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Stephen J. Hentschel and Ian E. McCutcheon

The most common cause of Cushing syndrome is Cushing disease, in which hypercortisolism is produced by a functional adrenocorticotropic hormone–producing adenoma of the anterior pituitary gland. The common therapies available include microsurgical resection, conventional fractionated radiotherapy, and stereotactic radiosurgery (SRS). In this article the authors review the indications, results, and complications associated with SRS in the treatment of Cushing disease.

In as many as 90% of patients SRS results in disease remission, which is defined as a normal 24-hour urinary free cortisol level and a normal or subnormal morning serum cortisol level. Although in most patients who are subsequently cured a marked decrease in the serum cortisol level is demonstrated within 3 months after treatment, a biochemical cure may be delayed up to 3 years in some cases. Complications following SRS for pituitary adenomas are uncommon, particularly in patients with microadenomas, which are most commonly seen in Cushing disease. The most common complication is hypopituitarism, which occurs in up to 50% of patients with a mean latency period of 5 years. Radiation-induced optic neuropathy has been reported in less than 2% of cases and induction of a secondary neoplasm in less than 1% of cases.

For patients with Cushing disease, the rate of endocrinological cure following SRS appears to be similar to that attained using microsurgical resection. In contrast to surgery, SRS has the benefit of being noninvasive and associated with a very low incidence of diabetes insipidus, although hypopituitarism may be more common with SRS. With continued follow-up patient reviews and additional experience with SRS, it may become possible to make more definitive statements regarding SRS as the initial treatment for patients with Cushing disease.

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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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Daryl R. Fourney, Dima Abi-Said, Frederick F. Lang, Ian E. McCutcheon and Ziya L. Gokaslan

Object. Few reports are available on the use of pedicle screw fixation for cancer-related spinal instability. The authors present their experience with pedicle screw fixation in the management of malignant spinal column tumors.

Methods. Records for patients with malignant spinal tumors who underwent pedicle screw fixation at the authors' institution between September 1994 and December 1999 were retrospectively reviewed.

Results. Ninety-five patients with malignant spinal tumors underwent 100 surgeries involving pedicle screw fixation: metastatic spinal disease was present in 81 patients, and locally invasive tumors were demonstrated in 14 patients. Indications for surgery were pain (98%) and/or neurological dysfunction (80%). A posterior (48%) or a combined anterior—posterior (52%) approach was performed depending on the extent of tumor and the patient's condition. At the mean follow up of 8.2 months, 43 patients (45%) had died; median survival, as determined by Kaplan—Meier analysis, was 14.8 months. At 1 month postsurgery, self-reported pain had improved in 87% of cases (p < 0.001), which is a finding substantiated by reductions in analgesic use, and 29 (47%) of 62 patients with preoperative neurological impairments were functionally improved (p < 0.001). Postoperative complications were associated only with preoperative radiation therapy (p = 0.002) and with preexisting serious medical conditions (p = 0.04). In two patients asymptomatic violation of the lateral wall of the pedicle was revealed on postoperative radiography. The 30-day mortality rate was 1%.

Conclusions. For selected patients with malignant spinal tumors, pedicle screw fixation after tumor resection may provide considerable pain relief and restore or preserve ambulation with acceptable rates of morbidity and mortality.

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Ben A. Strickland, Ian E. McCutcheon, Indro Chakrabarti, Laurence D. Rhines and Jeffrey S. Weinberg

OBJECTIVE

Metastasis to the spinal cord is rare, and optimal management of this disease is unclear. The authors investigated this issue by analyzing the results of surgical treatment of spinal intramedullary metastasis (IM) at a major cancer center.

METHODS

The authors retrospectively reviewed the medical records of 13 patients who underwent surgery for IM. Patients had renal cell carcinoma (n = 4), breast carcinoma (n = 3), melanoma (n = 2), non–small cell lung cancer (n = 1), sarcoma (n = 1), adenoid cystic carcinoma (n = 1), and cervical cancer (n = 1). Cerebrospinal fluid was collected before surgery in 11 patients, and was negative for malignant cells, as was MRI of the neuraxis. Eleven patients presented with neurological function equivalent to Frankel Grade D.

RESULTS

Radiographic gross-total resection was achieved in 9 patients, and tumor eventually recurred locally in 3 of those 9 (33%). Leptomeningeal disease was diagnosed in 4 patients after surgery. In the immediate postoperative period, neurological function in 6 patients deteriorated to Frankel Grade C. At 2 months, only 2 patients remained at Grade C, 8 were at Grade D, and 1 had improved to Grade E. One patient developed postoperative hematoma resulting in Frankel Grade A. Radiotherapy was delivered in 8 patients postoperatively. The median survival after spine surgery was 6.5 months. Three patients are still living.

CONCLUSIONS

Surgery was performed as a last option to preserve neurological function in patients with IM. In most patients, neurological function returned during the immediate postoperative period and was preserved for the patients’ remaining lifetime. The data suggest that surgery can be effective in preventing further decline in selected patients with progressive neurological deficit.

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Michele R. Aizenberg, Benjamin D. Fox, Dima Suki, Ian E. McCutcheon, Ganesh Rao and Laurence D. Rhines

Object

Patients presenting with spinal metastases from unknown primary tumors (UPTs) are rare. The authors reviewed their surgical experience to evaluate outcomes and identify predictors of survival in these patients.

Methods

This study is a retrospective analysis of patients undergoing surgery for metastatic spine disease from UPTs between June 1993 and February 2007 at The University of Texas M. D. Anderson Cancer Center.

Results

Fifty-one patients undergoing 52 surgical procedures were identified. The median age at spine surgery was 60 years. The median survival from time of diagnosis was 15.8 months (95% CI 8.1–23.6) and it was 8.1 months (95% CI 1.6–14.7) from time of spine surgery. Postoperative neurological function (Frankel score) was the same or improved in 94% of patients. At presentation, 77% had extraspinal disease, which was associated with poorer survival (6.4 vs 18.1 months; p = 0.041). Multiple sites (vs a single site) of spine disease did not impact survival (12.7 vs 8.7 months; p = 0.50). Patients with noncervical spinal disease survived longer than those with cervical disease (11.8 vs 6.4 months, respectively; p = 0.029). Complete versus incomplete resection at index surgery had no impact on survival duration (p > 0.5) or local recurrence (p = 1.0). Identification of a primary cancer was achieved in 31% of patients.

Conclusions

This is the first reported surgical series of patients with an unknown source of spinal metastases. The authors found that multiple sites of spinal disease did not influence survival; however, the presence of extraspinal disease had a negative impact. The extent of resection had no effect on survival duration or local recurrence. With an overall median survival of 8.1 months following surgery, aggressive evaluation and treatment of patients with metastatic disease of the spine from an unknown primary source is warranted.

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Ric Jensen, Ian E. McCutcheon and Franco DeMonte

✓ Two cases of florid swelling of pericranial pedicle grafts are reported. Intracranial mass effect produced by the grafts necessitated reoperation with graft removal in one case and graft revision in the other. No permanent neurological deficits were incurred by either patient. Venous congestion and associated swelling within the graft were considered to be related to constriction of the graft base at the frontal bone flap-skull base interface in one patient and torsion of the graft base in the other.

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Frederick F. Lang, Raymond Sawaya, Dima Suki, Ian E. McCutcheon and Kenneth R. Hess

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Julie E. York, Garrett L. Walsh, Frederick F. Lang, Joe B. Putnam, Ian E. McCutcheon, Stephen G. Swisher, Ritsuko Komaki and Ziya L Gokaslan

Object. Traditionally, superior sulcus tumors of the lung that involve the chest wall and spinal column have been considered to be unresectable, and historically, patients harboring these tumors have been treated with local radiation therapy with, at best, modest results. The value of gross-total resection remains unclear in this patient population; however, with the recent advances in surgical technique and spinal instrumentation, procedures involving more radical removal of such tumors are now possible. At The University of Texas M. D. Anderson Cancer Center, the authors have developed a new technique for resecting superior sulcus tumors that invade the chest wall and spinal column. They present a technical description of this procedure and results in nine patients in whom stage IIIb superior sulcus tumors extensively invaded the vertebral column.

Methods. These patients underwent gross-total tumor resection via a combined approach that included posterolateral thoracotomy, apical lobectomy, chest wall resection, laminectomy, vertebrectomy, anterior spinal column reconstruction with methylmethacrylate, and placement of spinal instrumentation. There were six men and three women, with a mean age of 55 years (range 36–72 years). Histological examination revealed squamous cell carcinoma (three patients), adenocarcinoma (four patients), and large cell carcinoma (two patients). The mean postoperative follow-up period was 16 months. All patients are currently ambulatory or remained ambulatory until they died. Pain related to tumor invasion improved in four patients and remained unchanged in five. In three patients instrumentation failed and required revision. There was one case of cerebrospinal fluid leakage that was treated with lumbar drainage and one case of wound breakdown that required revision. Two patients experienced local tumor recurrence, and one patient developed a second primary lung tumor.

Conclusions. The authors conclude that in selected patients, combined radical resection of superior sulcus tumors of the lung that involve the chest wall and spinal column may represent an acceptable treatment modality that can offer a potential cure while preserving neurological function and providing pain control.

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Ian E. McCutcheon, Allan Flyvbjerg, Holly Hill, Jessica Li, William F. Bennett, John A. Scarlett and Keith E. Friend

Object. The authors have previously demonstrated that modulation of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis can significantly affect meningioma growth in vitro. These studies were performed to evaluate the efficacy of GH receptor blockade in vivo.

Methods. Primary cultures from 15 meningioma tumors obtained in humans were xenografted into athymic mice. Approximately 1.5 million cells from each of the 15 tumors were implanted into the flanks of two female mice, one pair for each tumor. One animal from each of the 15 pairs was then treated with the GH receptor antagonist pegvisomant and the other with vehicle alone for 8 weeks. The tumor volume was measured using digital calipers three times per week. The mean tumor volume at the initiation of injections was 284 ± 18.8 mm3 in the vehicle group and 291.1 ± 20 mm3 in the pegvisomant group. After 8 weeks of treatment, the mean volume of tumors in the pegvisomant group was 198.3 ± 18.9 mm3 compared with 350.1 ± 23.5 mm3 for the vehicle group (p < 0.001). The serum IGF-I concentration in the vehicle group was 319 ± 12.9 µg/L compared with 257 ± 9.7 in the pegvisomant group (p < 0.02). A small but significant decrease was observed in circulating IGF binding protein (IGFBP)—3 levels, whereas slight increases occurred with respect to serum IGFBP-1 and IGFBP-4 levels. In the placebo group the tumor weight was 0.092 ± 0.01 g compared with 0.057 ± 0.01 g in the pegvisomant group (p < 0.02). The IGF-I and IGF-II concentrations were measured in the tumors by using a tissue extraction method. These human-specific immunoassays demonstrated that there was no autocrine production of IGF-I in any of the tumors, either in the pegvisomant or vehicle group. The IGF-II levels were highly variable (0–38.2 ng/g tissue) and did not differ significantly between treatment groups.

Conclusions. In an in vivo tumor model, downregulation of the GH/IGF-I axis significantly reduces meningioma growth and, in some instances, causes tumor regression. Because the concentrations of IGF-II in tumor did not vary with pegvisomant treatment and there was no autocrine IGF-I production by the tumors, the mechanism of the antitumor effect is most likely a decrease of IGF-I in the circulation and/or surrounding host tissues. Because the authors have previously demonstrated that the GH receptor is ubiquitously expressed in meningiomas, direct blockade of the GH receptor on the tumors may also be contributing to inhibitory actions.

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Julie E. York, Garrett L. Walsh, Frederick F. Lang, Joe B. Putnam, Ian E. McCutcheon, Stephen G. Swisher, Ritsuko Komaki and Ziya L Gokaslan

Traditionally, superior sulcus tumors of the lung that involve the chest wall and spinal column have been considered to be unresectable, and historically, patients harboring these tumors have been treated with local radiation therapy with, at best, modest results. The value of gross-total resection remains unclear in this patient population; however, with the recent advances in surgical technique and spinal instrumentation, procedures involving more radical removal of such tumors are now possible. At The University of Texas M. D. Anderson Cancer Center, the authors have developed a new technique for resecting superior sulcus tumors that invade the chest wall and spinal column. They present a technical description of this procedure and results in nine patients in whom stage IIIb superior sulcus tumors extensively invaded the vertebral column. These patients underwent gross-total tumor resection via a combined approach that included posterolateral thoracotomy, apical lobectomy, chest wall resection, laminectomy, vertebrectomy, anterior spinal column reconstruction with methylmethacrylate, and placement of spinal instrumentation. There were six men and three women, with a mean age of 55 years (range 36–72 years). Histological examination revealed squamous cell carcinoma (three patients), adenocarcinoma (four patients), and large cell carcinoma (two patients). The mean postoperative follow-up period was 16 months. All patients are currently ambulatory or remained ambulatory until they died. Pain related to tumor invasion improved in four patients and remained unchanged in five. In three patients instrumentation failed and required revision. There was one case of cerebrospinal leak that was treated with lumbar drainage and one case of wound breakdown that required revision. Two patients experienced local tumor recurrence, and one patient developed a second primary lung tumor. The authors conclude that in selected patients, combined radical resection of superior sulcus tumors of the lung that involve the chest wall and spinal column may represent an acceptable treatment modality that can offer a potential cure while preserving neurological function and providing pain control.