Initial clinical results of LINAC-based stereotactic radiosurgery and stereotactic radiotherapy for pituitary adenomas

PURPOSE: To retrospectively evaluate the initial clinical results of stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) for pituitary adenomas with regard to tumor and hormonal control and adverse effects of the treatment. SUBJECTS AND METHODS: Forty-eight patients with pituitary adenoma who underwent SRS or SRT between September 1989 and September 1995 were analyzed. Of these, 18 received SRS and 30 received SRT. The median tumor volumes were 1.9 cm3 for SRS and 5.7 cm3 for SRT. Eleven of the SRS and 18 of the SRT patients were hormonally active at the time of the initial diagnosis. Four of the SRS and none of the SRT patients had a history of prior radiation therapy. Both SRS and SRT were performed using a dedicated stereotactic 6-MV linear accelerator (LINAC). The dose and normalization used for the SRS varied from 1000 cGy at 85% of the isodose line to 1500 cGy at 65% of the isodose line. For SRT patients, a total dose of 4500 cGy at 90% or 95% of the isodose line was delivered in 25 fractions of 180 cGy daily doses. RESULTS: Disease control-The three year tumor control rate was 91.1% (100% for SRS and 85.3% for SRT). Normalization of the hormonal abnormality was achieved in 47% of the 48 patients (33% for SRS and 54% for SRT). The average time required for normalization was 8.5 months for SRS and 18 months for SRT. Adverse effects-The 3-year rate of freedom from central nervous system adverse effects was 89.7% (72.2% for SRS and 100% for SRT). Three patients who received SRS for a tumor in the cavernous sinus developed a ring enhancement in the temporal lobe as shown by follow-up magnetic resonance imaging. Two of these cases were irreversible and were considered to be radiation necrosis. None of the 48 patients developed new neurocognitive or visual disorders attributable to the irradiation. The incidence of endocrinological adverse effects were similar in the two groups, resulting in 3-year rates of freedom from newly initiated hormonal replacement of 78.4% (77.1% for SRS and 79.9% for SRT). CONCLUSION: Considering the relatively high incidence of morbidity observed in the SRS group, we recommend SRT as the primary method of radiation therapy for pituitary tumors. When treating a lesion in the cavernous sinus with SRS, special attention should be paid to dose distribution in the adjacent brain parenchyma. Longer follow-up is necessary before drawing any conclusions about the advantages of these techniques over conventional external beam radiation therapy.     

Accelerated radiotherapy regimen for malignant gliomas using stereotactic concomitant boosts for dose escalation

Parvovirus B19 (PV B19) infection was investigated in 29 pregnant women with fetal hydrops, after exclusion of feto-maternal incompatibility within red blood cell antigens, TORCH infections, feto-maternal hemorrhage and genetics reasons. The active viral infection was detected in 9 women (31%) by PCR amplification of DNA B19; in 2 of them IgM and IgG, in 1 IgM and in 4 IgG antibodies were also present. In 6 women (20%) IgG antibodies were only found, but not IgM and DNA B19, which confirmed infection in the past. In addition in 9 cases DNA B19 was evaluated in the fetal blood. The results in the mothers and their fetuses were concordant (4 positive, 5 negative). Our conclusion is that in nonimmune hydrops fetalis, PV B19 infection should be based on the viral DNA evaluation in the blood of mother (or fetus). IgM antibodies, in time of fetal disorders, might not be detected.     

Ultrasound-controlled stereotactic breast biopsy--description and initial clinical results of a new breast biopsy device

The aim of this prospective study was first to describe a new dedicated 3D-ultrasound guided stereotaxic breast biopsy unit and second its specificity, sensitivity, accuracy and positive predictive value (concerning malignant and benign lesions). Technical considerations are noted and discussed. SUBJECTS AND METHODS: 45 women (aged between 20 and 77 years; mean age: 49.73 years) with sonographically suspect breast lesions were assigned to the new biopsy device (Sonopsy, NeoVision Corporation, Seattle). All biopsies were performed by an experienced radiologists (G. Wolf) and the results compared to the surgical biopsies. RESULTS: Sensitivity and accuracy was 93.3%, specificity 100%, the positive predictive value (concerning malignant lesions) 95.4% and (concerning benign lesions) 97.8%. In 9/45 biopsies (20%) complications were noted (1 hematoma, 2 collapses, 5 vasovagale reactions). In 13/45 Cases (28.9%) the suspect lesions were more distinctively, respectively more clearly defined on the conventional/dedicated sonography unit. CONCLUSION: This dedicated unit combines all advantages of sonographic and stereotaxic guided core biopsies. Our results show that this technique is a promising new method for breast biopsy.     

Clinical commissioning of Laitinen Stereoadapter for fractionated stereotactic radiotherapy

PURPOSE: The purpose of this study was to investigate the distribution of shades selected for metal ceramic crowns provided at a dental teaching hospital. MATERIALS AND METHODS: Data on the selection of shade for 2,500 metal ceramic crown units, placed over a 5-year period at the University Dental Hospital of Manchester, were collected and analyzed. Only those crowns placed adjacent to minimally restored vital teeth were included in the study. RESULTS: The results indicate that the most frequently chosen shades were in the mid-range of reddish-brown hue. Furthermore, shades in the reddish-grey range of hue were rarely chosen. The selection of more than one shade for a crown ("mixed shades") was generally restricted to the maxillary anterior teeth. CONCLUSION: Knowledge of the distribution of shades selected for permanently luted metal ceramic crowns may be a useful adjunct in shade selection, particularly for the inexperienced operator.     

Surgical treatment combined with radiotherapy and chemotherapy in an unselected population of patients with malignant glioma

BACKGROUND: Malignant gliomas are tumors of bad prognosis with a mean survival of 12 months. In the present report 74 patients diagnosed of malignant glioma were studied with the following aims: 1) evaluate how many could receive combined radiotherapy (RT) and chemotherapy (BCNU) treatment following surgery and 2) analyze whether the patients treated presented a survival similar to that described in the literature. METHODS: The records of 74 patients operated on for malignant glioma between 1987-1990 and consecutively included in a protocol of treatment with RT and BCNU were reviewed. RESULTS: Out of the total of 74 patients, 29 (39%) were considered evaluable. The medians of progression free interval and survival were of 10 and 16 months, respectively in these patients. Forty-five (61%) patients could not fulfill the protocol mainly because of tumoral progression prior to completion of RT and severe post surgical complications. The evaluable patients were significantly younger (p = 0.004) and tumoral exeresis wider (p = 0.0003) than in those who were not evaluable. CONCLUSIONS: Most of the patients operated on for malignant glioma may not receive treatment considered as standard, principally due to tumor progression in the first weeks following surgery and the presence of severe post surgical complications.     

The use of active noise control (ANC) to reduce acoustic noise generated during MRI scanning: some initial results

The search of reprolysin inhibitors offers the possibility of intervention against both matrixins and ADAMs. Here we report the crystal structure of the complex between adamalysin II, a member of the reprolysin family, and a phosphonate inhibitor modeled on an endogenous venom tripeptide. The inhibitor occupies the primed region of the cleavage site adopting a retro-binding mode. The phosphonate group ligates the zinc ion in an asymmetric bidentate mode and the adjacent Trp indole system partly fills the primary specificity subsite S1'. An adamalysin-based model of tumor necrosis factor-alpha-converting enzyme (TACE) reveals a smaller S1' pocket for this enzyme.     

Testicular function after radiotherapy to inverted 'Y' field for malignant lymphoma

Testicular function was estimated by sperm counts, hormone assays and recording of reported conceptions in 9 patients irradiated for malignant lymphoma. The treatment had been an inverted 'Y' field including the inguinal regions with, in addition, a mantle field in 8 patients. Azoospermia or severe oligozoospermia was found in all but 1 patient, and the FSH levels were uniformly elevated. Testosterone and LH were within normal limits except in 2 patients with slightly subnormal testosterone levels. 7 of the patients were married to women of fertile age, and in 3 cases the wife became pregnant and give birth to a healthy child. The time lapses from irradiation to conception were 18, 40 and 57 months. 2 of these patients had severe oligozoospermia on examination 2 and 4 months respectively from conception. Thus fertility may possibly be underestimated by sperm counting and hormone assays after this type of radiotherapy.     

Dose characteristics of in-house-built collimators for stereotactic radiotherapy with a linear accelerator

Dose characteristics of a stereotactic radiotherapy unit based on a standard Varian Clinac 4/100 4 MV linear accelerator, in-house-built Lipowitz collimators and the SMART stereotactic radiotherapy treatment planning software have been determined. Beam collimation is constituted from the standard collimators of the linear accelerator and a tertiary collimation consisting of a replaceable divergent Lipowitz collimator. Four collimators with isocentre diameters of 15, 25, 35 and 45 mm, respectively, were constructed. Beam characteristics were measured in air, acrylic or water with ionization chamber, photon diode, electron diode, diamond detector and film. Monte Carlo simulation was also applied. The radiation leakage under the collimators was less than 1% at 50 mm depth in water. Specific beam characteristics for each collimator were imported to SMART and dose planning with five non-coplanar converging 140 degrees arcs separated by 36 degrees angles was performed for treatment of a RANDO phantom. Dose verification was made with TLD and radiochromic film. The in-house-built collimators were found to be suitable for stereotactic radiotherapy and patient treatments with this system are in progress.     

A technique for fractionated stereotactic radiotherapy in the treatment of intracranial tumors

PURPOSE: The excellent treatment results obtained with traditional radiosurgery have stimulated attempts to broaden the range of intracranial disorders treated with radiosurgical techniques. For major users of radiosurgery this resulted in a gradual shift from treating vascular diseases in a single session to treating small, well delineated primary tumors on a fractionated basis. In this paper we present the technique currently used in Montreal for the fractionated stereotactic radiotherapy of selected intracranial lesions. METHODS AND MATERIALS: The regimen of six fractions given every other day has been in use for "fractionated stereotactic radiotherapy" in our center for the past 5 years. Our current irradiation technique, however, evolved from our initial method of using the stereotactic frame for target localization and first treatment, and a "halo-ring" with tattoo skin marks for the subsequent treatments. Recently, we developed a more precise irradiation technique, based on an in-house-built stereotactic frame which is left attached to the patient's skull for the duration of the fractionated regimen. Patients are treated with the stereotactic dynamic rotation technique on a 10 MV linear accelerator (linac). RESULTS: In preparation for the first treatment, the stereotactic frame is attached to the patient's skull and the coordinates of the target center are determined. The dose distribution is then calculated, the target coordinates are marked onto a Lucite target localization box, and the patient is placed into the treatment position on the linac with the help of laser positioning devices. The Lucite target localization box is then removed, the target information is tattooed on the patient's skin, and the patient is given the first treatment. The tattoo marks in conjunction with the target information on the Lucite target localization box are used for patient set-up on the linac for the subsequent 5 treatments. The location of the target center is marked with radio-opaque markers on the target localization box and verified with a computerized tomography scanner prior to the second treatment. The same verification is done prior to other treatments when the target center indicated by the target localization box disagrees with that indicated by the tattoo marks. The new position of the target center is then determined and used for treatment positioning. CONCLUSION: The in-house-built frame is inexpensive and easily left attached to the patient's skull for the 12 day duration of the fractionated regimen. Positioning with the Lucite target localization box verified with tattoo marks ensures a high level of precision for individual fractionated treatments.     

DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma

PURPOSE: We evaluated the response to Temodal (Schering-Plough Research Institute, Kenilworth, NJ) of patients with newly diagnosed malignant glioma, as well as the predictive value of quantifying tumor DNA mismatch repair activity and O6-alkylguanine-DNA alkyltransferase (AGT). PATIENTS AND METHODS: Thirty-three patients with newly diagnosed glioblastoma multiforme (GBM) and five patients with newly diagnosed anaplastic astrocytoma (AA) were treated with Temodal at a starting dose of 200 mg/m2 daily for 5 consecutive days with repeat dosing every 28 days after the first daily dose. Immunochemistry for the detection of the human DNA mismatch repair proteins MSH2 and MLH1 and the DNA repair protein AGT was performed with monoclonal antibodies and characterized with respect to percent positive staining. RESULTS: Of the 33 patients with GBM, complete responses (CRs) occurred in three patients, partial responses (PRs) occurred in 14 patients, stable disease (SD) was seen in four patients, and 12 patients developed progressive disease (PD). Toxicity included infrequent grades 3 and 4 myelosuppression, constipation, nausea, and headache. Thirty tumors showed greater than 60% cells that stained for MSH2 and MLH1, with three CRs, 12 PRs, three SDs, and 12 PDs. Eight tumors showed 60% or less cells that stained with antibodies to MSH2 and/or MLH1, with 3 PRs, 3 SDs, and 2 PDs. Eleven tumors showed 20% or greater cells that stained with an antibody to AGT, with 1 PR, 2 SDs, and 8 PDs. Twenty-five tumors showed less than 20% cells that stained for AGT, with 3 CRs, 12 PRs, 4 SDs, and 6 PDs. CONCLUSION: These results suggest that Temodal has activity against newly diagnosed GBM and AA and warrants continued evaluation of this agent. Furthermore, pretherapy analysis of tumor DNA mismatch repair and, particularly, AGT protein expression may identify patients in whom tumors are resistant to Temodal.     

Synthetic, implantable polymers for local delivery of IUdR to experimental human malignant glioma

PURPOSE: Recently, polymeric controlled delivery of chemotherapy has been shown to improve survival of patients with malignant glioma. We evaluated whether we could similarly deliver halogenated pyrimidines to experimental intracranial human malignant glioma. To address this issue we studied the in vitro release from polymers and the in vivo drug delivery of IUdR to experimental human U251 glioblastoma xenografts. METHODS AND MATERIALS: In vitro: To measure release, increasing (10%, 30%, 50%) proportions of IUdR in synthetic [(poly(bis(p-carboxyphenoxy)-propane) (PCPP):sebacic acid (SA) polymer discs were serially incubated in buffered saline and the supernatant fractions were assayed. In vivo: To compare local versus systemic delivery, mice bearing flank xenografts had intratumoral or contralateral flank IUdR polymer (50% loading) treatments. Mice bearing intracranial (i.c.) xenografts had i.c. versus flank IUdR polymer treatments. Four or 8 days after implantation of polymers, mice were sacrificed and the percentage tumor cells that were labeled with IUdR was measured using quantitative microscopic immunohistochemistry. RESULTS: In vitro: Increasing percentage loadings of IUdR resulted in higher percentages of release: 43.7 + 0.1, 70.0 + 0.2, and 90.2 + 0.2 (p < 0.001 ANOVA) for the 10%, 30%, and 50% loadings, respectively. In vivo: For the flank tumors, both the ipsilateral and contralateral IUdR polymers resulted in similarly high percentages labeling of the tumors versus time. For the ipsilateral IUdR polymers, the percentage of tumor cellular labeling after 4 days versus 8 days was 45.8 +/- 7.0 versus 40.6 +/- 3.9 (p = NS). For the contralateral polymer implants, the percentage of tumor cellular labeling were 43.9 +/- 10.1 versus 35.9 +/- 5.2 (p = NS) measured 4 days versus 8 days after implantation. For the i.c. tumors treated with extracranial IUdR polymers, the percentage of tumor cellular labeling was low: 13.9 +/- 8.8 and 11.2 +/- 5.7 measured 4 and 8 days after implantation. For the i.c. tumors having the i.c. IUdR polymers, however, the percentage labeling was comparatively much higher: 34.3 +/- 4.9 and 35.3 +/- 4.0 on days 4 and 8, respectively. For the i.c. tumors, examination of the percentage cellular labeling versus distance from the implanted IUdR polymer showed that labeling was highest closest to the polymer disc. CONCLUSION: Synthetic, implantable biodegradable polymers provide the local, controlled release of IUdR and result in the high, local delivery of IUdR to experimental intracranial human malignant glioma. This technique holds promise for the local delivery of IUdR for radiosensitization of human brain tumors.     

Transradial approach for coronary procedures: initial experience and results

To characterize the myogenic response during the development of hypertension, we evaluated the myogenic response of small arteries isolated from the cremaster muscle of spontaneously hypertensive rats (SHR) aged 4-5 and 7-8 weeks, as compared with age-matched Wistar-Kyoto rats (WKY), using an in vitro system. The myogenic response of SHR aged 7-8 weeks (but not those aged 4-5 weeks) significantly exceeded that of WKY. Measurement of intracellular levels of free calcium ([Ca2+]i) in small arteries of the 7-8-week-old SHR and WKY loaded with a calcium-sensitive dye showed that the increase in [Ca2+]i in SHR was significantly greater than that in WKY during the myogenic response. The inhibitory effects of nitrendipine on the increased myogenic response and [Ca2+]i were greater in SHR. Thus, the myogenic response was enhanced in SHR and may be explained in part by an increase in Ca2+ entry through the voltage-dependent calcium channel (VDCC). The myogenic response and Ca2+ entry through the VDCC may be increased in association with the elevation of blood pressure.     

The results of radiotherapy for ependymomas: the Mayo Clinic experience

It is known that exogenous 11-cis-retinol inhibits the recovery of photosensitivity of bleached rod outer segments (ROS) and 11-cis-retinol exists in the interphotorecepter matrix. We examined the conversion of 11-cis-retinol with bovine ROS. ROS was incubated with 11-cis-retinol under dim red light. Retinoids were extracted from the reaction mixture with hexane and analyzed by HPLC coupled with a fluorescence spectrophotometer. Isomerization of 11-cis-retinol to all-trans-retinol was observed in the presence of ROS. This isomerization was not suppressed by heat treatment and did not have stereospecificity. In addition, we incubated purified rhodopsin and phospholipids extracted from ROS with 11-cis-retinol. Rhodopsin was found to isomerize 11-cis-retinol to all-trans-retinol as well as ROS, but phospholipids did not. In contrast, the phospholipids inhibited the isomerization of 11-cis-retinol to all-trans-retinol by the purified rhodopsin. Commercially available phospholipids, especially phosphatidylserine, also inhibited the isomerization. Our results suggest that rhodopsin has activity for the isomerization of 11-cis-retinol to all-trans-retinol and may play an important role in the detoxification of 11-cis-retinol in the ROS.     

MR tomography of acute pancreatitis: initial results

Magnetic resonance imaging (MRI) was evaluated for its potential in assessment of acute pancreatitis compared to computed tomography (CT). 15 patients with acute pancreatitis were examined using a routine protocol including T1- and T2-weighted sequences and a fat-suppressed T1-weighted spin-echo sequence. Gadopentant-Dimeglumin (Gd-DTPA) was given. For comparison, plain and contrast-enhanced CT was performed prior to MRI. MRI proved to be superior to CT in detection of bleeding, duodenitis and ascites. MRI failed to detect concrements. These first results show that, considering the latest development in technology, MRI is not inferior to CT in diagnostic imaging of acute pancreatitis.     

Pharmacokinetic/dynamic assessment in drug development: application to the investigational opioid mirfentanil

The safety, pharmacokinetics, and pharmacodynamics of the investigational partial opioid agonist, mirfentanil, were determined in a dose-escalating, Phase 1 study in healthy male volunteers. Hemodynamic, central nervous system, and respiratory monitoring were used for safety assessment. The electroencephalogram (EEG) was evaluated as a surrogate measure of drug effect. Butorphanol was chosen as the control drug. In the mirfentanil group (n = 8) the dose was increased in sequential subjects from 25 micrograms.kg-1.min-1 for 30 min to 450 micrograms.kg-1.min-1 for 15 min, and in the butorphanol group (n = 10) from 2 micrograms.kg-1.min-1 for 30 min to 25 micrograms.kg-1.min-1 for 15 min. In the mirfentanil group, serious side effects were observed at plasma concentrations more than 2000 ng/mL: heart rates exceeded 130 bpm (n = 2), epileptiform EEG potentials (n = 2), and a convulsion (n = 1). The clearance of mirfentanil was high (5.8-7.2 L/min), and the volume of distribution large (247-348 L). The EEG of the subjects receiving mirfentanil showed no changes typical for opioids. Butorphanol however, caused intermittent slowing in the delta and theta ranges. The results of our study define the upper limit of safe plasma concentrations in future mirfentanil studies.