Crosslink between Temozolomide and PD-L1 immune-checkpoint inhibition in glioblastoma multiforme.

BACKGROUND: In recent years, PD-1/PD-L1 immune checkpoint inhibitors have improved cancer therapy in many tumor types, but no benefit of immune checkpoint therapy has been found in glioblastoma multiforme (GBM). Based on the results of our earlier work, which showed a reduction of PD-L1 expression in patients treated with temozolomide (TMZ), we aimed to investigate the link between TMZ therapy and the immune control point target PD-L1. METHODS: RNA-sequencing data from de-novo and recurrent glioblastoma were analyzed by AutoPipe algorithm. Results were confirmed either in a cell model by two primary and one established GBM cell line and specimens of de-novo and recurrent GBM. PD-L1 and pathway activation of the JAK/STAT pathway was analyzed by quantitative real-time PCR and western blot. RESULTS: We found a significant downregulation of the JAK/STAT pathway and immune response in recurrent tumors. The cell model showed an upregulation of PD-L1 after IFNγ treatment, while additional TMZ treatment lead to a reduction of PD-L1 expression and JAK/STAT pathway activation. These findings were confirmed in specimens of de-novo and recurrent glioblastoma. CONCLUSIONS: Our results suggest that TMZ therapy leads to a down-regulation of PD-L1 in primary GBM cells. These results support the clinical findings where PD-L1 is significantly reduced in recurrent GBMs. If the target is diminished, it may also lead to impaired efficacy of PD-1/PD-L1 inhibitors such as nivolumab.

Smoking Functions as a Negative Regulator of IGF1 and Impairs Adipokine Network in Patients with Rheumatoid Arthritis.

OBJECTIVES: Smoking is pathogenic for rheumatoid arthritis (RA) being tightly connected to the genetic and serological risk factors for this disease. This study aims to understand connections between cigarette smoking and serum levels of IGF1 and adipokines in RA. METHODS: Serum levels of IGF1 and adipokines leptin, adiponectin, resistin, and visfatin were measured in two independent cohorts of RA patients from Gothenburg (n = 350) and Leiden (n = 193). An association of these parameters with smoking was tested in a direct comparison and proved by bivariate correlation analysis. The obtained associations were further tested in multivariate regression models where the confounders (age, gender, disease duration, and BMI) were controlled. RESULTS: The smokers had significantly lower serum levels of IGF1, adiponectin, and leptin compared to never smokers. In regression analysis, smoking and low leptin, but not adiponectin, were associated and predicted low IGF1. Additionally, high disease activity and high BMI increased the probability of low leptin. CONCLUSIONS: The study indicates cigarette smoking as an important cause of a relative IGF1 and leptin deficiency in RA patients. This novel association between smoking and hypoleptinemia may be of importance for long-term prognosis of RA and for prediction of comorbidities.

Surgery for intracranial arachnoid cysts in children-a prospective long-term study.

PURPOSE: Intracranial arachnoid cysts are cystic malformations found in both adults and children. While many are asymptomatic, some cause symptoms and warrant surgical treatment. In this prospective population-based study, we aimed to study the short- and long-term outcome after surgical intervention in children with arachnoid cysts referred to our centre. METHODS: Twenty-seven pediatric patients (13 f. 14 m, mean age 9.4 years) with de novo cysts were consecutively included during a 5-year period. The presenting symptoms were headache (n = 12), balance disturbance and dizziness (n = 6), seizures (n = 6), hydrocephalus (n = 5), and macrocephaly (n = 1). Twenty-two patients underwent surgical treatment with either microsurgical (n = 17) or endoscopic fenestration (n = 5) of the cyst wall. Cyst volume was measured with OsiriX® software pre- and postoperatively. Short-term and long-term follow-up of all patients was conducted 3 months and 8.6 years (7-10.5 years) postoperatively. RESULTS: Three months after surgery, 59 % of the patients were improved regarding at least one major complaint, and average cyst volume was reduced to 33.3 ml (0-145 ml). At the long-term follow-up of 8.6 years, 77 % of the patients were improved regarding at least one symptom but subjective symptoms remained in 59 %. There was no permanent postoperative morbidity. We found no association between radiological reduction of cyst volume and clinical improvement. CONCLUSION: Our findings support a restrictive attitude to surgery for intracranial arachnoid cysts, in the absence of objectively verified symptoms and signs or obstruction of CSF pathways.

[Spontaneous intracranial hypotension]. / ABC om Spontan intrakraniell hypotension.

Spontaneous intracranial hypotension (SIH) is a disease presenting mostly with orthostatic head and neck pain due to a spontaneous cerebrospinal fluid (CSF) leak or a CSF-venous fistula in the spinal region. It demonstrates typical MRI findings with sagging of the brain causing tension of the meninges and sometimes the cranial nerves. It shares some clinical similarities with post puncture headache but differs in its pathophysiological cause, diagnosis, and treatment. Many patients remain misdiagnosed or wait too long for the correct diagnosis. The diagnostic work-up includes an MRI of the head and spine in search of typical SIH signs. Myelography and CT scans are performed to identify the location of the CSF leak or CSF-venous fistula. Treatment options may involve (1) initial conservative treatment with bed rest, caffein and fluids, (2) interventions such as epidural blood patch, fibrin patch, and embolization, or (3) surgical closure of the leak.

Free-Hand MIS TLIF without 3D Navigation-How to Achieve Low Radiation Exposure for Both Surgeon and Patient.

BACKGROUND: Transforaminal lumbar interbody fusion (TLIF) is one of the most frequently performed spinal fusion techniques, and this minimally invasive (MIS) approach has advantages over the traditional open approach. A drawback is the higher radiation exposure for the surgeon when conventional fluoroscopy (2D-fluoroscopy) is used. While computer-assisted navigation (CAN) reduce the surgeon's radiation exposure, the patient's exposure is higher. When we investigated 2D-fluoroscopically guided and 3D-navigated MIS TLIF in a randomized controlled trial, we detected low radiation doses for both the surgeon and the patient in the 2D-fluoroscopy group. Therefore, we extended the dataset, and herein, we report the radiation-sparing surgical technique of 2D-fluoroscopy-guided MIS TLIF. METHODS: Monosegmental and bisegmental MIS TLIF was performed on 24 patients in adherence to advanced radiation protection principles and a radiation-sparing surgical protocol. Dedicated dosemeters recorded patient and surgeon radiation exposure. For safety assessment, pedicle screw accuracy was graded according to the Gertzbein-Robbins classification. RESULTS: In total, 99 of 102 (97.1%) pedicle screws were correctly positioned (Gertzbein grade A/B). No breach caused neurological symptoms or necessitated revision surgery. The effective radiation dose to the surgeon was 41 ± 12 µSv per segment. Fluoroscopy time was 64 ± 34 s and 75 ± 43 radiographic images per segment were performed. Patient radiation doses at the neck, chest, and umbilical area were 65 ± 40, 123 ± 116, and 823 ± 862 µSv per segment, respectively. CONCLUSIONS: Using a dedicated radiation-sparing free-hand technique, 2D-fluoroscopy-guided MIS TLIF is successfully achievable with low radiation exposure to both the surgeon and the patient. With this technique, the maximum annual radiation exposure to the surgeon will not be exceeded, even with workday use.

Astrogliosis Releases Pro-Oncogenic Chitinase 3-Like 1 Causing MAPK Signaling in Glioblastoma.

Although reactive astrocytes constitute a major component of the cellular environment in glioblastoma, their function and crosstalk to other components of the environment is still poorly understood. Gene expression analysis of purified astrocytes from both the tumor core and non-infiltrated cortex reveals a tumor-related up-regulation of Chitinase 3-like 1 (CHI3L1), a cytokine which is related to inflammation, extracellular tissue remodeling, and fibrosis. Further, we established and validated a co-culture model to investigate the impact of reactive astrocytes within the tumor microenvironment. Here we show that reactive astrocytes promote a subtype-shift of glioblastoma towards the mesenchymal phenotype, driving mitogen-activated protein kinases (MAPK) signaling as well as increased proliferation and migration. In addition, we demonstrate that MAPK signaling is directly caused by a CHI3L1-IL13RA2 co-binding, which leads to increased downstream MAPK and AKT signaling. This novel microenvironmental crosstalk highlights the crucial role of non-neoplastic cells in malignant brain tumors and opens up new perspectives for targeted therapies in glioblastoma.

fMRI after Phalloplasty with Nerve Anastomosis in a Trans-Man Patient.

We report on a case of a trans-man patient, who underwent penile reconstruction with the use of a radial forearm flap, urethroplasty, vaginectomy and scrotoplasty, insertion of testicle implants, and penile erection implants, similar to previously described methods. One of the requirements for an ideal phalloplasty is the preservation of erogenous sensitivity, which is often demanded by the patients for fulfilling their sexual well-being. For the first time known to us, we use a functional magnetic resonance imaging following radial forearm flap phalloplasty with nerve anastomosis to assess the cortical activation after clitoral stimulation. The patient was poked with a plastic pen on the neophallus and the groin. Regular block design with T1 and BOLD-T2* images were used. The results contradict the classic Penfield and Rasmussen homunculus, that is, the activations in the primary somatosensory cortex (S1) were bilateral with a left-sided dominance in the lateral parts of the medial postcentral gyrus (same region as the groin), and no activations were observed in the mesial parts of the postcentral gyrus. We also reported bilateral activations with a left-sided dominance in the secondary somatosensory cortex (S2) and near Broca's area at the sylvian fissure just posterior to ramus ascendens. Our findings are similar to previous studies reporting on imaging related to genital sensitivity.