Pietro Mortini

Results of Transsphenoidal Surgery in a Large Series of Patients with Pituitary Adenoma

OBJECTIVE: To report the efficacy and safety of microsurgical transsphenoidal surgery in a series of previously untreated patients with pituitary adenoma. METHODS: One thousand one hundred forty consecutive patients undergoing transsphenoidal resection of a pituitary adenoma at our department from January 1990 through December 2002 were included in our study. Postoperative results were classified uniformly during the period of the study. Patients were considered in remission of disease when strict hormonal and radiological criteria of cure were met. RESULTS: The most frequent tumor type was clinically nonfunctioning adenoma (NFPA) (33.2%), followed by growth hormone-secreting adenoma (28.1%), adrenocorticotropin-secreting adenoma (23.0%), prolactin-secreting adenoma (13.2%), and last, thyrotropin-secreting adenoma (2.5%). The patient population was 59.7% female and 40.3% male. Mean age was 43.0 ± 0.4 years. There were 788 macroadenomas (69.1%), and in 233 patients (20.4%), the tumor invaded one or both cavernous sinuses. The overall rate of early surgical success was achieved in 504 (66.1%) of the 762 patients with a hormone-active adenoma. Surgical outcome was better in patients with microadenomas than in patients with macroadenomas (78.9% and 55.5%, respectively), whereas tumors invading the cavernous sinus had a poorer outcome (7.4%). In patients with NFPA, no residual adenoma was present in 234 patients (64.8%). Normalization of visual defects occurred in 117 (40.5%) of the 289 patients with visual disturbances and improved in another 148 patients (51.2%). Three patients (0.3%) died as a consequence of surgery. CONCLUSION: Transsphenoidal surgery is an effective and safe treatment for most patients with pituitary adenoma and could be considered the first-choice therapy in all cases except for prolactinomas responsive to dopamine agonists. Other treatment methods, such as radiotherapy, stereotactic radiosurgery, and medical therapy, play an important role in patients not cured by surgery.

Immunobiological Characterization of Cancer Stem Cells Isolated from Glioblastoma Patients

Purpose: Cancer stem cells (CSC) have been isolated from human tumors, including glioblastoma multiforme (GBM). The aims of this study were the immunobiological characterization of GBM CSCs and the assessment of whether these cells represent suitable targets for immunotherapy. Experimental Design: GBM CSC lines and their fetal bovine serum (FBS)–cultured non-CSC pair lines were generated and examined by flow cytometry for expression of known tumor antigens, MHC-I and MHC-II molecules, antigen-processing machinery components, and NKG2D ligands. In addition, immunogenicity and immunosuppression of such cell lines for autologous or allogeneic T lymphocytes were tested by cytokine secretion (ELISPOT) or proliferation (carboxyfluorescein diacetate succinimidyl ester) assays, respectively. Results: Both GBM CSC and FBS lines were weakly positive and negative for MHC-I, MHC-II, and NKG2D ligand molecules, respectively. Antigen-processing machinery molecules were also defective in both cell types. Upregulation of most molecules was induced by IFNs or 5-Aza deoxycytidine, although more efficiently in FBS than in CSCs. Patient T-cell responses, mediated by both TH1 and the TH2 subsets, against autologous CSC could be induced in vitro. In addition, CSC but not their paired FBS tumor lines inhibited T-cell proliferation of healthy donors. Notably, a differential gene signature that was confirmed at the protein levels for some immunologic-related molecules was also found between CSC and FBS lines. Conclusions: These results indicate lower immunogenicity and higher suppressive activity of GBM CSC compared with FBS lines. The immunogenicity, however, could be rescued by immune modulation leading to anti-GBM T cell–mediated immune response. Clin Cancer Res; 16(3); 800–13

Early results of surgery in patients with nonfunctioning pituitary adenoma and analysis of the risk of tumor recurrence

OBJECT Nonfunctioning pituitary adenomas (NFPAs) are benign tumors of the pituitary gland that typically cause visual and/or hormonal dysfunction. Surgery is the treatment of choice, but patients remain at risk for tumor recurrence for several years afterwards. The authors evaluate the early results of surgery and the long-term risk of tumor recurrence in patients with NFPAs. METHODS Between 1990 and 2005, 491 previously untreated patients with NFPA underwent surgery at the Università Vita-Salute. Determinations of recurrence or growth of the residual tumor tissue during the follow-up period were based on neuroradiological criteria. RESULTS Residual tumor after surgery was detected in 173 patients (36.4%). Multivariate analysis showed that invasion of the cavernous sinus, maximum tumor diameter, and absence of tumor apoplexy were associated with an unfavorable surgical outcome. At least 2 sets of follow-up neuroimaging studies were obtained in 436 patients (median follow-up 53 months). Tumors recurred in 83 patients (19.0%). When tumor removal appeared complete, younger age at surgery was associated with a risk of tumor recurrence. In patients with incomplete tumor removal, adjunctive postoperative radiotherapy had a marked protective effect against growth of residual tumor. CONCLUSIONS Complete surgical removal of NFPAs can be safely achieved in > 50% of cases. Visual symptoms and, less frequently, pituitary function may improve after surgery. However, tumor can recur in patients after apparently complete surgical removal. In patients with incomplete tumor removal, radiation therapy is the most effective adjuvant therapy for preventing residual tumor growth.

The role of stereotactic radiotherapy in patients with growth hormone-secreting pituitary adenoma

CONTEXT Single-session stereotactic radiotherapy (SR) may be a potential adjuvant treatment in acromegaly. OBJECTIVE We analyzed the safety and efficacy of SR in patients who had previously received maximal surgical debulking at our center. DESIGN The study was a retrospective analysis of hormonal, radiological, and ophthalmologic data collected in a predefined protocol from 1994 through 2006. SETTING The study was performed at a university hospital. PATIENTS Eighty-three acromegalic patients, 52 women and 31 men, with a mean age of 42.6 +/- 1.2 yr, participated in the study. The median follow-up was 69 months (interquartile range 44-107 months). INTERVENTION The patients were treated with SR for residual or recurrent GH-secreting adenoma. MAIN OUTCOME MEASURE Normalization of age- and sex-adjusted IGF-I levels together with a basal GH level below 2.5 microg/liter without concomitant GH-suppressive drugs was the goal of therapy. RESULTS Fifty patients (60.2%) reached the main outcome of the study. The rate of remission was 52.6% at 5 yr [95% confidence interval (CI) 40.6-64.6%]. Another 13 patients (15.7%), who were resistant to somatostatin analogs, were in remission after SR. Multivariate analysis showed that low basal GH and IGF-I levels were associated with a favorable outcome. No serious side effects occurred after SR. The 5-yr cumulative risk of new onset hypogonadism, hypothyroidism, or hypoadrenalism was 3.6% (95% CI 0-8.6%), 3.3% (95% CI 0-7.7%), and 4.9% (95% CI 0-10.4%), respectively. CONCLUSION In a highly selected group of acromegalic patients, SR treatment had good efficacy and safety. This may lead to reconsider the role of SR in the therapeutic algorithm of acromegaly.

Salvage therapy with temozolomide in patients with aggressive or metastatic pituitary adenomas: experience in six cases

OBJECTIVE The prognosis of either pituitary carcinoma or aggressive pituitary adenoma resistant to standard therapies is poor. We assessed the efficacy of treatment with temozolomide, an oral second-generation alkylating agent, in a consecutive series of six patients with aggressive pituitary adenomas. DESIGN This was a 1-year prospective study of temozolomide therapy in six consecutive patients with pituitary carcinoma (one case) or atypical pituitary adenoma (five cases) resistant to standard therapies. There were three males and three females. Age at enrollment ranged between 52 and 64 years. Temozolomide was given orally at a dose of 150-200 mg/m(2) per day for 5 days every 4 weeks for a maximum of 12 cycles. METHODS Response assessment was based on measurable change in tumor size, as assessed on magnetic resonance imaging, and hormone levels. Response was defined as reduction of at least 50% of tumor size and hormone levels. RESULTS Four patients completed the 12 cycles of temozolomide treatment, as planned. Two patients stopped the drug after 3 and 6 months respectively because of the progression of disease. Two patients responded to temozolomide, while the remaining two patients had stable disease. Immunohistochemistry for O(6)-methylguanine-DNA methyltransferase (MGMT) in tumor sample showed a partial association with treatment response. CONCLUSIONS Temozolomide treatment has a wide range of efficacy in patients with pituitary carcinoma or locally aggressive pituitary adenoma. Positive staining for MGMT seems likely to predict a lower chance of response.

Delayed Remission after Transsphenoidal Surgery in Patients with Cushing's Disease

BACKGROUND Transsphenoidal surgery (TSS) is the treatment of choice for Cushings disease (CD). Postoperative hypercortisolemia mandates further therapy. OBJECTIVE The aim of the study was to characterize patients without immediate postoperative remission who have a delayed decrease to normal or low cortisol levels without further therapy. DESIGN AND SETTING A retrospective case series was conducted at three tertiary care centers. PATIENTS AND INTERVENTION We reviewed the records of 620 patients (512 females, 108 males; mean age, 38 +/- 13 yr) who underwent transsphenoidal pituitary surgery for CD between 1982 and 2007. RESULTS Outcomes were classified into the following three groups based upon the postoperative pattern of cortisol testing: group IC (immediate control) included 437 of the 620 patients (70.5%) with hypocortisolism and/or cortisol normalization throughout the postoperative follow-up; group NC (no control) included 148 of 620 patients (23.9%) with persistent hypercortisolism; and group DC (delayed control) included 35 of 620 patients (5.6%) who had early elevated or normal UFC levels and developed a delayed and persistent cortisol decrease after an average of 38 +/- 50 postoperative days. The total rate of recurrence was 13% at a median follow-up time of 66 months after TSS; the cumulative rate of recurrence at 4.5 yr was significantly higher in group DC vs. group IC (43 vs. 14%; P = 0.02). CONCLUSIONS Hormonal assessment in the immediate postoperative period after TSS for CD may be misleading because delayed remission can occur in a subset of patients. Expectant management and retesting may spare some patients from unnecessary further treatment. Optimal timing to determine the need for further therapy after TSS remains to be determined.

Altered structure of small cerebral arteries in patients with essential hypertension.

Objective Structural alterations in the microcirculation may be considered an important mechanism of organ damage. An increased media-to-lumen ratio of subcutaneous small resistance arteries has been demonstrated to predict the development of cardiocerebrovascular events in hypertensive patients. Alterations in the structure of small cerebral arteries have been demonstrated in animal models of experimental or genetic hypertension. However, no evaluation with reliable techniques has ever been performed in humans. Design and methods Twenty-eight participants were included in the present study: they were 13 hypertensive patients and 15 normotensive individuals. All participants underwent a neurosurgical intervention for benign or malign tumors. A small portion of morphologically normal cerebral tissue was excised from surgical samples and examined. Cerebral small resistance arteries (relaxed diameter around 200 μm) were dissected and mounted on an isometric and isobaric myograph, and the tunica media to internal lumen ratio was measured. In addition, cerebral cortical microvessel density (MVD) was also evaluated. The tissue was sectioned and stained for CD31, and MVD was measured with an automated image analyzer (percentage of area stained). Blood pressure values were evaluated, before surgical intervention, by standard sphygmomanometry. Results M/L was significantly greater and MVD significantly lower in hypertensive patients than that in normotensive individuals. No difference between groups in collagen content or mechanical properties of cerebral small arteries was observed. Conclusion Our results indicate that structural alterations of small cerebral vessels are present in hypertensive patients compared with normotensive individuals, similar to those previously observed in subcutaneous small arteries.

Desmopressin stimulation test before and after pituitary surgery in patients with Cushing's disease

OBJECTIVE The desmopressin test has been proposed as a useful tool for the differential diagnosis of Cushings disease. The aim of our study was to investigate, in a large series of patients with Cushings disease, the incidence of a positive ACTH and cortisol response to desmopressin. Moreover, we repeated the test soon after surgery to verify its usefulness in the assessment of early and late surgical results.

Mapping of candidate region for chordoma development to 1p36.13 by LOH analysis

Various cytogenetic and molecular findings indicate 1p36 loss as a consistent change in sporadic and inherited chordoma, a rare embryogenetic neoplasm arising from notochord remnants. We studied 27 sporadic chordomas by means of loss of heterozygosity (LOH) of 31 microsatellites localized to the 1p36.32–36.11 region, and restricted the minimal LOH interval shared by 85% of the tumours to 1p36.13. We also used RT‐PCR analysis to investigate the role of the candidate genes CASP9, EPH2A, PAX7, DAN and DVL1, which were selected on the basis of the physical mapping of the LOH region and their plausible oncosuppressor function. RT‐PCR analysis showed the presence of DAN and PAX7 transcript fragments of the expected size in all of 8 chordoma samples, whereas the CASP9‐specific fragment was observed in only 3 and EPH2A was absent in one. Smaller than expected DVL1 transcripts were found in 4 tumours as well as in their normal counterpart (nucleus pulposus), which also showed a typically sized transcript. Sequencing revealed the skipping of 3 exons in the smallest DVL1 fragment, thus leading to a frameshift and predicting a truncated DVL1 gene product. Our study of the largest cohort of chordoma patients recruited so far indicates a common molecular lesion at 1p36.13, and suggests that the CASP9, EPH2A and DVL1 genes may play an onco‐suppressing role and be involved in the development of chordoma.

Chemokine detection in the cerebral tissue of patients with posttraumatic brain contusions

OBJECT The clinical outcome of patients with severe head injuries is still critically dependent on their secondary injuries. Although hypoxia and hypotension appear to mediate a substantial proportion of secondary injuries, many studies associate secondary brain injury with neuroinflammatory responses. Chemokines have been detected in the cerebrospinal fluid but not in the brain tissue of patients with head trauma. This study was performed to determine if chemokines were expressed in pericontusional brain tissue in patients with moderate or severe head trauma who underwent surgical evacuation of their brain contusions. METHODS Twelve patients with posttraumatic cerebral contusion requiring a surgical evacuation were studied. A 20- to 40-mg sample of white matter was removed from the surgical cavity in the pericontusional area. Two patients undergoing elective surgery for clip ligation of an unruptured aneurysm were used as controls. The median interval from trauma to biopsy procedure was 44 hours (range 3-360 hours). Total RNA was isolated from these samples and a ribonuclease protection assay was performed to measure the mRNA levels of several chemokines: CCL2, CCL3, CCL4, CCL5, CXCL8, CXCL10, and XCL1. RESULTS The CCL2, a monocyte chemoattractant produced by activated astrocytes, was the most strongly expressed chemokine, followed by CXCL8, CCL3, and CCL4. The chemokines CXCL10 and CCL5 were expressed at very low levels, and XCL1 was not detected. CONCLUSIONS Chemokine activation occurs early after moderate or severe head trauma and is maintained for several days after trauma. This event may contribute to neuroinflammatory exacerbation of posttraumatic brain damage in the pericontusional brain tissue.