Metronomic Temozolomide in Heavily Pretreated Patients With Recurrent Isocitrate Dehydrogenase Wild-type Glioblastoma: A Large Real-Life Mono-Institutional Study.

AIMS: Glioblastoma (GBM) is the most common primary malignant brain tumour in adults and frequently relapses. The aim of this study was to assess the efficacy and safety of metronomic temozolomide (TMZ) in the recurrent GBM population. MATERIALS AND METHODS: All patients treated at our centre between September 2013 and March 2021 were retrospectively reviewed. The main inclusion criteria were first-line therapy with the Stupp protocol, relapse after the first or subsequent line of therapy, treatment with a metronomic TMZ schedule (50 mg/m2 continuously) and histological diagnosis of isocitrate dehydrogenase wild-type GBM according to World Health Organization 2016 classification. RESULTS: In total, 120 patients were enrolled. The median follow-up was 15.6 months, the median age was 59 years, Eastern Cooperative Oncology Group performance status (ECOG-PS) was 0-2 in 107 patients (89%). O6-methylguanine-DNA-methyltransferase (MGMT) was methylated in 66 of 105 (62%) evaluable patients. The median number of prior lines of treatment was 2 (range 1-7). Three (2%) patients showed a partial response; 48 (40%) had stable disease; 69 (57%) had progressive disease. The median overall survival from the start of metronomic TMZ was 5.4 months (95% confidence interval 4.3-6.4), whereas the median progression-free survival (PFS) was 2.6 months (95% confidence interval 2.3-2.8). At univariate analysis, MGMT methylated and unmethylated patients had a median PFS of 2.9 and 2.1 months (P = 0.001) and a median overall survival of 5.6 and 4.4 months (P = 0.03), respectively. At multivariate analysis, the absence of MGMT methylation (hazard ratio = 2.3, 95% confidence interval 1.3-3.9, P = 0.004) and ECOG-PS ≤ 2 (hazard ratio = 0.5, 95% confidence interval 0.3-0.9, P = 0.017) remained significantly associated with PFS, whereas ECOG-PS ≤ 2 (hazard ratio = 0.4, 95% confidence interval 0.3-07, P = 0.001) was the only factor associated with overall survival. The most common grade 3-4 toxicities were haematological (lymphopenia 10%, thrombocytopenia 3%). CONCLUSIONS: Rechallenge with metronomic TMZ is a well-tolerated option for recurrent GBM, even in pretreated patients. Patients with methylated MGMT disease and good ECOG-PS seem to benefit the most from this treatment.

Can fifth nerve mapping guide rhizotomy for recurrent trigeminal neuralgia? Case report.

INTRODUCTION: Microvascular decompression (MVD) is usually considered the first-line treatment for trigeminal neuralgia (TN) when medical treatments fail. Recurrence is rare and best treatment option is controversial. MVD was proposed as a feasible and effective technique for recurrent TN by many authors. Nevertheless, in a substantial number of cases, not any impingement or deterioration are found intraoperatively and partial selective rhizotomy is then advised. The rhizotomy site is mostly guided by anatomical landmarks, but variations due to scarring and adhesions are common pitfalls in these second surgeries. Intraoperative monitoring is infrequently used during MVD for trigeminal neuralgia. We describe the use of nerve mapping in a case of recurrence, revealing an unexpected rootlet distribution and thus safely guiding partial rhizotomy. CLINICAL PRESENTATION: A 53-year-old woman had suffered from bilateral trigeminal neuralgia for 10 years. Symptoms began on the right side. MVD resolved her symptoms but, after a few months, she developed left TN which persisted after left MVD, radiofrequency and radiosurgery. She was referred to our center for a second MVD on the left side. Intraoperative inspection detected no relevant findings, and nerve mapping followed by partial selective rhizotomy was performed. Complete pain relief was achieved. There were no complications. CONCLUSION: Rhizotomy is seldom employed for refractory trigeminal neuralgia. The effects of previous treatments can jeopardize anatomical landmarks. Nerve mapping seems a promising tool to improve results.

Balancing the 2 Hemispheres in Simple Calculation: Evidence From Direct Cortical Electrostimulation.

How do the parietal lobes contribute to simple calculation? Clinical and neuroimaging methods, which are based mainly on correlational evidence, have provided contrasting results so far. Here we used direct cortical electrostimulation during brain surgery to causally infer the role of the left and right parietal lobes in simple calculation. Stimulation provoked errors for addition and multiplication in different parietal areas on both hemispheres. Crucially, an innovative qualitative error analysis unveiled the functional contrast of the 2 parietal lobes. Right or left stimulation led to different types of substitution errors in multiplication, unveiling the function of the more active hemisphere. While inhibition of the left hemisphere led mainly to approximation errors, right hemisphere inhibition enhanced retrieval within a stored repertory. These results highlight the respective roles of each hemisphere in the network: rote retrieval of possible solutions by the left parietal areas and approximation to the correct solution by the right hemisphere. The bilateral orchestration between these functions guarantees precise calculation.

Cognitive Rehabilitation in Patients with Gliomas and Other Brain Tumors: State of the Art.

Disease prognosis is very poor in patients with brain tumors. Cognitive deficits due to disease or due to its treatment have an important weight on the quality of life of patients and caregivers. Studies often take into account quality of life as a fundamental element in the management of disease and interventions have been developed for cognitive rehabilitation of neuropsychological deficits with the aim of improving the quality of life and daily-life autonomy of patients. In this literature review, we will consider the published studies of cognitive rehabilitation over the past 20 years.

Assessing response using 99mTc-MIBI early after interstitial chemotherapy with carmustine-loaded polymers in glioblastoma multiforme: preliminary results.

Introduction. Early signs of response after applying wafers of carmustine-loaded polymers (gliadel) are difficult to assess with imaging because of time-related imaging changes. (99m)Tc-sestamibi (MIBI) brain single-photon emission tomography (SPET) has reportedly been used to reveal areas of cellularity distinguishing recurrent neoplasm from radionecrosis. Our aim was to explore the role of MIBI SPET in assessing response soon after gliadel application in glioblastoma multiforme (GBM). Methods. We retrospectively reviewed the charts on 28 consecutive patients with a radiological diagnosis of GBM who underwent MIBI SPET/CT before surgery (with intracavitary gliadel placement in 17 patients), soon after surgery, and at 4 months. The area of uptake was selected using a volume of interest that was then mirrored contralaterally to obtain a semiquantitative ratio. Results. After adjusting for ratio at the baseline, the effect of treatment (gliadel versus non-gliadel) was not statistically significant. Soon after surgery, however, 100% of patients treated with gliadel had a decreased ratio, as opposed to 62.5% of patients in the non-gliadel group (P = 0.0316). The difference between ratios of patients with radical versus partial resection reached statistical significance by a small margin (P = 0.0528). Conclusions. These data seem to suggest that the MIBI ratio could be a valuable tool for monitoring the effect of gliadel early after surgery.

Wnt activation promotes neuronal differentiation of glioblastoma.

One of the biggest challenges in tumour research is the possibility to reprogram cancer cells towards less aggressive phenotypes. In this study, we reprogrammed primary Glioblastoma multiforme (GBM)-derived cells towards a more differentiated and less oncogenic phenotype by activating the Wnt pathway in a hypoxic microenvironment. Hypoxia usually correlates with malignant behaviours in cancer cells, but it has been recently involved, together with Wnt signalling, in the differentiation of embryonic and neural stem cells. Here, we demonstrate that treatment with Wnt ligands, or overexpression of ß-catenin, mediate neuronal differentiation and halt proliferation in primary GBM cells. An hypoxic environment cooperates with Wnt-induced differentiation, in line with our finding that hypoxia inducible factor-1α (HIF-1α) is instrumental and required to sustain the expression of ß-catenin transcriptional partners TCF-1 and LEF-1. In addition, we also found that Wnt-induced GBM cell differentiation inhibits Notch signalling, and thus gain of Wnt and loss of Notch cooperate in the activation of a pro-neuronal differentiation program. Intriguingly, the GBM sub-population enriched of cancer stem cells (CD133(+) fraction) is the primary target of the pro-differentiating effects mediated by the crosstalk between HIF-1α, Wnt, and Notch signalling. By using zebrafish transgenics and mutants as model systems to visualize and manipulate in vivo the Wnt pathway, we confirm that Wnt pathway activation is able to promote neuronal differentiation and inhibit Notch signalling of primary human GBM cells also in this in vivo set-up. In conclusion, these findings shed light on an unsuspected crosstalk between hypoxia, Wnt and Notch signalling in GBM, and suggest the potential to manipulate these microenvironmental signals to blunt GBM malignancy.

BMP2 sensitizes glioblastoma stem-like cells to Temozolomide by affecting HIF-1α stability and MGMT expression.

Glioblastoma multiforme (GBM) is the most common brain tumour, characterized by a central and partially necrotic (i.e., hypoxic) core enriched in cancer stem cells (CSCs). We previously showed that the most hypoxic and immature (i.e., CSCs) GBM cells were resistant to Temozolomide (TMZ) in vitro, owing to a particularly high expression of O6-methylguanine-DNA-methyltransferase (MGMT), the most important factor associated to therapy resistance in GBM. Bone morphogenetic proteins (BMPs), and in particular BMP2, are known to promote differentiation and growth inhibition in GBM cells. For this reason, we investigated whether a BMP2-based treatment would increase TMZ response in hypoxic drug-resistant GBM-derived cells. Here we show that BMP2 induced strong differentiation of GBM stem-like cells and subsequent addition of TMZ caused dramatic increase of apoptosis. Importantly, we correlated these effects to a BMP2-induced downregulation of both hypoxia-inducible factor-1α (HIF-1α) and MGMT. We report here a novel mechanism involving the HIF-1α-dependent regulation of MGMT, highlighting the existence of a HIF-1α/MGMT axis supporting GBM resistance to therapy. As confirmed from this evidence, over-stabilization of HIF-1α in TMZ-sensitive GBM cells abolished their responsiveness to it. In conclusion, we describe a HIF-1α-dependent regulation of MGMT and suggest that BMP2, by down-modulating the HIF-1α/MGMT axis, should increase GBM responsiveness to chemotherapy, thus opening the way to the development of future strategies for GBM treatment.

Internal auditory canal metastasis.

Metastasis of the inner auditory canal is a really rare event. Clinically, it usually presents with rapid worsening cranial nerve palsy. Authors present a review of the literature reporting clinical features, radiological findings, intraoperative aspects of an illustrative case. A 56-year-old female patient presented with a peripheral facial nerve palsy. MRI showed two left p-fossa tumors whose one into the inner canal. Rapid worsening of facial damage despite corticosteroid treatment and the possibility to remove both tumors in the same surgical step suggested authors to operated on the patient. Intraoperatively, inner canal tumor looked totally involving the VII-VIII nerve complex so surgical extirpation was only partially feasible. Posterior wall drilling of the meatus was performed which improved facial palsy. Leptomeningeal spinal seeding occurred and spinal irradiation was performed. The case highlights the importance of maintaining a high degree of awareness of the auditory canal metastasis in patients with a previous history of malignancy who develop a rapid progressive peripheral VII nerve palsy. Furthermore, our case and literature data suggest that inner canal metastasis is a distinct entity from temporal bone and ponto-cerebellar angle metastasis on the base of the peculiarity of clinical features, prognosis, therapeutic strategies. In fact, inner canal metastases usually arise in patients apparently cured, and they imply a better prognosis even if with an higher risk of leptomeningeal seeding. Moreover, surgery rarely allows the removal of the lesion, also if symptoms relief may be achieved, as in our case.

Venous stroke can be the unusual clinical presentation of an arising naso-ethmoidal encephalo-meningocele in adulthood.

Trans-ethmoidal encephalo-meningocele is an extremely rare event among the adult population. It mainly affects young people who have previously reported a head injury. Even though early treatment is mandatory to avoid septic complications, the diagnosis is usually late because of the misleading symptomatology. We describe the unusual clinical history of an adult patient with a giant trans-ethmoidal encephalo-meningocele. A 61-year-old woman presented progressively more intense headache and rhinorrhea. No trauma was reported. We learned that she had a history of misunderstood spontaneous rhinorrhea beginning two years before, followed one year later by a lateral sinus thrombosis which worsened the cerebrospinal fluid leakage. Some months after stroke a new cerebral magnetic resonance scan revealed a giant trans-ethmoidal encephalo-meningocele. The brain herniation was surgically removed by a subfrontal intradural approach through a frontal craniotomy. Even rare, giant naso-ethmoidal encephalo-meningocele has to be considered in adult patients presenting with rhinorrhea even without a history of meningitis or neurological defects. Venous stroke can affect patients in whom prolonged CSF leakage occurs because of misunderstood cerebrospinal fistula. These patients must be monitored after stroke for the possible onset of an encephalo-meningocele.

Metastatic oligodendrogliomas: a review of the literature and case report.

Oligodendroglioma cells are detectable in the cerebro-spinal fluid in up to 14% of patients [10] and cerebellar and/or spinal cord involvement is a well known phenomenon [3]. Distant spread of oligodendroglioma is exceptional, probably due to the presence of the blood-brain barrier, the absence of lymphatic vessels and the short survival of patients. A review of the worldwide literature yielded 32 previously reported examples since 1951 to the present (Tab1e 1). This review was performed using NCBI-PubMed and "oligodendroglioma, oligodendrogliomas, metastatic, metastasis, metastases, extraneural", in different combinations, as key words and reviewing the bibliography of the consequent selected articles. New therapeutic approaches are prolonging the overall survival of patients with primitive brain tumours and in particular of those with high grade oligodendroglioma which is a chemo-sensitive disease. A longer overall survival could increase the risk of extracranial dissemination of gliomas that in the future might become a less rare clinical complication.

Assisted sedation: a safe and easy method for pain-free percutaneous vertebroplasty.

BACKGROUND: This study was performed to describe a method of assisted sedation for percutaneous vertebroplasty (PVP). METHODS: A non-randomized observational study was carried out on 20 patients ASA classes 2 and 3, who were undergoing PVP for vertebral body disruption. Patients, spontaneously breathing in prone position, were sedated using fentanyl and propofol. Sedation during PVP was maintained by continuous propofol infusion and was titrated to the patient's need. In addition to sedation, 2% mepivacaine was used as a local anesthetic. Electrocardiogram (ECG) and oxygen saturation (SpO(2)) were continuously monitored. Blood pressure was checked every 5 min. The length of the procedure was recorded and the patient's recovery from sedation was assessed according to a five-level scale, every 5 min from the end of the procedure. Time of discharge to the general ward was recorded. A four point (0-3) operator satisfaction score (OSS) was also used to evaluate surgeon's satisfaction. This score was based on patient movements and procedure interruptions. RESULTS: Sedation allowed a pain free procedure, with high surgeon satisfaction and rapid recovery of the patient. Sedation decreased blood pressure and heart rate, but not SpO(2); however, hypotension and bradycardia were not observed. Age was inversely correlated with propofol total dose. The mean total propofol dose was 4.5+/-1.4 mg/kg. The mean maintenance propofol dose rate was 5.7+/-1.4 mg/kg/h. CONCLUSION: Assisted sedation is a safe and easy method for pain free PVP procedures. Age is an important factor to titrate propofol dose. However, it is noteworthy that no adverse effects were observed independent of age and physical status.

Haemorrhagic presentation of low-grade glioma in adults.

Intracranial bleeding is rare in patients with low-grade gliomas, above all in adult population. We reviewed the literature of such cases and reported another case of a haemorrhagic low-grade glioma in a 54-year-old woman presenting with a left hemiparesis. Computer tomography (CT) images showed a right basal ganglia haemorrhage with no mass effect. Vascular malformations were ruled out by angiography. Eighteen fluoro-fluoro deossiglucosio (18F-FDG) positron emission tomography (PET/CT) showed a large hypometabolic area corresponding to the lesion. We waited for patient's improvement. Late magnetic resonance images revealed a low-grade glioma at the bleeding site. Tumour was removed and histopathologic examination revealed a WHO grade II mixed glioma. The authors emphasize that this evidence has to be kept in mind since it has important therapeutic implications.

Transverse sinus thrombosis after posterior fossa surgery for cerebellar tumor treated by endovascular thrombectomy. A case report.

Dural sinus thrombosis is a rare complication after posterior fossa surgery, particularly in cerebellar tumour surgery. The authors describe the case of a young male patient who presented a postoperative neurological deterioration due to transverse sinus thrombosis after surgery for cerebellar medulloblastoma. He was treated by mechanical clot thrombectomy using an endovascular catch system technique without anticoagulation therapy. Final angiographic recanalization was obtained. This kind of endoluminal mechanical revascularization is an efficacious method to treat dural sinus thrombosis during perioperative time but speed in diagnosis is crucial for clinical outcome.

Tracheal esophageal combitube: a useful airway for morbidly obese patients who cannot intubate or ventilate.

The tracheal esophageal combitube has been successfully used in many difficult airway circumstances. We report the dramatic case of a morbidly obese patient with a well-known difficult airway who was successfully rescued from a cannot ventilate-cannot intubate situation in our critical care unit by using the tracheal esophageal combitube. Surgical tracheostomy was performed while she was mechanically ventilated through the tracheal esophageal combitube. The tracheal esophageal combitube is a very important device that should be kept available in all cases of morbidly obese airway management.

[Use of pulse oximetry in the diagnosis of accidental bronchial intubation during laparoscopic surgery. Description of a clinical case]. / Utilità della pulsossimetria nella diagnosi di intubazione bronchiale accidentale nella chirurgia laparoscopia. Descrizione di un caso clinico.

In the present article a case of accidental bronchial intubation during laparoscopic cholecystectomy is described. Endotracheal tube was probably displaced by gas distension of the abdomen during laparoscopy. Indeed, under these circumstances, carina may move cephalad. Initially, tube displacement was not diagnosed by either auscultation of breath sounds, or ETCO2 monitoring. Instead, a decrease in arterial oxygen saturation, as monitored by pulse oximetry, quickly allowed diagnosis and correction of the problem. It is concluded that pulse oximetry is more sensitive than other methods in providing early warning of tube displacement during laparoscopy.