ABSTRACT
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.
Subject(s)
C-Peptide/drug effects , Hypoglycemic Agents/pharmacokinetics , Insulin/pharmacokinetics , Administration, Oral , Adult , Area Under Curve , Biological Availability , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/adverse effects , Insulin/administration & dosage , Insulin/adverse effects , Male , Treatment OutcomeABSTRACT
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.
Subject(s)
Glucagon-Like Peptide 1/pharmacokinetics , Peptide YY/pharmacokinetics , Administration, Oral , Adult , Area Under Curve , Dose-Response Relationship, Drug , Feasibility Studies , Ghrelin/blood , Ghrelin/metabolism , Glucagon-Like Peptide 1/administration & dosage , Glucagon-Like Peptide 1/adverse effects , Humans , Insulin/blood , Insulin/metabolism , Insulin Secretion , Male , Peptide Fragments , Peptide YY/administration & dosage , Peptide YY/adverse effectsABSTRACT
AIMS: The aim of our study was to examine the absorption of insulin from the gastrointestinal (GI) tract, using a novel oral formulation-adding a delivery agent SNAC (sodium N-[8-(2-hydroxybenzoyl)amino] caprylate) in combination with insulin. METHODS: Capsules containing insulin and SNAC, in various combinations, were administered orally, as a single dose, to 12 non-diabetic subjects and four control subjects (receiving SNAC or insulin only) in order to assess its biological effect and safety. Plasma glucose levels, insulin and C-peptide concentrations, as well as SNAC levels, were determined, at timed intervals up to 4 h. RESULTS: In all cases, a glucose-lowering effect was demonstrated, preceded by an increase in plasma insulin levels. The nadir of plasma glucose levels appeared after 30-50 min, following the ingestion of the mixture. The plasma insulin levels were found to parallel the blood SNAC levels. Plasma C-peptide levels were suppressed by the lowered glucose levels achieved concurrent with the increasing amount of exogenous insulin absorbed, indicating that the secretion of endogenous hormone was partially abolished. There were no biological effects regarding blood glucose levels upon administration of SNAC or insulin when given alone. No adverse effects were detected during the trial or several weeks after the trial. CONCLUSIONS: Insulin in combination with a novel delivery agent, SNAC, given orally, is absorbed through the GI tract in a biologically active form. This was demonstrated by a glucose lowering effect of the mixture as well as a suppression of an endogenous insulin secretion.
Subject(s)
Insulin/administration & dosage , Absorption , Administration, Oral , Adult , Blood Glucose/analysis , C-Peptide/blood , Caprylates/administration & dosage , Caprylates/blood , Gastrointestinal Tract/metabolism , Humans , Insulin/blood , Insulin/pharmacokinetics , MaleABSTRACT
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.
Subject(s)
Glioma/therapy , Immunotherapy, Adoptive/methods , Adult , Humans , Interleukin-2/administration & dosage , Interleukin-2/toxicity , Killer Cells, Lymphokine-Activated/transplantation , Male , Recurrence , Salvage TherapyABSTRACT
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.
Subject(s)
Glioma/therapy , Immunotherapy, Adoptive/methods , Eosinophils/cytology , Humans , Interleukin-2/administration & dosage , Interleukin-2/toxicity , Killer Cells, Lymphokine-Activated/transplantation , Time Factors , Transplantation, Autologous/methods , Treatment OutcomeABSTRACT
A brief history, classification, clinical presentation, and pertinent anatomy of spinal stenosis is presented. A thorough understanding of the etiology, pathologic features, and the correlation between symptoms and precisely where the thecal sac and nerve root impingement occurs is essential to interpret imaging studies and plan appropriate treatment.
Subject(s)
Lumbar Vertebrae , Spinal Stenosis , Humans , Lumbar Vertebrae/pathology , Spinal Stenosis/classification , Spinal Stenosis/diagnosis , Spinal Stenosis/etiology , Spinal Stenosis/pathologyABSTRACT
A mechanical drainage system, the "artificial lymphatic system" (ALS), consisting of a vacuum source and drain, is evaluated for its ability to aspirate the interstitial fluids responsible for the elevated interstitial fluid pressure (IFP) observed in solid tumors. IFP, pH, and pO2 radial profiles were measured before and after aspiration using wick-in-needle (WIN) probes, needle pH and oxygen electrodes, respectively. Laser Doppler flowmetry measured temporal changes in blood flow rate (BFR) at the tumor surface during aspiration. The WIN probe and IFP profile data were analyzed using numerical simulation and distributed mathematical models, respectively. The model parameter, P(E), reflecting central tumor IFP, was reduced from 15.3 to 5.7 mm Hg in neuroblastoma and from 13.3 to 12.1 mm Hg in Walker 256, respectively, following aspiration. The simulation demonstrated that spatial averaging inherent in WIN measurements reduced the calculated magnitude of the model parameter changes. IFP was significantly lower (p<0.05), especially in regions surrounding the drain, and BFR was significantly higher (p<0.05) following 25 and 45 min of aspiration, respectively; pH and pO2 profiles increased following aspiration. The experimental and mathematical findings suggest that ALS aspiration may be a viable way of reducing IFP and increasing BFR, pO2, and pH and should enhance solid tumor chemo and radiation therapy.
Subject(s)
Artificial Organs , Lymphatic System , Neoplasms, Experimental/therapy , Animals , Biomedical Engineering/instrumentation , Blood Flow Velocity , Extracellular Space/physiology , Hydrogen-Ion Concentration , Lymph/physiology , Male , Neoplasms, Experimental/blood supply , Neoplasms, Experimental/physiopathology , Oxygen/metabolism , Pressure , Rats , Rats, Nude , Rats, Sprague-DawleyABSTRACT
This paper presents findings from uptake studies to evaluate the ability of an "artificial lymphatic system" (ALS) to enhance large and small molecular weight drug transport into solid tumors and the therapeutic effect of the additional drug on their growth. These studies also served to test the effectiveness of an implantable multidrain ALS. Walker 256, Neuroblastoma, and Sarcoma dual-tumor models were used to evaluate the effect of ALS aspiration on the uptake of 3F8 monoclonal antibody, and doxorubicin. A tumor shrinkage experiment using Walker 256 dual tumors was used to evaluate the efficacy of an implantable ALS with cyclophosphamide chemotherapy. Drug uptake significantly increased in all aspirated tumors; 3F8 uptake was enhanced 37.4% in the Walker and 93.1% in the Neuroblastoma tumor lines (p<0.05). Doxorubicin uptake increased 23.2% in Sarcoma tumor (p<0.05). The shrinkage study demonstrated that one-drain aspirated tumors shrank 90% faster (p<0.01) than control tumors, while three-drain aspirated tumors shrank 123% faster than control tumors (p<0.01).
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Artificial Organs , Lymphatic System , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Animals , Biological Transport, Active , Biomedical Engineering , Carcinoma 256, Walker/drug therapy , Carcinoma 256, Walker/metabolism , Carcinoma 256, Walker/pathology , Cyclophosphamide/administration & dosage , Cyclophosphamide/pharmacokinetics , Doxorubicin/administration & dosage , Doxorubicin/pharmacokinetics , Male , Neoplasms, Experimental/pathology , Neuroblastoma/drug therapy , Neuroblastoma/metabolism , Neuroblastoma/pathology , Rats , Sarcoma, Experimental/drug therapy , Sarcoma, Experimental/metabolism , Sarcoma, Experimental/pathologyABSTRACT
OBJECT: Reports on the surgical treatment of brain metastases from melanoma in a large group of patients are sparse. The goal of this paper is to review the surgical experience in a series of 91 patients with brain metastases from primary melanoma treated at a single institution. METHODS: Seven hundred eighty patients underwent resection of brain metastases at Memorial Sloan-Kettering Cancer Center between 1974 and 1994. The records of 91 (11.7%) of these patients who had melanoma were retrospectively reviewed. The median time from diagnosis of the primary melanoma to diagnosis of the brain lesion was 14.1 months. The overall median length of survival following craniotomy was 6.7 months. Fifteen patients with resected multiple metastases had shorter median survival times than 76 patients with a single lesion (5.4 months compared with 7.8 months, p = 0.12). In eight patients with cerebellar metastases the median length of survival was significantly shorter than that found in patients with supratentorial lesions (2 compared with 7 months, p = 0.03). There was no difference in length of survival between 49 patients who underwent postoperative whole-brain radiation therapy (WBRT) and 29 patients who did not (9.5 compared with 8.3 months, p = 0.67). The incidence of brain metastasis recurrences in WBRT-treated and untreated patients was similar (56% and 45.7%, respectively). Only the presence of infratentorial metastases (p = 0.0013) and unresected recurrence of brain metastases (p = 0.0003) had an impact on outcome according to a Cox regression analysis. Five patients (5.5%) died within 31 days of surgery. Overall survival rates at 1, 2, 3, and 5 years were 36.3, 18.7, 13.2, and 6.6%, respectively. CONCLUSIONS: Although melanoma metastatic to the brain carries a foreboding prognosis, patients who do not display preoperative neurological deficits, harbor a single lesion situated supratentorially, and have no lung or visceral metastases may derive significant palliative benefit from surgical resection of brain metastases.
Subject(s)
Brain Neoplasms/secondary , Melanoma/secondary , Skin Neoplasms/surgery , Adult , Brain Neoplasms/mortality , Brain Neoplasms/surgery , Combined Modality Therapy , Cranial Irradiation , Craniotomy , Female , Follow-Up Studies , Humans , Male , Melanoma/mortality , Melanoma/surgery , Middle Aged , Palliative Care , Radiotherapy, Adjuvant , Skin Neoplasms/mortality , Survival RateABSTRACT
Despite the progress in neurosurgery and radiotherapy, almost all patients treated with malignant gliomas develop recurrent tumors and die of their disease. Eighty-eight patients (median age 56 years) with recurrent glioblastoma (median tumor volume 32.7 cm3) were treated with noninvasive fractionated stereotactic radiosurgery and concurrent paclitaxel used as a sensitizer. The median interval between diagnosis of primary glioblastoma and salvage radiosurgery was 7.8 months. Four weekly treatments (median dose: 6.0 Gy) were delivered after the 3-hour paclitaxel infusion (median dose: 120 mg/m2). Survival was calculated by the Kaplan-Meier method from radiosurgery treatment. Overall median survival was 7.0 months, and the 1-year and 2-year actuarial survival rates were 17% and 3.4%, respectively. When grouped by performance status, there was no difference in survival between the patients with low and high Karnofsky score. Patients with tumor volume less than 30 cm3 survived significantly longer than those with tumor greater than 30 cm3 (9.4 vs. 5.7 months, p = 0.0001). Their 1-year survival rate was 40% and 8%, respectively. Eleven patients (11%) had reoperation because of expanding mass. Stable disease was seen in 40% of patients (n = 34), and increase in radiographically detected mass was observed in 41 patients (48.8%). Although the treatment of recurrent GBM is mostly palliative, the fractionated radiosurgery offers a chance for prolonged survival, especially in patients with a smaller tumor volume.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Glioblastoma/drug therapy , Glioblastoma/surgery , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/surgery , Paclitaxel/therapeutic use , Radiosurgery , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Phytogenic/administration & dosage , Combined Modality Therapy , Female , Humans , Male , Middle Aged , Paclitaxel/administration & dosage , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: At the time of diagnosis of colorectal carcinoma, 2-3% of patients are likely to be harboring brain metastases, and another 10% of patients will develop brain lesions during the course of their disease. The purpose of this study was to examine the clinical course of a group of patients with metastatic brain disease who underwent surgical resection in a single institution. The authors believe this information will be useful for establishing prognostic factors and for clinical decision making. METHODS: Between 1974 and 1993, 709 consecutive patients underwent surgical resection of brain metastases at Memorial Sloan-Kettering Cancer Center. Seventy-three patients had histologically confirmed colorectal carcinoma. The medical records of these patients were reviewed retrospectively, and the data were analyzed by univariate and multivariate analysis. RESULTS: The median age of the 43 women and 30 men was 61.5 years. The median interval from the time of diagnosis of the primary tumor and the development of brain metastases was 27.6 months. The primary colorectal tumor was resected in all patients, and the median survival from the day of surgery was 38 months. The median survival from the time of craniotomy was 8.3 months. The 1-year and 2-year survival rates were 31.5% and 6.8%, respectively. Postoperative mortality was 4%. Gender, presence of multiple metastases, presence of lung lesions, and adjuvant brain radiation after craniotomy appeared to have no impact on survival as determined by multivariate Cox analysis. Only the presence of cerebellar brain metastases was associated with decreased survival. CONCLUSIONS: The results of this series, which the authors believe is the largest series of resected brain metastases from colorectal carcinoma published to date, indicate that surgical resection may increase the survival of these patients. Analysis of prognostic factors shows that infratentorial tumor location is associated with a poorer survival compared with supratentorial tumor location (5.1 months vs. 9.1 months; P < 0.002). In patients with recurrent brain disease, repeated resection is a worthwhile consideration because it may prolong survival compared with patients who do not undergo re-resection.
Subject(s)
Brain Neoplasms/secondary , Brain Neoplasms/surgery , Carcinoma/secondary , Colorectal Neoplasms/pathology , Adult , Aged , Brain Neoplasms/mortality , Brain Neoplasms/radiotherapy , Carcinoma/mortality , Carcinoma/radiotherapy , Carcinoma/surgery , Cause of Death , Cerebellar Neoplasms/mortality , Cerebellar Neoplasms/secondary , Cerebellar Neoplasms/surgery , Colorectal Neoplasms/surgery , Combined Modality Therapy , Craniotomy , Female , Humans , Liver Neoplasms/mortality , Liver Neoplasms/secondary , Lung Neoplasms/mortality , Lung Neoplasms/secondary , Lung Neoplasms/surgery , Male , Middle Aged , Palliative Care , Proportional Hazards Models , Radiotherapy, Adjuvant , Retrospective Studies , Survival Analysis , Survival Rate , Treatment OutcomeABSTRACT
Communicating hydrocephalus can be handled either by the ventriculoperitoneal or, occasionally, the ventriculoatrial shunt. The lumboperitoneal shunt is another option. It does not require a transcranial approach; therefore, it is safer for the patient. We describe a technique that can be performed easily by a skilled laparoscopic surgeon through an anterior approach transabdominally. The lumboperitoneal (LP) shunt is placed laparoscopically under direct videoscopic vision, with the catheter inserted transabdominally through the L3 disc space into the thecal sac. In our patient, the lumboperitoneal shunt was placed at the L3 disc space for communicating hydrocephalus. There were no intraoperative or postoperative complications. The LP shunt can be easily placed by a skilled laparoscopic surgeon. The incidence of infection and complications is lower, and the patency rate is higher. This should be the initial choice for communicating hydrocephalus.
Subject(s)
Cerebrospinal Fluid Shunts/methods , Hydrocephalus, Normal Pressure/surgery , Laparoscopy/methods , Aged , Female , Humans , Hydrocephalus, Normal Pressure/diagnosis , Peritoneum , Ventriculoperitoneal ShuntABSTRACT
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.
Subject(s)
Brain Neoplasms/surgery , Glioblastoma/surgery , Neoplasm Recurrence, Local/surgery , Paclitaxel/therapeutic use , Radiation-Sensitizing Agents/therapeutic use , Radiosurgery/methods , Adult , Aged , Aged, 80 and over , Brain Neoplasms/mortality , Combined Modality Therapy , Drug Administration Schedule , Female , Glioblastoma/mortality , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/mortalityABSTRACT
Tumors metastatic to the leptomeninges are often incurable despite current aggressive treatment modalities. Regional therapy by intrathecal administration of monoclonal antibodies (MoAbs) can maximize their concentration to tumor sites while reducing systemic toxicities. Anti-GD2 antibody 3F8 has successfully targeted human neuroectoderm derived tumors. Disialoganglioside GD2 expression in the central nervous system is identical between humans and cynomolgus monkeys. We studied the pharmacokinetics and the acute and subacute toxicities of intraventricular 131I-3F8 in 8 cynomolgus monkeys. Four animals were purposely immunized with intravenous 3F8 administered 2-4 weeks prior to injections. All animals remained clinically stable. Toxicities included weight loss, fever and CSF leukocytosis. One animal developed a left-sided hemiparesis following his seventh injection, presumably due to a local drug accumulation in the setting of an intermittently patent catheter. The estimated radiation dose to the CSF was 19-48 Gy in the immunized monkeys and 19-82 Gy in the nonimmunized monkeys, and to blood was 0.11-0.98 Gy and 0.29-2.03 Gy, respectively. Histopathology revealed chronic reactive changes adjacent to the region of catheter placement and a focal vasculitis in 2 animals. Peripheral blood counts and bone marrow examinations remained normal. Because of the blood-brain barrier, CSF monkey-anti-mouse antibody titers were less than 10 per cent of those in the serum. In contrast to the CSF radioactivity clearance which was similar in all animals, blood clearance was substantially accelerated in 3F8-immunized animals versus controls. Correspondingly, the CSF to blood dose ratio was improved 1.3 to 6.6 fold (mean 3.5). We conclude that intraventricular administration of 131I-3F8 in primates is tolerable. It can deliver very high doses of radiation to the CSF space with minimal toxicity to blood and bone marrow. Serum anti-mouse antibody accelerates the clearance of 131I-3F8 in blood and may improve the therapeutic index.
Subject(s)
Brain/metabolism , Gangliosides/pharmacokinetics , Animals , Antibodies, Monoclonal , Catheters, Indwelling , Gangliosides/toxicity , Injections, Intraventricular , Iodine Radioisotopes , Linear Models , Macaca fascicularis , Male , Radiation Dosage , Reference ValuesABSTRACT
BACKGROUND: Brain metastases are diagnosed in 15% of patients with metastatic breast carcinoma. Most patients are treated with whole-brain radiotherapy (WBRT) and/or chemotherapy. The information on surgical results is sparse. METHODS: Among 709 patients with tumors metastatic to the brain who underwent craniotomy at Memorial Hospital, New York, New York, between January 1974 and December 1993, 70 (10%) had a primary breast carcinoma. Their treatment outcomes were analyzed retrospectively. RESULTS: The median age at diagnosis of primary breast carcinoma and brain metastasis was 46 and 50 years, respectively. All but two patients had metachronous diagnoses of breast carcinoma and brain metastasis. The median interval between both diagnoses in this subgroup was 28 months. In all 70 patients, the overall median survival was 54 months after diagnosis of the primary breast tumor and 16.2 months after diagnosis of the brain tumor. Only 5 patients (7%) were alive at last follow-up. The overall median survival after brain surgery was 14 months. Four patients died within 30 days of craniotomy. Twelve patients had a solitary cerebellar metastasis and 16 had multiple metastases; their median survival was 10.9 months and 14.8 months, respectively. There was no statistical difference in survival for patients who had single or multiple lesions. The median survival of 22 patients with positive hormonal receptor (estrogen receptor [ER] or progesterone receptor [PR]) was significantly longer than the median survival of 20 patients with negative ER/PR (21.9 vs. 12.5 months, P < 0.05). For 35 patients (50%) who had brain lesions > or =4 cm, the median survival was 11 months, compared with 16.3 months for patients with smaller lesions (P = 0.16, not significant [NS]). Patients age < or =50 years versus >50 years had survival of 17.3 and 11.1 months, respectively (P = NS). Neurologic deficit prior to craniotomy shortened survival for 24 patients to 11.5 months, compared with 17.4 months for patients without deficit (P = NS). Fifteen patients experienced failure with WBRT prior to undergoing craniotomy, and their median survival was shorter than for those who underwent craniotomy as the initial treatment (6.3 vs. 15.8 months, P < 0.03). However, their survival after diagnosis of brain metastasis was not significantly different (19.2 vs. 16.1). Forty-seven patients received WBRT postoperatively, and 9 patients did not receive adjuvant radiation therapy. Subsequent relapse in the brain was diagnosed in 27 patients, and 8 of them underwent reresection. One-year, 2-year, 3-year, and 5-year survival rates were 53%, 25.7%, 18.6%, and 7%, respectively. In multivariate analysis, the adjuvant WBRT after craniotomy and the absence of meningeal carcinomatosis were the only significant predictive variables for longer survival. CONCLUSIONS: In a subset of selected patients, craniotomy followed by WBRT can positively impact survival.
Subject(s)
Brain Neoplasms/secondary , Brain Neoplasms/surgery , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Carcinoma, Lobular/pathology , Adult , Aged , Brain Neoplasms/mortality , Brain Neoplasms/radiotherapy , Craniotomy , Female , Humans , Middle Aged , Multivariate Analysis , Radiotherapy, Adjuvant , Retrospective StudiesABSTRACT
Tethered cord syndrome (TCS) usually involves tethering of the lower cord at the conus medullaris from dural abnormalities, but may occur after spinal cord herniation. A tethered thoracic spinal cord is rare. We present an unusual case of a 30-year-old woman with a history of myelopathy presumed to be secondary to T6 cord compression resulting from T6-T8 arachnoid cyst. She continued to deteriorate after partial excision of the cyst. Repeat magnetic resonance imaging suggested recurrence of the presumed arachnoid cyst with cord compression and showed tethering at T6-T8. Surgical exploration revealed myelocele with cord herniation through the anterior thoracic dura. Pathologic diagnosis showed neural tissue with gliosis. After physical therapy treatments, the patient had increased lower extremity strength, ambulated with a cane, and regained some bladder control. Progressive myelopathy may represent tethering of the cord resulting from cord herniation. Early recognition of TCS, even in patients with minimal neurologic deficits, could prevent progressive disability.
Subject(s)
Spina Bifida Occulta/etiology , Spinal Cord Compression/complications , Spinal Cord Diseases/complications , Adult , Arachnoid Cysts/complications , Arachnoid Cysts/surgery , Female , Hernia , Humans , Magnetic Resonance Imaging , Spinal Cord/pathology , Spinal Cord Compression/etiology , Spinal Cord Diseases/etiologyABSTRACT
UNLABELLED: A pilot protocol to treat recurrent glioblastoma was developed using fractionated stereotactic radiosurgery with concurrent intravenous Taxol as a radiation sensitizer. METHODS: The treatment outcome was analyzed in two groups of patients with recurrent glioblastoma. Group 1 was analyzed retrospectively, and consisted of 9 patients with a median tumor volume of 9.2 cm3 treated with single-fraction stereotactic radiosurgery alone (mean radiation dose of 19.2 Gy). In group 2, prospectively analyzed, were 14 patients treated with fractionated stereotactic radiotherapy and concurrent Taxol. RESULTS: The median survival in group 2 was 14.2 months versus 6.3 months in group 1 (p < 0.04). One-year survival for patients who received fractionated radiotherapy with Taxol was 50% compared to 11% for those treated with single-fraction radiotherapy only (p = 0.05). CONCLUSIONS: Survival for group 2 patients was significantly better compared to those treated with single-fraction radiotherapy alone. These data should stimulate the investigation of both fractionated stereotactic radiotherapy and the development of radiation sensitizers to further enhance treatment.