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SUMMARYGlioma cells hijack developmental transcriptional programs to control cell state. During neural development, lineage trajectories rely on specialized metabolic pathways. However, the link between tumor cell state and metabolic programs is poorly understood in glioma. Here we uncover a glioma cell state-specific metabolic liability that can be leveraged therapeutically. To model cell state diversity, we generated genetically engineered murine gliomas, induced by deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling cellular fate. N1IC tumors harbored quiescent astrocyte-like transformed cell states while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. N1IC cells exhibit distinct metabolic alterations, with mitochondrial uncoupling and increased ROS production rendering them more sensitive to inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Importantly, treating patient-derived organotypic slices with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles.

Topotecan is cytotoxic to glioma cells but is clinically ineffective because of drug delivery limitations. Systemic delivery is limited by toxicity and insufficient brain penetrance, and, to date, convection-enhanced delivery (CED) has been restricted to a single treatment of restricted duration. To address this problem, we engineered a subcutaneously implanted catheter-pump system capable of repeated, chronic (prolonged, pulsatile) CED of topotecan into the brain and tested its safety and biological effects in patients with recurrent glioblastoma.We did a single-centre, open-label, single-arm, phase 1b clinical trial at Columbia University Irving Medical Center (New York, NY, USA). Eligible patients were at least 18 years of age with solitary, histologically confirmed recurrent glioblastoma showing radiographic progression after surgery, radiotherapy, and chemotherapy, and a Karnofsky Performance Status of at least 70. Five patients had catheters stereotactically implanted into the glioma-infiltrated peritumoural brain and connected to subcutaneously implanted pumps that infused 146 μM topotecan 200 μL/h for 48 h, followed by a 5-7-day washout period before the next infusion, with four total infusions. After the fourth infusion, the pump was removed and the tumour was resected. The primary endpoint of the study was safety of the treatment regimen as defined by presence of serious adverse events. Analyses were done in all treated patients. The trial is closed, and is registered with ClinicalTrials.gov, NCT03154996.Between Jan 22, 2018, and July 8, 2019, chronic CED of topotecan was successfully completed safely in all five patients, and was well tolerated without substantial complications. The only grade 3 adverse event related to treatment was intraoperative supplemental motor area syndrome (one [20%] of five patients in the treatment group), and there were no grade 4 adverse events. Other serious adverse events were related to surgical resection and not the study treatment. Median follow-up was 12 months (IQR 10-17) from pump explant. Post-treatment tissue analysis showed that topotecan significantly reduced proliferating tumour cells in all five patients.In this small patient cohort, we showed that chronic CED of topotecan is a potentially safe and active therapy for recurrent glioblastoma. Our analysis provided a unique tissue-based assessment of treatment response without the need for large patient numbers. This novel delivery of topotecan overcomes limitations in delivery and treatment response assessment for patients with glioblastoma and could be applicable for other anti-glioma drugs or other CNS diseases. Further studies are warranted to determine the effect of this drug delivery approach on clinical outcomes.US National Institutes of Health, The William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, the Michael Weiner Glioblastoma Research Into Treatment Fund, the Gary and Yael Fegel Foundation, and The Khatib Foundation.

This article analyzes two of the last innovative financing instruments of the crowdfunding family: Initial Coin Offering (ICO) and Initial Exchange Offering (IEO). Having both a potential financial nature, they will be addressed as «sons» of Equity-based Crowdfunding (EBCF). The main scope of this paper is to show opportunities and dangers of ICO and IEO through a comparison with EBCF. Indeed, at the end of the analysis it will be possible to understand if ICO and IEO can be considered as positive evolution of EBCF or — at least one of them — can be considered so dangerous to appear as a sort of «involution».In order to answer our question, the discussion firstly focuses on EBCF, the innovative financing instrument being one of the most important figures of the «crowdfunding family». Its importance lies in its financial nature that makes this instrument different from the other models (meaning the donation, reward and lending). Participating in an EBCF-campaign, indeed, lets participants become shareholders of the company they are giving money to. So, the main pros and cons of the participation in an EBCF campaign will be disclosed. In particular, granting easier access to capitals together with the possibility to benefit from the so-called «wisdom of the crowd» allowed EBCF to become one of the most innovative financing tools of our age. However, these advantages need to be mitigated with the main risks occurring during a crowdfunding campaign. These are: moral hazard and frauds, arbitrary exclusion during pre-emptive screening by platform and, last but not least, illiquidity.Therefore, the discussion moves to the technological advanced new entry of the crowdfunding family, meaning ICO and IEO. In order to understand why ICO and IEO are so similar to EBCF, both the main characteristic of these instruments will be described. With reference to ICO, first of all this article provides a brief description of the technology that makes this innovative financing tool the advanced «son» of EBCF. Indeed, through the launch of an ICO, a company asks the crowd a precise amount of money in exchange of a «token»: an informatic instrument through which the participant may exercise also some financial rights towards the company. From this point of view, an ICO-campaign is very similar to an EBCF one, lying the main difference in the technological solutions used, the queen on those is blockchain. Furthermore, ICO characteristic will be outlined in order to disclose its functioning — meaning the relation with blockchain and smart contracts — and the different models of tokens.After that, also IEO will be described. IEO could be considered one of the last variants of ICO. The main difference, indeed, lies in the fact that IEO campaigns are not conducted in the website owned by the company but in a specific platform, that is a crypto-asset exchange.The exam of ICO and IEO potentialities (i.e. programmability, disintermediation and tokenization) will highlight how ICO and IEO may solve most of the mentioned EBCF cons. This will lead to the potential consideration of ICO and IEO as evolution of EBCF. However, also ICO and IEO cons will be highlighted (meaning lack of transparency, not clear regulatory regime and, for IEO in particular, dangerous proximity with investors and potential conflict of interest). From the comparison between ICO and IEO pros and cons it will be possible to discuss on if we are really in front of two evolution of EBCF or nearer to an «involution» of this instrument, considering regulatory solutions in order to avoid this second scenario.

We present the case of a 41-year-old man who developed worsening mid-thoracic back pain and imaging revealed a well-circumscribed intramedullary tumor in the thoracic spinal cord. Subtotal resection was performed, and histopathological analysis showed a cytologically bland, minimally proliferative glial neoplasm. Sequencing revealed H3 K27M and an activating PTPN11 mutation. Serial imaging revealed slow tumor regrowth over a three year period which prompted a second resection. The recurrent tumor displayed a similar low grade-appearing histology and harbored the same H3 K27M and PTPN11 mutations as the primary. While the prognostic importance of isolated H3 K27M in spinal gliomas is well-known, the combination of these two mutations in spinal low grade glioma has not been previously reported. Importantly, PTPN11 is a component of the MAPK signaling pathway. Thus, as building evidence shows that low grade-appearing gliomas harboring H3 K27M mutations along with BRAF or FGFR1 mutations have a relatively more favorable course compared to isolated H3 K27M-mutant midline gliomas, the present case provides new evidence for the prognostic importance of activating mutations in other components of the MAPK signaling pathway. This case further highlights the importance of clinico-radio-pathologic correlation when incorporating evolving genetic data into the integrated diagnosis of rare neuroepithelial tumors.

Glioblastoma, the most common primary brain malignancy, is invariably fatal. Systemic chemotherapy is ineffective mostly because of drug delivery limitations. To overcome this, we devised an internalized pump-catheter system for direct chronic convection-enhanced delivery (CED) into peritumoral brain tissue. Topotecan (TPT) by chronic CED in 5 patients with refractory glioblastoma selectively eliminated tumor cells without toxicity to normal brain. Large, stable drug distribution volumes were non-invasively monitored with MRI of co-infused gadolinium. Analysis of multiple radiographically localized biopsies taken before and after treatment showed a decreased proliferative tumor signature resulting in a shift to a slow-cycling mesenchymal/astrocytic-like population. Tumor microenvironment analysis showed an inflammatory response and preservation of neurons. This novel drug delivery strategy and innovative clinical trial paradigm overcomes current limitations in delivery and treatment response assessment as shown here for glioblastoma and is potentially applicable for other anti-glioma agents as well as other CNS diseases.

Bronchial artery embolization is a well accepted and widely used technique in the management of massive haemoptysis in cystic fibrosis (CF). It can be a complex procedure requiring a deep knowledge of the bronchial artery anatomy including the possible bronchial anastomoses. We report a case of complex vascular anatomy of the left bronchial artery with multiple anastomoses with the ipsilateral subclavian artery as cause of non-attempted embolization. © 2003 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

We report the embolization of an aberrant origin of haemoptysis - from the internal branch of the lateral thoracic artery - in a patient affected by cystic fibrosis. The technical implications for embolotheraphy in case of an aberrant origin of a haemorrhage are emphasized. Many different systemic arteries may contribute to the blood supply of the lung and many connections may exist between the systemic, bronchial and pulmonary circulations. The presence of non-bronchial systemic arteries supply should be investigated when inconclusive findings are seen during bronchial artery embolization for haemoptysis.

Bronchial artery embolisation (BAE) is an accepted method of controlling haemoptysis in patients with cystic fibrosis. However, anomalous origin of the bronchial arteries, documented in anatomical and angiographic studies, makes the procedure more difficult and increases the number of recurrences. Clinical records and films from three patients affected by cystic fibrosis with haemoptysis, in which the origin of the bleeding vessels was considered anomalous, out of a total of seven patients who underwent BAE, were reviewed. In two patients the source of bleeding was identified from, respectively, the left and the right internal mammary artery and in one from the left thyrocervical trunk. All the vessels considered to be the possible source of haemoptysis were embolised; immediate control of haemoptysis after embolisation was achieved in all patients, but minor haemoptysis recurred in two patients who were conservatively treated. In haemoptysis in patients with cystic fibrosis the possibility of anomalous origin of the bronchial arteries should be considered. This frequency may be higher than in other pulmonary diseases that cause haemoptysis, so a search for anomalous bronchial arteries is mandatory to achieve accurate embolisation and reduce the rate of recurrence.

We report the embolization of an aberrant origin of haemoptysis - from the internal branch of the lateral thoracic artery - in a patient affected by cystic fibrosis. The technical implications for embolotheraphy in case of an aberrant origin of a haemorrhage are emphasized. Many different systemic arteries may contribute to the blood supply of the lung and many connections may exist between the systemic, bronchial and pulmonary circulations. The presence of non-bronchial systemic arteries supply should be investigated when inconclusive findings are seen during bronchial artery embolization for haemoptysis.

The tuberculous meningitis is an uncommon but severe complication of the tuberculosis mainly in childhood. Neurological sequelae are frequent and high mortality rate, till now, occurs. We reviewed the medical records of 71 cases and we evaluated the most frequent symptoms before the admission and signs and symptoms on the admission according to prognosis. An early diagnosis and specific anti-tuberculous treatment are essential in order to prevent permanent neurological sequelae and fatal outcome