DIAPH3 predicts survival of patients with MGMT-methylated glioblastoma.

Background: Glioblastoma is one of the most aggressive primary brain tumors, with a poor outcome despite multimodal treatment. Methylation of the MGMT promoter, which predicts the response to temozolomide, is a well-established prognostic marker for glioblastoma. However, a difference in survival can still be detected within the MGMT methylated group, with some patients exhibiting a shorter survival than others, emphasizing the need for additional predictive factors. Methods: We analyzed DIAPH3 expression in glioblastoma samples from the cancer genome atlas (TCGA). We also retrospectively analyzed one hundred seventeen histological glioblastomas from patients operated on at Saint-Luc University Hospital between May 2013 and August 2019. We analyzed the DIAPH3 expression, explored the relationship between mRNA levels and Patient's survival after the surgical resection. Finally, we assessed the methylation pattern of the DIAPH3 promoter using a targeted deep bisulfite sequencing approach. Results: We found that 36% and 1% of the TCGA glioblastoma samples exhibit copy number alterations and mutations in DIAPH3, respectively. We scrutinized the expression of DIAPH3 at single cell level and detected an overlap with MKI67 expression in glioblastoma proliferating cells, including neural progenitor-like, oligodendrocyte progenitor-like and astrocyte-like states. We quantitatively analyzed DIAPH3 expression in our cohort and uncovered a positive correlation between DIAPH3 mRNA level and patient's survival. The effect of DIAPH3 was prominent in MGMT-methylated glioblastoma. Finally, we report that the expression of DIAPH3 is at least partially regulated by the methylation of three CpG sites in the promoter region. Conclusion: We propose that combining the DIAPH3 expression with MGMT methylation could offer a better prediction of survival and more adapted postsurgical treatment for patients with MGMT-methylated glioblastoma.

Long-term survival in patients with IDH-wildtype glioblastoma: clinical and molecular characteristics.

BACKG ROUND: Glioblastoma is an aggressive tumor that has a dismal prognosis even with multimodal treatment. However, some patients survive longer than expected. The objective of this study was to revisit patients diagnosed with glioblastoma according to the 2021 WHO classification and analyze clinical and molecular characteristics associated with long-term survival (LTS). METHODS: We retrospectively analyzed 120 IDH-wildtype glioblastomas operated on at our institution between 2013 and 2018. We divided them into LTS patients, surviving more than 3 years, and non-LTS patients, and then compared their features. Additionally, we performed DNA methylation-based brain tumor classification in LTS patients. RESULTS: Sixteen patients were long-term survivors. Age < 70 years, MGMT promoter methylation, extent of resection ≥ 95%, and administration of radiochemotherapy were associated with LTS (P = 0.005, P < 0.001, P = 0.048, and P = 0.008, respectively). In addition, when these factors were combined, the probability of LTS was 74% (95% CI: 62--84). The methylome analysis confirmed the diagnosis of glioblastoma in the majority of the tested LTS patients. Regarding subtypes, 29% of cases were mesenchymal (MES), 43% were RTK1, and 29% were RTK2. Interestingly, RTK1 and RTK2 cases tended to have longer overall survival than MES cases (P = 0.057). Moreover, the only tested LTS patient with an unmethylated MGMT promoter had an "adult-type diffuse high-grade glioma, IDH-wildtype, subtype E" rather than a glioblastoma. This tumor was characterized by multinucleated giant cells and a somatic mutation in POLE. CONCLUSIONS: We suggest that glioblastoma patients with a combination of favorable prognostic factors can achieve LTS in 74% of cases. In addition, methylome analysis is important to ascertain the type of glioma in LTS patients, especially when the MGMT promoter is unmethylated.

Chilblains observed during the COVID-19 pandemic cannot be distinguished from classic, cold-related chilblains

Background: Type 1 interferon (IFN-I) response induced by SARS-CoV-2 has been hypothesized to explain the association between chilblain lesions (CL) and SARS-CoV-2 infection. Objective: To explore direct cytopathogenicity of SARS-CoV-2 in CL and to focus on IFN-I expression in patients with chilblains. Materials & Methods: A monocentric cohort of 43 patients presenting with CL from April 2020 to May 2021 were included. During this period, all CL were, a priori, considered to be SARS-CoV-2-related. RT-qPCR on nasopharyngeal swabs and measurements of anti-SARS-CoV-2 antibodies were performed. Anti-SARS-CoV-2 immunostainings as well as SARS-CoV-2 RT-qPCR were performed on biopsy specimens of CL and controls. Expression of MX1 and IRF7 was analysed on patients' biopsy specimens and/or PBMC and compared with controls and/or chilblains observed before the pandemic. Serum IFN-α was also measured. Results: RT-qPCR was negative in all patients and serological tests were positive in 11 patients. Immunostaining targeting viral proteins confirmed the lack of specificity. SARS-CoV-2 RNA remained undetected in all CL specimens. MX1 immunostaining was positive in CL and in pre-pandemic chilblains compared to controls. MX1 and IRF7 expression was significantly increased in CL specimens but not in PBMC. Serum IFN-α was undetected in CL patients. Conclusion: CL observed during the pandemic do not appear to be directly related to SARS-CoV-2 infection, either based on viral cytopathogenicity or high IFN-I response induced by the virus.

Focal status epilepticus may trigger relapse of primary angiitis of the CNS.

The role of neuroinflammation in epileptogenesis is extensively investigated, but short-term effects of seizures on established CNS pathologies are less studied and less predictable. We describe the case of a woman with previous recurrent episodes of focal cerebral haemorrhage of unknown cause who developed a pseudo-tumoural oedema triggered by provoked focal status epilepticus. A brain biopsy revealed that the underlying condition was primary angiitis of the CNS. Ictal-induced blood-brain barrier dysfunction allows the entry of water and inflammatory molecules that, in the context of CNS inflammatory diseases, may trigger a self-reinforcing process. Caution should be observed when tapering antiepileptic drugs in patients with such conditions.

Pulmonary tumor thrombotic microangiopathy in a patient with a metastatic urothelial carcinoma.

A 78-year-old woman was admitted for acute dyspnoea. One year before, she had been treated with cisplatin and gemcitabine for a high grade urothelial carcinoma. Immunotherapy was discussed 9 months later due the progression of bone metastases but could not be administered before this episode of respiratory distress. There was a major discrepancy between the findings of a limited pulmonary embolism at thoracic tomodensitometry and the severity of a recently developed pulmonary hypertension at echocardiography. The patient presented cardiac arrest on day 6 and post-mortem findings were consistent with diffuse pulmonary tumor thrombotic microangiopathy, a rare complication of urothelial carcinoma.

The Liver in COVID-19-Related Death: Protagonist or Innocent Bystander?

INTRODUCTION: The coronavirus disease 2019 (COVID-19) infection, caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), involves several organs through participation of angiotensin-conversion enzyme 2 (ACE2) receptors. The presence of ACE2 receptors in the liver renders this organ a potential target for the novel coronavirus. METHODS: We performed 14 complete autopsies of patients infected with SARS-CoV-2. In each case we stained liver tissue sections with haematoxylin/eosin, Masson blue trichrome stain, periodic acid-Schiff (PAS), Perls, and performed cytokeratin-7 (CK7) immunochemistry. RESULTS: Macroscopically, livers were pale and yellowish in 8 of 14 (57%) patients, and had a nutmeg appearance in the other 6 cases (42%). Histologically, centrolobular necrosis was observed in 12 cases (86%), and was associated with discreet to moderate lobular or portal inflammation. Steatosis was seen in 8 cases (57%), but fibrosis was rare. Cholestasis and discrete bile duct proliferation was observed in 5 cases (36%). DISCUSSION/CONCLUSION: The main histological changes can be explained by the hypoxic status as a result of severe hypoxemic pneumonia leading to death. Drug toxicity may also play a role in certain cases. Other histological changes may be explained by previous hepatic conditions or underlying hepatic diseases. We concluded that COVID-19 infection was not associated with a specific histopathological pattern of the liver.

Clinical, radiological and molecular characterization of intramedullary astrocytomas.

Intramedullary astrocytomas (IMAs) are rare tumors, and few studies specific to the molecular alterations of IMAs have been performed. Recently, KIAA1549-BRAF fusions and the H3F3A p.K27M mutation have been described in low-grade (LG) and high-grade (HG) IMAs, respectively. In the present study, we collected clinico-radiological data and performed targeted next-generation sequencing for 61 IMAs (26 grade I pilocytic, 17 grade II diffuse, 3 LG, 3 grade III and 12 grade IV) to identify KIAA1549-BRAF fusions and mutations in 33 genes commonly implicated in gliomas and the 1p/19q regions. One hundred seventeen brain astrocytomas were analyzed for comparison. While we did not observe a difference in clinico-radiological features between LG and HG IMAs, we observed significantly different overall survival (OS) and event-free survival (EFS). Multivariate analysis showed that the tumor grade was associated with better OS while EFS was strongly impacted by tumor grade and surgery, with higher rates of disease progression in cases in which only biopsy could be performed. For LG IMAs, EFS was only impacted by surgery and not by grade. The most common mutations found in IMAs involved TP53, H3F3A p.K27M and ATRX. As in the brain, grade I pilocytic IMAs frequently harbored KIAA1549-BRAF fusions but with different fusion types. Non-canonical IDH mutations were observed in only 2 grade II diffuse IMAs. No EGFR or TERT promoter alterations were found in IDH wild-type grade II diffuse IMAs. These latter tumors seem to have a good prognosis, and only 2 cases underwent anaplastic evolution. All of the HG IMAs presented at least one molecular alteration, with the most frequent one being the H3F3A p.K27M mutation. The H3F3A p.K27M mutation showed significant associations with OS and EFS after multivariate analysis. This study emphasizes that IMAs have distinct clinico-radiological, natural evolution and molecular landscapes from brain astrocytomas.

Refractory shock during the anesthetic and surgical management of an intrahepatic tumor arising from the adrenal cortex: A case report.

INTRODUCTION: Adrenocortical carcinoma is a rare type of malignant adrenal tumor with a possibility of delayed metastases. Diagnosis may be delayed with a non-secreting tumor or metastasis, and even in this case, surgical management may be complicate. PRESENTATION OF CASE: A 55-year-old man underwent elective surgery for the resection of a large intra-hepatic mass from an undetermined type according to a recent liver biopsy. He had a previous history of a non-secreting adrenal tumor that was operated ten years before. Pre-operatively, he was poorly symptomatic, with a normal arterial blood pressure. Anesthesia induction was uneventful, but at the time of tumor resection and removal, he developed extreme vasoplegia and shock with anuric renal failure, lactic acidosis, four-limb and abdominal compartment syndrome. The patient died on day 9 from delayed septic complications. According to the pathological findings, the tumor was a non-secreting adrenocortical carcinoma. DISCUSSION: Adrenocortical carcinoma (ACC) is rare condition with diverse clinical manifestations due to excessive hormonal production when the tumor is secreting and mimicking pheochromocytoma. Our patient underwent the resection a large intrahepatic non-secreting metastasis more than ten years after the initial lesion. Peri-operative and post-operative management was complicated by a refractory shock with the characteristics of a secondary systemic capillary leak syndrome. The role of endothelial lesions may be discussed. CONCLUSION: Surgery of metastatic adrenocortical carcinoma may be complicated by severe hemodynamic complications, even in the absence of hormonal secretion.

Tryptophan 2,3-Dioxygenase Expression Identified in Human Hepatocellular Carcinoma Cells and in Intratumoral Pericytes of Most Cancers.

Tryptophan catabolism is used by tumors to resist immune attack. It can be catalyzed by indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO). IDO1 is frequently expressed in tumors and has been widely studied as a potential therapeutic target to reduce resistance to cancer immunotherapy. In contrast, TDO expression in tumors is not well characterized. Several human tumor cell lines constitutively express enzymatically active TDO. In human tumor samples, TDO expression has previously been detected by transcriptomics, but the lack of validated antibodies has precluded detection of the TDO protein and identification of TDO-expressing cells. Here, we developed novel TDO-specific monoclonal antibodies and confirmed by immunohistochemistry the expression of TDO in the majority of human cancers. In all hepatocarcinomas (10/10), TDO was expressed by most tumor cells. Some glioblastomas (10/39) and kidney carcinomas (1/10) also expressed TDO in tumor cells themselves but only in focal tumor areas. In addition, all cancers tested contained foci of nontumoral TDO-expressing cells, which were identified as pericytes by their expression of PDGFRß and their location in vascular structures. These TDO-expressing pericytes belonged to morphologically abnormal tumor vessels and were found in high-grade tumors in the vicinity of necrotic or hemorrhagic areas, which were characterized by neoangiogenesis. We observed similar TDO-expressing pericytes in inflammatory pulmonary lesions containing granulation tissue, and in chorionic villi, two tissue types that also feature neoangiogenesis. Our results confirm TDO as a relevant immunotherapeutic target in hepatocellular carcinoma and suggest a proangiogenic role of TDO in other cancer types.See article by Schramme et al., p. 32.

Large Epileptogenic Type IIIb Dysplasia: A Radiological and Anatomopathological Challenge.

BACKGROUND: Type IIIb dysplasia is a subtype of focal cortical dysplasia associated with a tumor, most frequently with gangliogliomas then with dysembryoplastic neuroepithelial tumors (DNETs). Their preoperative diagnosis often remains equivocal since specific features are missing. The functional results (i.e., seizure free) is good with 81%-87% of Engel Ia at 5-year follow-up. CASE DESCRIPTION: A 4-year-old boy presented with a 1-year history of severe, invalidating, drug-resistant epilepsy. Imaging workup demonstrated a huge left limbic lesion, of which diagnosis remained speculative. Because of worsening neurological status, resective surgery was recommended after multidisciplinary discussion. The resection was performed through left transtemporal approach under neuronavigation (C.R.). Postoperative magnetic resonance imaging assessed uncomplicated near-total resection. Histopathological analysis showed combined features of a DNET of nonspecific type and a focal cortical dysplasia. CONCLUSION: We describe a rare condition of type IIIb dysplasia combining a focal cortical dysplasia with a DNET. Preoperative diagnosis of the lesion was of utmost difficultly, thereby rendering mandatory a thorough histopathological examination of resected specimen in the vast majority of cases. Increased recognition of the condition brings up the hypothesis of a genetic continuum or linkage between the 2 conditions. Functional results on seizure activity after ablative surgery are good and maximal safe resection should be the goal.

Long-term survival after glioblastoma resection: hope despite poor prognosis factors.

BACKGROUND: In spite of aggressive multimodal treatment, survival for patients with glioblastoma (GBM) remains short. Nevertheless, some patients survive much longer than expected and become long-term survival patients. The extent of resection (EoR), Karnofsky Performance Scale (KPS), age and methyl-guanine methyltransferase gene (MGMT) methylation are well-defined prognostic factors, but the characteristics of patients with long-term survival (LTS, survival of at least three years after diagnosis) has not been fully determined yet. That is the reason why we analyzed the GBM patients with LTS at our center. METHODS: We retrospectively reviewed all consecutive patients who underwent surgery for GBM between January 2002 and November 2011, including patients treated with surgical resection under neuronavigation with or without intraoperative MRI (ioMRI) and those who had stereotactic biopsy. We identified and further analyzed those patients with LTS. RESULTS: A total of 127 patients underwent surgery for GBM during the study period. 101 (79.6%) of whom had surgical resection and 26 (20.4%) of whom had stereotactic biopsy. Of the 101 patients who were treated with surgical resection, 12 had LTS. After two other pathologists reviewed the patients' cases, they confirmed that 11 (11%) of the 12 patients had a GBM (female/male ratio 4.5; average age 50 years; preoperative Karnofsky Score 82%), and one patient had an anaplastic glioma. The mean survival in the LTS patients with confirmed GBM was 74 (36-150) months. Seven of the LTS patients (63.6%) had a gross total resection (GTR), including two with an additional resection after ioMRI. Three (27.3%) had a near total resection (NTR: residue ≤5%) and one (9.1%) had a partial resection. Ten (90.9%) patients had a methylation of MGMT, only two (18.8%) had an IDH1 mutation, and seven (63.6%) received a full Stupp protocol. CONCLUSIONS: Among patients with a GBM who were treated with one or more resections, 11% had LTS with 90.9% with at least a near total resection (36% with ioMRI) and a methylated MGMT. 50% of the patients with a second surgery survived at least two years postoperatively. Those encouraging observations emphasize the importance of maximizing the resection by using, if possible, an intraoperative guidance method like ioMRI with an analysis of biomarkers such as MGMT and if necessary, multiple surgical procedures.

Recurrent pituitary abscess: case report and review of the literature.

A 26-year-old woman presented with severe postpartum headaches. Magnetic resonance imaging (MRI) revealed a symmetric, heterogeneous enlargement of the pituitary gland. Three months later, she developed central diabetes insipidus. A diagnosis of postpartum hypophysitis was suspected and corticosteroids were prescribed. Six months later, the pituitary mass showed further enlargement and characteristics of a necrotic abscess with a peripheral shell and infiltration of the hypothalamus. Transsphenoidal surgery was performed, disclosing a pus-filled cavity which was drained. No bacterial growth was observed, except a single positive blood culture for Staphylococcus aureus, considered at that time as a potential contaminant. A short antibiotic course was, however, administered together with hormonal substitution for panhypopituitarism. Four months after her discharge, severe headaches recurred. Pituitary MRI was suggestive of a persistent inflammatory mass of the sellar region. She underwent a new transsphenoidal resection of a residual abscess. At that time, the sellar aspiration fluid was positive for Staphylococcus aureus and she was treated with antibiotics for 6 weeks, after which she had complete resolution of her infection. The possibility of a pituitary abscess, although rare, should be kept in mind during evaluation for a necrotic inflammatory pituitary mass with severe headaches and hormonal deficiencies. LEARNING POINTS: The possibility of a pituitary abscess, although rare, should be kept in mind during evaluation for a necrotic inflammatory pituitary mass with severe headaches and hormonal deficiencies.In a significant proportion of cases no pathogenic organism can be isolated.A close follow-up is necessary given the risk of recurrence and the high rate of postoperative pituitary deficiencies.

Both invasiveness and proliferation criteria predict recurrence of non-functioning pituitary macroadenomas after surgery: a retrospective analysis of a monocentric cohort of 120 patients.

INTRODUCTION: Additional robust criteria to predict early postoperative recurrence of non-functioning pituitary macroadenomas (NFMAs) are needed. Recently, a new classification of pituitary tumors has been proposed, which is based on both radiological and histological criteria and allows the grading into 5 groups of different potential aggressiveness. The aim of this study was to use this classification to further characterize predictive factors of recurrence in an independent series of NFMA. CASES AND METHODS: 120 patients operated for a NFMA were analyzed retrospectively. For each of them, the invasion of the cavernous and/or sphenoidal sinuses by the tumor was studied on the preoperative MRI and the proliferative character was based on precise histological and immunohistological examination. RESULTS: 26% (n = 31) of the adenomas were proliferative and 57% (n = 68) were invasive. The invasive lesions were larger (P < 0.001) and their removal was complete in only 82% of the cases. The distribution of NFMAs was as follows: 32% grade 1a, 11% (proliferative) grade 1b, 42% (invasive) grade 2a and 15% (proliferative and invasive) grade 2b. Their probability of recurrence at 5 years was 20, 39, 44 and 66%, respectively. A young age, the atypical character and the presence of postoperative residual tumor were all independent risk factors of recurrence (P < 0.025). DISCUSSION: The new clinicopathological classification proves to be very useful in predicting the risk of recurrence of non-functioning pituitary macroadenomas after a first surgery. In particular, grade 2b lesions showed an overall likelihood of recurrence that was 8.6 times greater than those of grade 1a.

Adult-onset Rasmussen encephalitis associated with focal cortical dysplasia.

Rasmussen encephalitis is a rare, devastating condition, typically presenting in childhood. Cases of adult-onset Rasmussen have also been described, but the clinical picture is less defined, rendering final diagnosis difficult. We present a case of adult-onset Rasmussen encephalitis with dual pathology, associated with focal cortical dysplasia and encephalitis. We interpreted the Rasmussen encephalitis to be caused by severe and continuous epileptic activity due to focal cortical dysplasia. The best therapeutic approach for such cases remains unclear.

A strange oculomotor palsy with eosinophilia.

A 75-year-old man was admitted to the Department of internal medicine because of a 2-month history of neurological deterioration. During the previous year, he complained of recurrent sinusitis, asthma, arthralgias, myalgias and asthenia. Later on, an oculomotor palsy, weakness and disturbance of the sensibility of the right upper limb appeared. Blood sample showed 6510 eosinophils per microlitre. The cerebral magnetic resonance demonstrated bilateral frontal and left parietal subcortical lesions from which the most voluminous presented large haemorrhagic areas. A cerebral biopsy showed small vessel's vasculitis, fibrinoid necrosis and extravascular eosinophilic encroachment. A diagnosis of oculomotor palsy secondary to eosinophilic granulomatosis with polyangeitis was then made, which was successfully treated with corticosteroids and cyclophosphamide.