Cytokine responses to intraventricular injection of interleukin 2 into patients with leptomeningeal carcinomatosis: rapid induction of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, gamma-interferon, and soluble interleukin 2 receptor (Mr 55,000 protein).

Interleukin 2 (IL-2) is a potent immunostimulant that causes the release of secondary cytokines and the production of lymphokine-activated killer cells. We investigated the cellular and cytokine responses to injection of recombinant human IL-2 into the human cerebrospinal fluid of 11 patients with metastatic tumors involving the spinal or cerebral leptomeninges. After initial intraventricular IL-2 administration (1.25 x 10(5) to 2 x 10(6) Cetus units/injection), cerebrospinal fluid samples were collected at intervals from 0 to 24 h. Enzyme-linked immunosorbent assay results indicated that IL-2 levels gradually decreased during the first 24 h, with an average t1/2 between 4 and 8 h. Induction of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, gamma-interferon, and interleukin 2 receptor (p55) was also assessed by enzyme-linked immunosorbent assay. Tumor necrosis factor alpha and interleukin 6 levels peaked at 2 to 4 h and 4 to 6 h, with concentrations between 71 to 1,714 pg/ml and 942 to 10,500 pg/ml, respectively. Interleukin 1 beta, gamma-interferon, and soluble IL-2 receptor peaked later, during 6 to 12 h; the levels achieved were 234 pg/ml, 25 NIH units/ml, and 207 units/ml, respectively. All cytokine concentrations returned to near baseline between 12 and 24 h; however, the soluble IL-2 receptor levels remained elevated. Additional observations included a rapid influx of neutrophilic leukocytes, followed by a prolonged presence of lymphocytes. These data indicate a broad and complex potential of the immune response in the central nervous system, as well as further define the cytokine cascade in response to IL-2 alone.

Altered expression and distribution of heparan sulfate proteoglycans in human gliomas.

The expression of heparan sulfate proteoglycans (HSPGs) by human glioma cells was examined by biochemical and immunological methods in vitro and in vivo. Chondroitin sulfate was shown to represent the major [3H]glucosamine-labeled glycosaminoglycan synthesized by cultured normal brain cells. However, high-grade glioma-derived cells were shown to express significantly increased quantities of hyaluronic acid and heparan sulfate and approximately equal amounts of chondroitin sulfate compared with normal glial cells. To investigate further the differential expression of HSPGs, proteoglycans were isolated from glioma cells and were used as an immunogen to generate monoclonal antibodies (MAbs). One of these MAbs, 39H (an IgM), was shown to bind more to high-grade glioma-derived cells then to low-grade glioma or normal brain cells in vitro. MAb 39H was also observed to bind to isolated HSPGs but not to heparan sulfate glycosaminoglycan chains or trypsin-treated cells. Immunofluorescence staining of the cultured high-grade glioma cells revealed an intense diffuse cell surface staining pattern over the entire cell and also isolated footpads. In contrast, the low-grade tumor or normal glial cells showed a distinctive punctated staining. A similar differential staining of MAb 39H was most prominent between tissue sections of glioblastoma multiforme and anaplastic astrocytomas versus low-grade astrocytomas and normal brain. The low grade gliomas exhibited a weak punctated staining, whereas the high-grade gliomas showed significantly more intense staining, particularly along the apical regions of the cells. These results suggest that altered expression of HSPGs may be related to the malignant transformation or growth potential of glial-derived cells.

Smokers' unrealistic optimism about their risk.

OBJECTIVE: Past studies have produced ambiguous or inconsistent results when testing whether smokers actually underestimate their own risks of experiencing tobacco related illness. Whereas smokers claim that they are less at risk than the average smoker on self administered questionnaires, this unrealistic optimism has not been found in telephone or face-to-face interviews. We avoided the measurement problems of past studies and examined responses to a number of new questions to assess different aspects of smokers' perceptions. METHODOLOGY: A US national telephone survey (n = 6369; 1245 current smokers) posed a variety of questions designed to examine beliefs about the risks of smoking. For key questions, separate samples of smokers were asked either about their own risk or about the risk of the average smoker. RESULTS: Smokers underestimated their relative risk compared to non-smokers and, contrary to previous interview surveys, believed they have a lower risk of developing lung cancer than the average smoker. Furthermore, their perceived risk of lung cancer and of cancer in general barely increases with the number of cigarettes smoked per day, and their estimates of their risk of cancer are actually slightly lower than their estimates of their risk of lung cancer. Substantial proportions of smokers and former smokers agree with several myths, more than half agreeing that exercise undoes most smoking effects. CONCLUSION: Smokers underestimate their risk of lung cancer both relative to other smokers and to non-smokers and demonstrate other misunderstandings of smoking risks. Smoking cannot be interpreted as a choice made in the presence of full information about the potential harm.

Oligoclonal expansion of V beta 8+ cells in interleukin-2-activated T cells residing in subcutaneous metastatic melanoma.

Oligoclonality was investigated in interleukin-2 (IL-2)-activated T cells (tumor-infiltrating lymphocytes, TILs) residing in metastatic melanomas using seven different monoclonal antibodies (mAbs) specific for T-cell receptor (TCR) V alpha or V beta regions and flow cytometry. IL-2-activated TILs from 25 of 42 metastatic melanomas (60%) displayed oligoclonal expansion, whereas IL-2-activated peripheral bllod mononuclear cells (PBMCs) from only 2 of 20 patients (10%) did so during 2-5 weeks in culture. Skin-derived lymphocytes from 20 patients were cultured; only four samples proliferated and none showed oligoclonal expansion. Preferential oligoclonal expansion of TILs was observed in V beta 8+ cells (10/42, P less than 0.05), V beta 6.7+ cells (7/42, P less than 0.05), and V alpha 2+ cells (7/42, not significant). Oligoclonal expansion of V beta 8+ cells was primarily found in T cells from subcutaneous metastases (8/20 cases, P less than 0.05), whereas that of V beta 6.7+ cells and V alpha 2+ cells was also found in T cells from lymph node or organ metastases. These mAbs to TCR V regions stimulated effector TILs to produce interferon-gamma, but not IL-2 or IL-4. Subcutaneous tumor-specific (V beta 8+ cells) and non-specific (V beta 6.7+ cells and V alpha 2+ cells) oligoclonalities were observed in IL-2-activated melanoma TILs, suggesting different immune responses among different sites of metastases.

Lymphocyte subpopulations in human cerebrospinal fluid.

Lymphocyte subpopulations in both human cerebrospinal fluid and peripheral blood were identified and compared by rosette techniques. In patients without neuroaxial disease, the percent distribution of Fc receptor and T-lymphocytes reflected peripheral blood values, although there was a significantly higher percentage of T cells in normal CSF. Alterations in lymphocyte cerebrospinal fluid populations were observed in various systemic and neurologic diseases.

Comparison of cell adhesion molecule expression between glioblastoma multiforme and autologous normal brain tissue.

We investigated glioblastoma multiforme (GBM) for a pattern of consistent alterations in cell adhesion molecules (CAM) expression that might distinguish tumor from normal autologous brain tissue. We used frozen section immunohistochemistry with anti-CAM and computerized image analysis to quantify staining intensity which we expressed as relative intensity units (RIU). Our results showed that normal brain tissue generally did not express alpha 1 beta 1, intercellular CAM-1 (ICAM-1), and sialylated Lewisx, slightly expressed alpha 2, alpha 4, alpha 5, alpha 6 beta 1, alpha v beta 3, lymphocyte function-associated antigen-3 (LFA-3), Lewisx, sialylated LewisLewisx, had a good expression of alpha 3 beta 1 and CD44, and strongly expressed neural CAM (NCAM). GBM expressed alpha 2, alpha 3, alpha 5, alpha 6 beta 1, alpha v beta 3, ICAM-1, LFA-3, CD44, Lewisx, sialylated Lewisx, and sialylated LewisLewisx significantly higher (2-11-fold RIU) than normal brain tissue. ICAM-1 and LFA-3 were the most distinctive markers of GBM. The small blood vessel endothelial cells of the normal brain and the GBM showed a few differences. The tumor endothelium expression of alpha 2 beta 1, alpha 4 beta 1, and LFA-3 RIU appeared twice higher than in normal endothelium and alpha 6 beta 1 showed an average of 40% RIU decrease in comparison to normal. These results show that the expression of several CAM is consistently altered in GBM and its microvasculature when compared with autologous normal brain tissue.

Outcome and patterns of failure following limited-volume irradiation for malignant astrocytomas.

Between January 1982 and June 1986, 60 consecutive patients with high-grade astrocytomas [39 glioblastoma multiforme (GBM), 21 anaplastic astrocytoma (AA)] were treated with radiation therapy after biopsy (13 patients) or resection (47 patients). Fifty-three patients were treated with limited-volume irradiation, and seven patients received whole-brain irradiation. The mean tumor dose was 65.4 Gy. In 35 patients, chemotherapy was given as part of their initial treatment. The 1- and 2-year survivals for GBM patients were 40 and 14%, respectively. Survival figures for AA patients were 76 and 52% at 1 and 2 years, respectively. The progression-free rate at 1 year was 13% in GBM and 29% in AA patients. Thirty-four of 48 patients who received limited-volume irradiation had evidence of progression on postirradiation CT scans. Six patients (3 GBM, 3 AA) had evidence of a new intracranial metastatic site on CT scan. In three patients the metastasis was within the previously irradiated volume, and in the other three patients, it was outside this volume. All six had evidence of progression of their primary tumor at the original location on CT scan prior to the discovery of the metastatic site. Twenty-one patients (15 GBM, 6 AA) had at least one postirradiation reoperation for a recurrent mass. Nineteen patients had recurrent tumors in the primary site, and two patients had necrosis but no tumor. Patients who received limited-volume irradiation for high-grade astrocytomas achieved the same survival results as patients treated previously with whole brain irradiation. New intracranial metastases did not influence the outcome, since these were always antedated by tumor progression at the primary site.

Effect of anti-CD3/anti-CD28/interleukin-2 stimulation of mononuclear cells on transforming growth factor beta inhibition of lymphokine-activated killer cell generation.

After simultaneous stimulation with anti-CD3 monoclonal antibody (mAb) at 10 ng/ml, anti-CD28 mAb at 125 ng/ml, and interleukin-2 (IL-2) at 20 U/ml, peripheral blood mononuclear cells (PBMC) were partially resistant to immunosuppression by transforming growth factor-beta (TGF beta 2). The doses of TGF beta 2 that inhibit cytotoxicity of IL-2 stimulated cells by 60%-70% were much less effective when the same cells were stimulated with anti-CD3/anti-CD28/IL-2. This favorable stimulation a generated a cell population characterized by high lytic activity, excellent expansion, and a greater resistance to immunosuppressive action of TGF beta 2. The secretion of secondary cytokines important for LAK generation is considered a crucial event, at least partially responsible for the antagonization of TGF beta immunosuppression.

Central nervous system metastases in epithelial ovarian carcinoma.

With the advent of systemic chemotherapy capable of controlling metastases at most sites, central nervous system metastases are becoming more common in patients with epithelial ovarian carcinoma. A retrospective epidemiologic review at The University of Texas M. D. Anderson Hospital and Tumor Institute revealed central nervous system metastases in 13 of 4456 patients with epithelial ovarian carcinoma (0.29%) registered between 1944 and 1984. No patients were identified as having central nervous system metastases before 1968. The median survival overall was 29 months; following the diagnosis of brain metastases it was five months. Five of eight patients treated for central nervous system metastases lived ten months or longer. Patients with isolated metastases to the central nervous system lived longer than patients with accompanying systemic metastases. Patients treated with surgical resection lived longer than those who did not undergo surgery. With surgical resection, postoperative irradiation, and systemic chemotherapy, significant symptomatic improvement and long-term remission are possible.

Computed tomography of gliosarcoma.

Five cases of rare gliosarcoma are described with pathologic correlation. Because of its sarcomatous component, gliosarcoma tends to present as a sharply defined, round or lobulated, hyperdense solid mass with relatively homogeneous contrast enhancement and peritumoral edema. Sharp demarcation of the tumor from surrounding tissue may lead to complete removal and prolonged survival despite high malignancy. However, aggressive tumor regrowth occurs often after incomplete resection. The genesis of gliosarcoma is also discussed.

An approach to primary bone tumors.

This article is designed to provide the busy, practicing physician with the essential information needed to approach the patient with a primary bone tumor. An algorithm provides a suitable method of assessing most patients with bone tumors, recognizing slight modification is necessary in each case. Following this approach should allow successful accomplishment of the therapeutic triad: (1) do not "over-treat" a benign bone tumor, (2) do not "under-treat" a malignant bone tumor, and (3) do not misdirect the biopsy approach to the lesion so as to convert a more conservative operation into a more radical operation.

Ewing's sarcoma.

Ewing's sarcoma is a highly malignant tumor of uncertain origin. A strong relationship is suggested between Ewing's sarcoma and tumors of neural origin. The radiologic manifestation of Ewing's sarcoma are protean and lesions may be lytic, mixed lytic-sclerotic, or rarely, predominantly sclerotic. The lower extremity long bones are predominantly affected and most lesions are diaphyseal or metadiaphyseal. CT and particularly MR imaging are invaluable in further delineating the extent of disease not readily manifested on plain radiographs. Gallium scintigraphy and gadolinium-enhanced MR images are best for following the response to therapy. Ewing's sarcoma must be distinguished from other round cell tumors including lymphoma, neuroblastoma, and primitive neuroectodermal tumor of bone as well as from osteosarcoma.

Cartilaginous bone tumors.

Cartilaginous tumors can be subdivided into several categories according to the following three criteria: (1) Is the lesion benign or malignant? (2) Is the lesion a pure or impure cartilaginous tumor? (3) Is the epicenter of the lesion intraosseous, juxtacortical, or in the soft tissues? This article focuses on the four most common benign cartilaginous tumors, enchondroma, osteochondroma, chondroblastoma, and chondromyxoid fibroma, and on chondrosarcoma. It reviews the biologic and developmental considerations of each and discusses in depth the basic concepts in the radiologic diagnosis of cartilaginous tumors.

Imaging of soft tissue tumors.

In summary, MR imaging is the preferred modality for the evaluation of a soft tissue mass after plain films have been taken. The radiologic appearance of certain soft tissue tumors or tumorlike processes such as myositis ossificans, benign fatty tumors, intramuscular hemangiomas, pigmented villonodular synovitis, and certain hematomas may be sufficiently unique to allow a strong presumptive radiologic diagnosis. It must be emphasized that MR cannot reliably distinguish between benign and malignant lesions, and when radiologic evaluation is nonspecific, one is ill advised to suggest a lesion is benign or malignant solely on the basis of its MR appearance. CT may be useful in specific instances for the identification of subtle soft tissue mineralization in those patients in whom lesions are not adequately evaluated by radiographs. Ultrasonography may be useful in the assessing of recurrent disease as well as in establishing tumor vascularity.

Anterior transcranial (craniofacial) resection of tumors of the paranasal sinuses: surgical technique and results.

Transfacial approaches, traditionally used for malignant tumors of the paranasal sinuses, provide limited exposure when several sinuses are involved and are unsuitable for tumors that erode through the floor of the anterior cranial fossa. A transcranial approach may aid in the removal of such lesions. To better understand the risks and benefits of this surgical approach, we reviewed all patients (n = 76) who underwent a transcranial approach as part of the excision of paranasal sinus lesions between 1984 and 1993 at our institution. The spectrum of disease included adenocarcinoma (13 patients), squamous cell carcinoma and olfactory neuroblastoma (11 patients each), adenoid cystic carcinoma and poorly differentiated forms of carcinoma (6 patients each), melanoma (5 patients), and miscellaneous others (24 patients). Most patients had ethmoid sinus involvement; tumors were also commonly found in the cribriform plate, sphenoid sinus, and nasal fossa. In each patient, a bifrontal craniotomy was performed with extradural dissection to the floor of the anterior fossa and osteotomies for resection of involved elements. In 47 patients (62%), disease in the orbit, the anterior nasal cavity, or the soft tissues of the face required transfacial as well as transcranial resections. Bony defect in the anterior fossa floor was repaired with a pedicled pericranial flap. Patients with major complications included six patients with epipericranial and/or epidural hematomas requiring evacuation, three with transient cerebrospinal fluid leaks, two who developed bifrontal cerebral infarcts, and one who died soon after surgery. No meningitis was seen. To date, 26 patients (34%) have died; of those living (mean follow-up, 34 mo), 42 (84%) remain in full remission. The transcranial approach can achieve removal of erosive, invasive tumors from this area with predictable morbidity and may be considered whenever sinus tumors breach the anterior cranial base or extend beyond the reach of conventional transfacial approaches.

In vitro cytolysis of primitive neuroectodermal tumors of the posterior fossa (medulloblastoma) by lymphokine-activated killer cells.

Short-term stimulation of nonantigen-primed peripheral blood mononuclear leukocytes with interleukin-2 generates a population of oncolytic effectors designated "lymphokine-activated killer" (LAK) cells. These LAK cells express potent lytic activity against a wide spectrum of fresh or cultured autochthonous (patient's own) and allogeneic (unrelated) tumors, yet specifically spare normal tissues. In this study, cells derived from primitive neuroectodermal tumors of the posterior fossa (PNET-PF) were examined for their sensitivity to LAK cytolysis utilizing an in vitro 4-hour chromium-51-release assay. Five early-passage cell lines, derived from primary PNET-PF, demonstrated significant sensitivity to LAK cell cytolysis. Lysis was equally effective in culture medium and cerebrospinal fluid. Three freshly excised PNET-PF exhibited similar susceptibility to lysis by autochthonous LAK cells. Greatly increased expansion of LAK cell cultures could be achieved by short-term stimulation with monoclonal anti-CD3 antibodies in addition to interleukin-2 activation. These findings constitute the preliminary in vitro foundations for potential intrathecal adoptive immunotherapy of PNET-PF with LAK cells.

Surgical management of brain metastases: how aggressive should we be?

Treatment of cancer metastatic to the brain is dictated by both the need to achieve immediate short-term palliation and the desire for durable symptom-free remission. Surgical resection of brain metastases makes available tissue for diagnosis and experimental study, permits prompt relief of neurological signs and symptoms secondary to tumor mass effect, enhances the potential for sustained local tumor control in those patients with solitary disease, and allows greater therapeutic flexibility by obviating the need for cranial radiation in some situations and by expanding patient access to alternative experimental protocols or systemic chemotherapy.

Rotating shiftwork schedules: can we enhance physician adaptation to night shifts?

OBJECTIVES: To evaluate the effectiveness of a broad, literature-based night shiftwork intervention for enhancement of emergency physicians' (EPs') adaptation to night rotations. METHODS: A prospective, double-blind, active placebo-controlled study was conducted on 6 attending physicians in a university hospital ED. Three data sets were collected under the following conditions: baseline, after active placebo intervention, and after experimental intervention. In each condition, data were collected when the physicians worked both night and day shifts. Measurements included ambulatory polysomnographic recordings of the main sleep periods, objective performance tests administered several times during the subjects' shifts, and daily subjective ratings of the subjects' sleep, moods, and intervention use. RESULTS: The subjects slept an average of 5 hr 42 min across all conditions. After night shifts, the subjects slept significantly less than they did after day shifts (5 hr 13 min vs 6 hr 20 min; p < 0.05). The physicians' vigilance reaction times and times for intubation of a mannequin were significantly slower during night shifts than they were during day shifts (p = 0.007 and p < 0.04, respectively), but performances on ECG analysis did not significantly differ between night and day shifts. Mood ratings were significantly more negative during night shifts than they were during day shifts (more sluggish p < 0.04, less motivated p < 0.03, and less clear thinking p < 0.04). The strategies in the experimental intervention were used 85% of the time according to logbook entries. The experimental and active placebo interventions did not significantly improve the physician's performance, or mood on the night shift, although the subjects slept more after both interventions. CONCLUSIONS: Although the experimental intervention was successfully implemented, it failed to significantly improve attending physicians' sleep, performance, or mood on night shifts. A decrease in speed of intubation, vigilance reaction times, and subjective alertness was evident each time the physicians rotated through the night shift. These findings plus the limited sleep across all conditions and shifts suggest that circadian-mediated disruptions of waking neurobehavioral functions and sleep deprivation are problems in EPs.

Atlantoaxial subluxation in Reiter's syndrome. A report of three cases and review of the literature.

Three patients with the unusual manifestation of atlantoaxial subluxation in Reiter's syndrome are studied. Each patient had mild symptoms referable to the cervical spine and radiologic evidence of erosive disease elsewhere in the skeleton. One patient had an 11-year history of Reiter's syndrome when the atlantoaxial subluxation was detected. The other two had atlantoaxial subluxation detected within 1 year of initial presentation, at variance with three other such patients that were reported previously, in whom there was a 6- to 10-year interval from initial presentation until radiographic documentation of atlantoaxial subluxation. Cervical spine radiographs, including flexion and extension views, are recommended for all patients with Reiter's syndrome and cervical spine symptoms.

Osteoblastoma of the spine. A review of 75 cases.

Clinical and radiologic features of 75 cases of osteoblastoma of the spine were reviewed. In addition to pain, which was the most frequent complaint, 18 patients demonstrated objective neurologic deficit, while scoliosis was observed in 17 patients. Aspirin yielded pain relief in 13 patients. Pathologic fracture was not encountered. The radiologic and histologic characteristics of osteoblastoma of the spine are indistinguishable from those arising in other sites. The typical lesion exhibited a well-defined, geographic margin with a sclerotic, frequently lobulated border. Approximately one half of the cases were predominantly lucent, the remainder displaying varying degrees of matrix mineralization. Distribution of the osteoblastomas through the spinal axis was as follows: cervical-29, thoracic-16, lumbar-17, sacral-13. Other significant findings included posterior element involvement in 73 of 75 cases, and a striking male to female ratio of 2.5 to 1.