Prognosis of glioblastoma patients improves significantly over time interrogating historical controls.

BACKGROUND: Glioblastoma (GBM) is the most common devastating primary brain cancer in adults. In our clinical practice, median overall survival (mOS) of GBM patients seems increasing over time. METHODS: To address this observation, we have retrospectively analyzed the prognosis of 722 newly diagnosed GBM patients, aged below 70, in good clinical conditions (i.e. Karnofsky Performance Status -KPS- above 70%) and treated in our department according to the standard of care (SOC) between 2005 and 2018. Patients were divided into two groups according to the year of diagnosis (group 1: from 2005 to 2012; group 2: from 2013 to 2018). RESULTS: Characteristics of patients and tumors of both groups were very similar regarding confounding factors (age, KPS, MGMT promoter methylation status and treatments). Follow-up time was fixed at 24 months to ensure comparable survival times between both groups. Group 1 patients had a mOS of 19 months ([17.3-21.3]) while mOS of group 2 patients was not reached. The recent period of diagnosis was significantly associated with a longer mOS in univariate analysis (HR=0.64, 95% CI [0.51 - 0.81]), p < 0.001). Multivariate Cox analysis showed that the period of diagnosis remained significantly prognostic after adjustment on confounding factors (adjusted Hazard Ratio (aHR) 0.49, 95% CI [0.36-0.67], p < 0.001). CONCLUSION: This increase of mOS over time in newly diagnosed GBM patients could be explained by better management of potentially associated non-neurological diseases, optimization of validated SOC, better management of treatments side effects, supportive care and participation in clinical trials.

Standardized one-day evaluation before urinary reconstructive surgery for neurogenic lower urinary tract dysfunction: Feasibility and impact on surgical strategy and care pathway.

OBJECTIVES: To describe a concept of standardized preoperative one-day evaluation before urinary reconstructive or diversion surgery for the treatment of neurogenic lower urinary tract (LUT) dysfunction, and to evaluate its feasibility and its impact on the care pathway. MATERIALS AND METHODS: All patients who underwent a one-day standardized evaluation before a urinary reconstructive or derivation surgery for the treatment of neurogenic LUT dysfunction between January 2017 and December 2021 in our institution were included. Data were collected retrospectively from standardized reports. The main outcome was the rate of completion of the tests and consultations planned during this evaluation. Secondary outcomes included the findings from the one-day evaluation and changes in the urological surgical strategy at different time points within one year. RESULTS: One hundred and thirty-one patients benefited from this one-day standardized evaluation. The overall completeness rate of the data collected was 77.5%, increasing from 62.3% in 2017 to 89.3% in 2021. The urological surgical plan was modified for 19.1% of patients following this preoperative evaluation. The indication was then confirmed for 114 patients (87.0%) by the multidisciplinary meeting and was carried out unchanged during the following year for 89 patients (67.9%). An associated colostomy procedure was proposed for 18.3% of patients and was finally performed in 11.5%. CONCLUSION: A standardized multidisciplinary preoperative one-day evaluation before performing reconstructive or diversion surgery for the treatment of neurogenic LUT dysfunction seems feasible and makes it possible to optimize the surgical plan and adapt the course of care.

Overcoming the blood brain barrier in glioblastoma: Status and future perspective.

Glioblastoma is the most common primary brain malignancy in adults. Treatment of glioblastoma patients is based on neurosurgery, radiation therapy and chemotherapy. Despite this multimodal therapeutic regimen, the prognosis of glioblastoma patients is poor. Indeed, glioblastoma is very resistant to treatments due to multiple molecular and cellular mechanisms including the existence of the blood-brain barrier (BBB). The BBB consists of multiple layers surrounding brain vessels and limits drug penetration within the brain. Therefore, overcoming the BBB is a strategy to increase bioavailability and efficacy of therapeutic agents against glioblastoma cells. The development of two approaches is ongoing: i) enhancing the delivery of drugs to the brain and ii) improving the penetration of drugs into the brain. One way to enhance drug delivery to the brain is through high-dose intravenous chemotherapy, with or without bone marrow transplantation, or via intra-arterial chemotherapy, with or without disrupting the BBB through osmotic means. Conversely, improving drug penetration within the brain can be achieved through modifying either the drug itself or the BBB. Promising results in terms of safety and signals of efficacy were obtained with these approaches in early phase clinical trials. More advanced comparative clinical trials are needed to investigate the clinical benefit for glioblastoma patients.

Preventive treatment of unruptured intracranial aneurysms in adult patients with sickle cell anemia: A cohort study.

BACKGROUND AND PURPOSE: Intracranial aneurysms are frequent in patients with sickle cell anemia, while subarachnoid hemorrhage is a major cause of death and disability in young adult patients. Several characteristics, such as younger age and smaller size at rupture, may incline therapeutic decision towards exclusion treatments. Clinical guidelines on treatment of unruptured intracranial aneurysms in this population are still missing. We aimed to assess the safety and efficacy of the treatment of unruptured intracranial aneurysm in patients with sickle cell anemia, using an adapted hematological preparation regimen. PATIENTS AND METHODS: Adult patients with sickle cell anemia and treated unruptured aneurysms by endovascular therapy or neurosurgery were included in this retrospective cohort study. Treatment decision was reached after multi-disciplinary assessment. A pre-operative blood transfusion protocol was undertaken targeting a HbS below 30%. Demographic data, hematological preparation parameters and clinical and radiological outcomes were documented. RESULTS AND CONCLUSIONS: Twenty-five procedures were performed in 18 patients encompassing 19 aneurysms treated by embolization and 6 by surgery. Median age at treatment was 34 years-old and median aneurysm dome size was 4.4 mm. Immediate aneurysm exclusion rate was 85.7% after endovascular therapy and 100% after neurosurgery. Median follow-up was 6 months, with all patients being asymptomatic at last follow-up. Two transitory ischemic neurological deficits, as well as four cases of iodine-induced encephalopathy were identified after embolization. No complication occurred after surgery. Endovascular therapy by coiling and neurosurgical treatment of unruptured intracranial aneurysms appears to be safe in patients with sickle cell anemia and should be considered given the specific hemorrhagic risk observed in this population. A rigorous hematological preparation, associated with a dedicated peri­operative protocol and an adequate therapeutic strategy are essential prerequisites.

Therapeutic ultrasound: The future of epilepsy surgery?

Epilepsy is one of the leading neurological diseases in both adults and children and in spite of advancement in medical treatment, 20 to 30% of patients remain refractory to current medical treatment. Medically intractable epilepsy has a real impact on a patient's quality of life, neurologic morbidity and even mortality. Actual therapy options are an increase in drug dosage, radiosurgery, resective surgery and non-resective neuromodulatory treatments (deep brain stimulation, vagus nerve stimulation). Resective, thermoablative or neuromodulatory surgery in the treatment of epilepsy are invasive procedures, sometimes requiring long stay-in for the patients, risks of permanent neurological deficit, general anesthesia and other potential surgery-related complications such as a hemorrhage or an infection. Radiosurgical approaches can trigger radiation necrosis, brain oedema and transient worsening of epilepsy. With technology-driven developments and pursuit of minimally invasive neurosurgery, transcranial MR-guided focused ultrasound has become a valuable treatment for neurological diseases. In this critical review, we aim to give the reader a better understanding of current advancement for ultrasound in the treatment of epilepsy. By outlining the current understanding gained from both preclinical and clinical studies, this article explores the different mechanisms and potential applications (thermoablation, blood brain barrier disruption for drug delivery, neuromodulation and cortical stimulation) of high and low intensity ultrasound and compares the various possibilities available to patients with intractable epilepsy. Technical limitations of therapeutic ultrasound for epilepsy surgery are also detailed and discussed.

Predictive factors of human cytomegalovirus reactivation in newly diagnosed glioblastoma patients treated with chemoradiotherapy.

The human cytomegalovirus (HCMV) is a ubiquitous herpes virus which infects 40 to 99% of the population. HCMV reactivation may occur in the context of immunosuppression and can induce significant morbidities. Several cases of HCMV infections or HCMV reactivation have thus been reported in glioblastoma (GBM) patients treated with radio(chemo)therapy. With the aim to identify the main risk factors associated with HCMV reactivation, we reviewed all patients treated for a newly diagnosed GBM in our institution from October 2013 to December 2015. Age, sex, Karnofsky performance status (KPS), absolute lymphocyte count (ALC), serological HCMV status, and steroid doses were recorded at the start and 1 month after the end of radiotherapy (RT). Within the 103 patients analyzed, 34 patients (33%) had an initial negative serology for HCMV, and none of them developed a seroconversion after treatment. Among patients with positive HCMV IgG (n = 69), 16 patients (23%) developed a viremia at one point during treatment. Age (> 60 years), steroid intake, and ALC (< 1500/mm3) before RT were correlated with HCMV reactivation. HCMV viremia was associated with neurological decline 1 month after chemoradiotherapy but progression-free survival was not impacted. A shorter overall survival was seen in these patients when compared with the others, but this could be biased by the older age in this subgroup. HCMV reactivation needs to be sought in case of a neurological decline during RT especially in older patients treated with steroids and low lymphocytes counts.

Management of cancer-related thrombosis in the era of direct oral anticoagulants: A comprehensive review of the 2019 ITAC-CME clinical practice guidelines. On behalf of the Groupe Francophone Thrombose et Cancer (GFTC).

Venous thromboembolism (VTE) is a common disease complication in cancer patients and the second cause of death after cancer progression. VTE management and prophylaxis are critical in cancer patients, but effective therapy can be challenging because these patients are at higher risk of VTE recurrence and bleeding under anticoagulant treatment. Numerous published studies report inconsistent implementation of existing evidence-based clinical practice guidelines (CPG), including underutilization of thromboprophylaxis, and wide variability in clinical practice patterns across different countries and various practitioners. This review aims to summarize the 2019 ITAC-CME evidence-based CPGs for treatment and prophylaxis of cancer-related VTE, which include recommendations on the use of direct oral anticoagulants specifically in cancer patients. The guidelines underscore the gravity of developing VTE in cancer and recommend the best approaches for treating and preventing cancer-associated VTE, while minimizing unnecessary or over-treatment. Greater adherence to the 2019 ITAC guidelines could substantially decrease the burden of VTE and improve survival of cancer patients.

Dose distribution of the brain tissue associated with cognitive functions in high-grade glioma patients.

PURPOSE: The purpose of this prospective dosimetric study was to assess the dose distribution regarding the brain areas implied in cognitive functions using two approaches: volumetric modulated arc therapy (VMAT) and helical tomotherapy (HT). PATIENTS AND METHODS: Thirty-seven patients were treated using a dual-arc VMAT approach for supratentorial glioblastoma between 2016 and 2018. The total dose of 60Gy in 30 daily fractions was administered to the planning target volume (PTV). The brain structures that play an important role in cognitive physiology, such as the hippocampi, corpus callosum, cerebellum, subventricular zones (SVZ), were delineated. For each patient, a new treatment plan in HT was determined by a second medical physicist in a blindly fashion according to the same dose constraints and priorities. Statistical analyses were performed using the Wilcoxon-signed rank test. RESULTS: Conformity indexes remained similar with both techniques. The mean values were 0.96 (0.19-1.00) for VMAT and 0.98 (range, 0.84-1.00) for HT, respectively (P=0.73). Significant D50% reductions were observed with VMAT compared to HT: 14.6Gy (3.8-28.0) versus 17.4Gy (12.1-25.0) for the normal brain (P=0.014); 32.5Gy (10.3-60.0) versus 35.6Gy (17.1-58.0) for the corpus callosum (P=0.038); 8.1Gy (0.4-34.0) versus 12.8Gy (0.8-27.0) for the cerebellum (P<0.001), respectively. CONCLUSION: The VMAT approach seemed to improve the sparing of the key brain areas implied in cognitive functions without jeopardizing PTV coverage.

Cylindroma spine metastasis: Long-term follow-up is required.

BACKGROUND: Adenoid cystic carcinoma (ACC), or cylindroma, is a rare malignancy believed to arise from epithelial cells of salivary glands. It is a slow-growing but aggressive tumor with a propensity for perineural invasion. Metastases are common to the lung, but rare to the spine. The natural history of ACC spine metastases is unknown and progression is unpredictable. METHODS: (1) A case report was described for a patient diagnosed with spine ACC metastasis of the T6/T7 vertebrae. (2) A literature search was conducted on Medline via PubMed and the Cochrane databases according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to identify articles from 1973 to March 2019 using following keywords: adenoid cystic carcinoma, cylindroma, metastasis, salivary glands. RESULTS/CASE REPORT: We report an unusual case of spine ACC metastasis of the T6/T7 vertebrae in a patient suffering from progressive radiculopathy and thoracic pain. Based on these findings, the patient underwent T6/T7 laminectomy. The diagnosis was confirmed by the pathology results. The primary parotid tumor had been resected 35 years before spine metastasis. A review of literature encompassing 40 years identified 16 patients treated for ACC spine metastases. Mean time to spine metastases was 4.1 years after primary treatment of ACC. Spine metastases were isolated, without local recurrence at the neck. CONCLUSION: This case highlights the critical importance of long follow up of ACC patients, due to late spine metastases. Diagnosis spinal metastasis of salivary carcinoma should be considered, to guide management, especially in clinical follow-up.

Whole brain radiotherapy with concurrent temozolomide in multifocal and/or multicentric newly diagnosed glioblastoma.

The standard medical care of glioblastoma (GBM) patients with good performance status is based on focal brain radiotherapy (40-60 Gy) with concurrent temozolomide (TMZ) followed by adjuvant TMZ. Newly diagnosed multifocal and/or multicentric GBM (M/M GBM) cases are usually treated with TMZ alone: whole brain chemoradiotherapy (CRT) is avoided for safety reasons. To our knowledge, no study has investigated the safety and efficacy of whole-brain radiotherapy (WBRT) with concurrent TMZ in M/M GBM patients. This retrospective study sought to assess the role of WBRT associated with concurrent TMZ followed by TMZ alone in this population. Eleven patients with pathologically proven M/M GBM (≥3 lobes) were treated with WBRT between April 2009 and September 2017. The median age was 50 years [34-74]. The median dose of radiotherapy was 45 Gy at 1.8 Gy per fraction over 37 days [29-41], with concurrent daily TMZ at the dose of 75 mg/m2. This treatment was followed by adjuvant monthly TMZ (150 mg/m2-D1-D5). All pathology slides and radiology images were reviewed. The median overall and progression-free survival times for all patients were 10 months [4-25] and 5 months [3-21], respectively. There was no grade 3-4 toxicity due to radiotherapy. One patient stopped the TMZ during the radiochemotherapy period and 9 patients received adjuvant TMZ with a median number of 5 cycles [2-8]. Our study supports the safety and the efficacy of WBRT with TMZ in newly diagnosed M/M GBM. Larger prospective studies are needed to support our results.

Angiotensin II receptor blockers, steroids and radiotherapy in glioblastoma-a randomised multicentre trial (ASTER trial). An ANOCEF study.

BACKGROUND: Glioblastomas (GBMs) induce a peritumoural vasogenic oedema impairing functional status and quality of life. Steroids reduce brain tumour-related oedema but are associated with numerous side-effects. It was reported in a retrospective series that angiotensin receptor blockers might be associated with reduced peritumoural oedema. The ASTER study is a randomised, placebo-controlled trial to assess whether or not the addition of Losartan to standard of care (SOC) can reduce steroid requirement during radiotherapy (RT) in patients with newly diagnosed GBM. PATIENTS AND METHODS: Patients with a histologically confirmed GBM after biopsy or partial surgical resection were randomised between Losartan or placebo in addition to SOC with RT and temozolomide (TMZ). The primary objective was to investigate the steroid dosage required to control brain oedema on the last day of RT in each arm. The secondary outcomes were steroids dosage 1 month after the end of RT, assessment of cerebral oedema on magnetic resonance imaging, tolerance and survival. RESULTS: Seventy-five patients were randomly assigned to receive Losartan (37 patients) or placebo (38 patients). No difference in the steroid dosage required to control brain oedema on the last day of RT, or one month after completion of RT, was seen between both arms. The incidence of adverse events was similar in both arms. Median overall survival was similar in both arms. CONCLUSIONS: Losartan, although well tolerated, does not reduce the steroid requirement in newly diagnosed GBM patients treated with concomitant RT and TMZ. Trial registration number NCT01805453 with ClinicalTrials.gov.

The Cape Town Declaration on Access to Cardiac Surgery in the Developing World.

Twelve years after cardiologists and cardiac surgeons from all over the world issued the 'Drakensberg Declaration on the Control of Rheumatic Fever and Rheumatic Heart Disease in Africa', calling on the world community to address the prevention and treatment of rheumatic heart disease (RHD) through improving living conditions, to develop pilot programmes at selected sites for control of rheumatic fever and RHD, and to periodically review progress made and challenges that remain, RHD still accounts for a major proportion of cardiovascular diseases in children and young adults in low- and middle-income countries, where more than 80% of the world population live. Globally equal in prevalence to human immunodeficiency virus infection, RHD affects 33 million people worldwide. Prevention efforts have been important but have failed to eradicate the disease. At the present time, the only effective treatment for symptomatic RHD is open heart surgery, yet that life-saving cardiac surgery is woefully absent in many endemic regions. In this declaration, we propose a framework structure to create a co-ordinated and transparent international alliance to address this inequality.

Neurological adverse events associated with immune checkpoint inhibitors: Review of the literature.

Immune checkpoint inhibitors (ICIs) targeting CTLA4 and PD1 constitute a promising class of cancer treatment but are associated with several immune-related disorders. We here review the literature reporting neurological adverse events (nAEs) associated with ICIs. A systematic search of literature, up to February 2016, mentioning nAEs in patients treated with ICIs was conducted. Eligible studies included case reports and prospective trials. One case seen in our ward was also added. Within the 59 clinical trials (totalling 9208 patients) analysed, the overall incidence of nAEs was 3.8% with anti-CTLA4 antibodies, 6.1% with anti-PD1 antibodies, and 12.0% with the combination of both. The clinical spectrum of neurological disorders was highly heterogeneous. Most of these nAEs were grade 1-2 and consisted of non-specific symptoms such as headache (55%). The incidence of high grade nAEs was below 1% for all types of treatment. Headaches, encephalopathies and meningitis were the most commonly reported (21%, 19% and 15%, respectively). Among the 27 case reports, the most common nAEs were encephalopathies, meningoradiculoneuritis, Guillain-Barré like syndromes and myasthenic syndromes. The median time of nAEs onset was 6 weeks. In most cases, drug interruption and steroids led to neurological recovery, even in conditions where steroids are not usually recommended such as Guillain-Barré syndrome.

Targeting the gut to treat obesity and its metabolic comorbidities: focus on bariatric surgery - view from the chair.

Over the past decade, bariatric surgery emerged as the most effective treatment modality for obesity and its complications, especially type 2 diabetes. Initially introduced on the basis of their capacity to restrict food intake and/or induce dietary fat malabsorption, the current bariatric surgery procedures result in many more physiological changes that may also partly explain their potent and sustained anti-obesity and anti-diabetic effects. In the session 2 of the 17th International Symposium of the Université Laval Research Chair in Obesity, outstanding speakers have provided insight into novel clinical and pathophysiological aspects in bariatric surgery. Dr Blandine Laferrère discussed the growing body of evidence implicating incretin hormones in the anti-diabetic effects of bariatric surgery and Dr Hans-Rudolf Berthoud explored emerging evidence suggesting that bariatric surgery may reset the defended body mass set point. As data are rapidly accruing about the beneficial effects of bariatric surgery, these procedures not only take a greater place in clinical practice, but they also offer outstanding occasions to peek into the intricate and complex links between diet and gastrointestinal track, and obesity and its complications.

Impact of renin-angiotensin system blockade on clinical outcome in glioblastoma.

BACKGROUND AND PURPOSE: Despite surgery, radiotherapy (RT) and temozolomide (TMZ), the prognosis of glioblastoma (GBM) patients remains dismal. Normally prescribed with the aim to lower blood pressure, angiotensin-II (Ang-II) inhibitors were reported to reduce angiogenesis and tumour growth in several tumour models including one glioma. Thus whether treatment with Ang-II inhibitors could be associated with a better clinical outcome in GBM patients was investigated. METHODS: A series of 81 consecutive patients, homogeneously treated with RT and TMZ for a newly diagnosed, supratentorial GBM, were analysed. The objective of this retrospective study was to assess the impact of angiotensin-converting enzyme inhibitors (ACEIs) and Ang-II receptor 1 blockers (ARBs) on functional independence, progression-free survival (PFS) and overall survival (OS). RESULTS: Amongst the 81 GBM patients analysed, 26 were already treated for high blood pressure (seven with ACEIs and 19 with ARBs). The number of patients who remained functionally independent at 6 months after RT was higher in the group of patients treated with Ang-II inhibitors compared to the other patients (85% vs. 56%, P = 0.01). In patients treated with Ang-II inhibitors, PFS was 8.7 months (vs. 7.2 months in the other patients) and OS was 16.7 months (vs. 12.9 months). The use of Ang-II inhibitors was a significant prognostic factor for both PFS (P = 0.04) and OS (P = 0.04) in multivariate analysis. CONCLUSION: Treatment with Ang-II inhibitors in combination with RT and TMZ might improve clinical outcome in GBMs. Prospective trials are needed to test this hypothesis.

[Systemic treatment of brain metastases from lung cancer]. / Traitement systémique des métastases cérébrales de cancer bronchique.

Systemic treatment of lung cancer patients with brain metastases is based on clinical (presence of symptomatic intracranial lesions), pathological and molecular characteristics of the disease. The efficacy of standard platinum-based chemotherapy is comparable inside and outside the brain, justifying its use as front-line therapy. The intracranial efficacy of targeted therapies (EGFR tyrosine kinase inhibitors, ALK inhibitors) is demonstrated, and is globally superior to the efficacy of standard chemotherapy, justifying their use as front-line therapy in case of EGFR activating mutation or ALK rearrangement (providing the change in the crizotinib label in France). The concomitant use of whole brain radiotherapy and a systemic treatment (chemotherapy or targeted therapy) is not recommended in the absence of a demonstrated better efficacy and/or acceptable safety profile. Several trials are ongoing to assess new whole brain radiotherapy modalities, new targeted therapies alone or in combination, especially exploring immunotherapy.

[Global brain metastases management strategy: a multidisciplinary-based approach]. / Stratégie globale de prise en charge des métastases cérébrales: une approche multidisciplinaire.

Brain metastases management has evolved over the last fifteen years and may use varying strategies, including more or less aggressive treatments, sometimes combined, leading to an improvement in patient's survival and quality of life. The therapeutic decision is subject to a multidisciplinary analysis, taking into account established prognostic factors including patient's general condition, extracerebral disease status and clinical and radiological presentation of lesions. In this article, we propose a management strategy based on the state of current knowledge and available therapeutic resources.

[ANOCEF guidelines for the management of brain metastases]. / Recommandations de l'Anocef pour la prise en charge des métastases cérébrales.

The incidence of brain metastases is increasing because of the use of new therapeutic agents, which allow an improvement of overall survival, but with only a poor penetration into the central nervous system brain barriers. The management of brain metastases has changed due to a better knowledge of immunohistochemical data and molecular biological data, the development of new surgical, radiotherapeutic approaches and improvement of systemic treatments. Most of the time, the prognosis is still limited to several months, nevertheless, prolonged survival may be now observed in some sub-groups of patients. The main prognostic factors include the type and subtype of the primitive, age, general status of the patient, number and location of brain metastases, extracerebral disease. The multidisciplinary discussion should take into account all of these parameters. We should notice also that treatments including surgery or radiotherapy may be proposed in a symptomatic goal in advanced phases of the disease underlying the multidisciplinary approach until late in the evolution of the disease. This article reports on the ANOCEF (French neuro-oncology association) guidelines. The management of brain metastases of breast cancers and lung cancers are discussed in the same chapter, while the management of melanoma brain metastases is reported in a separate chapter due to different responses to the brain radiotherapy.