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Supplemental material, JCB912405 Supplemental Material1 for Sonic hedgehog is expressed in human brain arteriovenous malformations and induces arteriovenous malformations in vivo by Igor Giarretta, Carmelo L Sturiale, Ilaria Gatto, Simone Pacioni, Eleonora Gaetani, Angelo Porfidia, Alfredo Puca, Ivana Palucci, Paolo Tondi, Alessandro Olivi, Roberto Pallini and Roberto Pola in Journal of Cerebral Blood Flow & Metabolism

The polymorphisms on chromosome 9p21 play a role in the risk for cardiovascular events in chronic myeloid leukemia patients? Chronic myeloid leukemia (CML) is an onco-haematological disease due to the aberrant expression of an onco-protein with constitutive tyrosine kinase activity. The average age of onset is 55-60 years. The treatment with tyrosine kinase inhibitors (TKIs) drastically changed the outcome of patients affected by chronic myeloid leukemia, allowing long-term improvement in overall survival and deep molecular responses. TKI treatment is also associated to an increased risk of cardiovascular event. The etiopathogenesis of this effects is not clear possibily due to a damage to the endothelial cell, the results of the interaction of genetical predisposition, risk factors and life style habit. The 9p21 region is the strongest genomic marker for cardiovascular disease that has been identified in multiple genome-wide association study. We retrospectively studied 182 patients affected by CML and treated with different TKIs for expression of polymorphism rs1333040C>T and rs7865618A>G of chromosome 9p21 in order to define the role of genetic cardiovascular risk profile to better tailor individualized treatment strategy and identify patients who require strict monitoring of additional risk factors during treatment. Patients and methods We analysed 182 CML patients in chronic phase. All patients were treated with either first, second or third generation TKIs. Patients were compared to a control group including 171 subjects. Genomic DNA was isolated from peripheral blood and the rs1333040C>T and rs7865618A>G polymorphisms were assessed by PCR-RFLP using the BsmI and MspI restriction endonucleases, respectively. Results Ninety-three out of 181 (51%) patients presented the C/T polymorphism, 82 (46%) presented T/T polymorphism and 6 (3%) patient presented wild type polymorphism C/C for rs1333040, test result was not evaluable in 1 patient. Eighty-five out of 181 (47%) patients presented the G/A polymorphism, 73 (40%) presented A/A polymorphism and 23 (13%) patient presented wild type polymorphism G/G for rs7875618 . Test result was not evaluable in 1 patient. The distribution of polymorphism C/C for rs1333040 and G/G for rs7875618 were statistically different compared to control group (p0.0004 and p0.0136 respectively) as showed in table 1. In a sub-analysis, including only 93 patients, a significantly higher incidence of cardiovascular events according to genotypes of SNP rs 1333040 was observed. In C/T group (54 patients) we retrospectively observed 3 cardiovascular events (5.55%) : 2 were transient ischemic attack (TIA) before the diagnosis of CML occurring in 2 female patients aged 69 and 73 respectively and a peripheral arterial obstructive disease (PAOD) in a female patient ,aged 74, with a baseline CAD score of 10, receiving nilotinib 800 mg/d as third line treatment. In T/T group (39 patients) we retrospectively observed 9 (23.1%) cardiovascular events at a median age of 60 years (range 44-82) and with a median estimated cardiovascular risk of 8 (range 0-20) Six patients developed a myocardial acute infarction (AMI) during treatment with TKIs, but 5 out of six had a previous history of AMI. One patient presented a TIA after history of previous of AMI. All patients with previous history of AMI were receving antiplatelets agents. One patient developed PAOD during first line treatment wih nilotinib and one developed an distal arteriopathy associated to an erectile dysfunction. The different incidence of cardiovascular events according to genotypes (T/T vs C/T ) was statistically significant by Fisher'sTest (p=0.0248). Discussion The role of 9p21 region , in particular the genes located in proximity of a noncoding RNA sequence named ANRIL, could be a useful guide for the prophylaxis of cardiovascular events during TKI therapy. Table 1 genotypes distribution between CML patients and controls rs1333040 rs7865618 Patients 82 93 6 23 85 73 46% 51% 3% 13% 47% 40% Controls 62 84 25 8 77 86 36% 49% 15% 5% 45% 50% p=0.0004 P=0.0136 Disclosures Bacigalupo: SANOFI: Speakers Bureau; PIERRE FABRE: Speakers Bureau.

Purpose The canonical isocitrate dehydrogenase 1 R132 mutation (IDH1 R132) is the most frequent mutation among IDH mutated gliomas. Non-canonical IDH1 mutations or IDH2 mutations are unusual and their clinical and biological role is still unclear.Methods We performed a systematic review and meta-analysis aimed to assess the clinical role of IDH non-canonical mutations. ResultsOverall, we selected 13 of 3513 studies reporting data of 4007 patients with a diagnosis of grade 2 and grade 3 including 3091 patients with a molecularly proven IDH1 or IDH2 mutation. Patients with non-canonical IDH1 mutations were younger and presented a higher DNA methylation level as compared to those with canonical IDH1 R132H alteration. The overall incidence of non-canonical IDH1 mutations was 7.9% (95% CI 5.4 – 10.7%) in patients with IDH mutated gliomas. There was no statistical difference in terms of incidence between patients with grade 2 or grade 3 glioma. Patients with non-canonical IDH mutations had a lower rate of 1p19q codeletion (risk difference: 31%, 95% CI 23 -38%) and presented a significantly prolonged survival (pooled-HR 0.47, 95% CI, 0.28-0.81) as compared to those with IDH1 R132H mutation. Conclusion Non-canonical IDH1 mutations occur in 7.9% of IDH mutated gliomas and recognize a specific subgroup of patients with an improved survival despite a lower rate of 1p19q codeletion. Data about the type of IDH mutation should be collected in clinical practice and within interventional trials as this could be a critical variable for an improved patient’s stratification and selection.

Breast cancer (BC) is the second most common tumour spreading to the central nervous system (CNS). The prognosis of patients with CNS metastases depends on several parameters including the molecular assessment of the disease. Although loco-regional treatment remains the best approach, systemic therapies are acquiring a role leading to remarkable long-lasting responses. The efficacy of these compounds diverges between tumours with different molecular assessments. Promising agents under investigation are drugs targeting the HER2 pathways such as tucatinib, neratinib, pyrotinib, trastuzumab deruxtecan. In addition, there are several promising agents under investigation for patients with triple-negative brain metastases (third-generation taxane, etirinotecan, sacituzumab, immune-checkpoint inhibitors) and hormone receptor-positive brain metastases (CDK 4/5, phosphoinositide-3-kinase-mammalian target of rapamycin [PI3K/mTOR] inhibitors). Also, the systemic treatment of leptomeningeal metastases, which represents a very negative prognostic site of metastases, is likely to change as several compounds are under investigation, some with interesting preliminary results. Here we performed a comprehensive review focusing on the current management of CNS metastases according to molecular subtypes, site of metastases (leptomeningeal vs brain), and systemic treatments under investigation.