11C-methionine PET aids localization of microprolactinomas in patients with intolerance or resistance to dopamine agonist therapy.

PURPOSE: To assess the potential for 11C-methionine PET (Met-PET) coregistered with volumetric magnetic resonance imaging (Met-PET/MRCR) to inform clinical decision making in patients with poorly visualized or occult microprolactinomas and dopamine agonist intolerance or resistance. PATIENTS AND METHODS: Thirteen patients with pituitary microprolactinomas, and who were intolerant (n = 11) or resistant (n = 2) to dopamine agonist therapy, were referred to our specialist pituitary centre for Met-PET/MRCR between 2016 and 2020. All patients had persistent hyperprolactinemia and were being considered for surgical intervention, but standard clinical MRI had shown either no visible adenoma or equivocal appearances. RESULTS: In all 13 patients Met-PET/MRCR demonstrated a single focus of avid tracer uptake. This was localized either to the right or left side of the sella in 12 subjects. In one patient, who had previously undergone surgery for a left-sided adenoma, recurrent tumor was unexpectedly identified in the left cavernous sinus. Five patients underwent endoscopic transsphenoidal selective adenomectomy, with subsequent complete remission of hyperprolactinaemia and normalization of other pituitary function; three patients are awaiting surgery. In the patient with inoperable cavernous sinus disease PET-guided stereotactic radiosurgery (SRS) was performed with subsequent near-normalization of serum prolactin. Two patients elected for a further trial of medical therapy, while two declined surgery or radiotherapy and chose to remain off medical treatment. CONCLUSIONS: In patients with dopamine agonist intolerance or resistance, and indeterminate pituitary MRI, molecular (functional) imaging with Met-PET/MRCR can allow precise localization of a microprolactinoma to facilitate selective surgical adenomectomy or SRS.

An audit of endoscopic third ventriculostomy (ETV) in a regional paediatric neurosurgical centre assessing the accuracy and feasibility of the ETV success score.

BACKGROUND: Endoscopic third ventriculostomy success score (ETVss) is widely utilised to predict outcomes for ETV. Accurate prediction of success for a procedure is of vital importance both for selecting the optimal management plan and for obtaining informed consent. Existing literature demonstrates a variety of opinions on the accuracy of the currently utilised ETVss and recommends a range of techniques to reduce the number of subsequent ventriculo-peritoneal (VP)-shunt insertions, prompting the present study. METHODS: We retrospectively analysed data for ETV cases since 2007 to review success rate in our regional paediatric neurosurgical centre and if the currently utilised ETVss successfully predicted outcomes. Failed ETV cases were defined as any patient who received a VP-shunt at any time following ETV. Data was analysed with MS ExcelR and RStudioR. RESULTS: 44 ETVs were performed over 13 years with approximately equal distribution between male and female patients; median age 7 years (IQR 4-13 years). Overall, mean ETVss for these 44 procedures was 78%; actual success rate was 70% with no statistically significant difference between them (p = 0.286; Welch two sample t-test). Accuracy of ETVss varied with pathology: tectal gliomas (mean ETVss 75% and actual success 78%); cerebellar tumours (mean ETVss 85% and actual success 81%); other tumours (mean ETVss 75% and actual success 81%); aqueduct stenosis (mean ETVss 71% and actual success 69%); and other pathologies (mean ETVss 70% and actual success 60%). < 1 month and 1-6 months and 1-10 years and > 10 years contributed equally to the accuracy of ETVss. CONCLUSION: Non-telencephalon tumours and obstruction at the level of the mid-brain are most strongly associated with successful ETV outcome. These findings can be used to modify the currently utilised ETVss to further improve accuracy of outcome prediction. We recommend a modified-ETVss (m-ETVss) and a future larger adequately powered prospective study to validate this.

Current concepts in the surgical management of glioma patients.

The scientific basis for the surgical management of patients with glioma is rapidly evolving. The infiltrative nature of these cancers precludes a surgical cure, but despite this, cytoreductive surgery remains central to high-quality patient care. In addition to tissue sampling for accurate histopathological diagnosis and molecular genetic characterisation, clinical benefit from decompression of space-occupying lesions and microsurgical cytoreduction has been reported in patients with different grades of glioma. By integrating advanced surgical techniques with molecular genetic characterisation of the disease and targeted radiotherapy and chemotherapy, it is possible to construct a programme of personalised surgical therapy throughout the patient journey. The goal of therapeutic packages tailored to each patient is to optimise patient safety and clinical outcome and must be delivered in a multidisciplinary setting. Here we review the current concepts that underlie surgical subspecialisation in the management of patients with glioma.

Delayed neurological deficit following resection of tuberculum sellae meningioma: report of two cases, one with permanent and one with reversible visual impairment.

The most common presentation of patients with tuberculum sellae meningiomas is visual loss, and surgical resection is the main mode of treatment. Preservation of vision is not only the main objective of the surgery; loss of vision is also its main risk. Visual deterioration following surgery is usually apparent immediately post-operatively. Here we present two cases of patients who underwent resection of tuberculum sellae meningioma and whose vision following surgery was initially unchanged until the postoperative day two when dramatic visual deterioration occurred. In the first case this resulted in blindness, whereas in the second case vision recovered back to the preoperative state. The possible mechanisms of visual deterioration and modes of treatment are discussed.

Role of surgery, radiotherapy and chemotherapy in papillary tumors of the pineal region: a multicenter study.

Papillary tumor of the pineal region (PTPR), recently described as a distinct clinicopathological entity, can show aggressive biological behavior. The optimal therapeutic approach of PTPR has not been well defined. The role of surgery, radiotherapy, and chemotherapy in the treatment of PTPR was analyzed in a large multicenter series. In order to determine factors that influence prognosis, outcome data of a series of 44 patients with histopathologically proven PTPR were retrospectively analyzed. Of the 44 patients, 32 were still alive after a median follow-up of 63.1 months. Twelve patients experienced progressive disease, with seven undergoing two relapses and five more than two. Median overall survival (OS) was not achieved. Median progression-free survival (PFS) was 58.1 months. Only gross total resection and younger age were associated with a longer OS, radiotherapy and chemotherapy having no significant impact. PFS was not influenced by gross total resection. Radiotherapy and chemotherapy had no significant effect. This retrospective series confirms the high risk of recurrence in PTPR and emphasizes the importance of gross total resection. However, our data provide no evidence for a role of adjuvant radiotherapy or chemotherapy in the treatment of PTPR.

LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition.

LKB1/STK11 is a multitasking tumour suppressor kinase. Germline inactivating mutations of the gene are responsible for the Peutz-Jeghers hereditary cancer syndrome. It is also somatically inactivated in approximately 30% of non-small-cell lung cancer (NSCLC). Here, we report that LKB1/KRAS mutant NSCLC cell lines are sensitive to the MEK inhibitor CI-1040 shown by a dose-dependent reduction in proliferation rate, whereas LKB1 and KRAS mutations alone do not confer similar sensitivity. We show that this subset of NSCLC is also sensitised to the mTOR inhibitor rapamycin. Importantly, the data suggest that LKB1/KRAS mutant NSCLCs are a genetically and functionally distinct subset and further suggest that this subset of lung cancers might afford an opportunity for exploitation of anti-MAPK/mTOR-targeted therapies.

Radiotherapy as an adjuvant in the management of intracranial meningiomas: are we practising evidence-based medicine?

Although increasingly used, the precise role of radiotherapy in the management of meningiomas is still disputed. The objective of this study, therefore, was to appraise the evidence for adjuvant radiotherapy in benign and atypical intracranial meningiomas, and to compare and contrast it with the current opinion and practice of neurosurgeons in the United Kingdom and the Republic of Ireland. The use of radiotherapy as a primary treatment strategy or its use in the treatment of recurrence was not considered. We performed a systematic review of the evidence for adjuvant radiotherapy in benign and atypical intracranial meningiomas, surveyed current opinion amongst neurosurgeons involved in such cases and ascertained local practice using data from the regional cancer registry. Overall, 10 cohorts were identified that fulfilled our eligibility criteria. Four studies showed significantly improved local control in patients receiving adjuvant radiotherapy for incompletely resected grade I meningiomas. Our survey demonstrated that the vast majority (98%) of neurosurgeons would not recommend adjuvant radiotherapy in grade I meningioma. In grade II meningioma, most (80%) would not advocate adjuvant radiotherapy if completely excised, but the majority (59%) would recommend radiotherapy in cases of subtotal resection. Significant variation in opinion between centres exists, however, particularly in cases of completely resected atypical meningiomas (p = 0.02). Data from the Eastern Cancer Registration and Information Centre appears to be in line with these findings: less than 10% of patients with grade I meningiomas, but almost 30% of patients with grade II meningiomas received adjuvant radiotherapy in the Eastern region. In conclusion, our study has highlighted significant variation in opinion and practice, reflecting a lack of class 1 evidence to support the use of adjuvant radiotherapy in the treatment of meningiomas. Efforts are underway to address this with a randomized multicentre trial comparing a policy of watchful waiting versus adjuvant irradiation.

Papillary tumour of the pineal region.

Papillary tumour of the pineal region (PTPR) is a relatively new and rare pathological entity, which appears to run a spectrum of clinical courses. We add another case with detailed description of the clinical course documented with serial imaging over the total of 7 years. In accordance with previous reports we recommend total surgical resection with subsequent focal radiotherapy. Clinical and radiological follow up of the entire cerebrospinal axis is mandatory.

Sporadic malignant nerve sheath tumour of the oculomotor nerve.

Malignant peripheral nerve sheath tumours (MPNST) are exceedingly rare in an intracranial location. In this report clinical and pathological evidence for the diagnosis of a MPNST arising from of the oclumotor nerve is presented. To our knowledge this is the first such case reported in the medical literature.

Therapeutic anti-angiogenesis for malignant brain tumors.

Malignant brain tumors, especially malignant gliomas, have a poor prognosis, a fact which has remained unchanged over the last decades despite the employment of multimodal therapeutic approaches. Malignant gliomas are among the most vascularized tumors known and the amount of vascularization has been correlated to their prognosis. Since tumor growth is dependent on concomitant vascularization, recent experimental studies have focused on the use of anti-angiogenic molecules as a novel strategy in brain tumor therapy. Angiogenesis inhibitors target at proliferating endothelial cells and suppress the formation of a sufficient vascular bed. Inhibitors such as TNP-470, suramin and angiostatin have shown their therapeutic potential in experimental studies. In a clinical setting, they could be applied for the treatment of multiple tumors or postsurgically as an adjuvant therapy to prevent recurrence. This article discusses presently available anti-angiogenic agents, emphasizing on substances already in clinical trials.

Audit of headache following resection of acoustic neuroma using three different techniques of suboccipital approach.

A retrospective case notes review using pain visual analogue scale (VAS) and assessment of analgesia required by patients in the post-operative period at 1, 3, 6, 12 and over 12 months following acoustic neuroma resection was performed. Glasgow Benefit Inventory (GBI) score was used to assess the change of quality of life and its relationship to pain following surgery. Questionnaires of 71 patients were included in the study, 23 of whom underwent wide craniotomy including dissection of upper cervical musculature (CE), 25 wide craniotomy with replacement of bone flap (CO) and 23 minimally invasive, approximately 2 x 2 cm, minicraniectomy (MCE). The minicraniectomy resulted in significantly diminished pain from third month post surgery as compared with wide craniectomy (p < 0.05) and patients required less analgesia. Similarly, CO patients have experienced significantly less pain than CE patients (p < 0.05), but only after 12 months following surgery. Although consistently less in absolute visual analogue scores, there was no statistically significant difference between the amount of pain recorded by CO and MCE patients. There was no correlation between gender or age and the VAS pain score. The mean Glasgow Benefit Inventory score for all patients was -6.6, and there was no significant difference between operation types, genders or age. Although bone flap replacement appears to diminish the amount of post-operative pain, minimal invasive technique resulted in least pain following acoustic neuroma resection in our patients.

Molecular analysis of alterations of the p18INK4c gene in human meningiomas.

Meningiomas are common primary brain tumours frequently presenting with deleted and/or mutated NF2 gene located on 22q.1p has been reported as the second most commonly deleted chromosomal region in these neoplasms. A new member of the INK4 family of CDK inhibitors, the p18INK4c gene, has recently been mapped to this chromosomal arm. By virtue of its structural and functional similarities with the p16 gene, p18 has been implicated as a tumour suppressor gene in a variety of cancers. In this paper 40 human meningiomas were analysed for loss of heterozygosity (LOH) at the p18 locus, mutations and inactivating methylation of the p18 gene. LOH at D1S193, D1S463 and D1S211 microsatellite marker loci mapped to 1p32 was detected in 13 of 35 (37%), four of 20 (20%), and six of 24 (25%) tumour samples, respectively. One sample presented with homozygous deletion at D1S193. Mutational analysis using single stranded conformational polymorphism (SSCP) and direct sequencing did not detect any missense mutation but revealed a novel silent mutation, G to T, at coding nucleotide 435. Analysis of HgaI, BsaHI, ScrFI and Eco0109I restriction sites of p18 exon 1 revealed absence of inactivating methylation. Immunohistochemistry with p18 monoclonal antibody detected presence of cytoplasmic p18 staining in 21 of 22 examined samples. One sample did not stain and was shown to carry homozygous deletion at D1S193. Despite the high frequency of LOH at 1p32 microsatellite markers, the lack of genetic and epigenetic aberrations in the p18 gene together with the presence of p18 protein in all but one meningioma samples argues against the role of p18 as a tumour suppressor gene important for meningioma development.

Screening for loss of heterozygosity and microsatellite instability in oligodendrogliomas.

To assess the frequency of loss of heterozygosity (LOH) and microsatellite instability (MI) in oligodendrogliomas, we performed an extensive screening of 16 oligodendrogliomas and nine anaplastic oligodendrogliomas by using 132 microsatellite markers on chromosomes 1 through 12 and 15 through 21. In total, 3,135 loci were examined in 25 tumor samples. Only 33/1,965 (1.7%) of oligodendroglioma (low-grade) and 11/1,070 (1.0%) of anaplastic oligodendroglioma (high-grade) loci exhibited MI. High-frequency LOH regions were identified on chromosome arms 1p (31-73% for oligodendrogliomas and 60-100% for anaplastic oligodendrogliomas) and 19q (23-69% for oligodendrogliomas and 100% for anaplastic oligodendrogliomas). In addition, regions on chromosomes 4, 6, and 11 were found to be lost in 30-80% of both oligodendrogliomas and anaplastic oligodendrogliomas. Increased LOH frequency of chromosome 17 (38-40%) was found only in high-grade oligodendrogliomas. The differences in LOH frequencies between low-grade and high-grade oligodendrogliomas in all loci combined and at three loci (DIS447, DIS226, and DIS252) on chromosome arm 1p were determined to be statistically significant [chi 2(1) = 20.2, P < 0.0001, and Fisher's exact test respective P values: 0.01, 0.03, and 0.02]. Our results provide evidence that microsatellite instability does not play an important role in the development of oligodendrogliomas. Furthermore, high LOH frequency on chromosomes 6 and 11 in addition to that identified previously on chromosomes 1, 19, and 4 suggests that multiple candidate tumor suppressor genes on these chromosomes may underlie the processes of initiation and/or progression in oligodendroglioma tumorigenesis.

Molecular aspects of neuro-oncology.

Detailed understanding of molecular events responsible for brain tumor growth is a prerequisite for the development of effective therapeutic modalities leading to improved prognosis and cure. Advances in molecular biology in the past decades have revolutionized our understanding of cancer, including brain tumors. We have learned that abnormal proliferation, inability of the cells to die and their potential to modify their tissue environment result from accumulation of genetic aberrations. This article reviews genetic mechanisms implicated in the pathogenesis of nervous system tumors, such as unactivation of tumor suppressor and replication error genes, generation of abnormal growth factor loops, alterations of apoptotic pathways and angiogenesis.

Microsatellite instability analysis of primary human brain tumors.

Microsatellite instability, as shown by the presence of additional alleles or shifts of electrophoretic mobility at simple sequence tandem repeat loci, has been demonstrated in hereditary and sporadic colorectal tumors and many other tumor types. To study microsatellite instability in human brain tumors, we examined a total of 144 sporadic neoplasms. These included 33 astrocytic tumors, 23 oligodendrogliomas, six gangliogliomas, 41 meningiomas, 10 vestibular schwannomas and 31 pituitary adenomas. Di-, tri- and tetranucleotide repeat microsatellite markers localized on chromosome 4 and 9, X, 13 and 22, respectively, were used to assess whether instability was a significant aspect of their abnormal chromosomal pattern. Instability of microsatellite markers was detected in four oligodendrogliomas (17.4%), one pituitary adenoma (3.2%), one meningioma (2.4%), one astrocytic tumor (3.0%) and not at all in gangliogliomas and schwannomas. Therefore, our results suggest that the microsatellite instability which occurs in colorectal cancers with defective mismatch repair is infrequent in many types of human brain tumors and that the lower level of instability observed in brain tumors may be reflective of other mechanisms of genetic instability.