Abstract: ABSTRACT: Purpose: to assess the safety and efficacy of fractionated stereotactic radiotherapy (FSRT) for large skull base meningiomas. Methods and Materials: Fifty-two patients with large skull base meningiomas aged 34-74 years (median age 56 years) were treated with FSRT between June 2004 and August 2009. All patients received FSRT for residual or progressive meningiomas more than 4 centimeters in greatest dimension. The median GTV was 35.4 cm3 (range 24.1-94.9 cm3), and the median PTV was 47.6 cm3 (range 33.5-142.7 cm3). Treatment volumes were achieved with 5-8 noncoplanar beams shaped using a micromultileaf collimator (MLC). Treatment was delivered in 30 daily fractions over 6 weeks to a total dose of 50 Gy using 6MV photons. Outcome was assessed prospectively. RESULTS: At a median follow-up of 42 months (range 9-72 months) the 3-year and 5-year progression-free survival (PFS) rates were 96% and 93%, respectively, and survival was 100%. Three patients required further debulking surgery for progressive disease. Hypopituitarism was the most commonly reported late complication, with a new hormone pituitary deficit occurring in 10 (19%) of patients. Clinically significant late neurological toxicity was observed in 3 (5.5%) patients consisting of worsening of pre-existing cranial deficits. CONCLUSION: FSRT as a high-precision technique of localized RT is suitable for the treatment of large skull base meningiomas. The local control is comparable to that reported following conventional external beam RT. Longer follow-up is required to assess long term efficacy and toxicity, particularly in terms of potential reduction of treatment-related late toxicity.
Abstract: to investigate the factors affecting survival and toxicity in patients treated with stereotactic radiosurgery (SRS), with special attention to volumes of brain receiving a specific dose (V10 - V16 Gy) as predictors for brain radionecrosis.
Abstract: PURPOSE: The authors report acute toxicity in 14 patients with locally advanced head and neck squamous cell carcinoma treated with radiotherapy and cetuximab. MATERIALS AND METHODS: Data collection was performed prospectively on patients treated from September 2007 to March 2009. Treatment consisted of 64.8-70 Gy radiotherapy in conventional fractions and cetuximab. RESULTS: Two out of 14 patients did not complete the planned combined treatment; radiotherapy was temporarily suspended in six other patients. Seven of 12 patients received cetuximab until the end of radiotherapy. Treatment breaks were principally due to severe acute cutaneous or mucous toxicity. Any grade acneiform rash occurred in all patients. In-field G3-4 cutaneous toxicity occurred in five (36%) patients and G3-4 mucous toxicity in seven (50%). One patient died of sepsis. CONCLUSIONS: In our experience, severe acute toxic reactions are common in patients treated with radiotherapy and concurrent cetuximab, resulting in frequent breaks or incomplete treatment with potential reduction in disease control.
Abstract: Magnetic resonance imaging (MRI) with a dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) sequence to study brain tumours provides information on the haemodynamic characteristics of the neoplastic tissue. Brain perfusion maps and calculation of perfusion parameters, such as relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV) and mean transit time (MTT) allow assessment of vascularity and angiogenesis within tumours of the central nervous system (CNS), thus providing additional information to conventional MRI sequences. Although DSC-PWI has long been used, its clinical use in the study of brain tumours in daily clinical practice is still to be defined. The aim of this review was to analyse the application of perfusion MRI in the study of brain tumours by summarising our personal experience and the main results reported in the literature.
Abstract: Epigenetic silencing of the O(6)-methylguanine-DNA-methyltransferase (MGMT) gene by promoter methylation is correlated with improved progression-free survival (PFS) and overall survival (OS) in adult patients with newly diagnosed glioblastoma multiforme (GBM) who receive alkylating agents. The aim of this study is to determine the correlation between MGMT and survival in elderly patients with GBM treated with radiotherapy (RT) and temozolomide (TMZ). Eighty-three patients aged 70Â years or older with histologically confirmed GBM treated with RT plus TMZ between February 2005 and September 2009 were investigated in this study. The methylation status of the MGMT promoter was determined by polymerase chain reaction analysis. Median PFS and OS were 7.5 and 12.8Â months, respectively. The MGMT promoter was methylated in 42 patients (50.6%) and unmethylated in 41 patients (49.4%). Median OS was 15.3Â months in methylated patients and 10.2Â months in unmethylated patients (PÂ =Â 0.0001). Median PFS was 10.5Â months in methylated tumors and 5.5Â months in unmethylated tumors (PÂ =Â 0.0001). On multivariate analysis MGMT methylation status emerged as the strongest independent prognostic factor for OS and PFS (PÂ =Â 0.004 and PÂ =Â 0.005, respectively). The results of the present study suggest that MGMT methylation status might be an important prognostic factor associated with better OS and PFS in elderly patients with GBM treated with RT and TMZ.
Abstract: The aim of this paper is to evaluate the efficacy of fractionated stereotactic radiotherapy (FSRT) and concomitant temozolomide (TMZ) as a salvage treatment option in patients with recurrent glioblastoma (GBM). Between May 2006 and December 2009, 36 patients with recurrent GBM received FSRT plus concomitant TMZ at University of Rome La Sapienza, Sant' Andrea Hospital. All patients had Karnofsky performance score ≥60 and were previously treated with standard conformal radiotherapy (RT) (60 Gy) with concomitant and adjuvant TMZ for 6-12 cycles. The median time interval between primary RT and reirradiation was 14 months. At the time of recurrence, all patients received FSRT plus concomitant daily TMZ at the dose of 75 mg/m(2), given 7 days per week from the first day of RT. Radiation dose was 37.5 Gy delivered in 15 fractions over 3 weeks. Median overall survival after FSRT was 9.7 months, and the 6- and 12-month survival rates were 84 and 33%, respectively. The median progression-free survival (PFS) was 5 months, and 6- and 12-month PFS rates were 42 and 8%, respectively. In univariate analysis, KPS (P = 0.04), the interval between primary RT and reirradiation (P = 0.02), and O6-methylguanine-DNA-methyltransferase (MGMT) methylation status at the time of diagnosis (P = 0.009) had an effect on survival; however, in multivariate analysis, only MGMT methylation was statistically significant (P = 0.03). In general, FSRT was well tolerated and the treatment was completed in all patients. Neurological deterioration due to radiation-induced necrosis occurred in three patients (8%). FSRT plus concomitant TMZ is a feasible treatment option associated with survival benefits and low risk of complications in selected patients with recurrent GBM. The potential advantages of combined chemoradiation schedules in patients with recurrent GBM need to be explored in future studies.
Abstract: BACKGROUND: To assess the accuracy of fractionated stereotactic radiotherapy (FSRT) using a stereotactic mask fixation system. PATIENTS AND METHODS: Sixteen patients treated with FSRT were involved in the study. A commercial stereotactic mask fixation system (BrainLAB AG) was used for patient immobilization. Serial CT scans obtained before and during FSRT were used to assess the accuracy of patient immobilization by comparing the isocenter position. Daily portal imaging were acquired to establish day to day patient position variation. Displacement errors along the different directions were calculated as combination of systematic and random errors. RESULTS: The mean isocenter displacements based on localization and verification CT imaging were 0.1 mm (SD 0.3 mm) in the lateral direction, 0.1 mm (SD 0.4 mm) in the anteroposterior, and 0.3 mm (SD 0.4 mm) in craniocaudal direction. The mean 3D displacement was 0.5 mm (SD 0.4 mm), being maximum 1.4 mm. No significant differences were found during the treatment (P=0.4). The overall isocenter displacement as calculated by 456 anterior and lateral portal images were 0.3 mm (SD 0.9 mm) in the mediolateral direction, -0.2 mm (SD 1 mm) in the anteroposterior direction, and 0.2 mm (SD 1.1 mm) in the craniocaudal direction. The largest displacement of 2.7 mm was seen in the cranio-caudal direction, with 95% of displacements<2 mm in any direction. CONCLUSIONS: The results indicate that the setup error of the presented mask system evaluated by CT verification scans and portal imaging are minimal. Reproducibility of the isocenter position is in the best range of positioning reproducibility reported for other stereotactic systems.
Abstract: PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is a side effect related to administration of the adjuvant temozolomide (TMZ) in patients affected by glioblastoma. After chemoradiotherapy, adjuvant TMZ is administered as an oral multiple-day regimen, and TMZ-associated CINV may interfere with the continuation of chemotherapy, with potentially negative consequences on clinical efficacy. The aim of the present study was to investigate the efficacy of palonosetron for prevention of CINV-induced by adjuvant TMZ. METHODS: From March 2007 to August 2008, 33 patients with confirmed glioblastoma and eligible for adjuvant treatment with TMZ were enrolled in the study. All patients with responding or stable disease after concomitant radiotherapy plus daily TMZ (75 mg/m(2)) received a single i.v. bolus 0.25 mg of palonosetron 30 min before the beginning of adjuvant TMZ (150-200 mg/m(2)/day for five consecutive days every 4 weeks). The primary endpoint was the percentage of patients with complete response (CR), defined as no emetic episodes and no rescue medication during the overall phase (0-168 h). Secondary endpoints included CR during the 0-120 h and 0-168 h phases and complete control (CC; CR and no more than mild nausea) during the 0-120 h, 120-168 h, and 0-168 h phases. RESULTS: Thirty-three patients were enrolled in the study (median age 57.6 years, 23 male and 10 female, median Karnofsky Performance Status = 80). Each patient was receiving fixed doses of dexamethasone (range 2-8 mg/day). CR in the 0-120 h, 120-168 h, and 0-168 h phases was seen in 91% of patients. CC was observed in 88%, 91%, and 88% of cases during the 0-120 h, 120-168 h, and 0-168 h phases, respectively. Anti-emetic prophylaxis with palonosetron was well tolerated and the most frequent adverse event was grade 1-2 headache reported by seven patients (21%). CONCLUSION: A single dose of palonosetron before the initiation of multiple oral doses of TMZ, in patients on treatment with steady doses of dexamethasone, provides a high protection against CINV throughout the overall phase (0-168 h). The pharmacological profile of palonosetron, compared to first-generation 5-HT3 receptor antagonists, may have an impact on its clinical efficacy.
Abstract: The aim of this study was to evaluate local control and survival rates after stereotactic radiosurgery (SRS) plus whole-brain radiotherapy (WBRT) for the treatment of multiple brain metastases from non-small cell lung cancer (NSCLC).
Abstract: OBJECTIVES: The optimal treatment for patients with glioblastoma with unfavorable prognostic factors, such as old age and low performance status, remains controversial. We conducted a prospective study to assess the effect of temozolomide and short-course radiation versus short-course radiation alone in the treatment of poor-prognosis patients with newly diagnosed glioblastoma. PATIENTS AND METHODS: Forty-five patients with a newly diagnosed glioblastoma, older than 70 years or aged 50-70 years and with a Karnofsky performance score <or=70 were enrolled in this prospective study. Twenty-three patients were treated with an abbreviated course of radiotherapy (30 Gy in 6 fractions over 2 weeks) and 22 patients with the same radiotherapy schedule plus adjuvant temozolomide at the dose of 150-200 mg/m(2) for 5 days every 28-day cycle. The primary end point was overall survival. Secondary end points included progression-free survival and toxicity. RESULTS: Median overall survival was 7.3 months in the radiotherapy group and 9.4 months in the radiotherapy plus temozolomide group (P = 0.003), with respective 6-month overall survivals of 78% and 95%, respectively. Median progression-free survival was 4.4 months in the radiotherapy group and 5.5 months in the radiotherapy plus temozolomide group (P = 0.01), and respective 6-month progression-free survival rates were 22% and 45%. In multivariate analysis, Karnofsky performance score was the only significant independent predictive factor of survival (P = 0.03). Adverse effects of radiotherapy were mainly represented by neurotoxicity (24%), which resolved in most cases with the use of steroids. Grade 3-4 hematologic toxicity occurred in 36% of patients treated with temozolomide. CONCLUSIONS: The addition of temozolomide to short-term radiotherapy resulted in a statistically significant survival benefit with minimal additional toxicity in poor-prognosis patients with newly diagnosed glioblastoma. Future studies need to define the best combined regimens of radiotherapy and temozolomide on survival and quality of life in this subgroup of patients.
Abstract: Current treatment of glioblastoma in the elderly includes surgery, radiotherapy and chemotherapy, but the prognosis remains extremely poor, and its optimal management is still debated. Longer survival after extensive resection compared with biopsy only has been reported, although the survival advantage remains modest. Radiation in the form of standard (60 Gy in 30 fractions over 6 weeks) and abbreviated courses of radiotherapy (30-50 Gy in 6-20 fractions over 2-4 weeks) has been employed in elderly patients with glioblastoma, showing survival benefits compared with supportive care alone. Temozolomide is an alkylating agent recently employed in older patients with newly diagnosed glioblastoma. The addition of concomitant and/or adjuvant chemotherapy with temozolomide to radiotherapy, which is currently the standard treatment in adults with glioblastoma, is emerging as an effective therapeutic option for older patients with favorable prognostic factors. The potential benefits on survival, improvement in quality of life and toxicity of different schedules of radiotherapy plus temozolomide need to be addressed in future randomized studies.
Abstract: To analyze the recurrence patterns in patients with newly diagnosed glioblastoma (GBM) treated with conformal radiotherapy (RT) plus concomitant and adjuvant temozolomide (TMZ), and to compare the patterns of failure according to different target volume delineations.
Abstract: Chondrosarcoma (CSA) of the skull base (SB) is an uncommon, slowly growing, neoplasm comprising approximately 0.1% of all intracranial tumors and 6% of SB lesions. Even though its growth is slow, CSA is a potentially lethal tumor. The therapeutic approach to CSA of the SB is still controversial and clinical experience is limited because of the relative rarity of this tumor. The use of proton therapy (PT) after maximal surgery is widely accepted, but there are no controlled studies demonstrating the need of PT and its superiority in comparison to radiotherapy with photons. We conducted a systematic review of the scientific literature published during the period between January 1980 and June 2008 on data regarding irradiation of CSA of the SB with PT and a series of inclusion criteria. During August 2008, two independent reviewers (M.A. and D.A.), by applying the key words "skull base", "chondrosarcoma", and "proton therapy" selected those studies from the PubMed database in which a minimum of ten patients received palliative, radical, or postoperative irradiation with protons and which furnished a minimum of 24 months of follow-up. Forty nine reports were retrieved. There were no prospective trials (randomized or nonrandomized) but just nine uncontrolled single-arm studies for PT mainly related to advanced and frequently incompletely resected tumors. According to the inclusion criteria, only four articles, reporting the most recent updated results of the publishing institution, were included in the analysis providing clinical outcomes for 254 patients in total. Therapeutic approach to CSA of the SB has traditionally relied on surgical control. Radiation therapy has demonstrated to be a valuable modality for local control in the postoperative setting or in advanced/inoperable cases treated with definitive intent. The use of PT following maximal surgical resection shows a very high probability of medium- and long-term cure with a relatively low risk of significant complications.
Abstract: OBJECTIVES: The optimal treatment for elderly patients (age >70 years) with glioblastoma (GBM) remains controversial. We conducted a prospective trial in 43 consecutive elderly patients with GBM treated with hypofractionated radiotherapy (RT) followed by adjuvant temozolomide. PATIENTS AND METHODS: Forty-three patients 70 years of age or older with a newly diagnosed GBM and a Karnofsky performance status (KPS) > or = 60 were treated with hypofractionated RT (6 fractions of 5 Gy each for a total of 30 Gy over 2 weeks) followed by up to 12 cycles of adjuvant temozolomide (150-200 mg/m(2) for 5 days during each 28 day cycle). The HRQOL was assessed with the EORTC Quality of Life Questionnaire C30. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), toxicity and quality of life. RESULTS: The median OS was 9.3 months and the median PFS was 6.3 months. The 6 and 12 month survival rates were 86% and 35%, respectively. The 6 and 12 month PFS rates were 55% and 12%, respectively. In multivariate analysis KPS was the only significant independent predictive factor of survival (P = 0.008). Neurological deterioration occurred during or after RT in 16% of patients and was resolved in most cases with the use of steroids. Grade 3-4 hematologic toxicity occurred in 28% of patients during the adjuvant chemotherapy treatment with temozolomide. The treatment had no negative effect on HRQOL, however, fatigue (P = 0.02) and constipation (P = 0.01) scales worsened over time. CONCLUSIONS: Hypofractionated RT followed by temozolomide may provide survival benefit maintaining a good quality of life in elderly patients with GBM. It may represent a reasonable therapeutic approach especially in patients with less favourably prognostic factors.
Abstract: Glioblastoma is the most frequent and devastating primary malignant brain tumor in adults. Surgery followed by standard radiotherapy with concomitant and adjuvant chemotherapy with temozolomide is the standard of care in patients with glioblastoma, however the prognosis remains poor with a median survival in the range of 12-15 months. Common genetic abnormalities in glioblastoma are associated with aberrant activation or suppression of cellular signal transduction pathways and resistance to radiation and chemotherapy. Special attention has been focused on targets such as epidermal growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and on pathways such as the phosphatidylinositol-3kinase/Akt/mammalian target of rapamycin and Ras/Raf/mitogen-activated protein-kinase pathways. Several signal transduction inhibitors have been examined in preclinical and clinical malignant glioma trials, including antiangiogenic agents (bevacizumab, enzastaurin), and inhibitors of epidermal growth factor receptor tyrosine kinase (gefitinib and erlotinib), mammalian target of rapamycin (temsirolimus, everolimus) and integrin (cilengitide). Although preliminary clinical results of the use of targeted agents have not translated into significantly better survival, more recent phase II trials are exploring the combination of multitargeted drugs with cytotoxic chemotherapy and radiotherapy in order to overcome the resistance of tumors to single-agent targeted therapies. This review summarizes the current results with cytotoxic and targeted molecular agents in glioblastoma and the development of new chemoradiation strategies under evaluation to increase their effectiveness.
Abstract: Radiotherapy (RT) remains an effective treatment for residual or recurrent pituitary adenomas with excellent rates of tumour control and normalisation of excess hormone secretion. The main late toxicity is hypopituitarism: other side effects are rare. We discuss technical developments in the delivery of radiotherapy (stereotactic conformal radiotherapy (SCRT) and stereotactic radiosurgery (SRS)), all aiming to reduce the amount of normal brain receiving significant doses of radiation. We provide a comprehensive review of published data on outcome of conventional fractionated radiotherapy and modern RT techniques. SCRT is a suitable treatment technique for all sizes of pituitary adenoma and efficacy is comparable to conventional RT; the lack of long term follow up means that currently there is no information on potential reduction in the incidence of late radiation induced toxicity. Single fraction SRS can only be safely delivered to small tumours away from critical structures. There is no evidence that it produces faster decline of elevated hormone levels than fractionated treatment and is not associated with lesser morbidity.
Abstract: The optimal management of craniopharyngiomas remains controversial. The first-line treatment usually consists of surgical resection. Complete tumor removal provides a high rate of long-term control; however, aggressive surgery is associated with significant incidence of complications. Radiotherapy (RT) is currently used in patients after limited surgery and achieves excellent long-term tumor control. Stereotactic radiotherapy, both in the form of radiosurgery (RS) or fractionated stereotactic radiotherapy (FSRT), has been developed as a more accurate technique of irradiation with more precise tumor localization and consequently a reduction in the volume of normal brain irradiated to high radiation doses. We provide a review of published data on outcome of conventional fractionated RT and modern radiation techniques. FSRT is a suitable treatment technique for all sizes of craniopharyngiomas, and efficacy is comparable to conventional RT. Single-fraction stereotactic radiosurgery is usually delivered to small tumors away from critical structures. Longer follow-up is necessary to confirm the excellent tumor control and the potential reduction of long-term radiation toxicity.
Abstract: Chordoma is a rare, slow-growing, locally aggressive, primary bone tumor that arises from the skull base region in approximately 25-35% of cases. The therapeutic approach to chordoma has traditionally been surgery, followed by radiation therapy. The advent of charged particle radiotherapy has let us consider protons as the postoperative treatment of choice, but no controlled studies have yet confirmed the superiority of protons over photons. During January 2008, two independent researchers conducted a systematic review of the current data on the treatment of base of the skull chordoma C with proton therapy (PT) and, for comparison, with other irradiation techniques (conventional radiation therapy, ion therapy, fractionated stereotactic radiation therapy, and radiosurgery). Two hundred and ten reports in total were retrieved (81 concerning PT). According to the inclusion criteria, 47 articles were considered in the analysis. There were no prospective trials (randomized or nonrandomized) but just seven uncontrolled single-arm studies for PT, providing clinical outcomes for 416 patients in total; these reports were mainly related to advanced inoperable or incompletely resected tumors. The therapeutic approach to chordoma of the base of the skull has traditionally relied on surgical control. Radiation therapy has demonstrated to be a valuable modality for local control in the postoperative setting, particularly with the advent of charged particle radiotherapy. The use of protons has shown better results in comparison to the use of conventional photon irradiation, resulting in the best long-term (10 years) outcome for this tumor with relatively few significant complications considering the high doses delivered with this therapeutic modality.
Abstract: OBJECTIVES: The optimal treatment for elderly patients (age > 70 years) with glioblastoma remains controversial. We conducted a prospective trial in 32 consecutive elderly patients with glioblastoma who underwent surgery followed by radiotherapy (RT) plus concomitant and adjuvant temozolomide. PATIENTS AND METHODS: 32 patients 70 years of age or older with a newly diagnosed glioblastoma and a Karnofsky performance status (KPS) > or = 70 were treated with RT (daily fractions of 2 Gy for a total of 60 Gy) plus temozolomide at the dose of 75 mg/m(2) per day followed by six cycles of adjuvant temozolomide (150-200 mg/m(2) for 5 days during each 28-day cycle). The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS) and toxicity. RESULTS: The median OS was 10.6 months and the median PFS was 7 months. The 6-month and 12-month survival rates were 91% and 37%, respectively. The 6-month and 12-month PFS rates were 56% and 16%, respectively. In multivariate analysis KPS was the only significant independent predictive factor of survival (P = 0.01). Adverse effects were mainly represented by neurotoxicity (40%), which resolved in most cases with the use of steroids, and Grade 3-4 hematologic toxicity in 28% of patients. Chemotherapy was stopped in 2 patients, delayed in 9 patients and reduced in 4 patients. CONCLUSIONS: Standard RT plus concomitant and adjuvant temozolomide is a feasible treatment for elderly patients with newly diagnosed glioblastoma who present with good prognostic factors.
Abstract: The initial management of nonfunctioning pituitary macroadenomas (NFAs) is usually surgery; however, a significant proportion of NFAs may require further treatment. Radiotherapy is currently used in patients with residual tumour and achieves excellent long-term control, but there are concerns about potential late toxicity. Stereotactic radiotherapy, both in the form of radiosurgery or fractionated stereotactic radiotherapy, has been developed as a more accurate technique of irradiation with more precise tumour localization and consequently a reduction in the volume of normal tissue, particularly the brain, irradiated to high radiation doses. A review of the literature suggests that new radiation techniques offer safe and effective treatment for recurrent or residual pituitary adenomas; however longer follow-up is necessary to confirm the excellent tumour control and the potential reduction of long-term radiation toxicity. Currently, radiotherapy has an important role in patients with residual or progressive disease after surgery. Patients with small or no residual tumours after surgery may generally continue on a policy of surveillance without immediate irradiation, in order to avoid the potential toxicity of treatment.
Abstract: Patients with residual or recurrent Cushing's disease receive external beam radiotherapy (RT) with the aim of achieving long-term tumour control and normalization of elevated hormone levels. Treatment is given either as conventional radiotherapy using conformal techniques or as stereotactic radiotherapy, which is either used as fractionated treatment (SCRT) or as single fraction radiosurgery (SRS). We describe the technical aspects of treatment and report a systematic review of the published literature on the efficacy and toxicity of conventional RT, SCRT and SRS. There are no studies directly comparing the different radiation techniques and the reported results are inevitably of selected patients by investigators with interest in the treatment tested. Nevertheless the review of the published literature suggests better hormone and tumour control rates after fractionated irradiation compared to single fraction radiosurgery. Hypopituitarism represents the most commonly reported late complication of radiotherapy seen after all treatments. Although the incidence of other late effects is low, the risk of radiation injury to normal neural structures is higher with single fraction compared to fractionated treatment. Stereotactic techniques offer more localized irradiation compared with conventional radiotherapy, however longer follow-up is necessary to confirm the potential reduction of long-term radiation toxicity of fractionated SCRT compared to conventional RT. On the basis of the available literature, fractionated conventional and stereotactic radiotherapy offer effective treatment for Cushing's disease not controlled with surgery alone. The lower efficacy and higher toxicity of single fraction treatment suggest that SRS is not the appropriate therapy for the majority of patients with Cushing's disease.
Abstract: BACKGROUND: Transsphenoidal surgery is safe and effective in patients with secreting pituitary adenomas; however, variable outcomes have been reported according to the different criteria used to define the biochemical remission of hormone hypersecretion. We report the long-term endocrinologic follow-up results of a large cohort of patients who underwent TSS for secreting pituitary adenomas according to the most recent stringent criteria of cure. METHODS: Two hundred ten consecutive patients were operated on by TSS between 1995 and 2004 for a secreting pituitary adenoma (65 PRL-, 109 GH-, and 36 ACTH-secreting adenomas) and were considered for the study. RESULTS: The overall remission rate was 65% for the whole series, being 64%, 61%, and 75% for PRL-, GH-, and ACTH-secreting adenomas, respectively. Eighty-six percent of microadenomas and 53% of macroadenomas were cured by surgery. Remission rates were significantly higher in GH- and ACTH-secreting pituitary macroadenomas than in macroprolactinomas. At a median follow-up of 56 months, tumor recurrence was 0%, 11%, and 14% for GH-, ACTH-, and PRL-secreting tumors. Tumor size, cavernous sinus invasion, and high hormone levels were negatively correlated to the outcome. CONCLUSION: Transsphenoidal surgery remains an effective treatment for secreting pituitary tumors according to the most recent criteria of cure. Patients with PRL- or ACTH-secreting adenomas may recur after apparently successful surgery, thereby justifying long-term careful endocrinologic follow-up.
Abstract: OBJECTIVES: Radiotherapy is currently used in patients with residual or recurrent pituitary adenomas after surgery. However, there is little information of long-term outcome of patients with Cushing's disease following radiotherapy. We assessed the long-term efficacy and toxicity of conventional radiotherapy in the control of Cushing's disease after unsuccessful transsphenoidal surgery. PATIENTS AND METHODS: Forty patients with Cushing's disease were treated with conventional external beam radiotherapy at our Institution between 1988 and 2002. The median age was 38. All patients received radiotherapy following unsuccessful surgery or at tumour recurrence to a dose of 45-50 Gy in 25-28 fractions. The persistence of active disease after surgery was diagnosed by the increased high plasma cortisol levels, high 24 h urinary cortisol levels and absence of cortisol suppression after administration of dexamethasone. RESULTS: The 5 and 10 year local tumour control was 93% and the 5 and 10 year survival was 97 and 95%. Normalization of plasma cortisol was seen in 28% of patients at 1 year, 73% at 3 years, 78% at 5 years and 84% at 10 years. The average timing to remission was 24 months. The most common side effect was hypopituitarism that increased progressively during the follow-up, being present in 62% and in 76% of patients at 5 and 10 years after RT. There were no other serious complications as radiation induced optic neuropathy or second tumours. CONCLUSION: Radiotherapy is effective in the long-term tumour- and hormone hypersecretion control of ACTH-secreting pituitary adenomas, however with a high prevalence of hypopituitarism. At the moment, it remains an important treatment option after failure of surgery.
Abstract: PURPOSE: To describe the technique and results of stereotactically guided conformal radiotherapy (SCRT) in patients with craniopharyngioma after conservative surgery. METHODS AND MATERIALS: Thirty-nine patients with craniopharyngioma aged 3-68 years (median age 18 years) were treated with SCRT between June 1994 and January 2003. All patients were referred for radiotherapy after undergoing one or more surgical procedures. Treatment was delivered in 30-33 daily fractions over 6-6.5 weeks to a total dose of 50 Gy using 6 MV photons. Outcome was assessed prospectively. RESULTS: At a median follow-up of 40 months (range 3-88 months) the 3- and 5-year progression-free survival (PFS) was 97% and 92%, and 3- and 5-year survival 100%. Two patients required further debulking surgery for progressive disease 8 and 41 months after radiotherapy. Twelve patients (30%) had acute clinical deterioration due to cystic enlargement of craniopharyngioma following SCRT and required cyst aspiration. One patient with severe visual impairment prior to radiotherapy had visual deterioration following SCRT. Seven out of 10 patients with a normal pituitary function before SCRT had no endocrine deficits following treatment. CONCLUSION: SCRT as a high-precision technique of localized RT is suitable for the treatment of incompletely excised craniopharyngioma. The local control, toxicity and survival outcomes are comparable to results reported following conventional external beam RT. Longer follow-up is required to assess long-term efficacy and toxicity, particularly in terms of potential reduction in treatment related late toxicity.
Abstract: OBJECTIVE: To assess the medium-term outcome in a cohort of patients with residual or recurrent pituitary adenoma treated with fractionated stereotactic conformal radiotherapy (SCRT). PATIENTS AND METHODS: Ninety-two patients (median age 50 years) with a residual or recurrent nonfunctioning (67) or a secreting (25) pituitary adenoma were treated between 1995 and 2003. Eighteen patients had a GH-secreting, five PRL-secreting and two an ACTH-secreting pituitary adenoma. Vision was impaired in 39 patients, with visual field deficit (35) and/or reduced visual acuity (25). Sixty-four patients had partial or complete hypopituitarism before SCRT. The treatment was delivered stereotactically by four noncoplanar conformal fixed fields using a 6-MV linear accelerator to a dose of 45 Gy in 25 fractions. RESULTS: At a median follow-up of 32 months (range 4-108) the 1, 3 and 5 years actuarial progression-free survival is 99%, 98% and 98%, and overall survival is 98%. Three patients recurred 5 months, 1 year and 9 years after SCRT requiring surgery. In secreting adenomas, hormone levels declined progressively, becoming normal in more than a third of patients with GH-secreting and PRL-secreting pituitary tumours. 50% of baseline GH level was achieved in just under 2 years. The treatment was well tolerated with minimal acute toxicity. Hypopituitarism was the most common long-term effect; 22% of patients had worsening of pituitary function. One patient developed unilateral quadrantopia without tumour progression. CONCLUSION: SCRT as a high-precision technique of localized irradiation achieves tumour and hormone control of pituitary adenomas comparable with previously published data on the efficacy of conventional radiotherapy. Despite the potential advantage of reducing the volume of normal brain irradiated, the theoretical benefit over conventional radiotherapy in terms of the reduction in long-term morbidity has not yet been demonstrated and requires longer follow-up. Potential effect on long-term cognitive function has not been tested.
Abstract: We assessed the risk of second brain tumors in a cohort of patients with pituitary adenoma treated with conservative surgery and external beam radiotherapy. Four hundred and twenty-six patients (United Kingdom residents) with pituitary adenomas received radiotherapy at the Royal Marsden Hospital (RMH) between 1962 and 1994. They were followed up for 5749 person-years. The cumulative incidence of second intracranial tumors and systemic malignancy was compared with population incidence rates through the Thames Cancer Registry and the National Health Service Central Register (previously OPCS) to record death and the potential causes. Eleven patients developed a second brain tumor, including five meningiomas, four high grade astrocytomas, one meningeal sarcoma, and one primitive neuroectodermal tumor. The cumulative risk of second brain tumors was 2.0% [95% confidence interval (CI), 0.9-4.4%] at 10 yr and 2.4% (95% CI, 1.2-5.0%) at 20 yr, measured from the date of radiotherapy. The relative risk of second brain tumor compared with the incidence in the normal population was 10.5 (95% CI, 4.3-16.7). The relative risk was 7.0 for neuroepithelial and 24.3 for meningeal tumors. The relative risks were 24.2 (95% CI, 4.8-43.5), 2.9 (95% CI, 0-8.5), and 28.6 (95% CI, 0.6-56.6) during the intervals 5-9, 10-19, and more than 20 yr after radiotherapy (four cases occurred >20 yr after treatment). There was no evidence of excess risk of second systemic malignancy. An additional 10-yr update confirmed our previous report of an increased risk of second brain tumors in patients with pituitary adenoma treated with surgery and radiotherapy. The 2.4% risk at 20 yr remains low and should not preclude the use of radiotherapy as an effective treatment option. However, an increased risk of second brain tumors continues beyond 20 and 30 yr after treatment.
Abstract: An increasing proportion of pituitary adenomas are recognized in the elderly, raising the question of their optimal diagnosis and management. Age-related endocrine changes and associated diseases may significantly modify the clinical presentation and hormonal evaluation of these patients. About 80% of pituitary adenomas in this age group are non-secreting, requiring careful differential diagnosis with non-adenomatous sellar lesions. In this group, visual deterioration and hypopituitarism remain the leading symptoms. Recognized secreting tumours are mainly GH-secreting, most of them intrasellar, followed by prolactinomas, which present as clinically non-secreting and are usually invasive. Cushing's disease appears as a very rare eventuality in the elderly. Optimal therapeutic management should aim to control the disease while preserving or improving patient's quality of life. Transsphenoidal surgery has proved to be an efficient and well-tolerated option for non-secreting adenomas with visual defects and intrasellar GH-secreting adenomas, being able to improve metabolic and cardiovascular complications of acromegaly even in this age group. In contrast, dopamine-agonist drugs can be proposed as a primary therapy for prolactinomas even in the presence of severe neurological complications. Because the use of radiotherapy is hampered by its delay of action and potential neurological side effects, its indications should be better defined in this age group. The clinical importance of hypopituitarism should not be underestimated, and thyroid- and adrenal-replacement therapy are mandatory in the presence of documented hormone deficiency, carefully avoiding overtreatment in order to limit possible side effects on the cardiovascular system and bone mineralization. Indications for GH- and sex steroid-replacement therapy still await age-specific guidelines.
Abstract: OBJECTIVE: To assess the long-term efficacy and safety of conventional radiotherapy (RT) in the control of acromegaly according to recent stringent criteria of cure. DESIGN: A retrospective longitudinal study. PATIENTS AND METHODS: Forty-seven patients with active acromegaly were treated with conventional RT between 1982 and 1994. All patients were first operated on and successively irradiated at a dose of 45-50 Gy in 25-28 fractions for persistent (n = 40) or recurrent (n = 7) disease. MEASUREMENTS: Long-term GH/IGF-I secretion and local tumour control were evaluated regularly, and possible side-effects were searched for systematically, especially in terms of secondary endocrine dysfunction. Biochemical cure of acromegaly was defined by glucose-suppressed plasma GH levels below 1 microg/l during an oral glucose tolerance test (OGTT) and normal age-corrected IGF-I values. RESULTS: The 5-, 10- and 15-year overall survival rates were 98%, 95% and 93%, respectively. Suppression of GH during OGTT was seen in 9% of patients at 2 years, 29% at 5 years, 52% at 10 years, and 77% at 15 years. Age-corrected IGF-I levels were normal in 8% of patients 2 years after RT, and this proportion increased to 23%, 42% and 61% after 5, 10 and 15 years, respectively. Normalization of GH/IGF-I mainly depended on pre-RT levels. Local tumour control was 95% at 5, 10 and 15 years after treatment. Late toxicity was mainly represented by progressive hypopituitarism, which was present in 33% of patients at baseline and increased to 57%, 78% and in 85% of patients at 5 10 and 15 years after RT, respectively. CONCLUSION: Conventional RT is effective in the long-term control of GH-secreting pituitary adenomas, although with a high prevalence of progressive hypopituitarism. At present, it remains a suitable option in acromegalic patients uncontrolled by surgery or medical therapy.
Abstract: Transsphenoidal surgery (TSS) is a well recognised treatment for secreting pituitary adenomas, however a very wide variation of clinical outcomes and recurrence rates has been reported, depending on the different criteria used to define the cure. We reported the clinical outcome of a large series of patients operated on for a secreting pituitary adenoma according to the most recent stringent criteria of biochemical remission nowadays accepted. One hundred and twenty-five consecutive patients with a secreting pituitary adenoma (42 PRL-, 67 GH- and 16 ACTH-secreting adenomas) who were operated on by the two same neurosurgeons were considered for the study. Biochemical remission of disease was achieved in 56% of patients; 78% for patients with microadenoma and 47% for patients with macroadenomas, respectively. No cases of mortality or major immediate postoperative complications were observed. Tumour size, high hormone levels and dural invasion were significantly correlated to a poor surgical outcome. The recurrence rates ranged between 0 and 24%, being higher for PRL-secreting tumours. In conclusion, TSS is safe and effective in secreting pituitary tumours. It is still the first treatment for GH- and ACTH-secreting adenomas, whereas in patients with prolactinomas, surgery should be reserved for cases of resistance or intolerance to dopamine agonists.
Abstract: BACKGROUND: Cardiac abnormalities develop in patients with acromegaly as a consequence of effects of GH/IGF-I on the heart and related cardiovascular risk factors. OBJECTIVE: To evaluate the possible contribution of postoperative variations in blood pressure (BP), glucose tolerance and insulin sensitivity to the cardiac improvement reported in patients who have been cured of acromegaly. DESIGN: Thirty-one patients with acromegaly were studied before and 6 Months after successful transsphenoidal surgery, defined by normal age-related IGF-I concentrations and glucose-suppressed GH concentrations <1 microg/l. METHODS: Cardiovascular parameters were assessed by Doppler echocardiography and 24-h ambulatory blood pressure monitoring. Insulin sensitivity indexes were calculated on the basis of fasting and post-load glycaemia and insulinaemia and referred to as HOMA(ISI) and OGTT(ISI), respectively. RESULTS: Successful surgery was confirmed to improve left ventricular mass index (LVMI) and diastolic filling significantly. Mean 24-h systolic BP values decreased (P=0.009) and BP rhythm was restored in 12 of 15 patients with a blunted preoperative profile. Glucose tolerance normalized in patients with preoperative glucose intolerance (n=7) or diabetes mellitus (n=3). HOMA(ISI) and OGTT(ISI) increased (P=0.0001 for each parameter), indicating a marked improvement in insulin sensitivity. The postoperative reduction in LVMI correlated with increased insulin sensitivity (P<0.001 for both indexes), but not with other parameters. Improved diastolic filling correlated with the reduction in LVMI. CONCLUSIONS: Successful surgery in patients with acromegaly induces a significant improvement in haemodynamic and metabolic risk factors. This study suggests a direct link between insulin resistance and acromegalic cardiomyopathy.
Abstract: BACKGROUND: Continuous research into new strategies and chemotherapy agents for the treatment of malignant high-grade gliomas have led to the synthesis of a new chemotherapy drug, temozolomide (TMZ), with a lower toxicity profile compared to conventional chemotherapy agents, such as nitrosoureas. Temozolomide is an oral alkylating chemotherapy agent licensed for the treatment of recurrent high-grade gliomas, anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). Because of its favorable pharmacokinetic and pharmacodynamic properties and improved tolerability, TMZ is now under investigation for concomitant use with radiotherapy in patients with newly-diagnosed GBM. We present a phase II clinical trial investigating the efficacy and safety of radio-chemotherapy combined treatment using TMZ, followed by six cycles of adjuvant chemotherapy with TMZ, in patients with newly-diagnosed GBM who have undergone debulking surgery or biopsy only. PATIENTS AND METHODS: Twenty-one patients with newly histologically-diagnosed GBM were enrolled into this phase II clinical trial. In phase I of the study, TMZ (75 mg/m2/day per 7 days/wk for 6 weeks) was orally administered to patients concomitantly with radiotherapy (RT) (2 Gy per fraction once daily, per 5 days/wk for 6 weeks). In phase II of the study, four weeks after completion of RT, a monochemotherapy using TMZ was administered at the dosage of 200 mg/m2/day per 5 days every 28 days for 6 cycles. Primary end-points were the safety and tolerability profile of this two-phase combined treatment and secondary end-points were the objective response and survival rates at twelve months and eighteen months from study entry. RESULTS: The one-year survival rate of patients treated with the investigated multimodality treatment was 58% and median survival time was 15.7 months. Concomitant RT plus TMZ (phase I) followed by adjuvant TMZ (phase 2) were well-tolerated; indeed, nonhematological adverse events were rare and mild to moderate in severity; grade 3 and 4 neutropenia and thrombocytopenia were the major-related hematological side-effects observed in only 2 and 3 of all patients in phase I and 4 patients in phase II. We found that the combination of radio- and chemo-therapy, in phase I of the study did not significantly increase the incidence and severity of hematological toxicity caused by the adjuvant TMZ-based chemotherapy administered in phase II of the study. CONCLUSION: The investigated multimodality treatment regimen was well-tolerated and prolonged survival while improving patients' quality of life.
Abstract: Among the transcription factors involved in pituitary ontogenesis and physiology, basic helix-loop-helix (bHLH) have been poorly studied. Members of bHLH family include NeuroD1 and ASH1, both involved in neuroendocrine differentiation. We evaluated their mRNA expression patterns, by semi-quantitative RT-PCR analysis (sq-RT-PCR) and/or Northern blot, in a series of 33 pituitary adenomas (PA), anterior pituitaries, and pituitary cell lines. Immunohistochemistry for NeuroD1 was also performed in 25 PA. Low levels of NeuroD1 were observed in normal pituitaries and in the somatomammotroph cell lines GH3/GH4C1, contrasting with high levels in corticotroph AtT20 cells. NeuroD1 mRNA was widely expressed in PA (82%), with measurable levels found especially in those derived from Pit-1 independent lineages, i.e. corticotroph (5/5) and clinically non-secreting (CNS) adenomas (9/11). According to sq-RT-PCR analysis, overexpression of NeuroD1 compared to normal pituitaries was frequent. Variable nuclear NeuroD1 immunopositivity was also present in about 70% of studied cases. ASH1 mRNA was widely detected in normal pituitaries, in all tumour cell lines and in most PA (84%), with measurable levels in corticotroph (5/5) and CNS (9/11) adenomas, and in a significant subset of PA derived from Pit-1 dependent lineages (9/16). We conclude that: a) NeuroD1 is differentially expressed in PA and its possible ontogenetic and/or pathogenetic implications in non-corticotroph PA are discussed; b) ASH1 is a neuroendocrine marker whose expression is largely conserved in normal and neoplastic pituitary cells.
Abstract: Criteria to define the biochemical remission of acromegaly following surgery have changed over the years, and the current use of stringent criteria needs a critical re-evaluation of the surgical results. On the other hand, few data are currently available concerning the possible impact of pituitary surgery on the quality of life of operated acromegalic patients. In this prospective study, we wished to evaluate the initial outcome and long-term recurrence rate in a large series of acromegalic patients operated on by transsphenoidal surgery (TSS), to carefully analyse predictive factors for surgical outcome and to point out possible additional effects of surgery in these patients. Ninety-two out of 98 operated patients could be considered for follow-up. Biochemical remission was strictly defined as plasma GH levels <1 ng/ml during an oral glucose tolerance test (OGTT) and normalisation of age-related IGF-I levels. Hormonal assessment, including an OGTT, was performed 6 months following surgery and then annually to evaluate pituitary function. Fifty-five per cent of patients achieved a biochemical remission of acromegaly. The remission rate at 6 months was 80% for patients with microadenoma and 50% for macroadenoma. Univariate analysis showed that a large extrasellar extension, preoperative high GH levels and dural invasion were correlated with a poor outcome of surgery while, according to multivariate analysis, only invasion of cavernous sinus and preoperative GH levels > 10 ng/ml were independent negative predictors. Mortality was 0% and the overall complication rate was about 10%. Pituitary function worsened in five patients but improved in 16 out of 30 patients with preoperative pituitary defects. No recurrence was observed during a median follow-up of about 8 years. We conclude that TSS is able to achieve a biochemical remission in more than half of acromegalic patients, and that the current criteria for remission seem to indicate a cure in most cases.
Abstract: BACKGROUND: Radiotherapy and more recently radiosurgery represent important therapeutic methods for the treatment of tumors and arterovenous malformations affecting the central nervous system, even though several significant side-effects have been described (radionecrosis, tumors, etc.). Gliomas induced by radiation therapy are decidedly unusual, and the first descriptions of this association only appeared in the 1960s. METHODS: The pertinent literature was reviewed to yield 116 cases in which a glioma developed after radiotherapy for cranial pathologies (included 10 personal cases treated in our Institution). One of our patients had undergone radiosurgery for a cavernous angioma. RESULTS: Patients who developed a radiation-induced glioma were younger, as a group, than those affected with so-called "spontaneous" gliomas. The tumor originated in the previously irradiated area, after average doses of 32 Gy and an average latency period of 9.6 years in accordance with the findings reported by the authors and in our experience as well. Radiotherapy had most frequently been performed for acute lymphoblastic leukemia. Our Case 10 is the fourth case of intracranial tumor arising after radiosurgery to be described in the literature. CONCLUSIONS: Though rare, gliomas may represent a late complication of radiation treatment. The behavior of the radiation-induced variety of glioma does not seem to differ significantly from that of its "spontaneous" counterpart. Late complications of the radiosurgery are probably underestimated because of the relatively recent introduction of this technique. On the contrary, these should be scrupulously evaluated when deciding whether to employ this method for therapeutic purposes for relatively benign or congenital lesions (which generally affect young patients with a long life expectancy).
Abstract: Although the human central nervous system used to be considered relatively resistant to the carcinogenic action of ionizing radiation, several lines of evidence now document a high incidence of secondary tumors in irradiated patients. The numerous reports of radiation-induced cerebral meningiomas generally distinguish those induced by high-dose radiation from those induced by low-dose radiation. We describe the case of patient who underwent subtotal resection of a chromophobe pituitary adenoma at the age of 18 years, who was successively treated by conventional fractionated radiotherapy with gamma rays emitted by a source of 60Co until a total dose of 41 Gy. Over the next 30 years the patient experienced all the known late effects of radiation, including panhypopituitarism, cranial-nerve deficits (II, III and VI), massive radiation necrosis involving the left cerebral hemisphere and causing right hemiparesis and aphasia and, ultimately, an atypical tentorial meningioma with early recurrence after total resection.
Abstract: Pituitary adenomas in the elderly represent an increasing proportion of pituitary tumors, making the surgical management of these patients of special importance. We therefore decided to review our experience with transsphenoidal surgery (TSS) in this age group, in order to better evaluate its efficacy, safety and outcome. A retrospective study was performed on 39 patients aged more than 70 years at the time of surgery (mean age 74.1 +/- 2.9 years) and with a minimum follow-up duration of 4 years at the time of the study. Thirty-one had a nonfunctioning pituitary adenoma, 5 had a GH-secreting adenoma and 3 a macroprolactinoma, respectively. The commonest presenting symptom was visual deterioration (60%), whereas hypopituitarism were present in 41% of patients. All patients underwent TSS without any major peri- and post-operative complications. Visual fields improved in 74% of patients. Post-operative radiotherapy was performed in 17 patients with partial surgical resection and/or persistent hormonal hypersecretion, whereas 22 patients with subtotal or total surgical resection were treated by surgery only. Long-term follow-up (mean 9.1 +/- 2.7 years) showed evidence for tumor regrowth in one irradiated (5.9%) and 3 non-irradiated patients (13.6%), respectively. A noticeable complication of radiotherapy was progressive hypopituitarism, which worsened or developed in 65% of patients. We conclude that TSS is safe and well tolerated even in elderly patients, with a low incidence of minor complications. The indications for post-operative radiotherapy in patients with incomplete tumor resection should be better defined.
Abstract: Pituitary tumours are usually benign neoplasia, but may have a locally aggressive or malignant evolution. This study aimed to identify factors which mostly influence their proliferative activity, in order to clarify its value for clinical and research purposes. The proliferative index was determined in a prospective series of 132 pituitary tumours as the percentage of monoclonal antibody MIB-1-immunopositive cells and referred to as the MIB-1 labelling index (LI). Its distribution was analysed according to both univariate and multivariate models. A life-threatening pituitary tumour is presented separately. The mean LI was 1.24+/-1.59%, with significant differences between clinically secreting (CS) and clinically non-secreting (CNS) adenomas. In CS adenomas (n=65), LI was highly variable and markedly influenced by pre-operative pharmacological treatment (0.80+/-1.03 vs 2.06+/-2.39% in treated vs untreated cases, P=0.009); it decreased with patient's age (P=0.025, r=0.28) and increased with tumour volume and invasiveness. The influence of pre-operative treatment and macroscopic features on LI in this group was confirmed by multivariate analysis. In CNS adenomas (n=67), LI distribution was less variable than in CS adenomas (P<0.0001), it was age-independent and correlations with tumour volume, invasiveness or recurrence did not reach significance. In a rapidly growing parasellar tumour, the mean LI was 24% at first surgery and exceeded 50% at second surgery performed 4 months later. LI should be interpreted according to hormone secretion and pre-operative treatment. Unusually high LI values deserve particular attention.
Abstract: BACKGROUND: Prolactinomas invading the skull base are rare, and could easily be confused with skull base tumors of nonpituitary origin. CASE DESCRIPTION: We report a series of 4 cases of giant prolactinomas invading the skull base and presenting with atypical symptoms. Case 1 presented with a short history of headache and nasal obstruction. Case 2 presented with progressive hypoacusia, dizziness, and ophthalmoplegia. In Case 3, the patient developed rapid progressive visual failure and psychiatric symptoms. Case 4 presented with a 1-year history of headache and retrorbital pain. The diagnosis of prolactinoma was made on the basis of tumor immunohistochemistry and/or high plasma prolactin levels (range from 650-6,500 ng/mL). Medical treatment with the dopamine agonist cabergoline was given; it was effective in normalizing prolactin levels and inducing tumor shrinkage. CONCLUSION: Prolactin levels should be measured in all large skull base tumors involving the pituitary region before any surgery or inappropriate radiotherapy is performed.
Abstract: Patients older than 65 years represent 3-5% of all acromegalic patients. The old age of the patients and the higher incidence of cardiovascular and metabolic complications related to acromegaly could increase the intra- and peri-operative risk, so that medical treatment is usually recommended as a therapy of choice. The aim of this retrospective study was to investigate the impact of transsphenoidal surgery in a series of 22 elderly patients with active acromegaly, with special regard to anaesthesiological risk, peri-operative complications, and clinical outcome. Despite an increased anesthesiological risk being present in 16/22 patients, no complication occurred during surgery. Similarly, no post-operative mortality or major complications were observed. Biochemical cure, defined at 6 months by glucose-suppressed plasma GH levels below 1 ng/ml and normal age-corrected IGF-I value levels, was achieved in 68% of patients and no recurrence of disease was observed in the subsequent follow-up (mean 5.2+/-2.1 years). A significant cardiovascular improvement was observed in cured patients, with a decrease of left ventricular mass index (91.3+/-20.1 vs 115.9+/-15.0 g/m(2); P<0.005), as measured by echocardiography, as well as a slight but significant decrease of systolic and diastolic blood pressure values (130.0+/-12.1 mmHg vs 137.6+/-13.5 mmHg P<0.05; and 84.2+/-6.4 mmHg vs 88.8+/-7.5 mmHg P<0.05, respectively). A significant post-operative improvement of glucose tolerance was also observed in this group. We conclude that transsphenoidal surgery, if well planned and carefully performed, is safe and able to induce a significant cardiovascular and metabolic improvement even in elderly acromegalic patients.
Abstract: OBJECTIVE: Transsphenoidal surgery results in biochemical remission of acromegaly in 45-80% of patients; however, few studies have addressed the impact of transsphenoidal surgery on cardiovascular function in acromegalic patients. The aim of this prospective study was to investigate the effects of postoperative GH/IGF-I normalization on echocardiographic parameters and blood pressure (BP) in a series of patients with active acromegaly. DESIGN: An open prospective study. PATIENTS: Thirty newly diagnosed acromegalic patients undergoing transsphenoidal surgery. MEASUREMENTS: Doppler echocardiography and 24-h ambulatory blood pressure monitoring were performed before and 6 months after transsphenoidal surgery. RESULTS: Fifteen patients were considered to be well controlled postoperatively (group A), as defined by normal age-corrected IGF-I levels and glucose-suppressed GH levels less than 2 mU/l, the remaining 15 patients being considered as poorly controlled (group B). In group A, a postoperative decrease of left ventricular mass index was observed (104.4 +/- 6.6 vs. 127.1 +/- 7.7 g/m2; P < 0.001), associated with an improvement of some indices of diastolic function, such as an increase of the early/late transmitral peak flow velocity (P < 0.05) and a decrease of isovolumic relaxation time (P < 0.01). No significant change was observed in group B. A significant decrease of 24-h systolic BP was also observed in group A (P < 0.05) and five of six patients normalized their BP circadian rythm. In contrast, a nonsignificant increase in BP values, with a persistent blunted BP profile where present, was observed in group B. CONCLUSIONS: We conclude that successful transsphenoidal surgery is able to induce a significant improvement in some cardiac parameters and a slight reduction in systolic blood pressure in acromegalic patients.
Abstract: The insulin-like growth factor (IGF) binding proteins (IGFBPs) were initially identified as carrier proteins for IGF-I and IGF-II in a variety of biologic fluids. Their presumed function was to protect IGF peptides from degradation and clearance, increase the half-life of the IGFs, and deliver them to appropriate tissue receptors. The concept of IGFBPs as simple carrier proteins has been complicated, however, by a number of observations: 1) the six IGFBPs vary in their tissue expression and their regulation by other hormones and growth factors; 2) the IGFBPs are subjected to proteolytic degradation, thereby altering their affinities for the IGFs; 3) IGFBP-3 and IGFBP-5, in addition to binding IGFs, also can associate with an acid-labile subunit, thereby increasing further the half-life of the IGFs; 4) in addition to modifying the access of IGF peptides to IGF and insulin receptors, several of the IGFBPs may be capable of increasing IGF action; 5) some of the IGFBPs may be capable of IGF-independent regulation of cell growth; 6) some of the IGFBPs are associated with cell membranes or possibly with membrane receptors; and 7) some of the IGFBPs have nuclear recognition sites and may be found within the nucleus. Additionally, a number of cDNAs identified recently have been found to encode proteins that bind IGFs, but with substantially lower affinities than is the case with IGFBPs. The N-terminal regions of the predicted proteins are structurally homologous to the classic IGFBPs, with conservation of the cysteine-rich region. These observations suggest that these low-affinity binders are members of an IGFBP superfamily, capable of regulating cell growth by both IGF-dependent and IGF-independent mechanisms.insulin-like growth factor, insulin-like growth factor binding proteins.
Abstract: Cardiac involvement, mostly characterized by left ventricular hypertrophy associated with various degrees of cardiac dysfunction, greatly contributes to the increased mortality and morbidity observed in acromegaly. Lanreotide is a new SRIF analog characterized by a slow-release (SR) formulation with the peculiarity of a 30-mg im administration every 10-14 days. In this study, 13 patients with postoperative active acromegaly (9 females, 4 males, 45.9 +/- 16.3 yr old) underwent an echo-Doppler and hormonal study before and during a 12-month period of treatment with SR-lanreotide. GH and insulin-like growth factor I plasma levels (mean +/- SD) decreased significantly throughout the study period (from 10.1 +/- 2.2 to 3.9 +/- 0.9 ng/mL for GH, P < 0.005; and from 511.0 +/- 33.0 to 305.0 +/- 34.2 ng/mL for insulin-like growth factor I, P < 0.0001). Left ventricular mass index (mean +/- SD, 137.1 +/- 7.5 g/m2 at baseline) decreased after 3 months (120.0 +/- 5.4 g/m2), 6 months (111.7 +/- 5.7 g/m2), and 12 months (110.3 +/- 5.2 g/m2) of treatment (P < 0.005 at each time-point). This reduction in left ventricular mass index was accompanied by an improvement in some indexes of left ventricular diastolic function, especially the isovolumetric relaxation time (mean +/- SD, 109.1 +/- 4.6 m/sec at baseline), which decreased after 3 months (91.9 +/- 2.8 m/sec), 6 months (92.3 +/- 3.2 m/sec), and 12 months (92.2 +/- 3.0 m/sec) of treatment (P < 0.005 at each time-point). We conclude that SR-lanreotide is able to improve cardiac morphology and functional abnormalities in acromegaly; whether such beneficial effects on cardiac parameters will contribute to improve life expectancy in these patients should be further investigated.
Abstract: The number of epidermal growth factor (EGF) binding sites was determined by competitive binding assays in a series of 46 pituitary macroadenomas. A single concentration of 125I-EGF (1 nM) was used for all experiments. In four cases, a displacement curve was obtained by adding increasing concentrations of cold EGF, and Scatchard analysis showed the presence of two classes of EGF binding sites, with Kd1 = 0.62 +/- 0.23 nM and Kd2 = 53.8 +/- 8.2 nM for the high- and low-affinity binding sites respectively. The distribution of EGF binding sites was studied in 42 cases by a single-point assay, in the presence and in the absence of a 100-fold cold EGF excess. A non-parametric distribution of EGF binding sites was observed (median 10.2 fmol/mg membrane protein, range 0.0-332.0). EGF-receptor positivity, defined as EGF binding > or = 10.0 fmol/mg protein, was observed in 23 samples (54.8%), especially in prolactinomas (76.5%, P < 0.05 vs other tumors taken together) and in gonadotrope adenomas (62.5%). EGF binding was higher in invasive than in non-invasive adenomas (median: 12.8 vs 0.0 fmol/mg membrane protein, P = 0.047), and especially in adenomas invading the sphenoid sinus (median 26.7 fmol/mg membrane protein, P = 0.008 vs other adenomas). EGF binding also tended to increase with the grade of supra/extrasellar extension according to Wilson (P = 0.15). Sex steroid receptors (SSRs) were simultaneously determined in both cytosolic and nuclear fractions of 31 pituitary adenomas. Estrogen and progesterone receptors were determined by an enzyme-linked immunoassay and androgen receptors by a competitive binding assay with [3H]methyltrienolone. No correlation could be found between EGF binding and either the gender and gonadal status of the patients, or the expression of SSRs by the adenomas. We conclude that the EGF family of growth factors may play a role in the evolution of a significant subset of human pituitary adenomas, especially in their invasiveness, and that a high EGF binding capacity may represent an additional marker of aggressiveness for these tumors. Sex steroids do not appear to have a significant role in the regulation of EGF binding in vivo in these tumors.
Abstract: Meningiomas of the tuberculum sellae can induce compression of the optic tract. We report the case of a 54-year-old female patient affected by a suspected pituitary macroadenoma with severe visual field defects, who experienced a significant clinical and visual improvement during short-term octreotide therapy, contrasting with the lack of neuroradiological evidence for tumor shrinkage. The patient subsequently underwent transcranial surgery with a final diagnosis of meningioma. The putative mechanisms of visual improvement during octreotide therapy are discussed.
Abstract: OBJECTIVE: The interpretation of echocardiographic abnormalities in acromegalic patients is complicated by non-specific age-related diseases, many of which are commoner in acromegaly. We have therefore investigated the cause-effect relationship between GH/IGF-I hypersecretion and precocious cardiovascular abnormalities in a series of young acromegalic patients. DESIGN: An open prospective study. PATIENTS: 20 acromegalic patients aged under 30 years, with normal blood pressure and glucose tolerance, and 20 age-matched control subjects. MEASUREMENTS: Cardiac morphological parameters and indices of systolic and diastolic function at rest were studied by Doppler echocardiography. RESULTS: Left ventricular mass (LVM) and LVM index (LVMi) were higher in acromegalics than in control subjects (215.0 +/- 15.4 g vs 140.8 +/- 8.5 g, P = 0.0002 and 109.8 +/- 5.9 g/m2 vs 82.1 +/- 3.7 g/m2, P = 0.0008, respectively), reaching values of left ventricular hypertrophy in 4 patients (20%). Both ejection fraction and fractional shortening were normal (66.4 +/- 2.1% vs 62.2 +/- 1.9% and 37.5 +/- 1.5% vs 35.8 +/- 1.3%, respectively), indicating normal left ventricular systolic function. Abnormalities of left and right diastolic ventricular filling were found, which consisted of an increased isovolumic relaxation time (99.2 +/- 2.7 ms vs 89.0 +/- 2.7 ms, P = 0.01) and impaired mitral and tricuspidal flow velocity curves. CONCLUSIONS: An increase in cardiac mass and subclinical biventricular diastolic dysfunction were observed in young acromegalic patients. These findings argue for a direct cause-effect relationship between GH/IGF-I hypersecretion and myocardial abnormalities, and indicate that careful cardiological evaluation is mandatory in all acromegalics, whatever their age.
Abstract: OBJECTIVE: Hypertension is thought to play an important role in the pathogenesis of acromegalic cardiomyopathy. So far, hypertension has been defined by clinical measurement, with considerable variations reported concerning its prevalence in acromegalics. DESIGN: To determine the mean blood pressure (BP) values and the prevalence of hypertension in patients with active acromegaly according to non-invasive 24-hour ambulatory BP monitoring (ABPM) and to compare the data obtained with those provided by clinical measurement. PATIENTS: Forty patients with active acromegaly (22 women, 18 men, mean age 48.6 +/- 12.5 years) were included. Patients were in wash-out for antihypertensive treatment and none had been using any medical treatment for acromegaly for at least 3 months before the study. All were studied as outpatients. MEASUREMENTS: Clinical BP values were calculated as the mean of BP values obtained by standard sphygmomanometric measurement in three separate occasions. Mean 24-hour, daytime and night-time BP values were obtained by ABPM. RESULTS: The mean 24-hour BP values were lower than clinical BP values, the difference being significant for both systolic BP (SBP: 131.1 +/- 21.5 versus 136.1 +/- 16.3 mmHg, P < 0.02) and for diastolic BP (DBP: 74.6 +/- 10.6 versus 88.8 +/- 9.1 mmHg, P < 0.0001). ABPM values recorded during the daytime were 137.8 +/- 20.9 mmHg for SBP and 78.6 +/- 11.5 mmHg for DBP, the latter being significantly lower than the corresponding clinical BP values (P < 0.0001). About 60% of the patients considered hypertensive by clinical measurement were found to be normotensive by ABPM, thereby decreasing the prevalence of hypertension in this series from 42.5% to 17.5% according to ABPM (P < 0.02). In contrast, all patients defined as normotensive by clinical measurement were also normotensive by ABPM. CONCLUSIONS: Ambulatory blood-pressure monitoring indicated a lower prevalence of hypertension in acromegalic patients then usually reported, suggesting that the role of hypertension in the pathogenesis of acromegalic cardiomyopathy is commonly overestimated. We propose that ambulatory blood-pressure monitoring should be routinely proposed in acromegalics with high or borderline clinical blood pressure values although it is not useful in patients defined normotensive according to repeated clinical measurement.
Abstract: PURPOSE: The acute GH lowering effects of a single dose of either octreotide (OCT) or cabergoline (CAB), given alone and in combination, were studied in a series of 21 patients with acromegaly. PATIENTS AND METHODS: Plasma GH was measured for 8 hours after a single subcutaneous injection of OCT (100 micrograms) and for 48 hours after a single oral dose of CAB (0.5 mg) in all patients. Fourteen patients, who did not suppress GH levels below 5 micrograms/L after either OCT or CAB given alone, also received a combination of both drugs (OCT 100 micrograms s.c. + CAB 0.5 mg p.o. 24 h before OCT). RESULTS: GH levels were acutely suppressed by more than 50% in 15/21 cases after OCT alone and in 5/21 after CAB alone, respectively (P < 0.01). In the 14 patients who received the combined test, the magnitude of GH suppression was significantly higher than after OCT alone 4, 6 and 8 hours after OCT administration (P < 0.02). In patients with mixed GH/PRL-secreting tumors, the additive effect of OCT and CAB was observed at each time point. CONCLUSION: These results suggest that combined therapy with OCT and CAB may be more effective in suppressing GH secretion than either compound given alone, especially in patients with GH/PRL-secreting adenomas.
Abstract: About 3-5% of pituitary tumors occur in pediatric patients, often showing a considerable severity during childhood and puberty and major difficulties in their therapeutic management. As far as macroprolactinomas are concerned, surgery is often not resolutive, so that the need for postoperative treatment, consisting of either radiotherapy or bromocriptine, is the rule for tumors with extrasellar extension. In the present manuscript we report two cases of macroprolactinomas in adolescent patients suffering from delayed puberty, short stature and ocular symptoms together with hormonal levels indicating the presence of hypopituitarism. In both patients bromocriptine therapy showed a particular efficacy both in controlling tumor size and growth and in reducing clinical signs and symptoms. We conclude proposing DA-therapy as a first line of management in adolescents affected by macroprolactinomas, even in the presence of neurological symptoms.
Abstract: The Calcitonin Gene-Related Peptide (CGRP) is a 37 aminoacid peptide displaying about 50% homology with amylin which is secreted from the pancreatic islets of Langerhans. The main form, the beta-CGRP, is produced by the enteric nervous system and perivascular nerves of the vasa vasorum. It represents the most powerful vasodilator yet discovered but its role is not yet completely clarified. Recently it has been implicated in the control of regional blood flow and some authors have hypothesized its role in the development of Non Insulin Dependent Diabetes Mellitus (NIDDM). CGRP and amylin seem to inhibit the release of insulin from beta-cells and to play a role in local paracrine control of insulin secretion. In addition it is also shown to decrease the uptake of glucose by striated muscle. This has led to the suggestion that CGRP might be a circulating hormone implicated in the regulation of peripheral insulin sensitivity. In this review we examine the possible role of CGRP in the development of peripheral insulin resistance and altered insulin secretion which is characteristic of NIDDM.
