Complications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials.

BACKGROUND: PI3K-AKT-mTOR inhibitors (PAMi) are promising anticancer treatments. Hyperglycaemia is a mechanism-based toxicity of these agents and is becoming increasingly important with their use in larger numbers of patients. METHODS: Retrospective case-control study comparing incidence and severity of hyperglycaemia (all grades) between a case group of 387 patients treated on 18 phase I clinical trials with PAMi (78 patients with PI3Ki, 138 with mTORi, 144 with AKTi and 27 with PI3K/mTORi) and a control group of 109 patients treated on 10 phase I clinical trials with agents not directly targeting the PAM pathway. Diabetic patients were excluded in both groups. RESULTS: The incidence of hyperglycaemia was not significantly different between cases and controls (86.6% vs 80.7%, respectively, P=0.129). However, high grade (grade 3-4) hyperglycaemia was more frequent in the PAMi group than in controls (6.7% vs 0%, respectively, P=0.005). The incidence of grade 3-4 hyperglycaemia was greater with AKT and multikinase inhibitors compared with other PAMi (P<0.001). All patients with high-grade hyperglycaemia received antihyperglycemic treatment and none developed severe metabolic complications (diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic state). High-grade hyperglycaemia was the cause of permanent PAMi discontinuation in nine patients. CONCLUSIONS: PI3K-AKT-mTOR inhibitors are associated with small (6.7%) but statistically significant increased risk of high-grade hyperglycaemia compared with non-PAM targeting agents. However, PAMi-induced hyperglycaemia was not found to be associated with severe metabolic complications in this non-diabetic population of patients with advanced cancers.

The neutrophil-lymphocyte ratio and its utilisation for the management of cancer patients in early clinical trials.

BACKGROUND: Inflammation is critical to the pathogenesis and progression of cancer, with a high neutrophil-lymphocyte ratio (NLR) associated with poor prognosis. The utility of studying NLR in early clinical trials is unknown. METHODS: This retrospective study evaluated 1300 patients treated in phase 1 clinical trials between July 2004 and February 2014 at the Royal Marsden Hospital (RMH), UK. Data were collected on patient characteristics and baseline laboratory parameters. RESULTS: The test cohort recruited 300 patients; 53% were female, 35% ECOG 0 and 64% ECOG 1. RMH score was 0-1 in 66% and 2-3 in 34%. The median NLR was 3.08 (IQR 2.06-4.49). Median OS for the NLR quartiles was 10.5 months for quartile-1, 10.3 months for quartile-2, 7.9 months for quartile-3 and 6.5 months for quartile-4 (P<0.0001). Univariate analysis identified RMH score (HR=0.55, P<0.0001), ECOG (HR=0.62, P=0.002) and neutrophils (HR=0.65, P=0.003) to be associated with OS. In multivariate analysis, adjusting for RMH score, ECOG, neutrophils and tumour type, NLR remained significantly associated with OS (P=0.002), with no association with therapeutic steroid use. These results were validated in a further 1000 cancer patients. In the validation cohort, NLR was able to discriminate for OS (P=0.004), as was the RMH score. This was further improved on in the RMH score+NLR50 and RMH score+Log10NLR models, with an optimal NLR cutoff of 3.0. CONCLUSIONS: NLR is a validated independent prognostic factor for OS in patients treated in phase 1 trials. Combining the NLR with the RMH score improves the discriminating ability for OS.

Metastatic breast cancer subtypes and central nervous system metastases.

BACKGROUND: Breast cancer (BC) subtypes have different survival and response to therapy. We studied predictors of central nervous system metastases (CNS-M) and outcome after CNS-M diagnosis according to tumor subtype. PATIENTS AND METHODS: 488 patients with diagnosis of metastatic BC were retrospectively evaluated. According to the combination of hormone receptors (HR) and HER2 status, tumors were grouped in: Luminal (Lum), Luminal/HER2+, pure HER2-positive (pHER2+) and triple negative (TN). Time to CNS progression, CNS-M free interval and Overall Survival (OS) after CNS-M occurrence were compared by the log-rank test. Cox-proportional hazard models were used to study predictor factors associated with CNS progression, including tumor subtype and all potentially clinical relevant variables. RESULTS: 115 patients (pts) developed CNS-M with a median time to CNS progression of 31 months. The rate of CNS-M by subtype was: Lum 14%, Lum/HER2+ 35%, pHER2+ 49%, TN 22% (p < 0.001). Compared with Lum tumors, Lum/HER2+ (HR 2.514, p < 0.001), pHER2+ (HR 6.799, p < 0.0001) and TN (HR = 3.179, p < 0.001) subtypes were at higher risk of CNS-M. Median OS in months after CNS-M was: Lum 7.4, Lum/HER2+ 19.2, pHER2+ 7, TN 4.9 (p < 0.002). Belonging to the Lum/HER2+ subtype (HR 0.48, p < 0.037) and having isolated CNS (HR 0.37, p < 0.004) predicted significantly reduced risk of death. CONCLUSIONS: After CNS-M, the Lum/HER2+ subtype appears associated with the longest OS. Prospective clinical trials would be required for evaluating the potential role of screening for asymptomatic CNS lesions and of more aggressive CNS-M treatment in Lum/HER2+ subtype.

Hemispheric cavernous angiomas: presumptive preoperative diagnosis.

Clinical history, CT scan and angiography may lead to a correct preoperative diagnosis of hemispheric cavernous angiomas. Surgical results and follow-up are favorable; considering the bleeding risk we think the operation to be mandatory.

Early postoperative angiographic findings after carotid endarterectomy.

This report reviews the early postoperative evaluation of 70 patients who underwent carotid bifurcation endarterectomy within our department (before patients' releasing). Angiography was performed by femoral catheterization or the retrograde brachial route; three times only digital venous techniques were employed. No complications due to radiological procedures occurred. Postoperative angiographic findings include asymptomatic occlusion of ICA, occlusion of ECA, the presence of mural thrombi, diffuse surface roughness, intimal flaps and kink of ICA. Dilatation of the arteriotomized segment was detected with a high rate of frequency. Postoperative vascular changes are then analyzed in relation to surgical techniques, to early postoperative clinical course and to the occurrence of late re-stenoses.

[Cystic meningioma simulating glioblastoma in x-ray computed tomography]. / Les méningiomes kystiques simulateurs de glioblastomes en tomodensitométrie.

Seven cases of supratentorial meningiomas are reported. CT-Scan showed irregular hypo-hyperdense zones and features of intratumoral cysts. At surgery a well circumscribed tumor has always been found and easily removed "en bloc". In two cases stereotaxic biopsy was performed previously. CT-Scan findings of meningiomas with microcystic structure and/or necrotic areas may mimic a malignant glioma and lead to an incorrect presumptive diagnosis: then, both therapy and prognosis will be very different. It comes that stereotaxic biopsy is mandatory in all suspected cases of cerebral tumors, in the absence of classical angiographic patterns.

[Hemangiopericytoma of the petrous bone. Considerations apropos of 5 surgically treated cases]. / Les hémangiopéricytomes du rocher. Considérations à propos de 5 cas opérés.

5 cases of infratentorial hemangiopericytomas involving petrous bone are described. They show significant tendency to invade and destroy the bony base reaching into the soft parapharyngeal tissue of the neck. Radiography, tomography and CT scan of the skull demonstrate a large erosion of the petrous bone. At CT scan the lesion appears slightly hyperdense with marked enhancement. Selective angiography shows an important vascular supply from the external carotid artery, the deep and ascending cervical arteries and the extracranial part of the vertebral artery. Embolisation or surgical occlusion of the branches of external carotid artery and cervical arteries are useful to reduce bleeding during biopsy. Radiotherapy is advisable.

Course of intracranial pressure after extirpation of posterior fossa tumours.

Forty-seven patients with posterior fossa tumours underwent continuous monitoring of intracranial pressure (ICP) in the early postoperative period by means of an intraventricular catheter. ICP values were very low on the day of operation and subsequently became normal in 37 patients. ICP values were raised in 10 patients. The relationship between the ICP and the clinical course was investigated. Patients were subdivided according to the clinical postoperative course into three groups: good, temporarily deteriorated, poor clinical course. The two first groups showed lower values in the ICP than he third one, nevertheless the relationship between the ICP and the postoperative clinical course is marked but not strict. Our data may have some clinical relevance for the treatment of hydrocephalus before extirpation of posterior fossa tumours.

Multiple meningiomas. Report of nine cases.

Multiple meningiomas are a seldom encountered neoplasm. Most authors report an incidence ranging from 1 to 3% of all meningiomas. The routine use of CT has resolved diagnostic problems involved with multiple meningiomas; nevertheless, they still present several nosologic problems. In fact, it may be difficult to differentiate "true multiple meningiomas", defined as a distinct entity by Cushing in 1938, from simple recurrences or the special variant (forme fruste) of von Recklinghausen's disease. Our report deals with nine cases of multiple meningiomas selected from a series of 372 meningiomas operated from 1968 to 1981 at our hospital. Cases were divided into a) multiple simultaneous meningiomas (five cases), b) multiple meningiomas successively detected at different localizations (two cases), and c) multiple meningiomas associated with neurofibromatosis (two cases). Only five of these nine cases, four from the first group and one from the second, were true multiple meningiomas. Pathogenetic factors related to true multiple meningiomas are discussed in relation to the literature reports. However, the different hypotheses proposed do not offer a definite explanation of the multicentricity of these tumours.

Septum pellucidum oligodendroglioma. Case report and review of literature.

Neoplasms of septum pellucidum are rare. Only 124 cases have been published to which we must add the present case report. The literature is concerned with subependymomas and glioblastomas in most cases; there are only 13 cases of oligodendrogliomas. Surgical removal was performed in about 60 cases. This report presents one case of oligodendroglioma of the septum pellucidum which was surgically removed; it demonstrates the peculiar angiographic features of this kind of tumor, stresses the importance of CT scan in the determination of the possibility of surgical removal and finally discusses the therapeutic problems involved.