Open-label study to assess the safety and pharmacodynamics of five oral insulin formulations in healthy subjects.

AIM: Orally delivered insulin is predicted to bear therapeutic advantages in diabetes management when compared to injectable insulin, because of its ability to mimic the natural route of endogenous insulin secreted by the pancreas into the portal vein and directly to the liver. Oramed Pharmaceuticals is developing an oral insulin product which consists of unmodified recombinant human insulin combined with adjuvants that protect it from enzymatic degradation in the gastrointestinal tract and promote its absorption from the gut. The aim was to determine the optimal adjuvants to insulin ratio which can provide for the best pharmacodynamic profile, while maintaining the safety of the product. METHODS: Eight healthy, male volunteers participated in this open-label study which included five independent visits. During each visit, subjects were administered one of the five encapsulated oral insulin formulations which contained equal amounts of insulin but varying proportions of adjuvants. Parameters measured included safety, C(max) and T(max) for insulin and C(min), T(min) and area under the curve (AUC) for glucose and c-peptide. Comparisons were made between formulations and between post-treatment time periods within each visit. RESULTS: All five oral insulin formulations were well tolerated and no serious adverse events were reported. All formulations resulted in a significant response in the response period (60-300 min) in comparison to baseline (0-60 min); this was captured both in the c-peptide response and the glucose response (all five formulations p < 0.05). However, none of the formulations turned out significantly different in response over the other. Formulation 5 showed the most profound reduction in c-peptide when AUC(0-60) (baseline) was compared to AUC(60-300) (p < 0.007). CONCLUSIONS: All five oral insulin formulations resulted in glucose and c-peptide reductions, where formulation 5 demonstrated the most pronounced effect on c-peptide concentration reduction. This formulation was deemed the lead formulation to be advanced to future clinical studies. This study also reinforces the notion that oral insulin can maintain its biological activity after delivery, suggesting a potential role for this product in management of diabetes.

Pharmacokinetics and pharmacodynamic effects of oral GLP-1 and PYY3-36: a proof-of-concept study in healthy subjects.

This proof-of-concept study was performed in order to establish the pharmacokinetics and pharmacodynamics of increasing oral doses of the satiety peptides glucagon-like peptide-1 (GLP-1) and peptide YY3-36 (PYY3-36). Six healthy male subjects were given oral doses of either a placebo or GLP-1 in a dose-escalating schedule (doses of 0.5, 1.0, 2.0, and 4.0 mg). Next, another group of six healthy male subjects were given oral doses of either a placebo or PYY3-36 in the same pattern of escalating doses (doses of 0.25, 0.5, 1.0, 2.0, and 4.0 mg). In healthy male volunteers, (i) oral administration of either of the peptides induced a rapid and dose-dependent increase in plasma drug concentrations; (ii) oral administration of GLP-1 induced a potent effect on insulin release; and (iii) both peptides suppressed ghrelin secretion. In conclusion, this study showed, for the first time, that satiety peptides such as GLP-1 and PYY3-36 can be orally delivered safely and effectively in humans.

Postoperative radiation for lung cancer metastatic to the brain.

PURPOSE: Although resection of single brain metastases and postoperative whole-brain radiation therapy (WBRT) improves survival, compared with treatment using WBRT alone, the value of postoperative WBRT after resection of brain metastases is controversial. We analyzed the largest reported series of lung cancer patients with resected brain metastases to evaluate the impact of postoperative WBRT. MATERIALS AND METHODS: Between 1974 and 1989, 185 patients with non-small-cell lung cancer (NSCLC) underwent resection of brain metastases. Patients who had received preoperative WBRT (23%, 42 of 185) were excluded. The remaining patients were divided into group A (no WBRT; n = 32), group B (patients received WBRT and were prognostically matched to group A; n = 32), and group C (all other WBRT patients; n = 79). Most patients received postoperative doses of 30 Gy in 10 fractions. Higher doses were used in 16% of group B and 18% of group C patients. RESULTS: Overall 5-year survival rates were as follows: group A, 12%; B, 8%; C, 16%. Overall brain failures occurred in 38% of patients in group A, 47% in group B, and 42% in group C. The use of WBRT (group A v groups B plus C) had no apparent impact on survival or on overall brain failure rates. In particular, no improvement in either of these parameters could be demonstrated when group B was compared with group A. Focal failure (defined as failure within the brain adjacent to the site of the resected brain metastases) occurred as follows: group A, 34% (11 of 32); groups B plus C, 23% (25 of 111) (P = .07). WBRT significantly reduced focal failure for patients with adenocarcinoma (group A, 33% [eight of 24]; groups B plus C, 14% [11 of 79]; P = .05). Nonfocal failure (anatomically distinct from the resected metastasis) occurred in 9% of patients in group A (three of 32), 21% in groups B plus C (23 of 111) (P = .07). CONCLUSION: Long-term survival is possible when NSCLC brain metastases are resected. Postoperative WBRT as used in this series only had an impact on the focal control of brain metastases and this effect was of borderline significance. The lack of conclusive benefit supports the need for ongoing randomized trials to test the value of adjuvant postoperative WBRT. Brain failures were relatively common in all three groups of patients, which suggests that doses greater than 30 Gy need to be studied.

Inability of computed tomography appearance of recurrent malignant astrocytoma to predict survival following reoperation.

Computed tomographic (CT) scans of 39 patients who underwent reoperation for recurrent malignant astrocytoma at Memorial Sloan-Kettering Cancer Center from 1980 through 1987 were reviewed and correlated with the patients' clinical course. Histologic diagnosis (anaplastic astrocytoma v glioblastoma multiforme) had a statistically significant impact on survival following reoperation (P = .038). Patients with high preoperative performance status (P = .29), total resection by postoperative CT scan (P = .15), and frontal lobe tumors (P = .17) tended to survive longer following reoperation. The size of the tumor at the time of recurrence did not correlate with survival following reoperation. Patients with a small amount of peritumoral edema at the time of recurrence tended to survive longer, but the effect was small (P = .16). Prognosis following reoperation cannot be accurately predicted on the basis of tumor appearance on CT scan.

Global cerebral vasodilatation elicited by focal electrical stimulation within the dorsal medullary reticular formation in anesthetized rat.

We examined the effects of electrical stimulation of a restricted area of the dorsal medullary reticular formation (DMRF) on regional cerebral blood flow (CBF) in anesthetized (by chloralose), paralyzed (by curare) rats. CBF was measured in tissue samples by the Kety principle, with 14C-iodoantipyrine as indicator. Stimulation of DMRF elicited a widespread, significant increase in CBF in 12 of 13 areas. The increase in flow was greatest in cerebral cortex, up to 240% of control. However, it was also substantially increased in selected regions of telencephalon, diencephalon, mesencephalon, and lower brainstem, but not cerebellum. In contrast, electrical stimulation of the midline (interstitial nucleus of the medial longitudinal fasciculus) 1 mm medial to the DMRF did not change CBF. The increase in CBF evoked by DMRF stimulation persisted after transection of the spinal cord at C1 or cervical sympathetic trunk. We conclude that excitation of neurons originating in or passing through the DMRF can elicit a potent and virtually global increase of CBF. The effect appears to be mediated by intrinsic pathways of the central nervous system.

Treatment of refractory recurrent malignant glioma with adoptive cellular immunotherapy: a case report.

We report the successful treatment of a patient with recurrent malignant glioma with adoptive cellular immunotherapy. The patient is a young adult with recurrent progressive disease refractory to aggressive multi-modality therapy including repetitive surgical resection, radiation, radiosurgery and chemotherapy. He received multiple courses of local administration of autologous lymphokine-activated killer (LAK) cells in combination with a low dose of interleukin-2 (IL-2) through an Ommaya reservoir-catheter system. The side-effects of this treatment were limited and manageable. The patient achieved a complete remission, as demonstrated by MRI and confirmed by glucose-positron emission tomography (PET) imaging 11 months after initiation of immune therapy. Twenty-six months later, the patient is still in remission with improving performance status. Adoptive cellular immunotherapy utilizing autologous LAK cells with low dose IL-2 appears to be a safe and effective therapy for a subset of patients with primary, recurrent or progressive malignant glioma following conventional therapy.

Adoptive cellular immunotherapy for the treatment of malignant gliomas.

UNLABELLED: The median survival for adults with recurrent primary malignant gliomas is 56 weeks following surgery, radiation, and chemotherapy. Generally, reoperation can extend the median survival an additional 26-32 weeks. We have developed an aggressive treatment program that utilizes low doses of interleukin-2 (IL-2) combined with ex vivo activated killer cells (LAK) infused via an indwelling catheter placed into the surgical resection cavity. Autologous leukocytes were collected during a standard 3-4 h, outpatient leukapheresis procedure, then activated ex vivo for 4-5 days with high doses of IL-2. The treatment protocol consisted of two 2-week cycles of therapy over a 6-week period. Patients with stable disease or objective response on follow-up MRI scans were retreated at 3-month intervals. Acute and cumulative IL-2-related toxicities were observed, but limited, and included fever, headache and transient neurologic irritation. Corticosteroid levels and usage were strictly controlled during immunotherapy, although higher doses were used intermittently to mitigate toxicity. Biologic changes included lymphocytic infiltration, regional eosinophilia, tumor necrosis, and the localized production of IL-2, IFN-gamma and IL-12, demonstrated by in situ hybridization and immunohistochemistry. SUMMARY: IL-2 plus autogeneic LAK cells can be safely administered intracavitary to treat high grade primary brain tumors with limited toxicity within the central nervous system. Six out of 28 patients had long-term survival of greater than 2 years post-reoperation plus immunotherapy with 2 patients alive over 8 years. The presence of a marked regional eosinophilia appeared to correlate with increased survival and may be predictive of a biologic and therapeutic response. Regional adoptive immune therapy was well tolerated and should be considered an option for patients with high-grade tumors refractive to standard therapeutic approaches.

Reversible diencephalic dysfunction: episodic hyperhidrosis due to a trapped third ventricle.

We present a patient with episodic hyperhidrosis (EH) who had 15 attacks per day for 3 years following placement of a lateral ventricular shunt. MRI revealed that she had an isolated third ventricle. Stereotactic shunting of the third ventricle resulted in immediate and complete resolution of her symptoms. We suggest that this patient had periodic rises in third ventricular pressure resulting in episodic diencephalic dysfunction and EH.

Aphemia resulting from a left frontal hematoma.

A 15-year-old right-handed woman had selective impairment of speech--aphemia--after drainage of a left frontal hematoma caused by an arteriovenous malformation. There was no buccofacial or pharyngeal muscle dysfunction. Computerized tomography demonstrated residual injury extending from the Broca area to the inferior left precentral gyrus. Aphemia may have resulted from disruption of the connection between Broca's area and the portion of the motor cortex that controls oral and pharyngeal muscles.

Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma.

Recurrence patterns of glioblastoma multiforme (25) and anaplastic astrocytoma (9) were studied using CT scans of 34 patients who received all or a portion of their surgical treatment at Memorial Sloan-Kettering Cancer Center from January 1983 through February 1987. Thirty-two patients presented with unifocal tumors and two with multifocal tumors. All patients received radiation therapy following initial surgery. Eighteen patients who underwent re-operation following CT evidence of recurrence had histologic verification of recurrent tumor; sixteen patients had radiographic evidence of recurrence only. Seventy-eight percent (25/32) of unifocal tumors recurred within 2.0 cm of the pre-surgical, initial tumor margin, defined as the enhancing edge of the tumor on CT scan. Fifty-six percent (18/32) of tumors recurred within 1.0 cm of the initial tumor margin. Tumors for which a gross total resection was accomplished tended to recur closer to the initial tumor margin than did subtotally resected tumors (p greater than 0.1). Extensive pre-operative edema was associated with a decreased distance between initial and recurrent tumor margins. Large tumors were generally not more likely to recur further from the initial tumor margin than were smaller tumors. No unifocal tumor recurred as a multifocal tumor. Only one tumor (initially near the midline) recurred in the contralateral hemisphere. The findings support the use of partial brain irradiation for post-operative treatment of glioblastoma multiforme and anaplastic astrocytomas, and may help to determine the most appropriate treatment volume for interstitial irradiation.

The relationship between the technical accuracy of stereotactic interstitial implantation for high grade gliomas and the pattern of tumor recurrence.

PURPOSE: To correlate the pattern of failure and subsequent survival with the technical accuracy of stereotactic brain tumor implantation. METHODS AND MATERIALS: The patterns of failure of 47 consecutive patients with primary or recurrent gliomas after stereotactic implantation delivering 60 Gy via removable high activity 125I sources were reviewed. When the tumor was covered at all levels by the chosen isodose distribution, the implant was considered to be "ideal." If the coverage was not complete, a numerical description of the volume of tumor outside the isodose was assigned. Criteria for "adequate" and "inadequate" implants were defined. Standard radiographic criteria, with pathologic confirmation in 26 cases, were used to categorize the patterns of failure into the following components: central, peripheral, distant (within the brain parenchyma), leptomeningeal, and spinal. A peripheral failure was scored as being in the "direction of error" when the prescribed isodose did not cover the tumor volume and the subsequent tumor progression was in this region. Survival was calculated from the date of implantation. RESULTS: Of 47 cases examined, 72% had an element of central and/or peripheral failure and 23% had a component of distant or meningeal failure. Among the patients with "adequate" or "inadequate" ("nonideal") implants who had a component of peripheral failure, only 19% were in the "direction of error." All patients with technically "inadequate" implants progressed in both the central and peripheral region. Among the groups who had "ideal," "adequate," and "inadequate" implants; 37%, 70%, and 75%, respectively, underwent reoperation [p = not significant (NS)]. Patients who underwent reoperation had a longer median survival than those who did not; 521 days vs. 298 days, respectively (p = 0.035). For patients with "nonideal" implants, a median survival of 470 days was found for patients undergoing reoperation vs. 184 days for those who did not (p = 0.016). CONCLUSIONS: (a) Patients with "inadequate" implants failed in both the central and peripheral region in all cases. This pattern, while less common in those with "ideal" or "adequate" implants, occurred in the majority of cases. (b) The technical excellence of the implant had no impact on survival. (c) Patients with "nonideal" implants were more likely to have reoperation than those with "ideal" implants, and this intervention was associated with a significant survival advantage.

Fractionated stereotactic radiosurgery and concurrent taxol in recurrent glioblastoma multiforme: a preliminary report.

PURPOSE: Surgery and systemic chemotherapy offer modest benefit to patients with recurrent glioblastoma multiforme. These tumors are associated with rapid growth and progressive neurological deterioration. Radiosurgery offers a rational alternative treatment, delivering intensive local therapy. A pilot protocol to treat recurrent glioblastoma was developed using fractionated stereotactic radiosurgery with concurrent intravenous (i.v.) Taxol as a radiation sensitizer. METHODS AND MATERIALS: The treatment outcome was analyzed in 14 patients with recurrent glioblastoma treated with fractionated stereotactic radiosurgery and concurrent Taxol. Median tumor volume was 15.7 cc and patients received a mean radiation dose of 6.2 Gy at 90% isodose line, 4 times weekly. The median dose of Taxol was 120 mg/m2. RESULTS: The median survival was 14.2 months, 1-year survival was 50%. CONCLUSIONS: Survival for this small group of patients was similar to or better than historical controls or patients treated with single-fraction radiosurgery alone. This data should stimulate the investigation of both fractionated radiosurgery and the development of radiation sensitizers to further enhance treatment.

Paraspinal tumors: techniques and results of brachytherapy.

Because of their proximity to nerve roots and the spinal cord, it is frequently difficult to achieve complete resection of paraspinal tumors. We have used brachytherapy in an attempt to prevent local recurrence and its associated neurological sequelae. This report analyzes our experience with 35 patients to determine the feasibility, optimal techniques, and efficacy of this approach. The tumor types were non small-cell lung cancer (18), sarcomas (9), and other tumor types (8). Temporary, single plane implants using Ir-192 (median minimum peripheral dose 3000 cGy) were used in 21 patients, and permanent I-125 implants were used in 14 cases (median matched peripheral dose 12,500 cGy). Local control was achieved in 51% (18/35). However, local control was poor when lung cancers were implanted and in cases where the dura was exposed. Radiation myelitis did not occur despite the combined effects of previous external beam radiotherapy (N = 21) and brachytherapy. Our experience demonstrates that combined surgery and paraspinal brachytherapy can be performed with acceptable toxicity and is reasonably effective in preventing local relapse and its neurologic sequelae, particularly for tumors other than lung cancers.

Resection of brain metastases from non-small-cell lung carcinoma. Results of therapy. Memorial Sloan-Kettering Cancer Center Thoracic Surgical Staff.

The treatment of patients with a solitary brain metastasis has been evolving, with most centers recommending resection in patients with good performance status. To evaluate the results of resection of brain metastases from non-small-cell lung cancer, we reviewed our 16-year experience with 185 consecutive patients undergoing resection of brain metastases from 1974 to 1989, inclusive. There were 89 men and 96 women; ages ranged from 34 to 75 years (median 54). Sixty-five (35%) had synchronous and 120 (65%) metachronous brain metastases. Discounting the brain metastasis, 68 patients (37%) had stage I, 13 (7%) stage II, 62 (33%) stage IIIA, 30 (16%) stage IIIB, and 12 (6%) stage IV carcinoma. There was no significant difference in age, locoregional stage (TN), or histologic features in patients with synchronous versus metachronous lesions. The overall survival rates (n = 185) were as follows: 1 year, 55%; 2 years, 27%; 3 years, 18%; 5 years, 13%; and 10 years, 7% (median 14 months). There was no significant difference in survival between patients with synchronous and metachronous lesions. To evaluate the impact of locoregional stage and treatment of the primary site, we analyzed only those patients with synchronous brain metastases. Multivariate analysis demonstrated that locoregional stage had no significant effect on survival (p = 0.97), but complete resection of the primary disease significantly prolonged survival (p = 0.002). Therefore complete resection, and not stage, of the locoregional primary lesion is the primary determinant of survival in patients undergoing resection of brain metastases from non-small-cell lung cancer.

Measurement of brain tissue specific gravity using pycnometry.

In this paper we introduce and characterize pycnometry, a method used to measure fluid density, for determining a tissue's specific gravity. It uses a 2-ml glass pycnometer filled with distilled water to determine a tissue sample's displacement volume. The tissue's density is determined when it's weight is divided by this volume and specific gravity is computed by dividing the tissue density by the density of water. Pycnometry was validated using pre-calibrated glass, specific gravity standards over the range 1.03-1.26, and compared to the density gradient method using rat brain tissue. We observed that the specific gravity values obtained using pycnometry were highly correlated with the specific gravity standards (slope = 1.0107, r = 0.996) and with the density gradient column when tissue volumes larger than 0.120 ml were used with the pycnometer (slope = 1.0707, r = 0.9826). Good correlation was also observed between percent water content values computed using the Nelson equation with pycnometry or density gradient specific gravity values versus the measured percent water content values obtained with the wet weight/dry weight method. Pycnometry is an accurate, reproducible technique to measure tissue specific gravity and brain edema and is best suited for use in a laboratory that engages sporadically in brain edema measurement.

Modified open thoracic rhizotomy for treatment of intractable chest wall pain of malignant etiology.

We describe the surgical technique of modified open thoracic rhizotomy for treatment of intractable chest wall pain of malignant etiology. In a series of 14 patients, 9 (64%) had an excellent result, 4 (29%) had a good result, and 1 (7%) had a poor result. Successful palliation was made possible by identification with computed tomographic scan or magnetic resonance imaging of the nerve roots involved. Pain control lasted in most patients until death (median, 22 weeks; range, 6 to 45 weeks). The extrathecal procedure described has certain advantages over intradural transection of nerve roots. Indications for performing this procedure are discussed along with other therapeutic options.

Surgical resection of brain metastases from renal cell carcinoma in 50 patients.

OBJECTIVES: Metastases are frequently diagnosed among patients with renal cell carcinoma (RCC). Of 709 patients with brain metastases (BMET) who were operated on at our institution between 1974 and 1993, 50 (7%) were of renal origin. METHODS: Medical records were reviewed retrospectively. Survival time was calculated by the Kaplan-Meier method and Cox proportional hazards model. RESULTS: There were 38 men and 12 women. The median age was 60 years. The primary RCC was resected in 47 patients. Forty patients had a metachronous diagnosis of RCC and BMET. Median interval between the diagnosis of RCC and BMET was 17 months. In all 50 patients overall median survival (MS) from diagnosis of primary RCC was 31.4 months and from craniotomy was 12.6 months. Postoperative mortality was 10% (5 patients). In patients with primary RCC in the left kidney (n=25) versus right kidney (n=25) median survival from craniotomy was longer; 21.3 versus 7.4 months (P<0.014). Twenty-three patients (46%) had intratumoral hemorrhage. Eight patients had cerebellar metastasis (MS, 3.0 months) and 9 had multiple metastases resected (MS, 7.6 months). Thirty-eight patients had both brain and pulmonary metastases, and 16 of them had pulmonary resection (MS, 18.6 versus 8.0 months; P<0.03). Twenty-two patients received whole-brain radiation therapy (WBRT) after craniotomy and 18 did not receive WBRT (MS, 13.3 versus 14.5 months; P<0.62). The 1-year, 2-year, 3-year, and 5-year survival was 51%, 24%, 22%, and 8.5% respectively. CONCLUSIONS: Only the resection of lung metastasis, supratentorial location of BMET, left-sided localization of primary RCC, and lack of neurologic deficit before craniotomy were statistically significant prognostic factors in Cox regression analysis. In the absence of effective systemic treatment, we suggest that patients with BMET from RCC be considered for operative resection for treatment and palliation.

Utilization of the HTSCA and CFU-C assay to identify two new 2-chloroethylnitrosourea congeners of amino acid amides with increased in vitro activity against human glioma compared with BCNU.

AspCNU and SarCNU are two amino acid amide congeners (L-asparaginamide and sarcosinamide congeners) of chloroethylnitrosoureas. The in vitro myelotoxicity of these agents compared with BCNU at 1-8 micrograms/ml was determined in bone marrow cells from normal volunteers in the CFU-C assay. AspCNU and SarCNU were significantly (P less than 0.05) less myelotoxic than BCNU at equivalent microgram concentrations. SarCNU or AspCNU at 3 micrograms/ml demonstrate equivalent in vitro myelotoxicity to BCNU 1 microgram/ml. We used the human tumor stem cell assay (HTSCA) to investigate in vitro antitumor activity. We obtained four specimens of malignant glioma and one specimen of meningioma from patients not previously treated with chemotherapy. AspCNU and SarCNU were significantly (P less than 0.05) more active than BCNU at 1-3 micrograms/ml concentrations in the HTSCA in all four malignant glioma specimens. In the one meningioma specimen, BCNU was significantly (P less than 0.05) more active than either AspCNU or SarCNU at all concentrations studied. These results suggest that AspCNU or SarCNU at doses that should produce less myelotoxicity than BCNU may be more active than BCNU against gliomas.

Invasive techniques in the management of cancer pain.

Familiarity with potentially useful anesthetic and neurosurgical techniques is important in the management of patients who are unable to achieve a satisfactory balance between analgesia and side effects from systemic analgesic therapies. The ability to make specific recommendations is limited by the paucity of controlled data, incorporating details of pain syndromes, prior therapies, validated pain assessment, meticulous reporting of adverse effects, and longitudinal follow-up.

A versatile method for planning stereotactic brain implants.

Our approach to planning stereotactic 125I brachytherapy of brain tumors has involved least-squares optimization of individual seed positions within the target contour, followed by repeated combining of seeds from nearest-neighbor catheters in order to achieve an acceptably low number of catheters and an acceptable-separation of entry points. In one option, the catheters diverge from an extra-cranial point that can be close to the skull if all catheters are to be placed through a small craniectomy to treat a larger-diameter target. In another option, catheters converge toward a point beyond the target, to facilitate perpendicularity at the skull surface if a separate opening is to be drilled for each catheter. In either case, the fact that seed orientations are known, permits including anisotropy in dose calculations. Trial seed locations are constrained to a target region defined on a 1-mm mesh, both in the initial optimization of single-seed catheters and in subsequent combinations followed by tune-up optimizations. In the optimization process, sum-of-squares contributions are weighted more heavily when the dose rate is lower than the target dose rate; the weighting imbalance falls short of keeping all target points above the target dose rate and requires targeting on a dose rate about 25% higher than the desired minimum dose rate.