A Sequential Targeting Strategy Interrupts AKT-Driven Subclone-Mediated Progression in Glioblastoma

Purpose: Therapy resistance and fatal disease progression in glioblastoma are thought to result from the dynamics of intra-tumor heterogeneity. This study aimed at identifying and molecularly targeting tumor cells that can survive, adapt, and subclonally expand under primary therapy. Experimental design: To identify candidate markers and to experimentally access dynamics of subclonal progression in glioblastoma, we established a discovery cohort of paired vital cell samples obtained before and after primary therapy. We further used two independent validation cohorts of paired clinical tissues to test our findings. Follow-up preclinical treatment strategies were evaluated in patient-derived xenografts. Results: We describe, in clinical samples, an archetype of rare ALDH1A1+ tumor cells that enrich and acquire AKT-mediated drug resistance in response to standard-of-care temozolomide (TMZ). Importantly, we observe that drug resistance of ALDH1A1+ cells is not intrinsic, but rather an adaptive mechanism emerging exclusively after TMZ treatment. In patient cells and xenograft models of disease, we recapitulate the enrichment of ALDH1A1+ cells under the influence of TMZ. We demonstrate that their subclonal progression is AKT-driven and can be interfered with by well-timed sequential rather than simultaneous antitumor combination strategy. Conclusions: Drug-resistant ALDH1A1+/pAKT+ subclones accumulate in patient tissues upon adaptation to TMZ therapy. These subclones may therefore represent a dynamic target in glioblastoma. Our study proposes the combination of TMZ and AKT inhibitors in a sequential treatment schedule as a rationale for future clinical investigation

Do Tumour Size, Type and Localisation Affect Resection Rate in Patients with Spinal Schwannoma?

Background and Objectives: Spinal schwannomas are benign tumours that can present with various symptoms such as pain, radiculopathy and neurological deficit. Gross total resection (GTR) is of key importance for local recurrence. The aim of this study is to describe the clinical characteristics, resection rate, clinical outcome, as well as tumour recurrence, in patients with non-syndromic spinal schwannomas and to clarify which factors affect the resection rate. Materials and Methods: Patients with non-syndromic spinal schwannomas that underwent surgical resection between January 2009 and December 2018 at a single institution were included. Demographic parameters, clinical symptoms, tumour localisation and size, surgical approach and complications were noted. Factors influencing the extent of resection, the surgeon’s decision regarding the approach and the occurrence of new postoperative deficits were evaluated. Results: Fifty patients (18 females) were included. The most common presenting symptom was radiculopathy (88%). The lumbar spine was the most commonly affected site (58%). Laminotomy (72%) was the preferred surgical approach overall and specifically for exclusively intraspinal schwannomas (p = 0.02). GTR was achieved in 76.0% (n = 38). In multivariate analysis, only tumour localisation within the spinal canal (p = 0.014) independently predicted GTR, whereas the type of approach (p = 0.50) and tumour volume (p = 0.072) did not. New postoperative persisting deficits could not be predicted by any factor, including the use and alteration of intraoperative neuromonitoring. Recurrence was observed in four cases (8%) and was significantly higher in cases with STR (p = 0.04). Conclusions: In this retrospective study, GTR was solely predicted by tumour localisation within the spinal canal. The decision regarding the utilisation of different surgical approaches was solely influenced by the same factor. No factor could predict new persisting deficits. Tumour recurrence was higher in STR

Towards clinical applicability and computational efficiency in automatic cranial implant design ::an overview of the AutoImplant 2021 cranial implant design challenge

Cranial implants are commonly used for surgical repair of craniectomy-induced skull defects. These implants are usually generated offline and may require days to weeks to be available. An automated implant design process combined with onsite manufacturing facilities can guarantee immediate implant availability and avoid secondary intervention. To address this need, the AutoImplant II challenge was organized in conjunction with MICCAI 2021, catering for the unmet clinical and computational requirements of automatic cranial implant design. The first edition of AutoImplant (AutoImplant I, 2020) demonstrated the general capabilities and effectiveness of data-driven approaches, including deep learning, for a skull shape completion task on synthetic defects. The second AutoImplant challenge (i.e., AutoImplant II, 2021) built upon the first by adding real clinical craniectomy cases as well as additional synthetic imaging data. The AutoImplant II challenge consisted of three tracks. Tracks 1 and 3 used skull images with synthetic defects to evaluate the ability of submitted approaches to generate implants that recreate the original skull shape. Track 3 consisted of the data from the first challenge (i.e., 100 cases for training, and 110 for evaluation), and Track 1 provided 570 training and 100 validation cases aimed at evaluating skull shape completion algorithms at diverse defect patterns. Track 2 also made progress over the first challenge by providing 11 clinically defective skulls and evaluating the submitted implant designs on these clinical cases. The submitted designs were evaluated quantitatively against imaging data from post-craniectomy as well as by an experienced neurosurgeon. Submissions to these challenge tasks made substantial progress in addressing issues such as generalizability, computational efficiency, data augmentation, and implant refinement. This paper serves as a comprehensive summary and comparison of the submissions to the AutoImplant II challenge. Codes and models are available at https://github.com/Jianningli/Autoimplant_II

The influence of subventricular zone involvement in extent of resection and tumor growth pattern of glioblastoma

Isocitrate dehydrogenase (IDH1/2) mutations and O6-alkylguanine DNA methyltransferase (MGMT) promoter methylations are acknowledged survival predictors in patients with glioblastoma (GB). Moreover, tumor growth patterns like multifocality and subventricular zone (SVZ) involvement seem to be associated with poorer outcomes. Here, we wanted to evaluate the influence of the SVZ involvement and the multifocal tumor growth on the extent of surgical resection and its correlation with overall survival (OS) and molecular characteristics of patients with GB

Dynamic O-(2-[18F]fluoroethyl)-L-tyrosine PET imaging for the detection of checkpoint inhibitor-related pseudoprogression in melanoma brain metastases

Identifying patients with pseudoprogression, which is characterized by an initial increase of contrast-enhancing lesions that resolve or at least stabilize spontaneously on follow-up imaging without any treatment change, is critical for avoiding premature termination of potentially effective treatment. With the advent and success of checkpoint inhibitors such as ipilimumab, nivolumab, or pembrolizumab in particular, detecting pseudoprogression in patients with malignant melanoma has become a major challenge in clinical practice given a frequency as high as 7%–10% of cases.1,2 Diagnosing progressive disease and excluding pseudoprogression in melanoma metastases using the immune-related Response Criteria (irRC)2 require the initial increase of at least 25% in lesions load to be confirmed by follow-up imaging at least 4 weeks later.2 However, particularly for brain metastases from malignant melanoma, follow-up imaging might not be feasible for patients with clinical deterioration at the time of initial increase of lesions load. These patients might not be able to wait 4 weeks for a follow-up investigation to decide o

Baseline and average platelet count can predict the outcome of patients with aneurysmal subarachnoid hemorrhage

Background: Baseline values and the change of platelet count (PLT) during disease were reported to be associated with prognosis of patients with cancer and intensive care treatment. We aimed to evaluate the association between PLT with the course and prognosis of aneurysmal subarachnoid hemorrhage (SAH). Methods: Admission (AdmPLT) and the 14-days mean PLT (MeanPLT) values of 763 SAH patients treated between 01/2005 and 06/2016 were recorded and, for further analysis, divided into four categories:  400 × 109/L. Primary endpoints were cerebral infarcts in follow-up computed tomography scans, in-hospital mortality and unfavorable outcome at 6-months follow-up defined as modified Rankin scale>3. Adverse events during SAH were assessed as secondary endpoints. Results: Higher PLT values were independently associated with lower risk of cerebral infarction (MeanPLT: aOR = 0.65 per-PLT-category-increase, p = 0.001), in-hospital mortality (AdmPLT: aOR = 0.64, p = 0.017; MeanPLT: aOR = 0.23, p < 0.0001) and unfavorable outcome (AdmPLT: aOR = 0.70, p = 0.031; MeanPLT: aOR = 0.35, p < 0.0001). Moreover, individuals with poorer outcome were less prone to PLT increase during SAH (mean values: -+20.3 vs + 30.5 × 109/L for cerebral infarction; +9.3 vs + 32.8 × 109/L for in-hospital mortality; +14.4 vs + 31.1 × 109/L for unfavorable outcome). The following adverse events during SAH were related to AdmPLT and/or MeanPLT: non-aneurysm related secondary rebleeding, intracranial hypertension requiring conservative treatment or decompressive craniectomy, sepsis and acute kidney failure. Conclusion: Low PLT at admission and their less prominent increase during SAH were strongly linked with poor outcome of SAH. Further analysis is required to clarify the background of this association and potential therapeutic implications

Morphometric Study of the Initial Ventricular Indices to Predict the Complications and Outcome of Aneurysmal Subarachnoid Hemorrhage

Objective: Acute hydrocephalus is a common complication in patients with aneurysmal subarachnoid hemorrhage (SAH). Several ventricular indices have been introduced to enable measurements of ventricular morphology. Previously, researchers have showed their diagnostic value for various neurological disorders. In this study, we evaluated the association between ventricular indices and the clinical course, occurrence of complications and outcome of SAH. Methods: A total of 745 SAH patients with available early admission computed tomography scans were included in the analyses. Six ventricular indices (bifrontal, bicaudate, ventricular and third ventricle ratios and Evans’ and Huckman’s indices) were measured. Primary endpoints included the occurrence of cerebral infarctions, in-hospital mortality and a poor outcome at 6 months. Secondary endpoints included different adverse events in the course of SAH. Clinically relevant cut-offs for the indices were determined using receiver operating curves. Univariate analyses were performed. Multivariate analyses were conducted on significant findings in a stepwise backward regression model. Results: The higher the values of the ventricular indices were and the older the patient was, the higher the WFNS and Fisher’s scores were, and the lower the SEBES score was at admission. Patients with larger ventricles showed a shorter duration of intracranial pressure increase > 20 mmHg and required decompressive craniectomy less frequently. Ventricular indices were independently associated with the parameters of inflammatory response after SAH (C-reactive protein in serum and interleukin-6 in cerebrospinal fluid and fever). Finally, there were independent correlations between larger ventricles and all the primary endpoints. Conclusions: The lower risk of intracranial pressure increase and absence of an association with vasospasm or systemic infections during SAH, and the poorer outcome in individuals with larger ventricles might be related to a more pronounced neuroinflammatory response after aneurysmal bleeding. These observations might be helpful in the development of specific medical and surgical treatment strategies for SAH patients depending on the initial ventricle measurements

Radiographic markers of breast cancer brain metastases: relation to clinical characteristics and postoperative outcome

Objective!#!Occurrence of brain metastases BM is associated with poor prognosis in patients with breast cancer (BC). Magnetic resonance imaging (MRI) is the standard of care in the diagnosis of BM and determines further treatment strategy. The aim of the present study was to evaluate the association between the radiographic markers of BCBM on MRI with other patients' characteristics and overall survival (OS).!##!Methods!#!We included 88 female patients who underwent BCBM surgery in our institution from 2008 to 2019. Data on demographic, clinical, and histopathological characteristics of the patients and postoperative survival were collected from the electronic health records. Radiographic features of BM were assessed upon the preoperative MRI. Univariable and multivariable analyses were performed.!##!Results!#!The median OS was 17 months. Of all evaluated radiographic markers of BCBM, only the presence of necrosis was independently associated with OS (14.5 vs 22.5 months, p = 0.027). In turn, intra-tumoral necrosis was more often in individuals with shorter time interval between BC and BM diagnosis (&amp;lt; 3 years, p = 0.035) and preoperative leukocytosis (p = 0.022). Moreover, dural affection of BM was more common in individuals with positive human epidermal growth factor receptor 2 status (p = 0.015) and supratentorial BM location (p = 0.024).!##!Conclusion!#!Intra-tumoral necrosis demonstrated significant association with OS after BM surgery in patients with BC. The radiographic pattern of BM on the preoperative MRI depends on certain tumor and clinical characteristics of patients