Antonello Vidiri

Brain metastases from solid tumors: disease outcome according to type of treatment and therapeutic resources of the treating center

BackgroundTo evaluate the therapeutic strategies commonly employed in the clinic for the management of brain metastases (BMs) and to correlate disease outcome with type of treatment and therapeutic resources available at the treating center.MethodsFour Cancer centres participated to the survey. Data were collected through a questionnaire filled in by one physician for each centre.ResultsClinical data regarding 290 cancer patients with BMs from solid tumors were collected. Median age was 59 and 59% of patients had ≤ 3 brain metastases. A local approach (surgery and stereotactic radiosurgery) was adopted in 31% of patients. The local approach demonstrated to be superior in terms of survival compared to the regional/systemic approach (whole brain radiotherapy and chemotherapy, p = <.0001 for survival at 2 years). In the multivariate analysis local treatment was an independent prognostic factor for survival. When patients were divided into 2 groups whether they were treated in centers where local approaches were available or not (group A vs group B respectively, 58% of patients with ≤ 3 BMs in both cohorts), more patients in group A received local strategies although no difference in time to brain progression at 1 year was observed between the two groups of patients.ConclusionsIn clinical practice, local strategies should be integrated in the management of brain metastases. Proper selection of patients who are candidate to local treatments is of crucial importance.

Retromolar trigone tumors: evaluation by magnetic resonance imaging and correlation with pathological data

The aim of this study was to evaluate the diagnostic accuracy of magnetic resonance (MR) images to establish both the T stage and the relationships between the tumors and the surrounding structures in retromolar trigone tumors. Twenty-two patients with squamous cell carcinoma of the retromolar trigone were examined by MR with a superconductive scanner operating at 1.5T. The study was performed with spin-echo (SE) T1 and T2 and short SE T1 sequences (TR 180 ms, TE 15 ms) after the administration of 0.2 mmol/kg of gadolinium-DTPA (Gd-DTPA). The mandible was studied with SE T1 weighted sequences and GE sequences. The results were compared with the pathological data on the T stage (TNM classification) and the involvement of the surrounding structures. A positive correlation was found in 19 of the 22 patients with an accuracy of 86%. In one patient, the lesion was classified as T1 by MR which, at surgery, resulted being T4, given the infiltration of the cortical mandible (this infiltration was too limited). In another, the MR showed a T4 lesion because of the presence of low signal intensity in the mandibular marrow with enhancement after the Gd-DTPA injection without cortical erosion, while pathological data revealed a T2 lesion (this signal intensity was secondary to inflammation). In another case, the lesion was classified as T1 by MR which, at surgery, proved to be a T2 lesion. In assessing the involvement of the surrounding structures. MR showed a high accuracy, specificity and sensitivity (> 90%). Five false positive cases were observed: in two because of infiltration of the masseter muscle and in the other three, because of infiltration to the pterigoid muscle, mandible and tonsillar bed, respectively, due to the close contact between the tumors and the surrounding structures. Only one false negative case was observed with infiltration of the mandibular marrow. In evaluating the low signal intensity of the mandibular marrow, the accuracy of MR was 87% the specificity 77% and the sensitivity 100%. In one case, perineural spread along the mandibular nerve was found. In conclusion, MR proved to be highly accurate to study the T stage and examine the relationships between the surrounding structures in cases of retromolar trigone tumors.

Assessment of diffusion parameters by intravoxel incoherent motion MRI in head and neck squamous cell carcinoma

The objectives of this study were to assess the diffusion parameters derived from intravoxel incoherent motion (IVIM) MRI in head and neck squamous cell carcinoma (HNSCC) and to investigate the agreement between different methods of tumor delineation and two numerical methods to extract the perfusion fraction f. Thirty‐seven untreated patients with histopathologically confirmed primary HNSCC were included retrospectively in the study. The entire volume of the primary tumor was outlined on diffusion‐weighted images using co‐registered morphological images as a guide to the tumor location. Apparent diffusion coefficient (ADC) and IVIM diffusion parameters were estimated considering the largest tumor section as well as the entire tumor volume. A bi‐exponential fit was implemented to extract f, D (pure diffusion coefficient) and D* (pseudo‐diffusion coefficient). A second simplified method, based on an asymptotic extrapolation, was used to determine f. The agreement between ADC and IVIM diffusion parameters derived from the delineation of single and multiple slices, and between the two f estimations, was assessed by Bland–Altman plots. The inter‐slice variability of ADC and IVIM diffusion parameters was evaluated. The Kruskal–Wallis test was used to investigate whether the tumor location had a statistically significant influence on the values of the parameters. Comparing the tumor delineation methods, a better accordance was found for ADC and D, with a mean percentage difference of less than 2%. Larger discrepancies were found for f and D*, with mean differences of 4.5% and 5.5%, respectively. When comparing the two f estimation methods, small mean differences were found (<3.5%), suggesting that the two methods may be considered as equivalent for the assessment of f in our patient population. The observed ADC and IVIM diffusion parameters were dependent on the anatomic site of the lesion, carcinoma of the nasopharynx showing more homogeneous and dissimilar estimations than other HNSCCs. Copyright

Early radiation-induced changes evaluated by intravoxel incoherent motion in the major salivary glands

To investigate the potential of intravoxel incoherent motion (IVIM) MRI for early evaluation of irradiated major salivary glands.

Treatment of recurrent malignant gliomas with fotemustine monotherapy: impact of dose and correlation with MGMT promoter methylation

BackgroundIn recurrent malignant gliomas (MGs), a high rate of haematological toxicity is observed with the use of fotemustine at the conventional schedule (100 mg/m2 weekly for 3 consecutive weeks followed by triweekly administration after a 5-week rest period). Also, the impact of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status on fotemustine activity has never been explored in the clinical setting.Methods40 patients with recurrent pretreated MG were identified as being treated with fotemustine at doses ranging from 65 mg/m2 to 100 mg/m2. Patients were classified into 3 groups according to the dose of fotemustine received, from the lowest dosage received in group A, to the highest in group C. Analysis of MGMT promoter methylation in tumor tissue was successfully performed in 19 patients.ResultsOverall, 20% of patients responded to treatment, for a disease control rate (DCR, responses plus stabilizations) of 47.5%. Groups A and B experienced a response rate of 40% and 26.5% respectively, while the corresponding value for group C was 10%. Out of 19 patients, MGMT promoter was found methylated in 12 cases among which a DCR of 66.5% was observed. All 7 patients with unmethylated MGMT promoter were progressive to fotemustine.ConclusionLow-dose fotemustine at 65–75 mg/m2 (induction phase) followed by 75–85 mg/m2 (maintenance phase) has an activity comparable to that of the conventional schedule. By determination of the MGMT promoter methylation status patients might be identified who are more likely to benefit from fotemustine chemotherapy.

Unilateral limited laminectomy as the approach of choice for the removal of thoracolumbar neurofibromas

Study Design. The paper reports a minimally invasive approach to the dorsolumbar spine for the removal of neurofibromas. Objectives. Demonstrating that a limited unilateral approach is the one of choice for this kind of tumors. Summary of Background Data. Spinal intradural extramedullary tumors are generally removed by single-level or multilevel laminectomy with midline dural incision. Cases of delayed postoperative kyphosis and spinal instability (6%) may be reduced by unilateral microsurgery, causing minimum damage to ligaments and joints. Methods. Ten patients with dorsolumbar neurofibroma were operated on between June 2000 and June 2002. There were 5 males (all with lumbar) and 5 females (2 with lumbar and 3 with inferior dorsal neurofibromas). One female had 3 lumbar tumors and required two operations. Surgery was performed in the prone position with a unilateral approach, sparing the joint and the ligamentum interspinosum. The dura was opened paramedially and the tumor dissected from the root and removed in one piece when possible. Water-tight dural closure was done with 5–0 or 6–0 stitches. Results. All the patients were mobilized on day 2 and discharged on day 4 or day 5. No complications resulting from the technique were observed. Static and dynamic plain radiograph films showed that none of them had kyphosis and/or instability 6 months postoperatively. Neurologic results were good. Conclusions. Hospital stay may be reduced and stability may be preserved with an appropriate microsurgical technique. The technique reported in the paper should thus become the one of choice and extended to other spinal intradural extramedullary tumors.

Early perfusion changes in patients with recurrent high-grade brain tumor treated with Bevacizumab: preliminary results by a quantitative evaluation

BackgroundTo determine whether early monitoring of the effects of bevacizumab in patients with recurrent high-grade gliomas, by a Perfusion Computed Tomography (PCT), may be a predictor of the response to treatment assessed through conventional MRI follow-up.MethodsSixteen patients were enrolled in the present study. For each patient, two PCT examinations, before and after the first dose of bevacizumab, were acquired. Areas of abnormal Cerebral Blood Volume (CBV) were manually defined on the CBV maps, using co-registered T1- weighted images, acquired before treatment, as a guide to the tumor location. Different perfusion metrics were derived from the histogram analysis of the normalized CBV (nCBV) maps; both hyper and hypo-perfused sub-volumes were quantified in the lesion, including tumor necrosis. A two-tailed Wilcoxon test was used to establish the significance of changes in the different perfusion metrics, observed at baseline and during treatment. The relationships between changes in perfusion and morphological MRI modifications at first follow-up were investigated.ResultsSignificant reductions in mean and median nCBV were detected throughout the entire patient population, after only a single dose of bevacizumab. The nCBV histogram modifications indicated the normalization effect of bevacizumab on the tumor abnormal vasculature. An improvement in hypoxia after a single dose of bevacizumab was predictive of a greater reduction in T1-weighted contrast-enhanced volumes at first follow-up.ConclusionsThese preliminary results show that a quantification of changes in necrotic intra-tumoral regions could be proposed as a potential imaging biomarker of tumor response to anti-VEGF therapies.

Venous angiomas: plain and contrast- enhanced MRi and MR angiography

We studied 17 patients with venous angiomas, 4 of whom had associated cavernous angiomas. All underwent MRI with spin-echo T1- and T2-weighted images and T1-weighted images after Gd-DTPA; MR angiography (MRA) was also performed with 3D and 2D time-of-flight technique; 5 patients underwent conventional angiography. Contrast-enhanced MRI demonstrated all the lesions, showing the peripheral medullary veins, the collector and the type of drainage. Both 3D and 2D MRA provided diagnostic information identical to that obtained after infusion of Gd-DTPA. Contrast-enhanced were T1-weighted images and MRA superior in all the cases to images without gadolinium. The possible association with cavernous angiomas (24% in our study) indicates T2-weighted imaging.

Progress of brown tumors in patients with chronic renal insufficiency undergoing dialysis

In a group of 73 patients, affected by chronic renal insufficiency, whose skeleton was periodically checked, three cases of brown tumors were found. These cases demonstrated a variety of locations that were involved, especially the pelvis, ribs and mandible. During therapeutic treatment the brown tumors presented a different behavior; while some lesions tended toward complete sclerosis, others increased in size and in both instances new lesions appeared. Parathyroidectomy, carried out in two patients, determined a definitive sclerosis of these lesions. Brown tumors also correlate with high PTH levels and with lesions from osteitis fibrosa.

Rash in four patients with brain tumor-related epilepsy in monotherapy with oxcarbazepine, during radiotherapy.

Antiepileptic drug (AED)-related rash is well documented with older AEDs such as carbamazepine, phenobarbital, and phenytoin, and recent studies have implicated newer AEDs such as lamotrigine, oxcarbazepine (OXC), and zonisamide [1–4]. In patients with brain tumor-related epilepsy (BTRE) treated with old AEDs, the appearance of rash may be severe during radiotherapy (RT). The frequency is approximately 20% of cases where traditional AEDs such as carbamazepine, phenobarbital, and phenytoin are used [4]. The appearance of rash during RT among the new AEDs has not yet been described in the literature. Skin rash is an idiosyncratic adverse drug reaction that can vary from mild maculopapular to life-threatening hypersensitivity [2]. According to the FDA, the incidence of OXC-related serious dermatological reactions including Stevens–Johnson syndrome and toxic epidermal necrolysis is estimated to range between 0.5 and 6/10 early in the non-oncological epileptic population [5]. Although rare, this potential life-threatening adverse reaction should be recognized and treated promptly. The toxicity is unpredictable for the most part. The pathogenesis appears to be multi-factorial and has been explained by drug hyper sensitivity, which implies both metabolic and immunological mechanisms [2]. Literature data show that AEDs containing aromatic rings, phenytoin, and carbamazepine, are associated with a higher incidence of adverse cutaneous skin reactions [2, 3]. A lower incidence was found with levetiracetam, gabapentin, valproic acid, primidone, felbamate, topiramate, and vigabatrin. Clobazam, OXC, phenobarbital, tiagabine, and zonisamide produced intermediate reactions [3]. In the literature, descriptions of OXC-induced Stevens–Johnson syndrome are rare [3]. OXC has recently been demonstrated efficacious in reducing seizure frequency in BTRE with scarce appearance of side-effects both mild and severe [6]. Here, we present four patients with BTRE treated with OXC monotherapy, who, during brain radiation therapy, presented a major skin reaction that disappeared after OXC suspension. The study included three males and one female, with a mean age of 54.8 years, affected by epilepsy secondary to cerebral high-grade glioma, with simple partial seizures (n = 3) and simple partial with secondary generalization seizures (n = 1). We introduced OXC monotherapy (mean dose = 1,050 mg/day) with a good effect on seizure control during the treatment period (monthly mean seizure frequency at baseline = 18; monthly mean seizure frequency before OXC withdrawal = 3; responder rate [50%) (see Table 1). For the treatment of oncological disease, patients underwent brain RT (total dose 60 Gy), in association with concomitant temozolomide treatment dose of 75 mg/m per day in three patients (Stupp protocol) [7]. All patients were on steroids. After the start of RT (min 2 days, max 14 days), all patients presented a major skin reaction characterized by macules, papules, and boils at departure from the scalp, which spread to the face, shoulders, and M. Maschio (&) L. Dinapoli Department of Neuroscience and Cervical-Facial Pathology, Center for Tumor-related Epilepsy, National Institute for Cancer ‘‘Regina Elena’’, Via Elio Chianesi 53, 00144 Rome, Italy e-mail: maschio@ifo.it