Paul J. Muller

The Significance of Spinal Cord Compression as the Initial Manifestation of Lymphoma

Eighteen patients with spinal cord compression caused by previously undiagnosed lymphoma were treated at our institution between 1976 and 1991. There were 14 male and 4 female patients (mean age, 58.2 years). The absence of bony involvement on radiographic images was a feature in 16 of the cases. All patients underwent laminectomy for decompression and tissue diagnosis, after which 5 underwent radiotherapy, 3 underwent chemotherapy, and 10 underwent combined-modality treatment. The functional outcome was improvement in 8 patients and no change in 10; no patient worsened after surgery. Eleven had advanced disease at diagnosis, while seven had limited disease, including three patients with localized extradural lymphoma. There were 16 cases of non-Hodgkins lymphoma and 2 of Hodgkins disease. Two patients had T-cell lymphoma and were among the longest survivors. DNA flow cytometry identified the low-grade tumors as diploid with very low proliferative indices, while the high-grade tumors all had high indices. At a mean observation time of 41.7 months, five patients have died of their disease, and seven remain in complete remission. Survival is markedly better than that reported for other malignant extradural tumors; however, even limited stage lymphoma can behave aggressively. Similarities in age, sex distribution, histological features, and the results of flow cytometry suggest behavior similar to extranodal lymphoma at other sites. Surgery to provide a tissue diagnosis, followed by combined radiotherapy and chemotherapy, is indicated for all cases.

PHOTODYNAMIC THERAPY OF MALIGNANT PRIMARY BRAIN TUMOURS: CLINICAL EFFECTS, POSTOPERATIVE ICP, and LIGHT PENETRATION OF THE BRAIN

Abstract We are reporting our experience with intraoperative PDT in 32 patients with malignant supratentorial gliomas; in 19 cases the tumour was recurrent. There were 20 males and 12 females with an age range of 17‐73 (mean = 45) yr. The first 8 patients in this series received HpD (Photofrin I) and the next 24 received DHE (Photofrin II). A photo‐illuminating device, of the authors design, was coupled to an argon dye pump laser in order to deliver light at 630 nm to a tumour cavity created by radical tumour resection and/or tumour cyst drainage. The total light energy delivered ranged from 440 to 3888 J and the light energy density ranged from 8 to 68 J cm−2.

Photodynamic therapy of malignant brain tumours

Fifty patients with malignant supratentorial tumours were treated with intra-operative photodynamic therapy (PDT); in 33 cases the tumour was recurrent. In 45 patients the tumour was a cerebral glioma and in 5 cases a solitary cerebral metastasis. All patients received a porphyrin photosensitizer 18-24 hours pre-operatively. Photoillumination was carried out at 630 nm to a tumour cavity created by radical tumour resection and/or tumour cyst drainage. The light energy density ranged from 8 to 175 J/cm 2 . In 8 patients additional interstitial light was administered. The operative mortality was 4%. Follow up has ranged from 1 to 30 months. The median survival for the 45 primary malignant tumours was 8.6 months with a 1 and 2 year actuarial survival rate of 32% and 18%, respectively. In 12 patients a complete or near complete CT scan response was identified post PDT. These patients tended to have a tumour geometry (eg. cystic) that allowed complete or near complete light distribution to the tumour. The median survival for this group was 17.1 months with a 1 and 2 year actuarial survival of 62% and 38%, respectively. In the 33 cases who did not have a complete response the median survival was 6.5 months with a 1 and 2 year actuarial survival of 22% and 11%, respectively. Photodynamic therapy of malignant brain tumours can be carried out with acceptable risk. Good responses appear to be related to adequate light delivery to the tumour.

Photo-Dynamic Therapy: Cavitary Photo-Illumination of Malignant Cerebral Tumours Using a Laser Coupled Inflatable Balloon

Interest in photodynamic therapy of malignant brain tumours has been growing in recent years as intra-operative laser applications become more available. We have developed an inflatable balloon which can be coupled to an argon dye pump laser in order to deliver light to a brain tumour cavity created by the subtotal resection of tumour. Eight patients with primary malignant brain tumors have been treated with photodynamic therapy (PDT) using this device. The 8 patients tolerated the treatment well; morbidity attributable to the PDT was acceptably low.

Estrogen Receptor Gene Expression in CraniopharyngiomasAn In Situ Hybridization Study

Craniopharyngiomas are histologically benign epithelial neoplasms of the sellar region that frequently exhibit invasive and aggressive local growth. In this study, we have investigated the presence and cellular distribution of estrogen receptor messenger ribonucleic acid by in situ hybridization in 23 surgically removed craniopharyngiomas. All craniopharyngiomas studied, including 19 adamantinomatous and 4 papillary variants, uniformly expressed the estrogen receptor gene. In all cases, an intense estrogen receptor messenger ribonucleic acid hybridization signal was demonstrated; one localized exclusively to the epithelial cells of the tumor. Connective tissue and vascular elements were devoid of hybridization signal. Coexpression of the estrogen receptor protein was also studied by immunohistochemistry. Despite the relative abundance of estrogen receptor message in all cases studied, the estrogen receptor protein was focally but conclusively detected in only two tumors. The basis of this discrepancy is unclear. Progesterone receptor protein was also studied in all cases; however, its definitive presence was noted in only one instance and, in that case, in only occasional nuclei. The expression of the estrogen receptor gene by the proliferative epithelial elements of craniopharyngiomas raises the questions of a possible hormonal component to the genesis and/or progression of the craniopharyngiomas and a potential responsiveness to therapeutic hormonal manipulation.

Surgical treatment of spontaneous intracranial hypotension secondary to degenerative cervical spine pathology: a case report and literature review

Objective and importanceA rare cause of intracranial hypotension is leakage of cerebrospinal fluid (CSF) through a dural breach from degenerative cervical spine pathology. To our knowledge there have been only four cases described in the English literature. Treatment is challenging and varies from case to case, with complete symptom resolution reported for only one patient. Herein we review the literature and describe our surgical management of a 46-year-old woman with symptomatic intracranial hypotension from the penetration of the cervical thecal sac.Clinical presentation The patient presented with a 3-month history of progressive orthostatic headaches. Magnetic resonance imaging demonstrated bilateral subdural hematomas and pachymeningeal gadolinium enhancement. An anterior epidural CSF collection commencing at a C4–5 calcified disc protrusion and osteophyte was evident on a computed tomography spinal myelogram.InterventionAfter three unsuccessful lumbar blood patches, we elected to attempt surgical removal of the causative pathology with exposure and primary closure of the dural defect by anterior cervical discectomy as described previously. After resection of the disc–osteophyte complex and dural exposure, immediate high volume egression of CSF mixed with blood at the surgical site. The dural defect was not visible but CSF egression promptly ceased. Cervical corpectomy for greater exposure and primary repair of the defect has been described, but we considered this unwarranted and felt the intraoperative blood collection formed a local blood patch. A collagen dural substitute membrane was inserted through the discectomy space for reinforcement.Conclusion Two months after this novel surgical blood patch procedure the patient was asymptomatic and follow-up imaging demonstrated complete resolution.

Photodynamic therapy of brain tumours — post-operative “field fractionation”

Malignant primary cerebral tumours account for 3% of the cancer burden and constitute the most common solid tumour in the paediatric age group. In spite of the advances in the surgical treatment, radiation therapy and chemotherapy of these tumours, the prognosis remains very poor. Patients with glioblastoma multiforme, the most common primary cerebral glioma, have a median survival of less than 1 year and a 2 year survival rate of less than 20%. Malignant primary cerebral gliomas cause disability and death as the consequence of local effects. Their invasion and destruction of brain tissue results in neurological disability and the associated increase in intracranial pressure eventually leads to coma and death. Most malignant primary cerebral tumours do not metastasize. Therefore, these tumours represent an excellent example of a highly malignant solid tumour where local tumour control should be of survival value. However, patients with malignant glial brain tumours tend to present clinically with sizable tumours. In a series of 100 consecutive patients with malignant cerebral astrocytic tumours, computed tomography (CT) scan assessment showed the median tumour mass to be 35 g (not including tumour-associated cerebral oedema) [l]. This mass is within two or three doublings of the lethal mass of 100 g. The penetration depth of 630 nm light in brain tumour tissue in vivo is limited to approximately 3 mm [2, 31; the killing distance might thus be estimated to be 8-12 mm. By assuming a spherical geometry, the mass of tissue destroyed with a 1 cm killing radius is estimated to be only 4 g when a point source is used for interstitial photoillumination. A diffusion fibre with a 2 cm cylindrical tip might destroy 6-10 g of tumour tissue if the killing radius is 1 cm. By creating a spherical cavity with a radius of 2 cm within the solid tumour by surgical means and then using intracavitary photoillumination with a 1 cm killing radius, a much larger tumour mass of 80 g of tissue could be destroyed. Thus a combination of intraoperative intracavitsry photoillumination and multiple interstitially placed diffusion fibres may result in a substantial volume of tissue photoillumination and destruction.

Impact of technique on cushing disease outcome using strict remission criteria.

BACKGROUND Cushing disease (CD) constitutes a challenging condition for the pituitary surgeon. Given the variety of factors affecting outcomes in CD, it is uncertain whether the newer endoscopic technique improves the results of surgery. METHODS A review was conducted of CD cases at our institution between 2000 and 2010. Analysis was done to: determine if surgical technique had an effect on outcome, identify the predictors of outcome and provide details of failed cases. Remission was defined as normal postoperative 24-hour urinary free cortisol (24-h UFC), suppression of morning serum cortisol to <50 nmol/L after 1mg of dexamethasone or being dependent on steroid replacement. RESULTS Forty-two patients met our inclusion criteria. Average follow-up period was 33 months. There were 15 macroadenomas and 27 microadenomas. Seventeen patients had an endoscopic transsphenoidal surgery and twenty-five patients had a microscopic transsphenoidal procedure. Long-term overall remission was achieved in 26 (62%) patients. There was no significant difference in remission rates between the two techniques (p value 0.757). Patients subjective symptomatic improvement and drop of morning serum cortisol in the postoperative period to less than 100 nmol/L correlated with long-term remission (p value 0.0031 and 0.0101, respectively) while repeat surgery was the only predictor of the lack of postoperative remission (p value 0.0008). CONCLUSIONS Revision surgery predicted poor remission rate for CD. Within the power of our study size, there was no difference in outcome between the endoscopic and microscopic approaches. Surgical outcomes should be reviewed in association with remission criteria used in a study.

Primary Pituitary Lymphoma: A Histological, Immunohistochemical, and Ultrastructural Study with Literature Review

We report the case of a 62-year-old man with headache and left sixth cranial nerve palsy. A computerized tomography scan revealed an osteolytic process involving the sella turcica and clivus. A partial tumor resection was achieved via an endoscopic transsphenoidal approach. Morphologic investigation revealed a diffuse large B cell lymphoma involving pituitary parenchyma. No systemic disease was found upon staging. Primary pituitary lymphoma is extremely rare. An accurate histologic diagnosis is key to successful treatment and a favorable prognosis. The literature is reviewed.

Photofrin photodynamic therapy for malignant brain tumors

In a phase II trial we treated more than 100 patients with malignant brain tumors with 2-mg/kg Photofrin iv. and intraoperative cavitary PDT. We concluded that PDT was safe in patients with newly diagnosed or recurrent supratentorial malignant gliomas. Regression analysis showed that pathology, performance grade and light dose were significantly related to survival time. We identified a prolongation of survival in selected patients when an adequate light dose was used. The surgical mortality rate was less than 3%. We have initiated two randomized prospective trials - the first, to determine if the addition of PDT to standard therapy [surgery, radiation and/or chemotherapy] prolongs the survival of patients with newly diagnosed malignant astrocytic tumors; and the second, to determine whether high light dose PDT [120 J/cm2] is superior to low light dose PDT [40 J/cm2] in patients with recurrent malignant astrocytic tumors. In the first 20 months of these clinical studies, 90 patients have been recruited. There were 52 in the recurrent study and 37 in the newly diagnosed study. 64% of the tumors were glioblastoma and 23% malignant astrocytoma or malignant mixed glioma. In the trial of newly diagnosed tumors 17 were randomized to surgery with a mean age of 58 ! 2.9 [sem] and 20 to surgery plus PDT with a mean age of 54 ! 2.5. In recurrent glioma trial 26 were randomized to low light dose PDT [mean age 48.1 ! 2.7] and 26 to high light dose [age 52 ! 2.7]. An update of our phase 2 data and a description of brain tumor PDT techniques is presented below. The clinical studies are supported in part by grant CA 43892 awarded by DHHS/NIH/NCI.