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The therapeutic landscape in patients with advanced non-small-cell lung cancer harboring oncogenic biomarkers has radically changed with the development of targeted therapies. Although lung cancers are known to frequently metastasize to the brain, oncogene-driven non-small-cell lung cancer patients show a higher incidence of both brain metastases at baseline and a further risk of central nervous system progression/relapse. Recently, a new generation of targeted agents, highly active in the central nervous system, has improved the control of intracranial disease. The intracranial activity of these drugs poses a crucial issue in determining the optimal management sequence in oncogene-addicted non-small-cell lung cancer patients with brain metastases, with a potential change of paradigm from primary brain irradiation to central nervous system penetrating targeted inhibitors.

Rearrangement in the anaplastic lymphoma kinase (ALK) gene is one of the oncogenic drivers in non-small cell lung cancer (NSCLC) patients. Several ALK inhibitors (ALKis) have been developed and have demonstrated their efficacy, however the best treatment strategy for ALK positive NSCLC patients has yet to be determined. Our retrospective study has investigated the outcome of 40 ALK-rearranged NSCLC patients treated with two different sequential strategies in our Institute; a "classical group", treated with crizotinib followed by second or third generation ALKis, and the "experimental group", treated upfront with a second generation ALK inhibitor. The primary endpoints investigated were Progression-free survival (PFS) and intracranial activity. The analysis has revealed a significant improvement in PFS ( p = 0.050) in the experimental group, furthermore none of these patients developed brain metastasis. There was no statistically significant difference in OS, but all patients in the experimental group were still alive after a median follow up of 15 months. Our retrospective analysis suggests that systemic and intracranial efficacy tends to be better in the experimental group; randomized prospective studies could confirm our observations., Competing Interests: CONFLICTS OF INTEREST The authors have declared no conflicts of interest.

Background: Treatment of metastatic NSCLC patients with immune-checkpoint medicine is intriguing for the potential efficacy; however it may be difficult to evaluate the clinical response due to the lack of reliable immune-monitoring markers up to now and the possibility of radiological pseudo-progression., Case Presentation: Herein we report the case of a patient ex-smoker with adenocarcinoma of the lung, stage IV for liver metastases, in progression after cisplatin-based chemotherapy and treated with antiPD-L1 (MPDL3802-Roche Genentech) e.v. every 3 weeks in a clinical trial. Treatment with antiPD-L1 was well tolerated and CT scan after 6 weeks of treatment showed stabilization of mediastinal lymph nodes, while progression of liver metastases; liver progression only was confirmed by further CT-scans. Patient was asymptomatic and it was unclear if we faced a pseudo-progression in the liver or a real progression. Data about his PDL1 expression were not available because the patient was in a clinical trial. Eventually a biopsy of the liver metastasis confirmed that there was a massive neoplastic invasion with tumor infiltrating lymphocytes <5 %. We stopped anti-PD-L1 therapy due to progression., Conclusion: Evaluation of response may be difficult with immune checkpoint inhibitors, in particular radiologic images may be a matter of debate; eventually we performed a biopsy to study tumor infiltrating lymphocytes to decide whether it was pseudo-progression or real progression.

Aim: In psychiatric rehabilitation the individual treatment plan can be formulated from tools that provide a multidimensional assessment of the patient. This study aims to analyze the relationship between distress and recovery style (integration and sealing over) from the psychosis. Assuming that this relationship affects the burden management, the study has the additional target of gaining more elements to direct the formulation of more effective therapeutic / rehabilitation programs., Methods: The study was carried out in a psychiatric day center, semi-residential structure of mental health services of the National Health System in Italy. 45 patients enrolled have been evaluated by the Neuropsychiatric Inventory (NPI - Italian version) and Integration / Sealing Over Scale (ISOS - Italian version), within three months (March-June 2014)., Results: In the sample, the symptoms which cause a greater distress in the health workers, in an absolute sense, are uninhibition, irritability and apathy. Moreover, the results indicate that depression and anxiety cause a greater degree of distress in sealer patients., Discussion and Conclusions: Uninhibition, irritability and apathy were more burdensome for mental health workers, because they require a greater engagement in the therapeutic relationship. Anxious and depressive symptoms cause a greater degree of distress in the sealers patients, reporting lower endurance of the denial of psychosis. The data seem to prove that knowing, differentiating and deepening the different aspects of the recovery style of each patient enable us to estimate the burden management, starting from the taking in charge, and to reduce the distress and the risk of burn out of the mental health workers.

Herpes simplex virus types 1 and 2 (HSV1 and HSV2) are common infectious agents in both industrialized and developing countries. They cause recurrent asymptomatic and/or symptomatic infections, and life-threatening diseases and death in newborns and immunocompromised patients. Current treatment for HSV relies on antiviral medications, which can halt the symptomatic diseases but cannot prevent the shedding that occurs in asymptomatic patients or, consequently, the spread of the viruses. Therefore, prevention rather than treatment of HSV infections has long been an area of intense research, but thus far effective anti-HSV vaccines still remain elusive. One of the key hurdles to overcome in anti-HSV vaccine development is the identification and effective use of strategies that promote the emergence of Th1-type immune responses against a wide range of epitopes involved in the control of viral replication. Since the HIV1 Tat protein has several immunomodulatory activities and increases CTL recognition of dominant and subdominant epitopes of heterologous antigens, we generated and assayed a recombinant attenuated replication-competent HSV1 vector containing the tat gene (HSV1-Tat). In this proof-of-concept study we show that immunization with this vector conferred protection in 100% of mice challenged intravaginally with a lethal dose of wild-type HSV1. We demonstrate that the presence of Tat within the recombinant virus increased and broadened Th1-like and CTL responses against HSV-derived T-cell epitopes and elicited in most immunized mice detectable IgG responses. In sharp contrast, a similarly attenuated HSV1 recombinant vector without Tat (HSV1-LacZ), induced low and different T cell responses, no measurable antibody responses and did not protect mice against the wild-type HSV1 challenge. These findings strongly suggest that recombinant HSV1 vectors expressing Tat merit further investigation for their potential to prevent and/or contain HSV1 infection and dissemination.

In the recent years many advances have been achieved in the field of the treatment of lung cancer; with the development of novel therapeutic pathways due to the knowledge of oncologic drivers involved in the carcinogenesis of the lung, as well as the involvement of new radiotherapic and surgical techniques. Nevertheless, the standard treatment for elderly is still debated, mainly because of an underrepresentation of elderly patients in clinical trials. Herein we try to summarize the main guidelines for the treatment of lung cancer, with particular attention for the elderly patients, what we know and what has changed.

Aim: Aim of the study was to validate the Italian version of the Neuropsychiatric Inventory-Nursing Home (NPI-NH). The evaluation of neuropsychiatric symptoms in elderly patients with cognitive impairment and/or a chronic psychiatric disorder, is an essential need in nursing home., Methods: The Italian version of the NPI-NH was administered in 53 patients in a nursing home in Northern-Italy., Results: The internal consistency of the NPI-NH reported a value (α=0.62) according to the literature. The inter-rater reliability was ρ=0.991 and ρ=0.999 for the caregiver distress. There was an almost complete overlap between the assessments of individual items ranging from (ρ) 1 and 0.952. The test-retest reliability was ρ=0.961 and ρ=0.943 for the distress of the caregiver. Factor analysis revealed 4 factors that can explain 62.167% of the total variance: factor 1 hyperactivity, factor 2 mood, factor 3 psychosis and factor 4 withdrawal., Conclusions: The NPI-NH can be used as an instrument for follow-up of patients and as a tool to support the activities of psychiatric referring and research in nursing home because of his demonstrated psychometric validity and its ease of use.

Background: Although first-line therapy for patients affected by advanced mesothelioma is well established, there is a lack of data regarding the impact of second-line treatment., Methods: We retrospectively collected data of patients affected by advanced mesothelioma, already treated with first-line therapy based on pemetrexed and platin, with a response (partial response or stable disease) lasting at least 6 months, and re-treated with a pemetrexed-based therapy at progression. The primary objective was to describe time to progression and overall survival after re-treatment., Results: Overall across several Italian oncological Institutions we found 30 patients affected by advanced mesothelioma, in progression after a 6-month lasting clinical benefit following a first-line treatment with cisplatin and pemetrexed, and re-challenged with a pemetrexed-based therapy. In these patients we found a disease control rate of 66%, with reduction of pain in 43% of patients. Overall time to progression and survival were promising for a second-line setting of patients with advanced mesothelioma, being 5.1 and 13.6 months, respectively., Conclusions: In our opinion, when a patient has a long-lasting benefit from previous treatment with pemetrexed combined with a platin compound, the same treatment should be offered at progression.

Purpose: We have recently reported that viral vector-mediated supplementation of fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF) in a lesioned, epileptogenic rat hippocampus limits neuronal damage, favors neurogenesis, and reduces spontaneous recurrent seizures. To test if this treatment can also prevent hippocampal circuit reorganization, we examined here its effect on mossy fiber sprouting, the best studied form of axonal plasticity in epilepsy., Methods: A herpes-based vector expressing FGF-2 and BDNF was injected into the rat hippocampus 3 days after an epileptogenic insult (pilocarpine-induced status epilepticus). Continuous video-electroencephalography (EEG) monitoring was initiated 7 days after status epilepticus, and animals were sacrificed at 28 days for analysis of cell loss (measured using NeuN immunofluorescence) and mossy fiber sprouting (measured using dynorphin A immunohistochemistry)., Key Findings: The vector expressing FGF-2 and BDNF decreased both mossy fiber sprouting and the frequency and severity of spontaneous seizures. The effect on sprouting correlated strictly with the cell loss in the terminal fields of physiologic mossy fiber innervation (mossy cells in the dentate gyrus hilus and CA3 pyramidal neurons)., Significance: These data suggest that the supplementation of FGF-2 and BDNF in an epileptogenic hippocampus may prevent epileptogenesis by decreasing neuronal loss and mossy fiber sprouting, that is, reducing some forms of circuit reorganization., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Under certain experimental conditions, neurotrophic factors may reduce epileptogenesis. We have previously reported that local, intrahippocampal supplementation of fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF) increases neurogenesis, reduces neuronal loss, and reduces the occurrence of spontaneous seizures in a model of damage-associated epilepsy. Here, we asked if these possibly anti-epileptogenic effects might involve anti-inflammatory mechanisms. Thus, we used a Herpes-based vector to supplement FGF-2 and BDNF in rat hippocampus after pilocarpine-induced status epilepticus that established an epileptogenic lesion. This model causes intense neuroinflammation, especially in the phase that precedes the occurrence of spontaneous seizures. The supplementation of FGF-2 and BDNF attenuated various parameters of inflammation, including astrocytosis, microcytosis and IL-1β expression. The effect appeared to be most prominent on IL-1β, whose expression was almost completely prevented. Further studies will be needed to elucidate the molecular mechanism(s) for these effects, and for that on IL-1β in particular. Nonetheless, the concept that neurotrophic factors affect neuroinflammation in vivo may be highly relevant for the understanding of the epileptogenic process.

Here we review the role of tissutal and circulating biomarkers in the management of lung cancer. In the past they were considerate quite ineffective tools as regards prognosis and prediction of treatment activity, nowadays instead, they are becoming a crucial key point as potential predictive issues in driving therapy, with possibly prognostic values as well.

A loss of neurons is observed in the hippocampus of many patients with epilepsies of temporal lobe origin. It has been hypothesized that damage limitation or repair, for example using neurotrophic factors (NTFs), may prevent the transformation of a normal tissue into epileptic (epileptogenesis). Here, we used viral vectors to locally supplement two NTFs, fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF), when epileptogenic damage was already in place. These vectors were first characterized in vitro, where they increased proliferation of neural progenitors and favored their differentiation into neurons, and they were then tested in a model of status epilepticus-induced neurodegeneration and epileptogenesis. When injected in a lesioned hippocampus, FGF-2/BDNF expressing vectors increased neuronogenesis, embanked neuronal damage, and reduced epileptogenesis. It is concluded that reduction of damage reduces epileptogenesis and that supplementing specific NTFs in lesion areas represents a new approach to the therapy of neuronal damage and of its consequences.

Genetic mosaicism is the presence of genetically different cell populations within an individual and can be associated with a milder disease phenotype. We describe a somatic mosaicism in a Lynch syndrome patient with a MLH1 gene mutation (c.1050delA). Since she was the sister of a heterozygous proposita, the mosaicism appeared to be caused by reversion of an inherited mutation and not a de novo mutation. In order to better understand her cancer risk, we tested different tissues to quantify the amount of mutated allele in several districts. The mosaicism was analyzed using DNA sequencing, primer extension, and dHPLC. The MLH1 mutation was present in somatic cells representative of the three embryonic layers and its percentage was > or =80% in both blood and tissues. Since this patient had a relevant quota of mutated cells, a significantly milder phenotype is not expected., ((c) 2009 Wiley-Liss, Inc.)