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Simo M.,Hospital Universitari Of Bellvitge Ico Duran ynals | Root J.C.,Sloan Kettering Cancer Center | Vaquero L.,Hospital Universitari Of Bellvitge Ico Duran ynals | Ripolles P.,Hospital Universitari Of Bellvitge Ico Duran ynals | And 8 more authors.
Journal of Thoracic Oncology | Year: 2015

Introduction: No study has examined structural brain changes specifically associated with chemotherapy in a lung cancer population. The aim of this cross-sectional study was to assess differences in brain structure between small-cell lung cancer patients (C+) following chemotherapy, non-small-cell lung cancer patients (C-) before chemotherapy and healthy controls (HC). Methods: Twenty-eight small-cell lung cancer patients underwent a neuropsychological assessment and a structural magnetic resonance imaging, including T1-weighted and diffusion tensor imaging to examine gray matter density and white matter (WM) integrity, respectively, 1 month following completion of platinum-based chemotherapy. This group was compared with 20 age and education-matched non-small-cell lung cancer patients before receiving chemotherapy and 20 HC. Results: Both C+ and C- groups exhibited cognitive impairment compared with the HC group. The C+ group performed significantly worse than HC in verbal fluency and visuospatial subtests; C- performed significantly worse than both C+ and HC in verbal memory. Voxel-based morphometry analysis revealed lower gray matter density in the insula and parahippocampal gyrus bilaterally, and left anterior cingulate cortex in C+ compared with HC. Diffusion tensor imaging indices showed focal decreased WM integrity in left cingulum and bilateral inferior longitudinal fasciculus in the C+ group and more widespread decreased integrity in the C- group compared with the HC group. Conclusion: This study demonstrates that lung cancer patients exhibit cognitive impairment before and after chemotherapy. Before the treatment, C- showed verbal memory deficits as well as a widespread WM damage. Following treatment, the C+ group performed exhibited lower visuospatial and verbal fluency abilities, together with structural gray matter and WM differences in bilateral regions integrating the paralimbic system. Copyright © 2014 by the International Association for the Study of Lung Cancer.


Simo M.,Hospital Universitari Of Bellvitge Ico Duran ynals | Argyriou A.A.,Saint Andrews General Hospital of Patras | Macia M.,Hospital Universitari Of Bellvitge Ico Duran ynals | Plans G.,Hospital Universitari Of Bellvitge Ico Duran ynals | And 5 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2014

Purpose: A prospective, two-stage phase II trial with octreotide in patients with recurrent high-grade meningioma was conducted. The radiographic partial response (RPR) was set as the primary study endpoint, whereas progression-free survival at 6 months (PFS6) was defined as the secondary endpoint. Methods: Nine patients (eight men; median age 65) with histological high-grade meningioma (five with grade II and four with grade III) and progression after prior surgery and radiotherapy were included. All had positive brain octreotide SPECT scanning. Octreotide was administered intramuscularly once every 28 days at a dose of 30 mg for the first two cycles and 40 mg for subsequent cycles until progression. Magnetic resonance imaging was performed every 3 months. Progression and RPR were defined as an increase of ≥25 % and as a decrease of ≥50 % in two-dimensional maximum diameters, respectively. Results: Patients received a median of three octreotide cycles (range 1-8) without grade ≥2 toxicities. No RPRs were observed. Stable disease was the best response in 33.3 % (n = 3). All patients had progressive disease at 10 months of follow-up. Median time to progression was 4.23 months (range 1-9.4), and the PFS6 was 44.4 % (n = 4). Conclusion: Our study failed to provide evidence to support the use of monthly long-acting somatostatin analogue schedule in recurrent high-grade meningiomas, as none of our patients demonstrated RPR. The modest median PFS of 4-5 months along with the unknown natural history of recurrent meningiomas render the use of this therapy against these aggressive brain tumors uncertain. © 2014 Springer-Verlag.


Velasco R.,Hospital Universitari Of Bellvitge Ico Duran ynals | Velasco R.,Autonomous University of Barcelona | Videla S.,Laboratorios del Doctor Esteve S.A. | Villoria J.,Medicxact S.L. | And 3 more authors.
Acta Neurologica Scandinavica | Year: 2015

Objectives: Thermal quantitative sensory testing (QST) is a non-invasive procedure helpful in the assessment of the function of small Aδ and C nerve sensory fibres. Oxaliplatin (OXA) is an effective chemotherapeutic agent, but is frequently associated with neurotoxic dose-limiting side effects. This controlled clinical trial evaluated the reliability and accuracy of thermal QST for assessing the OXA-induced acute neuropathic syndrome, whose clinical hallmark is cold-triggered painful paraesthesia. Materials & methods: A testing protocol with the Thermal Sensory Analyzer (Medoc) was carried out in 20 colorectal cancer patients during the initial four cycles of OXA-based chemotherapy and in 20 age- and sex-matched healthy volunteers. Testing was carried out on the hands and included the determination of thermal detection and pain thresholds and the intensity of pain evoked by cold stimuli. Calculations were made of: coefficients of test-retest and inter-rater reliability, indices of responsiveness and parameters that quantify diagnostic accuracy. Results: Thermal thresholds showed moderate to good reliability (ρ ≥ 0.383), but were not consistently responsive to the effects of chemotherapy (cold pain thresholds decreased in both groups, although almost twice in patients compared to healthy volunteers). Conversely, the intensity of pain evoked by suprathreshold cold stimuli was reliable (ρ ≥ 0.822), responsive (detected changes over time) and discriminated between patients and healthy volunteers (area under the ROC curve = 0.700). Conclusions: The procedure was reliable and accurate to evaluate cold hyperalgesia resulting from OXA administration. The data provided may be used to define efficacy endpoints for future clinical trials of therapies for OXA-induced neuropathies and calculate appropriate sample sizes. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Briani C.,University of Padua | Argyriou A.A.,Saint Andrews State General Hospital of Patras | Argyriou A.A.,University of Patras | Izquierdo C.,Hospital Universitari Of Bellvitge Ico Duran ynals | And 11 more authors.
Journal of the Peripheral Nervous System | Year: 2014

This prospective study sought to identify the potential reversibility of oxaliplatin-induced peripheral neuropathy (OXAIPN) by following-up its long-term course 2 years after discontinuation of oxaliplatin (OXA)-based chemotherapy. Participants were 91 colorectal cancer patients treated with OXA-based chemotherapy. Neurological assessment, clinical Total Neuropathy Score© (TNSc©) and nerve conduction studies were performed at baseline (T0), the end of chemotherapy (T1) and 2 years (T2) after discontinuation of chemotherapy. A total of 73 of 91 (80%) patients experienced OXAIPN at T1. At a median follow-up of 25 months, persistence of chronic OXAIPN was present in 61 of 73 patients (84%) and complete resolution was present in 12 patients (17%). Longitudinal comparison of TNSc© values between T1 and T2 revealed that the overall severity of OXAIPN in those 61 patients significantly decreased over time. Median TNSc© values were nine (range: 2-15) at T1 vs. four (range: 2-12) at T2 (P < 0.001). Likewise, sensory nerve conduction measures at T2 significantly improved in all sensory nerves tested, compared with T1. Severity of OXAIPN at T2 was significantly associated (P < 0.001) with high severity of OXAIPN at T1. In conclusion, persistence of OXAIPN beyond 2 years after finishing chemotherapy is common. Clinical and neurophysiological improvement is observed, although recovery is often incomplete. © 2015 Peripheral Nerve Society.


Sanchez-Osuna M.,Autonomous University of Barcelona | Sanchez-Osuna M.,Research Center Biomedica en Red Sobre Enfermedades Neurodegenerativas | Martinez-Escardo L.,Autonomous University of Barcelona | Granados-Colomina C.,Autonomous University of Barcelona | And 15 more authors.
Neuro-Oncology | Year: 2016

Background Glioblastoma (GBM) or grade IV astrocytoma is one of the most devastating human cancers. The loss of DFF40/CAD, the key endonuclease that triggers oligonucleosomal DNA fragmentation during apoptosis, has been linked to genomic instability and cell survival after radiation. Despite the near inevitability of GBM tumor recurrence after treatment, the relationship between DFF40/CAD and GBM remains unexplored. Methods We studied the apoptotic behavior of human GBM-derived cells after apoptotic insult. We analyzed caspase activation and the protein levels and subcellular localization of DFF40/CAD apoptotic endonuclease. DFF40/CAD was also evaluated in histological sections from astrocytic tumors and nontumoral human brain. Results We showed that GBM cells undergo incomplete apoptosis without generating oligonucleosomal DNA degradation despite the correct activation of executioner caspases. The major defect of GBM cells relied on the improper accumulation of DFF40/CAD at the nucleoplasmic subcellular compartment. Supporting this finding, DFF40/CAD overexpression allowed GBM cells to display oligonucleosomal DNA degradation after apoptotic challenge. Moreover, the analysis of histological slices from astrocytic tumors showed that DFF40/CAD immunoreactivity in tumoral GFAP-positive cells was markedly reduced when compared with nontumoral samples. Conclusions Our data highlight the low expression levels of DFF40/CAD and the absence of DNA laddering as common molecular traits in GBM. These findings could be of major importance for understanding the malignant behavior of remaining tumor cells after radiochemotherapy. © 2016 The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.


Bruna J.,Hospital Universitari Of Bellvitge Ico Duran ynals | Simo M.,Hospital Universitari Of Bellvitge Ico Duran ynals | Velasco R.,Hospital Universitari Of Bellvitge Ico Duran ynals
Current Treatment Options in Neurology | Year: 2012

Leptomeningeal cancer dissemination is a metastatic complication with growing impact in clinical oncology. Advances in treatment have been hampered by difficulties in diagnosis and response assessment, and nihilistic attitudes of physicians due to the poor prognosis, even when treating patients. However, relevant advances in therapeutic management have been achieved. In selected patients, survival and time to neurological progression can be improved with therapy, although an early diagnosis is critical (hence the importance of a high suspicion index). It is mandatory to perform an MRI of the entire neuraxis and cerebrospinal fluid (CSF) examination of up to two samples if the first lumbar puncture is negative, with appropriate volume and processing methods. It is advisable to supplement CSF analysis using flow cytometry techniques and new biomarker determinations (not yet validated) to improve diagnostic yield sensitivity. Currently, patients with good performance status and the option to receive effective systemic treatment must be treated with added intrathecal chemotherapy through Ommaya reservoirs and focal radiotherapy to bulky lesions or refractory painful areas. However, a standard treatment approach is not wellestablished due to the lack of well-designed randomized clinical trials and the mix of different cancer subtypes treated with the same drug in most studies. Liposomal cytarabine offers some advantages over methotrexate, both being first-line treatments for intrathecal administration. Recently, new agents have proven safe and feasible, broadening the available treatment options. The individualized choice of intrathecal agent based on the primary malignancy and appropriate treatment of underlying systemic disease are critical to improved outcomes in these patients. © Springer Science+Business Media, LLC 2012.


Argyriou A.A.,Saint Andrews State General Hospital of Patras | Argyriou A.A.,University of Patras | Cavaletti G.,University of Milan Bicocca | Bruna J.,Hospital Universitari Of Bellvitge Ico Duran ynals | And 2 more authors.
Archives of Toxicology | Year: 2014

This review paper provides a critical exploration of updates concerning the spectrum of characteristics and treatment options of bortezomib-induced peripheral neuropathy (BIPN). Emphasis is given on pathogenesis issues. Although the mechanism underlying BIPN still remains elusive, it is increasingly acknowledged that the inhibition of proteasome activity in dorsal root ganglia and peripheral nerves, the mitochondrial-mediated disruption of Ca++ intracellular homeostasis and the disregulation in nuclear factor κB and brain-derived neurotrophic factor play a significant pathogenic role. Assessment of BIPN is based on comprehensive grading scales, using a combination of "subjective" and "objective" parameters, which turn out to be ambiguously interpreted, thus leading to both under- and misreporting of its true incidence and severity. BIPN is clinically defined as a typical example of a dose-dependent, distally attenuated painful, sensory neuronopathy. Patients pre-treated with neurotoxic regimens and those with pre-existing neuropathy are more likely to develop severe neurotoxicity. To date, there is no effective pharmacological treatment to prevent BIPN, and therefore, interventions remain merely symptomatic to focus on the alleviation of neuropathic pain. Hence, strict adherence to the dose reduction and schedule change algorithm is recommended in order to prevent treatment-emergent BIPN and allow the continuation of treatment. Further studies in animal models and humans, including experimental, clinical, neurophysiological and pharmacogenetic approaches, are needed to allow the identification of the true spectrum of BIPN pathogenesis and characteristics. It is expected that such comprehensive approaches would be the starting point for the development of early preventive and therapeutic interventions against BIPN. © 2014 Springer-Verlag.


Velasco R.,Hospital Universitari Of Bellvitge Ico Duran ynals | Velasco R.,Autonomous University of Barcelona | Bruna J.,Hospital Universitari Of Bellvitge Ico Duran ynals | Bruna J.,Autonomous University of Barcelona
Current Colorectal Cancer Reports | Year: 2014

Oxaliplatin (OXA) is a first-line agent in the systemic treatment of colorectal cancer (CRC). OXA-induced neuropathy is the most prominent adverse effect, both during and after the completion of chemotherapy. OXA neurotoxicity (OXA-NTX) is a dose-limiting, frequent, and long-lasting adverse event that may compromise therapeutic outcome and the quality-of-life of CRC patients. Increased knowledge of the pathophysiology and clinical profile of this neuropathy is being achieved. Two types of neuropathy are usually observed, and evidence suggests a link between the acute symptoms and the development of chronic NTX. In this paper we review the main advances and the outstanding issues concerning OXA-NTX, for example calcium/magnesium and other drugs in the prophylaxis and treatment of this neuropathy. Recently available and ongoing investigation of pharmacogenomics, clinical and neurophysiological risk factors, and early markers of OXA-NTX are of great value in clinical decision-making, contributing to minimizing the risk of severe neuropathy. © 2014 Springer Science+Business Media New York.


Izquierdo C.,Hospital Universitari Of Bellvitge Ico Duran ynals | Velasco R.,Hospital Universitari Of Bellvitge Ico Duran ynals | Velasco R.,Autonomous University of Barcelona | Vidal N.,Hospital Universitari Of Bellvitge Ico Duran ynals | And 6 more authors.
Neuro-Oncology | Year: 2016

Background. Primary central nervous system lymphomas may present as diffuse, nonenhancing infiltrative lesions. This rare variant is termed lymphomatosis cerebri (LC). We did a systematic review and analysis of the literature, adding our own cases, to better characterize LC in order to improve early diagnosis and treatment. Methods. PubMed, ISI Web of Knowledge, and hospital databases were reviewed. Information was extracted regarding demographic, clinical, histological, cerebrospinal fluid (CSF), neuroimaging, and treatment variables. The impact of single parameters on overall survival (OS) was determined by applying univariate and multivariate analyses. Results. Forty-two patients were included (median age: 58 y; range: 28-80 y). At consultation, 52% of patients had a poor KPS. The most common presenting symptom was cognitive decline (59.5%). Imaging studies showed supratentorial and infratentorial infiltration in 55% of patients and bilateral hemispheric involvement in 95%. CSF pleocytosis was present in 51.5% of the patients. Median time to diagnosis was 4.5 (range: 1-30) months, and the diagnosis was not established until autopsy for 33% of patients. The median OS was 2.95 (range: 0.33-56) months; however, those patients who received methotrexate had a median OS of 13.8 (range: 0.7-56) months. Analysis identified KPS ≥ 70 (HR: 0.32; 95% CI: 0.114-0.894; P =. 03) and treatment with methotrexate (HR: 0.19; 95% CI: 0.041-0.886; P =. 034) as independent favorable prognostic factors, whereas T-cell lymphoma was independently related with a worse outcome (HR: 6.62; 95% CI: 1.317-33.316; P =. 022). Conclusions. LC is a misdiagnosed entity associated with considerable diagnostic delay. MRI evidence of bilateral hemispheric involvement and CSF pleocytosis should be alerts for this diagnosis. Treatment with methotrexate-based chemotherapy must be considered, especially for patients with good KPS. © 2015 The Author(s). Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.


PubMed | Hospital Universitari Of Bellvitge Ico Duran ynals
Type: Journal Article | Journal: Current treatment options in neurology | Year: 2012

Leptomeningeal cancer dissemination is a metastatic complication with growing impact in clinical oncology. Advances in treatment have been hampered by difficulties in diagnosis and response assessment, and nihilistic attitudes of physicians due to the poor prognosis, even when treating patients. However, relevant advances in therapeutic management have been achieved. In selected patients, survival and time to neurological progression can be improved with therapy, although an early diagnosis is critical (hence the importance of a high suspicion index). It is mandatory to perform an MRI of the entire neuraxis and cerebrospinal fluid (CSF) examination of up to two samples if the first lumbar puncture is negative, with appropriate volume and processing methods. It is advisable to supplement CSF analysis using flow cytometry techniques and new biomarker determinations (not yet validated) to improve diagnostic yield sensitivity. Currently, patients with good performance status and the option to receive effective systemic treatment must be treated with added intrathecal chemotherapy through Ommaya reservoirs and focal radiotherapy to bulky lesions or refractory painful areas. However, a standard treatment approach is not well-established due to the lack of well-designed randomized clinical trials and the mix of different cancer subtypes treated with the same drug in most studies. Liposomal cytarabine offers some advantages over methotrexate, both being first-line treatments for intrathecal administration. Recently, new agents have proven safe and feasible, broadening the available treatment options. The individualized choice of intrathecal agent based on the primary malignancy and appropriate treatment of underlying systemic disease are critical to improved outcomes in these patients.

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