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Ian E. McCutcheon, Rachel A. Baranco, David A. Katz and Stephen C. Saris

✓ Lymphokine-activated killer (LAK) cells are a heterogeneous population of immune effector cells that nonspecifically destroy neoplastic cells but not normal cells. Although parenteral treatment with interleukin-2 (IL-2) alone or a combination of IL-2 and LAK cells reduces tumor load and prolongs survival in mice with pulmonary, peritoneal, or hepatic metastases, the effect of these treatments on brain metastases has not been studied. To determine in an animal model if intracerebral metastases would be protected by the immunologically privileged status of the brain, intracardiac and intravenous injections of 105 KHT sarcoma cells were performed in C3H mice to create brain and lung metastases, respectively. The mice were treated with adoptive immunotherapy to determine if efficacy seen in an extracerebral site could be reproduced in the brain, and if histological examination of these brains would reveal a significant degree of lymphocyte infiltration and cytolytic activity. Animals were treated with either parenteral IL-2 (7500 U three times daily on Days 3 to 7 after tumor injection), or IL-2 plus LAK cells (7500 U IL-2 three times daily on Days 3 to 7, and 108 LAK cells intravenously on Days 3 and 6 after tumor injection), or IL-2 excipient (three times daily on Days 3 to 7 after tumor injection).

As compared to control animals, pulmonary metastases on Day 14 after tumor injection were reduced or eliminated in animals treated with either IL-2 or IL-2 plus LAK cells (p < 0.01). In these same animals, there was no reduction in the number of intracerebral metastases and no evidence of lymphocytic infiltration or cytolytic activity in the brain. This is the first study that reveals an organ-specific resistance to the treatment of metastases with adoptive immunotherapy, and affirms the concern that due to inadequate trafficking of endogenous or exogenous-activated lymphocytes or due to inadequate activation of in situ brain lymphoid precursors, there is no rejection of tumors in the brain. This information suggests that brain metastases in patients with systemic malignancies will not respond to intravenous treatment with LAK cells and IL-2, and that alternative forms of treatment are needed. Furthermore, this modification of a previously existing model of murine brain metastasis provides a method for concurrently evaluating the effectiveness of treatments for intra- and extracranial cancers.

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Ian E. McCutcheon, Bruce D. Weintraub and Edward H. Oldfield

✓ Thyrotropin-secreting pituitary adenomas have been diagnosed more frequently as radiographic techniques and biochemical assays have improved; however, they remain uncommon and are unfamiliar to most neurosurgeons. This report concerns eight patients with hyperthyroidism, inappropriately elevated levels of serum thyrotropin and α-subunit, and radiographic evidence of pituitary tumor. All underwent surgery and had pathological confirmation of a thyrotropin-secreting adenoma, and most had been subjected to prior ablation of the thyroid gland. Only one tumor was a microadenoma; the others ranged in size from 1.4 to 12 cm, and invasion of parasellar structures was common. Thyrotropin, triiodothyronine, thyroxine, and α-subunit were measured preoperatively and at intervals postoperatively. Coexistent hormonal abnormalities (which occurred in all patients) included acromegaly and hyperprolactinemia and were also monitored. All four patients who had tumors less than 2 cm in diameter remain alive. Complete extirpation of tumor in these patients produced rapid correction of all hormonal abnormalities and resolution of clinical hyperthyroidism. The other four patients had larger invasive tumors: two died soon after surgery, one died of disseminated tumor 8 years after presentation, and one remains alive with residual tumor.

Tumors secreting thyroid-stimulating hormone are less easily cured by surgery than are other types of pituitary adenoma because of the large size and invasive features that many attain during the delay to diagnosis; medical therapy can subdue the tumor but not cure it. The experience with these patients establishes the importance of early diagnosis and surgical excision for successful treatment, and demonstrates the utility of modern diagnostic techniques for finding these lesions. As occurs in Nelson's syndrome after adrenalectomy for Cushing's disease, ablation of the target organ may allow the tumor to convert to a more clinically malignant form which is resistant to cure.

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Ian E. McCutcheon and Edward H. Oldfield

✓ The authors report a nulliparous patient presenting with infertility and hyperprolactinemia. She underwent transsphenoidal surgery after radiological investigation disclosed an enlarged pituitary gland which did not respond to bromocriptine therapy. The removed tissue had histological features consistent with adenohypophysitis including a diffuse lymphocytic infiltrate. The lymphocyte subsets present in the infiltrate were characterized by immunohistochemical methods to establish the contribution of different elements of the cellular immune response.

Lymphocytes bearing CD4 antigen (helper-inducer cells) were most prominent and appeared to bear the majority of the interleukin-2 receptor (expressed during lymphocytic activation) present in the pituitary gland. A few B lymphocytes were also observed. The location of the major histocompatibility antigen (classes I and II) and interleukin-2 receptor correlated with the lymphocytes and macrophages rather than with the stromal or parenchymal elements of the pituitary.

Lymphocytic adenohypophysitis is an unusual cause of pituitary enlargement which can mimic a pituitary tumor, and is sometimes associated with hyperprolactinemia. In women of child-bearing age, it almost always occurs during pregnancy or the postpartum stage. The autoimmune disorder reported here has not previously been associated with infertility nor has the lymphocytic infiltrate of the pituitary previously been analyzed in detail by modern immunological methods.

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Ian E. McCutcheon, John L. Doppman and Edward H. Oldfield

✓ Although most vascular abnormalities of the spinal cord are now ascribed to an abnormal communication between a dural artery and a medullary vein on the dura near a sensory nerve root, these lesions are too small for their anatomy to be demonstrated directly by spinal arteriography. Thus, it is unknown whether the site of dural arteriovenous shunting is an arteriovenous malformation (AVM), implying a congenital origin, or is a direct arteriovenous fistula (AVF), implying an acquired etiology.

The authors treated six patients by en bloc resection of the involved dural root sleeve, proximal nerve root, and adjacent spinal dura. All of the patients presented with myelopathy and their arteriograms were consistent with a spinal dural vascular malformation. The lesions occurred between T-6 and T-12, levels at which clinical deficits from such resection are minimal. The dural artery or medullary vein associated with the vascular malformation was cannulated and a dilute solution of barium sulfate was injected during sequential fine-grain radiography. In all of the lesions the artery split into daughter vessels that coalesced one to three times to form a skein of arterial loops in the dura that invariably emptied into a medullary vein without an intervening capillary plexus. Several medium-to-small collateral vessels arising from adjacent intercostal or lumbar arteries were commonly present in the dura and converged at the site of the AVF to join a single medullary vein.

These results show that spinal dural AVMs are direct AVFs that link the dural branch of the radiculo-medullarydural artery with the intradural medullary vein. They also provide an anatomical explanation for the presence of a multiple segmental arterial supply and a single draining medullary vein of spinal dural AVFs, and the propensity for reestablishment of flow through the arteriovenous shunt after embolic occlusion.

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Edward W. Akeyson, Ian E. McCutcheon, Mark A. Pershouse, Peter A. Steck and Gregory N. Fuller

✓ The authors describe a malignant peripheral primitive neuroectodermal tumor (PNET) that originated in the median nerve in an elderly adult. After the diagnosis was made by biopsy, the patient underwent radical local resection with interpositional vein grafting of the brachial artery. The tumor had the typical appearance of a primitive neural tumor with small, round cells forming rosettes. It stained positively for both the Ewing's sarcoma/peripheral PNET antigen (HBA-71) and neuron-specific enolase, confirming its neural origin. Ultrastructural examination revealed dense core granules and suggested neural differentiation of the neoplasm. Cytogenetic analysis suggested a chromosome (11;22) translocation typical of peripheral PNET. Early reports consisted of tumors arising solely in peripheral nerves, but recent series have focused mainly on tumors arising in the soft tissues other than nerves. There are no other cases of true PNET of peripheral nerve in the modern literature that have been fully characterized by immunohistochemical, ultrastructural, and cytogenetic criteria. Although peripheral PNETs occur more commonly in children, this unusual neoplasm should be considered in the differential diagnosis of peripheral nerve neoplasms in adults. Early diagnosis is desirable because of its aggressive nature and poor outcome.

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Edward W. Akeyson and Ian E. McCutcheon

✓ The authors present a series of 25 patients who underwent single-stage complete spondylectomy, vertebral body reconstruction, and posterior segmental spinal stabilization for malignant metastatic disease involving multiple columns of the thoracolumbar spine. Patients were selected for this approach primarily because they were poor candidates for a transcavitary or lateral extracavitary approach or because the tumor involved both anterior and posterior columns of the spine. The operative approach used combines radical local resection of tumor via a bilateral transpedicular route, methylmethacrylate vertebral body reconstruction, and Luque rectangle stabilization in a single operation. Following surgery, the majority of patients experienced improvement in their neurological status, reduction in pain, or both. Most patients were functionally improved, or at least no worse, and spinal alignment was maintained in all. There was one local recurrence in a long-term survivor. Complications included cerebrospinal fluid fistulas, migrating graft material, and wound healing problems. The authors conclude that this surgical approach is safe and feasible for the radical resection of vertebral metastasis when combined with reconstruction and stabilization. This technique represents a useful alternative to other commonly used surgical approaches for the treatment of spinal metastases, and it should aid surgeons in selecting the optimum approach for individual patients.

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Thomas S. F. Chow and Ian E. McCutcheon

✓ The authors retrospectively reviewed the surgical outcomes in 10 cases of symptomatic intradural extramedullary spinal metastases of nonneurogenic origin because the collective experience in treating this rare manifestation of systemic cancer is limited. Pain and weakness were the presenting complaints in 70% of the patients and sensory changes were found in all cases. Cytological tests on one specimen of cerebrospinal fluid (CSF) from each of seven patients showed malignant cells in two cases. Gadolinium contrast-enhanced biplanar magnetic resonance (MR) imaging was effective in localizing the lesion and showed evidence of leptomeningeal carcinomatosis in two cases; myelography showed leptomeningeal carcinomatosis in one case and erroneously identified the lesion as intramedullary in the other. Eight of 10 cases had antecedent intracranial metastatic foci with the interval from presentation of the intracranial lesion to appearance of the spinal disease ranging from 3 to 51 months. The majority of the spinal lesions occurred in the thoracolumbar area. The most frequent histological type was adenocarcinoma and the most frequent source was the lung. In all cases laminectomies, intradural exploration, and biopsy or subtotal excision aided by microscopy and ultrasonography were performed. Results of surgical decompression were poor with only 30% of the patients showing improvement, at a 20% risk of perioperative mortality and a 60% risk of morbidity. Plans for surgical intervention in patients with intradural extramedullary metastases from a distant nonneurogenic source should be weighed against the high association with intracranial lesions, overall poor prognosis, and modest symptomatic results of decompression. Comprehensive evaluation including multiple specimens of CSF for cytology and contrast-enhanced MR imaging should be undertaken to exclude patients with diffuse leptomeningeal involvement, who should be treated by means other than surgery.

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Ziya L. Gokaslan, Julie E. York, Garrett L. Walsh, Ian E. McCutcheon, Frederick F. Lang, Joe B. Putnam Jr., David M. Wildrick, Stephen G. Swisher, Dima Abi-Said and Raymond Sawaya

Anterior approaches to the spine for the treatment of spinal tumors have gained acceptance; however, in most published reports, patients with primary, metastatic, or chest wall tumors involving cervical, thoracic, or lumbar regions of the spine are combined. The purpose of this study was to provide a clear perspective of results that can be expected in patients who undergo anterior vertebral body resection, reconstruction, and stabilization for spinal metastases that are limited to the thoracic region.

Outcome is presented for 72 patients with metastatic spinal tumors who were treated by transthoracic vertebrectomy at The University of Texas M. D. Anderson Cancer Center. The predominant primary tumors included renal cancer in 19 patients, breast cancer in 10, melanoma or sarcoma in 10, and lung cancer in nine patients. The most common presenting symptoms were back pain, which occurred in 90% of patients, and lower-extremity weakness, which occurred in 64% of patients. All patients underwent transthoracic vertebrectomy, decompression, reconstruction with methylmethacrylate, and anterior fixation with locking plate and screw constructs. Supplemental posterior instrumentation was required in seven patients with disease involving the cervicothoracic or thoracolumbar junction, which was causing severe kyphosis. After surgery, pain improved in 60 of 65 patients. This improvement was found to be statistically significant (p < 0.001) based on visual analog scales and narcotic analgesic medication use. Thirty-five of the 46 patients who presented with neurological dysfunction improved significantly (p < 0.001) following the procedure. Thirty-three patients had weakness but could ambulate preoperatively. Seventeen of these 33 regained normal strength, 15 patients continued to have weakness, and one patient was neurologically worse postoperatively. Of the 13 preoperatively nonambulatory patients, 10 could walk after surgery and three were still unable to walk but showed improved motor function. Twenty-one patients had complications ranging from minor atelectasis to pulmonary embolism. The 30-day mortality rate was 3%. The 1-year survival rate for the entire study population was 62%.

These results suggest that transthoracic vertebrectomy and spinal stabilization can improve the quality of life considerably in cancer patients with spinal metastasis by restoring or preserving ambulation and by controlling intractable spinal pain with acceptable rates of morbidity and mortality.

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Ziya L. Gokaslan, Julie E. York, Garrett L. Walsh, Ian E. McCutcheon, Frederick F. Lang, Joe B. Putnam Jr., David M. Wildrick, Stephen G. Swisher, Dima Abi-Said and Raymond Sawaya

Object. Anterior approaches to the spine for the treatment of spinal tumors have gained acceptance; however, in most published reports, patients with primary, metastatic, or chest wall tumors involving cervical, thoracic, or lumbar regions of the spine are combined. The purpose of this study was to provide a clear perspective of results that can be expected in patients who undergo anterior vertebral body resection, reconstruction, and stabilization for spinal metastases that are limited to the thoracic region.

Methods. Outcome is presented for 72 patients with metastatic spinal tumors who were treated by transthoracic vertebrectomy at The University of Texas M. D. Anderson Cancer Center. The predominant primary tumors included renal cancer in 19 patients, breast cancer in 10, melanoma or sarcoma in 10, and lung cancer in nine patients. The most common presenting symptoms were back pain, which occurred in 90% of patients, and lower-extremity weakness, which occurred in 64% of patients. All patients underwent transthoracic vertebrectomy, decompression, reconstruction with methylmethacrylate, and anterior fixation with locking plate and screw constructs. Supplemental posterior instrumentation was required in seven patients with disease involving the cervicothoracic or thoracolumbar junction, which was causing severe kyphosis. After surgery, pain improved in 60 of 65 patients. This improvement was found to be statistically significant (p < 0.001) based on visual analog scales and narcotic analgesic medication use. Thirty-five of the 46 patients who presented with neurological dysfunction improved significantly (p < 0.001) following the procedure. Thirty-three patients had weakness but could ambulate preoperatively. Seventeen of these 33 regained normal strength, 15 patients continued to have weakness, and one patient was neurologically worse postoperatively. Of the 13 preoperatively nonambulatory patients, 10 could walk after surgery and three were still unable to walk but showed improved motor function. Twenty-one patients had complications ranging from minor atelectasis to pulmonary embolism. The 30-day mortality rate was 3%. The 1-year survival rate for the entire study population was 62%.

Conclusions. These results suggest that transthoracic vertebrectomy and spinal stabilization can improve the quality of life considerably in cancer patients with spinal metastasis by restoring or preserving ambulation and by controlling intractable spinal pain with acceptable rates of morbidity and mortality.