Personalizing non-small cell lung cancer treatment through patient-derived xenograft models: preclinical and clinical factors for consideration.

PURPOSE: In the pursuit of creating personalized and more effective treatment strategies for lung cancer patients, Patient-Derived Xenografts (PDXs) have been introduced as preclinical platforms that can recapitulate the specific patient's tumor in an in vivo model. We investigated how well PDX models can preserve the tumor's clinical and molecular characteristics across different generations. METHODS: A Non-Small Cell Lung Cancer (NSCLC) PDX model was established in NSG-SGM3 mice and clinical and preclinical factors were assessed throughout subsequent passages. Our cohort consisted of 40 NSCLC patients, which were used to create 20 patient-specific PDX models in NSG-SGM3 mice. Histopathological staining and Whole Exome Sequencing (WES) analysis were preformed to understand tumor heterogeneity throughout serial passages. RESULTS: The main factors that contributed to the growth of the engrafted PDX in mice were a higher grade or stage of disease, in contrast to the long duration of chemotherapy treatment, which was negatively correlated with PDX propagation. Successful PDX growth was also linked to poorer prognosis and overall survival, while growth pattern variability was affected by the tumor aggressiveness, primarily affecting the first passage. Pathology analysis showed preservation of the histological type and grade; however, WES analysis revealed genomic instability in advanced passages, leading to the inconsistencies in clinically relevant alterations between the PDXs and biopsies. CONCLUSIONS: Our study highlights the impact of multiple clinical and preclinical factors on the engraftment success, growth kinetics, and tumor stability of patient-specific NSCLC PDXs, and underscores the importance of considering these factors when guiding and evaluating prolonged personalized treatment studies for NSCLC patients in these models, as well as signaling the imperative for additional investigations to determine the full clinical potential of this technique.

Visualization of both proximal M2-MCA segments in patients (the Tilted-V Sign) with acute M1-MCA occlusion stroke is associated with better procedural and prognostic outcomes.

Introduction: We aimed to assess the clinical significance of M1-MCA occlusion with visualization of both MCA-M2 segments ["Tilted-V sign" (TVS)] on initial CT angiography (CTA) in patients with acute ischemic stroke (AIS) undergoing endovascular thrombectomy (EVT). Methods: Data for patients with consecutive AIS undergoing EVT for large vessel occlusion (LVO) in two academic centers are recorded in ongoing databases. Patients who underwent EVT for M1-MCA occlusions ≤ 6 h from symptom onset were included in this retrospective analysis. Results: A total of 346 patients met the inclusion criteria; 189 (55%) had positive TVS. Patients with positive TVS were younger (68 ± 14 vs. 71 ± 14 years, P = 0.028), with similar rates of vascular risk factors and baseline modified Rankin scores (mRS) 0-2. The rates of achieving thrombolysis in cerebral ischemia (TICI) 2b-3 were similar to the two groups (79%), although successful first-pass recanalization was more common with TVS (64 vs. 36%, p = 0.01). On multivariate analysis, higher collateral score [odds ratio (OR) 1.38 per unit increase, p = 0.008] and lower age (OR 0.98 per year increase, p = 0.046) were significant predictors of TVS. Patients with positive TVS had higher post-procedural Alberta Stroke Program Early CT Score (ASPECTS; 6.9 ± 2.2 vs. 5.2 ± 2.3, p = 0.001), were discharged with lower National Institutes of Health Stroke Score (NIHSS; 6±6 vs. 9±7, p = 0.003) and higher rates of mRS 0-2 (29.5 vs. 12%, p = 0.001), and had lower rates of 90-day mortality (13.2 vs. 21.6%, p = 0.038). However, TVS was not an independent predictor of functional independence (OR 2.51; 95% CI 0.7-8.3). Conclusion: Tilted-V Sign, an easily identifiable radiological marker, is associated with fewer recanalization attempts, better functional outcomes, and reduced mortality.

Minimally Invasive Subtemporal Intradural Approach for Penetrating Orbitocranial Injury by Wooden Foreign Body Into the Lateral Wall of the Cavernous Sinus.

Non-missile transorbital penetrating head injuries are relatively rare, though potentially fatal injuries. Trajectory for intracranial entrance is typically via the orbital roof, the superior orbital fissure (SOF), or the optic canal. Non-metallic intracranial penetrating injuries are even scarcer and may pose unusual diagnostic and surgical challenges. Here we present and discuss a unique case of a penetrating injury by a wooden foreign body (FB) which entered and expanded the inter-dural space of the lateral cavernous sinus (CS) sinus wall without intracavernous or intradural involvement. The patient was a 71 year-old male who fell face-down and sustained a penetrating transorbital injury by a dry twig fragment, which passed through the SOF and into the interdural space of lateral wall of the ipsilateral CS. The patient was fully conscious (GCS15) at presentation but had severe ocular injury (complete ophthalmoplegia and blindness of the injured eye). The wooden FB was successfully removed via a minimally invasive subtemporal intradural approach with no apparent immediate or long-term complications. We emphasize the unusual diagnostic and surgical challenges related to this kind of rare injuries as reflected by the decision-making considerations taken in the presented case.

The Chiasmal Compression Index: An Integrative Assessment Tool for Visual Disturbances in Patients with Pituitary Macroadenomas.

OBJECTIVE: Visual status is routinely evaluated by neuro-ophthalmologic examination and computerized visual field (VF) tests in patients with chiasmal compression secondary to pituitary macroadenoma. Currently, no relevant data exists to accurately quantify the extent of optic apparatus compromise to further guide clinical decision-making. We aimed to assess for a possible quantitative correlation between optic chiasm geometric properties on magnetic resonance imaging (MRI) and VF deficits. METHODS: Visual assessments and concurrent MRI scans were retrospectively reviewed from patients treated for pituitary macroadenoma in a single medical institution. Chiasm width, chiasm minimal and maximal height, and chiasm angle were measured on MRI coronal plane images by 3 independent reviewers (for the sake of variability analysis). VF numerical summary parameters were also retrieved. RESULTS: A total of 30 patients were included in the final analysis. Average VF index was 70% (±30), and averaged mean deviation was 10.0 db (±9). Chiasm angle and width (which together represents the bending and stretching of the chiasm by the upward directed compression; both of which demonstrated high inter- and intraobserver agreement) showed strong correlation with VF loss. Chiasmal compression index derived from those parameters showed even stronger correlation. CONCLUSIONS: The strong correlation demonstrated by our results of this relatively simple radiologic measurement with VF status, despite the relatively small cohort, calls for further investigation in this promising direction, and may facilitate with basic assessment and clinical decision-making for patients with equivocal neuro-ophthalmologic evaluation, as well as with poor compliance.

Repeated spontaneous intra-tumoural and subarachnoid haemorrhage in an anticoagulated patient with a previously-irradiated vestibular Schwannoma: Case report.

Subarachnoid hemorrhage caused by vestibular schwannomas (VS) is rare with no clear pathological mechanism supported in the existing literature. However, anticoagulation treatment as well as previous radiation therapy appear to be a crucial risk factor for subarachnoid haemorrhage from a VS. We report an unusual case of both intratumoural and subarachnoid haemorrhage in a patient with a VS on anticoagulation treatment previously treated with stereotactic radiosurgery. We emphasize the need for caution when considering the use of radiation therapy for treatment of VS in patients on chronic anticoagulation therapy.

Tractography-Guided Deep Brain Stimulation of the Anteromedial Globus Pallidus Internus for Refractory Obsessive-Compulsive Disorder: Case Report.

BACKGROUND AND IMPORTANCE: Obsessive-compulsive disorder (OCD) is a disabling psychiatric disorder, mainly treated with psychotherapy and pharmacotherapy. Surgical intervention may be appropriate for patients with treatment-refractory OCD. Deep brain stimulation (DBS) is an alternative for previously common ablative surgical procedures. Tractography has been proposed as a method for individualizing DBS treatment and may have the potential to improve efficacy. CLINICAL PRESENTATION: We present a patient with treatment-refractory OCD previously treated with bilateral leucotomies, who underwent DBS surgery with targeting informed by tractography. Preoperative tractography to identify suitable DBS targets was undertaken. Structural images were also utilized for standard stereotactic surgical planning. The anteromedial globus pallidus internus (amGPi) was chosen as the target bilaterally after consideration of white matter projections to frontal cortical regions and neurosurgical approach. Bilateral amGPi DBS surgery was undertaken without adverse events. At 16-mo follow-up, there was a 48.5% reduction in OCD symptom severity as measured by the Yale-Brown Obsessive Compulsive Scale. CONCLUSION: The amGPi can be a successful DBS target for OCD. This is the first known case to report on DBS surgery postleucotomies for OCD and highlights the utility of tractography for surgical planning in OCD.

Solitary intraventricular Hodgkin lymphoma post-transplant lymphoproliferative disease (HL-PTLD): Case report.

Lymphomas affecting the central nervous system (CNS), both primarily and secondarily, are uncommon malignancies. Immunosuppressed states, including iatrogenic immunosuppression following organ transplantation, are the most significant risk factors for developing primary CNS lymphoma (PCNSL). Post-transplant lymphoproliferative disease (PTLD) is a well described complication following bone marrow or solid organ transplantation. PTLD is usually a systemic disease with occasional CNS involvement. The incidence of CNS involvement in PTLD is low, and the majority of these cases tend to be PCNSL. Hodgkin lymphoma PTLD (HL-PTLD) constitutes only a very small percentage of PTLD. We report a rare case of a primary intraventricular CNS classical HL-PTLD in a male patient, 18 years following renal transplantation. The location allowed for safe neurosurgical intervention which resolved the symptom of elevated intracranial pressure and allowed for induction of a Rituximab-based chemotherapy regimen. Both the ventricular location of the PTLD and Hodgkin Lymphoma PTLD are themselves individually quite rare and have not previously been reported together. The unique location allowed safe neurosurgical intervention which quickly resolved the symptom of elevated intracranial pressure and allowed for induction of a Rituximab-based chemotherapy regimen.

Unfavorable functional outcome is expected for elderly patients suffering from acute subdural hematoma even when presenting with preserved level of consciousness.

Alongside an increase in life expectancy, median age of patients presenting with traumatic acute subdural hematomas (ASDH) has increased as well. Treatment guidelines are based on studies performed on relatively young patients. The optimal management of elderly (>70 years old) patients with ASDH, specifically those with relatively preserved level of consciousness, was not thoroughly investigated so far. We retrospectively examined elderly patients presented to our medical center between the years 2006-2016 with traumatic convexity ASDH and GCS of 13-15. 773 patients were included in the initial cohort and 54 patients were included in the final analysis. The mean age at presentation was 81.5 years and the means of hematoma thickness and midline shift were 15.5 mm and 6.6 mm, respectively. Patients in our cohort had an overall unfavorable outcome (mRS 5-6) of 28% and 56% at discharge and at 1 year following injury, respectively. The results were not significantly different for the subgroups of patients older than 80 years and patients with high ASA-PS. Surgical evacuation of the ASDH was undertaken in 28 patients with focal neurologic deficit and/or worsening on subsequent brain scans. At 1 year, 64% (18 patients) in the surgery group had unfavorable outcome compared to 48% (12 patients) in the conservative group. We believe that these numbers should be taken under consideration when assessing elderly patients with convexity ASDH and relatively preserved level of consciousness.

Glioblastoma in a patient with tuberous sclerosis.

Tuberous sclerosis complex (TSC) is a multisystem, autosomal dominant disorder with a wide clinical spectrum. The most common brain tumor associated with TSC is the low grade subependymal giant cell astrocytoma. Reports of high grade primary brain tumors in patients with TSC are rare. TSC1/2 mutation has been identified in glioblastoma (GBM) even though it probably does not increase the overall risk for GBM in patients with TSC. We present a 58-year-old patient with known TSC, admitted for new neurological symptoms, diagnosed with a large heterogeneous tumor involving most of the corpus callosum. Stereotactic needle brain biopsy confirmed the diagnosis to be GBM. Five previously reported similar cases are reviewed, reflecting diversity in clinical and radiological findings and indicating that a high index of clinical suspicion must be maintained in patients with TSC.

Solid non-enhancing cerebellar pilocytic astrocytoma case report.

Pilocytic astrocytomas (PA) are slow-growing low-grade gliomas, commonly diagnosed as cerebellar tumors among the pediatric and adolescent population. Characteristic neuroradiologic findings in PA include a cystic mass with enhancing solid nodule. While uncommon radiologic features of PA, including non-enhancing cystic tumors, have been previously described, we present a unique case of a patient with a non-enhancing solid cerebellar PA. The main clinical, radiologic, and pathologic findings are discussed and the relevant literature reviewed. To our knowledge, this is the first reported patient with these radiologic features of PA, highlighting the need for awareness of uncommon presentations when discussing differential diagnosis and pre-operative planning for cerebellar tumors in the relevant age group.

Ovarian hyperstimulation syndrome leading to ventriculoperitoneal shunt malfunction: Case report.

Ventriculoperitoneal shunt (VPS) insertion is a common neurosurgical procedure for hydrocephalus. Unfortunately, VPS malfunction is not uncommon, with an estimated cumulative rate of 32% at 5 years. As flow through the shunt is influenced by the pressure gradient between the ventricles and the peritoneal cavity, malfunction may be caused by elevated intra-abdominal pressure. We present a rare patient with ascites following ovarian hyperstimulation syndrome (OHSS) leading to shunt malfunction. OHSS is a potentially life-threatening complication of controlled ovarian stimulation caused by the administration of exogenous gonadotropins. In this patient clinical and radiological resolution of shunt dysfunction were achieved following peritoneocentesis. To our knowledge this is the first described case of OHSS leading to shunt malfunction, emphasizing the importance of awareness, early recognition and proper management of abdominal etiologies of VPS malfunction.

[Common complaint, forgotten diagnosis: spontaneous intracranial hypotension syndrome].

Violation of the balance between the production and absorption rate of the cerebrospinal fluid (CSF) might result in hydrocephalus or the spontaneous intracranial hypotension syndrome (SIH), which is usually presented with a unique type of headache. Several hypotheses have been suggested regarding the pathogenesis of this syndrome, including spinal CSF leakage due to located damage to the spinal dura. Another theory suggests increased CSF absorption from the spinal epidural space caused by declined inferior vena cava pressure. SIH is characterized by typical radiological findings, including the presence of subdural collections or hematomas, sagging of the brain parenchyma and the cerebellar tonsils, and brain meninges enhancement. Spinal imaging studies may help in locating the CSF leakage site when it exists. The diagnosis is based on the presence of orthostatic headaches together with typical clinical and imaging characteristics, after the exclusion of any recent medical interventions or other possible etiologies for the presence of SIH. The main treatment includes autologous epidural bloodpatch, even though symptomatic relief may be achieved with supportive or medical treatment alone. The presence of subdural collections or hematomas among patients presenting with orthostatic headaches suggests the need for further clinical and imaging evaluation prior to the surgical drainage, whenever possible. Two patients who were recently treated in our institution are presented, together with a proposed management algorithm.