René L. Bernays

Combined thalidomide and temozolomide treatment in patients with glioblastoma multiforme.

AbstractObjectives: Glioblastoma multiforme (GBM) may potentially be responsive to antiangiogenic therapies as these tumors are highly vascularized and overexpress angiogenic factors. Thalidomide exhibits antiangiogenic activity and may provide additive or synergistic antitumor effects when given concurrently with temozolomide, an alkylating agent. To further evaluate this new concept of combining an antiangiogenic with an alkylating agent, efficacy and tolerability of thalidomide alone and in combination with temozolomide were explored in a single-institution, nonrandomized open-label phase II study. Patients and methods: Forty-four patients with GBMs, who received thalidomide for a period of at least three months, were evaluated for survival, time to tumor progression (TTP), and side effects. Microsurgical tumor extirpation and radiotherapy preceded chemotherapy. Nineteen patients (43%) received thalidomide only (T), and 25 patients (57%) had a combined chemotherapy of thalidomide and temozolomide (TT). Median thalidomide dosage was 200 mg/day. Median temozolomide dosage was 200 mg/m2/day for five days, in monthly cycles. Neuroradiological outcomes were assessed by a semiquantitative grading system. Results: Median survival was 103 weeks (95% CI, 65–141 weeks) for TT-patients and 63 weeks (95% CI, 49–77 weeks) for T-patients (p <  0.01). Median TTP for the TT-group was 36 weeks (95% CI, 20–52 weeks) and 17 weeks (95% CI, 13–21 weeks) for the T-group (p <  0.06). Neuroradiologically, 14 patients (56%) of the TT-group and six (32%) of the T-group had evidence of stable disease on at least two successive neuroradiological follow-ups. Progressive disease was found in nine patients (36%) of the TT-group and in 13 (68%) of the T-group. In two patients (8%) of the TT-group, a response with tumor regression was found. Thalidomide and concurrent temozolomide were safe and well tolerated with mild to moderate toxicities. Conclusions: The combination of thalidomide and temozolomide in the treatment of GBM appears to be more effective than that of thalidomide alone with respect to survival, TTP, and neuroradiological documentation of progression, stable disease or response. Further concurrent prospective studies of these agents in a larger group of patients with GBM will be required to establish the soundness of these intriguing observations.

PITUITARY APOPLEXY: RE-EVALUATION OF RISK FACTORS FOR BLEEDING INTO PITUITARY ADENOMAS AND IMPACT ON OUTCOME

OBJECTIVE To assess frequency, symptoms and outcome of pituitary apoplexy (PA) among pituitary adenoma patients, to gain better insight into risk factors for bleeding into pituitary adenoma and to estimate the sequelae of PA by means of a matched control group. METHOD By reviewing charts of 574 patients with pituitary adenoma, we analysed incidence, symptoms and outcome of PA and potential risk factors for developing PA by means of a control group (patients with pituitary adenoma without PA). RESULTS In total, 42 suffered from PA, all had macroadenomas; 30/217 male (14%) and 12/179 female (7%) macroadenoma patients, 32/194 patients with clinically non-functioning (16.5%) and 10/202 with clinically active (5.0%) macroadenoma were affected. Antithrombotic therapy predisposed patients to PA (P=0.026), diabetes mellitus and hypertension did not (P=1.00). Patients with PA and pituitary adenoma patients without PA had similar frequencies of hypopituitarism (45 vs 48%, P>0.05) and visual field defects (38 vs 55%, P>0.05), but ophthalmoplegia was significantly more common (76 vs 5%, P<0.001) in patients with PA. Nearly all patients were treated by surgery; most recovered from ophthalmoplegia, whereas visual function improved only moderately. Endocrine outcome was worse in patients with PA than in patients without PA. CONCLUSIONS Male sex and characteristics of the adenoma itself (especially tumour size and tumour type) rather than patients cardiovascular risk factors such as diabetes and hypertension seem to predispose to PA; antithrombotic therapy may also be important.

Fractionated stereotactic radiotherapy boost after post-operative radiotherapy in patients with high-grade gliomas

PURPOSE To determine the value and the toxicity of an additional fractionated stereotactic boost as used in the joint randomized EORTC-22972/MRC-BR10 study in patients with malignant gliomas. MATERIALS AND METHODS Seventeen patients (11 male, six female) with a high-grade glioma (two WHO III, 15 WHO IV) < or =4 cm in maximum diameter, with a good performance status (WHO > or =2), were treated with a fractionated stereotactic radiotherapy (SRT) boost to 20 Gy in four fractions following partial brain irradiation to a dose of 60 Gy in 30 fractions. This patient group was compared with historical data in a matched-pair analysis. RESULTS All patients were treated by conventional radiotherapy and a SRT boost (15 patients received 20 Gy and two patients 10 Gy). Acute side effects included fatigue (two), impairment of short-term memory (one) and worsening of pre-existing symptoms (one). No patient developed steroid dependence after SRT. One patient was re-operated for radiation necrosis. At a median follow-up of 25 months (9-50 months) 14 patients recurred locally. Survival was 77% at 1 year and 42% at 2 years; progression-free survival was 70% at 1 year and 35% at 2 years for all patients, respectively. Median survival for the whole patient group is 20 months. Comparison with a matched historical group showed a significantly better survival for the group treated with a stereotactic boost (P<0.0001). CONCLUSION A fractionated stereotactic boost after standard external beam radiotherapy in selected patients with high-grade glioma is feasible and well tolerated with low toxicity. Compared to historical data survival is significantly better with an additional SRT boost. However, its effectiveness has to be proven in a randomized trial.

Impact of Ultra-Low-Field Intraoperative Magnetic Resonance Imaging on Extent of Resection and Frequency of Tumor Recurrence in 104 Surgically Treated Nonfunctioning Pituitary Adenomas

OBJECTIVE To analyze the impact of intraoperative ultra-low-field magnetic resonance imaging (MRI) on the extent of tumor resection in nonfunctioning pituitary adenomas (NFPAs). METHODS Retrospective analysis was performed of 104 consecutive cases undergoing intraoperative MRI-guided transsphenoidal surgery for NFPA. General patient data; endocrinologic parameters; neurologic examinations; preoperative and postoperative symptoms; preoperative, intraoperative, and postoperative imaging; and proliferation index were evaluated with an overall mean follow-up of 34 months. RESULTS The use of intraoperative MRI led to an increase of the overall remission rate by 52.2%, from 44.2% to 67.3%. Tumor characteristics such as size and invasiveness had an important impact on postoperative remission rate. In patients with macroadenoma and without previous pituitary surgery, a remission rate of 82.2% was achieved. Overall, the sensitivity of intraoperative MRI in the study was 32.4%. There were no false-positive interpretations. A higher proliferation index was found in the 15 patients with postoperative enlargement of residual adenomas or tumor recurrence compared with the other patients of the study group. CONCLUSIONS This study shows that the outcome of surgical treatment of NFPAs was improved by the use of intraoperative MRI owing to more radical resection. The remission rate seems to depend on tumor characteristics. Recurrent disease might be reduced by the use of intraoperative MRI leading to more complete surgical resection of NFPAs.

Prognostic factors for impaired plasma sodium homeostasis after transsphenoidal surgery

Abstract Objective. Surgical manipulation of the pituitary stalk, neurohypophysis or the hypothalamus may disturb control of the plasma sodium level. The factors that might predict the risk of postoperative sodium imbalance are not clear, and were investigated in this study. Methods. A retrospective survey of 129 surgical records for the occurrence of plasma sodium levels outside the normal range, following transsphenoidal procedures. Median patient age was 49 (range 20–78) years, 65 female. 73 of the operated lesions were non-functioning pituitary adenomas. Patients were considered to have impaired plasma sodium balance if the range of 135–145 mmol/L was not maintained. Results. Of all 129 surgical cases, 68 (53%) experienced an imbalance in sodium levels. Severe sodium imbalance (≥ 149 or ≤ 131 mmol/L) was observed in 28 patients (22%). 13 showed hypernatraemia (median day 1), and 15 hyponatraemia (median day 6). Tumour size was associated with an increased incidence of sodium imbalance, particularly in patients younger than 49 years; surgery resulted in sodium imbalance in 38% of young patients operated on for tumours < 22 mm and in 76% of young patients, operated on for tumours ≥ 22 mm. Overall, tumour size increased with patients’ age, and tumour size was less predictive for sodium disturbances in elderly patients. Median time in hospital was 5 days for patients without sodium imbalance, 6 days for patients with hypernatraemia and 11 days for patients with hyponatraemia. Conclusions. Following pituitary surgery, patients with large tumours, in particular those of young age, are at higher risk for losing control of their plasma sodium level. Increased ADH secretion (hyponatraemia), but not transient diabetes insipidus was associated with a prolonged hospital stay. Postoperative follow-up of patients with sellar tumours should include careful monitoring of plasma sodium levels within the first two postoperative weeks and clear patients’ instructions.

Gender dependence of serum soluble Klotho in acromegaly

In acromegaly, disease activity is biochemically assessed by growth hormone (GH) and insulin‐like growth factor‐1 (IGF‐1) levels. However, they are often discrepant, as several factors including gender influence their relationship. We recently found excessively high serum levels of soluble Klotho (sKl) in acromegalic patients, which depended on GH to a comparable extent as IGF‐1. To further elucidate the relationship between GH and sKl, we examined the effect of gender on sKl in patients with untreated acromegaly.

Impact of Growth Hormone on Cystatin C

Background: Cystatin C (CysC) is an alternative marker to creatinine for estimation of the glomerular filtration rate (GFR). Hormones such as thyroid hormones and glucocorticoids are known to have an impact on CysC. In this study, we examined the effect of growth hormone (GH) on CysC in patients with acromegaly undergoing transsphenoidal surgery. Methods: Creatinine, CysC, GH and insulin-like growth factor-1 (IGF-1) were determined in 24 patients with acromegaly before and following transsphenoidal surgery. Estimated GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula. Results: In all patients, surgical debulking resulted in decreased clinical disease activity and declining GH/IGF-1 levels. Postoperatively, biochemical cure was documented in 20 out of 24 patients. Creatinine levels (mean ± SEM) increased from 72 ± 3 to 80 ± 3 µmol/l (p = 0.0004) and concurrently, estimated GFR decreased from 99 ± 3 to 91 ± 3 ml/min (p = 0.0008). In contrast to creatinine, CysC levels decreased from 0.72 ± 0.02 to 0.68 ± 0.02 mg/l (p = 0.0008). Conclusions: Our study provides strong evidence for discordant effects of GH on creatinine and CysC in patients with acromegaly undergoing transsphenoidal surgery, thus identifying another hormone that influences CysC independent of renal function.

Expression of somatostatin receptors, angiogenesis and proliferation markers in pituitary adenomas: an immunohistochemical study with diagnostic and therapeutic implications.

PRINCIPLES Pituitary adenomas are common intracranial neoplasms that generate symptoms as a result of either mass effect or the increased production of pituitary hormones. Although mostly benign, these tumours can be associated with considerable morbidity. We investigated a panel of immunohistochemical preparations to identify potential therapeutic targets and surrogate markers of clinical outcome. METHODS Tumour tissue from 25 patients was evaluated for immunohistochemical expression of somatostatin receptors 1‒5, von Willebrand-factor (vWF), interleukin-8 (IL-8), vascular endothelial growth factor receptor 2 (VEGFR-2), kinesin spindle protein (Eg5) and MIB-1 (Ki-67), and its relationship with clinical features was analysed. RESULTS The proliferation marker MIB-1 (Ki-67) was the only marker predictive of adenoma recurrence. Of note, 67% of all relapses were associated with tumours showing luteinising hormone expression. All pituitary adenomas showed variable somatostatin receptor, IL-8, Eg5, vWF and VEGFR-2 expression; a relationship between these parameters and clinical outcome could not be demonstrated in this cohort. CONCLUSIONS This study validates MIB-1 (Ki-67) as a reliable marker of tumour recurrence in pituitary adenomas. Considering the consistently increased expression of Eg5, IL-8, VEGFR-2, somatostatin receptors and vWF in these tumours, further investigation as potential therapeutic targets is warranted.

Aesthetic outcome in patients after polymethyl-methacrylate (PMMA) cranioplasty — a questionnaire-based single-centre study

Abstract Objectives: Acquired skull deformities are common and most likely treated surgically by cranioplasty. Since data on patient aesthetic outcome after cranioplasty are rare in literature, we aimed to assess patient satisfaction after polymethyl-methacrylate (PMMA) cranioplasty in this study using a questionnaire. Methods: A patient questionnaire was developed to evaluate the grade of satisfaction after surgery. After approval by the institutional ethical review board, we were allowed to send to all 115 patients, who received a cranioplasty from 2001 to 2008 at the University Hospital of Zurich, our questionnaire once to retrospectively analyze the patient response together with the patient hospital records. Results: Out of 115 patients, 36 patients were lost to follow-up and our questionnaire was sent out once to 79 patients. Sixty-three of 79 patients replied to the questionnaire (79·7%) and 16 did not reply. Seventeen declined to participate in this study and out of the remaining 46 patients (58·2%, 18 women, mean age 54 years, range 20–83 years), who agreed to participate in this study, 22 (47·8%) judged their cranioplasty to be aesthetically ‘excellent’, 16 (34·8%) ‘favorable’ and 4 (8·7%) ‘poor’. Another four patients (8·7%) were not satisfied, asking for a surgical revision. Patient age and gender was not related to the assessment of the aesthetic result. A higher satisfaction grade was found in patients with primary PMMA cranioplasty compared to PMMA cranioplasty implanted during a second surgery (Fisher’s exact test, P = 0·031). A dent was strongly associated with absence of satisfaction (P<0·01, Fisher’s exact test). Conclusion: Our questionnaire was suitable to assess patient satisfaction after cranioplasty. Localization of cranioplasty showed to be an important factor of aesthetic outcome, especially in the fronto-temporal region where a carefully planned reconstruction should be performed to guarantee an excellent grade of satisfaction after surgery.

Intraoperative color-coded duplex sonography for localization of a distal middle cerebral artery aneurysm: technical case report.

OBJECTIVE AND IMPORTANCE We describe the surgical treatment of a small, distal, middle cerebral artery (MCA) aneurysm, performed using intraoperative color-coded duplex sonography for localization. CLINICAL PRESENTATION A 55-year-old man presented with a sudden intense headache. Computed tomographic scans revealed a subarachnoid hemorrhage. Angiography demonstrated two MCA aneurysms, one arising from the proximal bifurcation of the right MCA and the other from its distal bifurcation. TECHNIQUE On Day 1, the proximal MCA aneurysm was clipped via the standard transsylvian approach. The distal MCA aneurysm was identified with the aid of color-coded duplex sonography and was successfully clipped with minimal additional dissection of the sylvian fissure. CONCLUSION Color-coded duplex sonography provides a two-dimensional image of the brain parenchyma and color-coded flow imaging of cerebral vessels in real time. It may be used for rapid intraoperative localization of small, distally located, cerebral aneurysms.