune responses in patients with malignant gliomas.

The leukocyte adherence inhibition assay was used to measure cell-mediated immunity in 26 patients with malignant glial neoplasms and 41 control subjects. A significant inhibition of leukocyte adherence was observed in 21 of 26 (80%) glioma patients in the presence of a 3 M KCl extract of glioma tissue, as compared to that of normal brain extract. Among the control group, no significant difference in the percentage of nonadherent leukocytes was noted in the presence of either antigen. To study the specificity of the reaction, a 3 M KCl extract of meningioma, pituitary tumor, carcinomas of breast, and lung, melanoma, brain, and heart tissues were used as nonspecific antigens. Such studies revealed significantly lower values of nonadherent leukocytes. These data indicate that patients with malignant glial neoplasms manifest a cellular immune response to glioma-associated antigens which can be measured by the tube leukocyte adherence inhibition assay and that leukocyte adherence inhibition assay may render additional useful information in diagnostic and prognostic evaluation of malignant glial neoplasms.

Organ-function preservation in advanced oropharynx cancer: results with induction chemotherapy and radiation.

PURPOSE: To evaluate the feasibility and efficacy of a strategy using induction chemotherapy followed by radiation therapy (RT) as a means of organ-function preservation in patients with advanced oropharynx cancer. PATIENTS AND METHODS: From January 1983 to December 1990, 33 patients with advanced squamous cell oropharynx cancer whose appropriate surgical management would have required a tongue procedure and potential total laryngectomy were treated with one to three cycles of cisplatin (CDDP)-based induction chemotherapy. Patients with a complete response (CR) or partial response (PR) at the primary site then received definitive external-beam RT with or without interstitial implant with or without neck dissection with surgery to the primary tumor site reserved for disease persistence or relapse; patients with less than a PR after chemotherapy had appropriate surgery and postoperative RT recommended. RESULTS: With a median follow-up period of 6.2 years, actuarial overall and failure-free survival rates at 5 years are 41% and 42%, respectively. Chemotherapy toxicity contributed to the death of two patients and was possibly a factor in two others. Local control was achieved in 14 patients (42%) without any surgery to the larynx or tongue. Among 13 patients currently alive, all had a preserved larynx and only one required tongue surgery; 12 of 13 have speech subjectively described as always understandable; and nine of 13 have no significant restrictions in their diet. CONCLUSION: This treatment program is feasible and effective in patients with advanced oropharynx cancer and produces an excellent functional outcome in most long-term survivors. Modifications to optimize patient selection, minimize toxicity, and improve local control are indicated. The relative toxicity, efficacy, and functional outcome provided by this and other chemotherapy and RT programs versus either standard surgery and/or RT options can only be addressed in a randomized comparison of these therapies.

Fascicular conduction disturbances and ischemic heart disease: adverse prognosis despite coronary revascularization.

In patients with ischemic heart disease, fascicular conduction disturbances are associated with increased mortality. This study reveals that increased mortality also exists for certain types of fascicular conduction disturbances after myocardial revascularization. In 227 consecutive patients undergoing bypass surgery, 24 had preoperative and an additional 52 developed at surgery a fascicular conduction disturbance. At 66 +/- 14 months of follow-up, 6 (4%) of 148 control patients without pre- or postoperative fascicular conduction disturbances had died from cardiac causes. Although right bundle branch block and left hemifascicular block were the most common form of fascicular conduction disturbance, only 1 of 55 of these patients died (p = NS). Mortality rates were much higher for patients with left bundle branch block or an intraventricular conduction defect; 8 (38%) of 21 died from cardiac causes (p less than 0.05). A high risk subgroup was identified by comparing 14 consecutive patients with left bundle branch block or an intraventricular conduction defect who survived more than 1 year postoperatively with 21 consecutive patients with these same conduction defects who died within 1 year of surgery. The following variables were significantly (p less than 0.05) different (survivors versus nonsurvivors): age (58 +/- 7 versus 65 +/- 9 years); class IV angina (2 of 14 versus 16 of 21), prior myocardial infarction (9 of 14 versus 21 of 21), left ventricular ejection fraction (53 +/- 18 versus 41 +/- 15%), three vessel disease (9 of 14 versus 20 of 21) and left ventricular aneurysm (2 of 14 versus 13 of 21).(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen.

The present clinical trial was undertaken to assess the clinical safety and possible efficacy of administering tamoxifen to patients with recurrent malignant glial tumors at dosages calculated to achieve levels sufficient to inhibit protein kinase C within the tumor cells. Chronic p.o. tamoxifen was administered in very high dosages to 32 patients (20 males and 12 females; age range, 26-75 years; mean, 49 years) with histologically verified malignant glioma [anaplastic astrocytoma (12 patients) or glioblastoma multiforme (20 patients)] who had demonstrated clinical and radiographical progression or recurrence following external beam radiation therapy (and additional chemotherapy in 11; immunotherapy in 2). The dosage of tamoxifen administered was 200 mg/day to males and 160 mg/day to females given in a twice daily schedule. Clinical and radiographical (defined as a greater than 50% decrease in volume of the enhancing lesion volume on magnetic resonance imaging and a decrease in metabolic activity on serial positron emission tomographic scans) response was noted in 8 patients (25%; 4/12 with anaplastic astrocytoma and 4/20 glioblastoma multiforme), with an additional 6 patients (19%) exhibiting stabilization of disease with minimal side effects. Median survival from the time of diagnosis for the entire cohort was 24 months (104 weeks), for the anaplastic astrocytoma group 42.5 months (185 weeks), and for the glioblastoma group 17.4 months (75.5 weeks). From the initiation of tamoxifen, median survival for the entire cohort was 10.1 months (44 weeks), for the anaplastic astrocytoma group 16 months (69 weeks), and for the glioblastoma group 7.2 months (31 weeks). The mean length of follow-up of all patients after initiating tamoxifen was 16 months (69 weeks), while the mean length of follow-up of alive patients is 22.6 months (98 weeks) (range up to 51 months). These data suggest that a subgroup of patients with malignant gliomas respond or stabilize with chronic high-dose tamoxifen therapy. This therapy may represent an alternative or adjuvant to existing chemotherapies for these tumors; further clinical trials are warranted.

Enhancement of radiosensitivity in human malignant glioma cells by hypericin in vitro.

Hypericin, an antidepressant and antiviral agent being evaluated in phase I and II trials for patients with HIV infection, is known to be a potent protein kinase C inhibitor. We have investigated its effects on cellular response to radiation via a tetrazolium-formazan cell growth rate assay using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and clonogenic assay in three human glioblastoma cell lines, U87-MG, A-172, and T98G, and a low-passage malignant glioma culture, 93-492. At a concentration of 5 microM, hypericin inhibited these cells slightly but caused significant radiosensitization (e.g., the cell survival rate after the radiation treatment was 50.2 and 26.0% in cells treated with 6 Gy and 6 Gy plus 5 microM hypericin in U87-MG cells, respectively; P = 0.0285). Hypericin also enhanced the radiosensitivity significantly in the low-passage glioma 93-492 cells. These findings suggest that hypericin represents a potential new agent in combination with radiation therapy of malignant gliomas.

Intravenous RMP-7 increases delivery of ganciclovir into rat brain tumors and enhances the effects of herpes simplex virus thymidine kinase gene therapy.

Herpes simplex virus thymidine kinase (HSV-tk) gene therapy for brain tumors depends on ganciclovir (GCV) and its transport across the blood-brain tumor barrier (BBTB). We examined whether RMP-7, the bradykinin analog and potent BBTB permeabilizer, could enhance the efficacy of GCV treatment of brain tumors by increasing the BBTB delivery of GCV. In vitro, a significant bystander cytocidal effect of GCV was shown in mixed HSV-tk-transduced (HSV-tk+) and control vector-transduced (HSV-tk-) C6 glioma cultures. A dose-dependent cytotoxic effect of GCV on untransformed C6 cells was also shown. In vivo, rats with 100% HSV-tk+ or 100% HSV-tk- intracerebral C6 gliomas were treated for 7 days with intravenous infusions of GCV alone or with GCV and RMP-7 (2.5 microg/kg/day). The growth of HSV-tk+ and HSV-tk- gliomas decreased with increasing doses of GCV. A high dosage (100 mg of GCV/kg/day) eradicated all HSV-tk- and HSV-tk+ tumors. An intermediate dosage (5 mg of GCV/kg/day) reduced the growth of HSV-tk- gliomas by 42% if given alone, and by 88% in combination with RMP-7. A low dosage (0.5 mg of GCV/kg/day) in combination with RMP-7 enhanced the regression of HSV-tk+ gliomas by 87% compared with GCV alone. Low-dose GCV was ineffective in HSV-tk- tumors. RMP-7 increased [3H] GCV tumoral uptake by 2.6- and 1.7-fold in the tumor center and periphery, respectively. We conclude that RMP-7 could be an important adjunctive treatment for suicide gene therapy of brain tumors, while an RMP-7/GCV combination may also have a significant antitumor effect in untransfected gliomas.

Protein kinase C inhibitors induce apoptosis in human malignant glioma cell lines.

Previous work has demonstrated the importance of the protein kinase C (PKC) system in regulating glioma growth, and has led to clinical trials utilizing PKC inhibitors as adjuncts in the therapy of patients harboring malignant gliomas. This study was performed to explore the possibility that inhibition of PKC in gliomas was triggering an apoptosis signal. Glioma cell lines were treated with PKC inhibitors staurosporine (10 nM), and tamoxifen (10 microM). DNA from cells treated with each of these drugs exhibited a 'ladder' pattern of oligonucleosome-sized fragments characteristic of apoptosis, thus suggesting that in glioma cells, these drugs may be cytocidal in action.

Modulation of CSF production by alterations in cerebral perfusion pressure.

The rate of CSF production in cats was studied in relation to changes in intracranial pressure (ICP), systemic arterial pressure (SAP), and the resultant alterations in cerebral perfusion pressure (CPP). When ICP is raised to the point where CPP falls below 55 mm Hg, CSF production will diminish. Elevation of ICP does not appear to influence CSF production rate if CPP is maintained above 70 mm Hg.

Galactose-induced cataract formation in guinea pigs: morphologic changes and accumulation of galactitol.

PURPOSE: To develop and characterize a new model of galactose-induced cataract formation in young, 3- to 4-week-old Hartley guinea pigs. METHODS: Experimental animals were fed 50% galactose in powdered guinea pig chow containing 0.5 g ascorbate/kg diet. Control animals were fed normal powdered guinea pig chow (0.5 g ascorbate/kg diet). Lenses from all animals were subjected to photo-slit-lamp examination, light microscopic analysis, and high-pressure liquid chromatography (HPLC) analysis of polyol content. RESULTS: Photo-slit-lamp examination indicated initial opacities in equatorial subcapsular region between 3 and 5 days in all galactose-fed animals (20/20); opacities progressed toward the anterior pole when diet was extended to 14 days. Histologic analysis of the equatorial changes confirmed progressive cataract formation consisting of small intra-fibrillar vacuoles in the pre-equatorial region (3 days), an increased number of enlarged and coalesced vacuoles (6 days), and progressive tissue swellings with cellular disruption and signs of epithelial multilayering (14 days). The anterior epithelium showed increased cell height and swelling after 3 days of the galactose diet. HPLC analysis of lens tissue indicated progressive accumulation of galactitol, 18 mM after 3 days, which plateaued to about 30 mM between 6 and 14 days. The level of myo-inositol dropped from a control value of 2.8 +/- 0.7 mM to 1.5 +/- 0.7 mM after 3 days, and was nearly undetectable after 14 days of the galactose diet. CONCLUSIONS: The current study suggests that the guinea pig model may serve as a valuable new tool to study sugar-induced cataract formation and to characterize the early morphologic and biochemical events in cataractogenesis.

Loss of Rb expression in an ACTH-secreting pituitary carcinoma.

Little is known about the molecular mechanisms of tumor progression in the pituitary. However, animal studies suggest that the Rb gene may be involved in the development of pituitary carcinoma. Pathologic examination of a pituitary tumor that included both benign and malignant components provided insight into this mechanism. Both benign and malignant tumors were immunoreactive for ACTH. The benign adenoma showed strong nuclear immunoreactivity for Rb, however, both the adjacent sellar carcinoma and its metastases were Rb-negative. This study suggests that loss of Rb may in some cases be important in the progression of pituitary adenoma to carcinoma.

Blood-cerebrospinal fluid barrier alteration following intraventricularly administered cholera toxin.

Cholera toxin (CT) has been reported to double cerebrospinal fluid (CSF) formation following its introduction into the ventricular system of cats and dogs. In our laboratory we noted that CT used in a similar fashion in rabbits and cats resulted in only a slight increase in CSF formation and was associated with a steadily rising protein content in the cisterna magna effluent. To further investigate this finding, rabbits and cats underwent ventriculo-cisternal perfusions, one group with CT introduced into the ventricles and the other without. In the rabbit only, radioiodinated serum albumin (125I-RISA) was given i.v. Other groups of rabbits had 125I-RISA or 125I-CT injected into the ventricles. The group of rabbits receiving intraventricular CT experienced a 4-10-fold elevation in the amount of both protein and 125I-RISA in the cisterna magna effluent compared with the control group. Electrophoretic pattern of the protein present in the effluent was similar to that of rabbit plasma. Autoradiography of the brains of those animals given intraventricular 125I-CT were found to have a very high uptake of 125I-CT in the choroid plexus and along all exposed ventricular surfaces, a finding not evident when 125I-RISA alone was given intraventricularly. It is concluded that CT altered the blood-CSF barriers allowing the reference marker to penetrate these barriers and plasma to leak into the CSF. These findings appear to account for most if not all of what was thought to be an increase in CSF formation in response to intraventricular CT.

Transoral exposure of the atlantoaxial region.

A broad spectrum of disease entities affects the atlantoaxial-clival region. This area is readily accessible through a transoral approach, which offers capabilities for canal decompression and fusion. A case is reported that required transoral odontoidectomy with concurrent excision of an osteophyte from the base of an ununited odontoid fracture. Operative preparation, technique, and postoperative management are described in detail. The advantage and applications of the procedure are discussed.

High dose glucocorticoids in the management of severe head injury.

Eighty-eight patients with a Glasgow coma score of 8 or less 6 hours after nonpenetrating head trauma were given either high dose methylprednisolone sodium succinate (30 mg/kg q6h X2, then 250 mg q6h X6, then tapering over 8 days), low dose methylprednisolone (1.5 mg/kg q6h X2, then 25 mg q6h X6, then tapering over 8 days), or placebo. Standard care including the removal of traumatic hematomas, assisted ventilation, and intracranial pressure monitoring and control was carried out. Follow-up assessments were performed on all surviving patients at 6 months and were graded according to the Glascow outcome scale. No statistically significant difference in outcome was seen between the low dose group and the placebo group. The high dose group experienced a mortality of 39% as compared to a 52% mortality in the low dose and placebo groups (P less than 0.05). Mortality differences were most marked in patients less than 40 years old, with the high dose group experiencing a mortality of 6% as compared to a 43% mortality for the low dose and placebo groups (P less than 0.05). For patients under 50 years old, the incidence of recovery of speech was 62% compared to 36% in the low dose and placebo groups (P less than 0.5). The increased survival in those treated with high dose corticoids, however, was associated with an increase in the poorer outcome categories.

Transmaxillary approach to the anterior cavernous sinus: a microanatomic study.

OBJECTIVE: Several approaches to expose the anterior cavernous sinus have been used, such as frontotemporal, orbitofrontal, anterior subtemporal, and various transfacial approaches. In an effort to gain exposure to the anterior cavernous sinus without necessitating a craniotomy or wide transfacial exposure, the authors in the present study have developed a transmaxillary approach to the cavernous sinus. METHODS: The approach was developed using data obtained by performing 24 cadaveric dissections. Using a sublabial incision to expose the maxilla, maxillotomy is performed and the course of the infraorbital nerve is identified as a guide to the maxillary branch of the trigeminal nerve. After an osteotomy of the posterior sinus wall and pterygoid plate, the foramen rotundum is identified, which lies a mean of 10 mm from the posterior wall of the maxilla. A superomedial enlargement of the foramen rotundum is then undertaken to ultimately expose the anterior cavernous sinus. RESULTS: This technique offers access to all cavernous cranial nerves, as well as the entire course of the anterior loop of the internal carotid artery to the origin of the ophthalmic artery. With a mean operative range of 38 mm from the posterior wall of the maxilla to the anterior loop of the internal carotid artery, this approach offers adequate exposure with a short operative distance. CONCLUSION: The approach may be useful in limited exposure of tumors of the anterior cavernous sinus and some intracavernous vascular lesions.

Checkerboard visual evoked response in evaluation and management of pituitary tumors.

As a routine part of the evaluation of patients with pituitary tumor, visual evoked responses (VERs) to checkerboard pattern reversal were recorded from 83 patients with tomographically documented pituitary tumor. VER tests were correlated with examinations of visual acuity, color perception, and visual fields and with computerized tomographic scan evidence of suprasellar extension of the tumor. The purpose of the VER recording was to determine the presence of visual system compression by the tumor and thus contribute to the decision of whether surgery was necessary. Each of the patients who had suprasellar extension of the tumor sufficient to produce a visual field abnormality also had an abnormal VER. In addition, some patients with suprasellar extension had normal visual fields but abnormal visual evoked responses. Thus, the VER provided earlier evidence of suprasellar extension causing visual system compromise than did conventional visual tests.

Influence of nitroprusside on cerebral pressure autoregulation.

The authors studied 10 cats to assess the question of abolition of cerebral autoregulation attendant on the use of nitroprusside for hypotensive anesthesia. After the establishment of stable base line parameters, a continuous infusion of sodium nitroprusside was begun in a dose sufficient to maintain a mean systemic arterial pressure of 65 mm Hg. Infusion was continued for incremental periods of 30 seconds to 10 minutes, increasing the time of infusion by 30 seconds after each subsequent trial. At 10 seconds after the cessation of nitroprusside administration, intravenous dopamine was infused to raise the systemic arterial pressure to a mean of 100 mm Hg, and the subsequent response in intracranial pressure was recorded in each instance. In no animal was a loss of cerebral autoregulation noted when the nitroprusside infusion was maintained for 3 minute or less. When the infusion was maintained for 4 minutes or longer, cerebral autoregulation was lost in each animal, and the length of time to return of cerebral autoregulation correlated with the duration of nitroprusside infusion. Sodium nitroprusside disturbs the integrity of cerebral pressure autoregulation, and the onset and extent of this disturbance is a dose-dependent phenomenon.

Bromocriptine treatment of prolactin-secreting tumors: surgical implications.

Ten of 19 patients with Stage III-IV prolactin-secreting tumors experienced significant reduction in the size of the tumor when treated with therapeutic doses of bromocriptine. Those tumors that responded favorably to preoperative pharmacological manipulation were found to have an improved surgical cure rate. These preliminary data suggest that a preoperative effort to reduce the size of large prolactin-secreting tumors may result in significant improvement of our surgical ventures.

Computed tomographic guidance stereotaxis in the management of lesions of the third ventricular region.

The initial management strategies for lesions of the 3rd ventricular region are often controversial. Current techniques for computed tomographic guidance stereotaxis allow accurate access to any intracranial point. A Brown-Roberts-Wells stereotactic system was used as a technical adjunct in the initial management of 42 mass lesions of the 3rd ventricular region. Objectives included biopsy, culture, aspiration, visualization, and installment of drainage conduits. Forty-five point placements were accomplished, and 140 tissue specimens were retrieved without complication. The pathological diagnosis was substantiated in all cases and included lesions of developmental (1 case), neoplastic (31 cases), and infectious (10 cases) origins. Information based on stereotactic assessment provided a rational substrate for the initiation of management, which included craniotomy, cerebrospinal fluid diversion, radiotherapy, chemotherapy, and antibiotic or antiviral therapies. Based on this experience, it is apparent that these methods offer acceptably safe and accurate access to lesions of the entire 3rd ventricular region. Histological or microbiological diagnosis without the need for craniotomy may be readily realized and offers logical guidance for therapeutic strategies. Dependent on the pathological condition, definitive treatment may be achieved.

Clinical and radiographic response in a minority of patients with recurrent malignant gliomas treated with high-dose tamoxifen.

Previous work has demonstrated the importance of the Protein Kinase C (PKC) signal transduction system in regulating the growth rate of malignant gliomas in vitro. Tamoxifen inhibits PKC in a minority of malignant gliomas within the micromolar concentration range in vitro, a property distinct from its estrogen receptor blockade effect. Tamoxifen was administered orally in very high dosages to 11 patients (9 males:2 females, age range 26-73, mean 45 years) with malignant gliomas (anaplastic astrocytoma or glioblastoma multiforme) who had failed treatment with external beam radiation therapy (and additional chemotherapy in 2). The dosage administered was estimated to be that necessary to achieve tissue concentrations within the low micromolar range, shown necessary to inhibit PKC in these tumors in vitro, and is approximately 5 times that used for standard antiestrogen therapy. Tumor reduction on radiographic images (MRI and PET [18FdG uptake]) with clinical improvement occurred in 3 patients; halting of tumor progression clinically and radiographically occurred in an additional patient. Of the remaining seven patients, three patients had marked and rapid progression of their disease despite treatment (dead after 3, 4, and 6 months respectively). Complications of treatment included a deep venous thrombosis requiring anticoagulation in one patient, nausea in one patient, and "hot-flashes" in a third patient. Tumor biopsy and measurement of tamoxifen and its active metabolite within the tumor of one patient (non-responder) showed levels within the middle of the in vitro therapeutic range. Follow-up of alive patients ranges from 4-18 months (mean 10 months). These encouraging preliminary results in a minority of these patients suggests some potential for this type of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)