Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by neurofibromin haploinsufficiency due to pathogenic variants in the
NF1
gene. Tumor predisposition has long been associated ...with NF1, and an increased breast cancer (BC) incidence and reduced survival have been reported in recent years for women with NF1. As breast density is another known independent risk factor for BC, this study aims to evaluate the variability of breast density in patients with NF1 compared to the general population. Mammograms from 98 NF1 women affected by NF1, and enrolled onto our monocentric BC screening program, were compared with those from 300 healthy subjects to verify differences in breast density. Mammograms were independently reviewed and scored by a radiologist and using a Computer-Aided Detection (CAD) software. The comparison of breast density between NF1 patients and controls was performed through Chi-squared test and with multivariable ordinal logistic models adjusted for age, body mass index (BMI), number of pregnancies, and menopausal status.breast density was influenced by BMI and menopausal status in both NF1 patients and healthy subjects. No difference in breast density was observed between NF1 patients and the healthy female population, even after considering the potential confounding factors.Although NF1 and a highly fibroglandular breast are known risk factors of BC, in this study, NF1 patients were shown to have comparable breast density to healthy subjects. The presence of pathogenic variants in the
NF1
gene does not influence the breast density value.
Background and purpose
Patients with a history of brain radiotherapy can experience acute stroke‐like syndromes related to the delayed effects of brain radiation, including stroke‐like migraine ...attacks after radiation therapy syndrome, peri‐ictal pseudoprogression and acute late‐onset encephalopathy after radiation therapy syndrome. The aim of this study was to collect evidence on the long‐term outcome and treatment of these conditions, whose knowledge is undermined by their rarity and fragmented description.
Methods
Cases were collected, both prospectively and retrospectively, amongst six neuro‐oncology departments. Inclusion criteria were as follows: (i) history of brain radiotherapy (completed at least 6 months before the acute episode); (ii) new onset of acute/subacute neurological symptoms; (iii) exclusion of all etiologies unrelated to brain irradiation. A review of current literature on stroke‐like syndromes was performed to corroborate our findings.
Results
Thirty‐two patients with acute neurological conditions attributed to the delayed effects of radiation were identified, including 26 patients with stroke‐like syndromes. Patients with stroke‐like syndromes commonly presented with a mosaic of symptoms, including focal deficits (77%), encephalopathy (50%), seizures (35%) and headache (35%). Seventy‐three percent of them had acute consistent magnetic resonance imaging alterations. Treatment included high‐dose steroids in 65% of cases. Twenty‐two patients recovered completely (85%). Sixteen patients (62%) experienced relapses (median follow‐up 3.5 years). A literature review identified 87 additional stroke‐like cases with similar characteristics.
Conclusions
Stroke‐like events related to brain irradiation may be associated with permanent sequelae. Steroids are often administered on empirical grounds, as they are thought to accelerate recovery. Relapses are common, highlighting the need to elaborate adequate prevention strategies.
Purpose
The use of central venous catheters with peripheral insertion (PICC) has increased rapidly in recent years, particularly in cancer patients. The benefits provided may occasionally be affected ...by relevant complications, such as infections and thrombotic events, especially in neuro-oncological patients. To date, the risk of PICC-related complications in this subset of patients is unknown, as is tolerability. As a primary objective, this study aimed to collect complications related to PICCs in primary neuro-oncological patients. As a secondary objective, the study aimed to evaluate PICC tolerability.
Methods
Neuro-oncological patients with PICCs that were placed as part of normal clinical practice at IRCCS Neurologico C. Besta were consecutively enrolled in the study. PICC-related complications were recorded immediately (during the procedure), early (within 1 week after PICC insertion), and late (1–3-5 months after PICC placement). At the same time points, all patients were also evaluated for tolerability through interviews with semi-structured, open-ended questions.
Results
Sixty patients were enrolled (41 males and 19 females, with a median age of 56.2 years). Excluding loss to follow-up, 33/49 patients developed at least one complication related to the PICC. Immediate complications mainly included hematoma (8), accidental arterial puncture (4), and primary malpositioning (3). Regarding early and late complications, 3 device-related infections, 8 thrombotic events, and 20 mechanical complications were registered. Semi-structured interviews revealed an overall positive experience with the device. The most negative impact was on hygiene habits, with 34 patients becoming caregiver-dependent. Over time, almost all patients became used to the device and perceived greater security during chemotherapy. A strongly negative issue was the difficulty of relying on competently trained healthcare personnel in outpatient setting.
Conclusion
The results showed a nonnegligible increased thromboembolic risk in neuro-oncological patients with PICCs, almost double that in historical oncological populations. It is essential to extend the study to a greater number of patients to achieve reliable results and to identify patients at high risk. The device seems to be positively accepted by the majority of patients, without affecting activities of daily living.
MRI grading of grade II and III gliomas may have an important impact on treatment decisions. Occasionally, both conventional MRI (cMRI) and histology fail to clearly establish the tumour grade. Three ...cMRI features (no necrosis; no relevant oedema; absent or faint contrast enhancement) previously validated in 196 patients with supratentorial gliomas directed our selection of 68 suspected low-grade gliomas (LGG) that were also investigated by advanced MRI (aMRI), including perfusion weighted imaging (PWI), diffusion weighted imaging (DWI) and spectroscopy. All the gliomas had histopathological diagnoses. Sensitivity and specificity of cMRI pre-operative diagnosis were 78.5 and 38.5 %, respectively, and 85.7 and 53.8 % when aMRI was included, respectively. ROC analysis showed that cut-off values of 1.29 for maximum rCBV, 1.69 for minimum rADC, 2.1 for rCho/Cr ratio could differentiate between LGG and HGG with a sensitivity of 61.5, 53.8, and 53.8 % and a specificity of 54.7, 43 and 64.3 %, respectively. A significantly longer OS was observed in patients with a maximum rCBV <1.46 and minimum rADC >1.69 (80 vs 55 months, p = 0.01; 80 vs 51 months, p = 0.002, respectively). This result was also confirmed when cases were stratified according to pathology (LGG vs HGG). The ability of aMRI to differentiate between LGG and HGG and to predict survival improved as the number of aMRI techniques considered increased. In a selected population of suspected LGG, classification by cMRI underestimated the actual fraction of HGG. aMRI slightly increased the diagnostic accuracy compared to histopathology. However, DWI and PWI were prognostic markers independent of histological grade.
BACKGROUND: Fluorescein is a fluorescent tracer that can be used for many applications. It is able to accumulate in brain areas with blood-brain barrier disruption, and thus it can be considered an ...ideal dye for intraoperative visualization of high-grade gliomas (HGG). We report the preliminary results of a phase II trail (FLUOGLIO) on a new fluorescein-guided technique to remove HHG with a dedicated filter on the surgical microscope. METHODS: In September 2011 we started a prospective phase II-trial (FLUOGLIO) to evaluated safety and obtain initial indications about efficacy of fluorescein-guided surgery for HGG. Patients with suspected HGG amenable to complete resection of contrast-enhancing area were eligible to participate in this study. This report is based on the analysis of the short- and long-term results in 28 consecutive patients with HGG (age range 45-74 years), enrolled since September 2011. Fluorescein was intravenous (i.v.) injected after intubation (5-10 mg/Kg). Tumor was removed with microsurgical technique and fluorescence visualization by BLU400 or YELLOW560 filters on Pentero microscope (Carl Zeiss, Germany). The study was approved by our Ethical Committee and registered on the European Regulatory Authorities website (EudraCT No. 2011-002527-18). RESULTS: Median pre-operative tumor volume was 33.1 cm3 (2.4-87.8 cm3). We found no adverse reaction to fluorescein administration. Tumor was completely removed in 80% of the patients. Median follow-up was 10 months. 6 months Progression-free Survival (PFS) and median survival were respectively 71.4 % and 11 months. CONCLUSION: Our analysis suggested that fluorescein-guided technique with a dedicated filter on the surgical microscope is safe and allows high-rate of complete resection of contrast-enhanced tumor at the early post-operative MRI.
Mechanisms responsible for telomere maintenance are been recently elucidated: many cancers harbor mutations in alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene resulting in a ...phenomenon known as alternative lengthening of telomeres (ALT) or point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene leading to an increased telomerase expression. ATRX and TERT mutations have been recently identified also in brain tumors. In gliomas, a molecular stratification based on IDH and ATRX mutational status and 1p/19q codeletion has been suggested. ATRX mutations have been observed mainly in astrocytic tumors and TERT promoter mutations mainly in oligodendroglial tumors. Aim of our study was to evaluate the expression of both ATRX and TERT in WHO grade II gliomas and in their resected recurrences, related to a set of confirmed molecular markers and to clinical data. We performed an immunohistochemical analysis of ATRX and TERT expression in 30 grade II gliomas (astrocytomas, oligoastrocytomas and oligodendroglioma) and in their respective recurrences (grade III-IV). Also evaluation of IDH1 and p53 status and 1p/19q LOH were carried out. Loss of expression of ATRX protein has been associated to the mutated gene and ALT phenotype, while expression of TERT protein could be related to TERT promoter mutations. We found a loss of ATRX expression in 70% of cases; recurrences showed the same pattern of ATRX expression. In the most part of cases ATRX loss was associated to IDH1 and p53 mutation and intact 1p/19q, as previously observed. In the major part of cases with ATRX loss of expression TERT was not detected. TERT high expression was observed in about 30% of grade II gliomas at the first surgery, minor expression of TERT was found in grade III-IV recurrent tumors. In most case high expression of TERT was associated to 1p/19q deletion. We observed a statistically significant correlation between TERT high expression and a better outcome. Our study of protein expression of both ATRX and TERT in low grade gliomas and in their recurrences in relationship with established molecular markers and follow-up data, confirm the possibility of using immunohistochemistry in routine diagnostic procedures for better define this subset of neoplasm.
Oncogenic fusions consisting of fibroblast growth factor receptor (FGFR) and TACC are present in a subgroup of glioblastoma (GBM) and other human cancers and have been proposed as new therapeutic ...targets. We analyzed frequency and molecular features of FGFR-TACC fusions and explored the therapeutic efficacy of inhibiting FGFR kinase in GBM and grade II and III glioma.
Overall, 795 gliomas (584 GBM, 85 grades II and III with wild-type and 126 with IDH1/2 mutation) were screened for FGFR-TACC breakpoints and associated molecular profile. We also analyzed expression of the FGFR3 and TACC3 components of the fusions. The effects of the specific FGFR inhibitor JNJ-42756493 for FGFR3-TACC3-positive glioma were determined in preclinical experiments. Two patients with advanced FGFR3-TACC3-positive GBM received JNJ-42756493 and were assessed for therapeutic response.
Three of 85 IDH1/2 wild-type (3.5%) but none of 126 IDH1/2-mutant grade II and III gliomas harbored FGFR3-TACC3 fusions. FGFR-TACC rearrangements were present in 17 of 584 GBM (2.9%). FGFR3-TACC3 fusions were associated with strong and homogeneous FGFR3 immunostaining. They are mutually exclusive with IDH1/2 mutations and EGFR amplification, whereas they co-occur with CDK4 amplification. JNJ-42756493 inhibited growth of glioma cells harboring FGFR3-TACC3 in vitro and in vivo. The two patients with FGFR3-TACC3 rearrangements who received JNJ-42756493 manifested clinical improvement with stable disease and minor response, respectively.
RT-PCR sequencing is a sensitive and specific method to identify FGFR-TACC-positive patients. FGFR3-TACC3 fusions are associated with uniform intratumor expression of the fusion protein. The clinical response observed in the FGFR3-TACC3-positive patients treated with an FGFR inhibitor supports clinical studies of FGFR inhibition in FGFR-TACC-positive patients.
BACKGROUND AND AIM: RANO criteria are widely used for response assessment in brain tumor clinical trials based on cytotoxic and/or anti-angiogenic treatments. In cancer immunotherapy the induction of ...inflammatory responses may be relevant and careful evaluation of changes in tumor size may help discriminating therapy-driven changes from tumor progression. We compared volume measurements on post-contrast, three dimensional (3D) T1-weighted images (T1WI) with cross-sectional areas on two dimensional (2D) T1WI, according to RANO, in patients with first diagnosis of glioblastoma multiforme (GBM) enrolled in a phase I-II phase study based on dendritic cell (DC) immunotherapy associated to the Stupp regimen. MATERIALS AND METHODS: We reviewed 118 MRI studies from 22 adult patients with newly diagnosed GBM. The main radiological inclusion criteria was residual tumor volume 10mm) of the contrast-enhancing lesion. In 3D measurements volume was estimated by the PACS workstation software (MedStation version 4.9.902.6). Volumetric analysis was performed on isotropic high resolution 3D T1WI. the enhancing tumor was outlined in all slices excluding the cystic areas. RESULTS: 11/118 studies (9.3%) were excluded because no enhancing lesions were present. 30 of 107 remaining scans (25.4%) were evaluated for volume only because one diameter <10 mm. The median area on 2D was 547 mm2, the median volume on 3D was 577 mm3. A high correlation between the two measurements was observed in the 77 scans in which both the area and the volume were measurable (r = 0.85, p<0.0001). When looking at the difference between scans performed at two consecutive time points, no significant difference was observed in percentage variations calculated by the two methods (Wilcoxon test p = 0.49). Furthermore there was a high correlation between the percentage differences in the two measurements (r = 0.66, p<0.0001). CONCLUSIONS: Our study suggests that tumor cross-sectional areas on post contrast 2D T1WI are comparable to volumes on 3D T1WI. However approximately 25% of scans were lost to the 2D evaluation because they had at least a diameter less than the RANO cut off (10 mm). Thus, volumetric measurements can provide a more informative evaluation of tumor size, a feature that can be particularly useful in immunotherapy trials.
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