Tumor Treating Fields (TTFields) combined with the drug repurposing approach CUSP9v3 induce metabolic reprogramming and synergistic anti-glioblastoma activity in vitro.

BACKGROUND: Glioblastoma represents a brain tumor with a notoriously poor prognosis. First-line therapy may include adjunctive Tumor Treating Fields (TTFields) which are electric fields that are continuously delivered to the brain through non-invasive arrays. On a different note, CUSP9v3 represents a drug repurposing strategy that includes 9 repurposed drugs plus metronomic temozolomide. Here, we examined whether TTFields enhance the antineoplastic activity of CUSP9v3 against this disease. METHODS: We performed preclinical testing of a multimodal approach of TTFields and CUSP9v3 in different glioblastoma models. RESULTS: TTFields had predominantly synergistic inhibitory effects on the cell viability of glioblastoma cells and non-directed movement was significantly impaired when combined with CUSP9v3. TTFields plus CUSP9v3 significantly enhanced apoptosis, which was associated with a decreased mitochondrial outer membrane potential (MOMP), enhanced cleavage of effector caspase 3 and reduced expression of Bcl-2 and Mcl-1. Moreover, oxidative phosphorylation and expression of respiratory chain complexes I, III and IV was markedly reduced. CONCLUSION: TTFields strongly enhance the CUSP9v3-mediated anti-glioblastoma activity. TTFields are currently widely used for the treatment of glioblastoma patients and CUSP9v3 was shown to have a favorable safety profile in a phase Ib/IIa trial (NCT02770378) which facilitates transition of this multimodal approach to the clinical setting.

Cyclic testing of standalone ALIF versus TLIF in lumbosacral spines of low bone mineral density: an ex vivo biomechanical study.

PURPOSE: Screwed anterior lumbar interbody fusion (SALIF) alleviates the need for supplemental posterior fixation leading to reduction of perioperative morbidity. Specifically, elderly and multimorbid patients would benefit from shorter operative time and faster recovery but tend to have low bone mineral density (BMD). The current study aimed to compare loosening, defined as increase of ROM and NZ, of SALIF versus transforaminal lumbar interbody fusion (TLIF) under cyclic loading in cadaveric spines with reduced BMD. METHODS: Twelve human spines (L4-S2; 6 male 6 female donors; age 70.6 ± 19.6; trabecular BMD of L5 84.2 ± 24.4 mgHA/cm3, range 51-119 mgHA/cm3) were assigned to two groups. SALIF or TLIF were instrumented at L5/S1. Range of motion (ROM) and neutral zone (NZ) were assessed before and after axial cyclic loading (0-1150 N, 2000 cycles, 0.5 Hz) in flexion-extension (Flex-Ext), lateral bending, (LB), axial rotation (AR). RESULTS: ROM of the SALIF specimens increased significantly in all loading directions (p ≤ 0.041), except for left AR (p = 0.053), whereas for TLIF it increased significantly in left LB (p = 0.033) and Flex (p = 0.015). NZ of SALIF showed increase in Flex-Ext and LB, whereas NZ of TLIF did not increase significantly in any motion direction. CONCLUSIONS: Axial compression loading caused loosening of SALIF in Flex-Ext and LB, but not TLIF at L5/S1 in low BMD specimens. Nevertheless, Post-cyclic ROM and NZ of SALIF is comparable to TLIF. This suggests that, neither construct is optimal for the use in patients with reduced BMD.

[Rare Compression Syndrome of the Median Nerve due to a Supracondylar Humeral Process and a Ligament of Struthers]. / Seltenes Kompressionssyndrom des N. medianus durch den Processus supracondylaris und das Struthers-Ligament.

INTRODUCTION: A supracondylar process is a bony spur on the distal anteromedial surface of the humerus, and it is considered an anatomical variant with a prevalence of 0.4-2.7% according to anatomical studies. In almost all cases, it is associated with a fibrous, sometimes ossified ligament, which extends from the supracondylar process to the medial epicondyle. This ligament is known in the literature as the ligament of Struthers, named after the Scottish anatomist who first described it in detail in 1854. In rare cases, the supracondylar process can be a clinically relevant finding as a cause of nerve compression syndrome. The median and ulnar nerve can be trapped by the ring-shaped structure formed by the ligament of Struthers and the supracondylar process. CASE REPORT: A 59-year-old patient with symptoms of a cubital tunnel syndrome and additional ipsilateral sensory deficits in his thumb was referred to our clinic. Electroneurography showed no signs of an additional carpal tunnel syndrome. Preoperative x-ray and CT scans of the upper arm revealed a supracondylar process, which led us to suspect an associated entrapment of the median nerve. An MRI scan of the upper arm showed a ligament of Struthers and signs of a related median nerve compression as we initially assumed. We performed a surgical decompression of the median nerve in the distal upper arm and of the ulnar nerve in the cubital tunnel. Intraoperatively, there was evidence of compression of the median nerve due to the supracondylar process and the ligament of Struthers. The latter was cleaved and then resected along with the supracondylar process. Three months after surgery, the patient had no motor or sensory deficits. SUMMARY: The ring-shaped structure formed by the supracondylar process and ligament of Struthers represents a rare cause of compression syndrome of the median and ulnar nerve. Its incidence remains unknown so far. This anatomical variant should be considered a differential diagnosis in case of possibly related nerve entrapment symptoms after ruling out other, more frequent nerve compression causes. Moreover, the supracondylar process should be completely resected including the periosteum during surgery to minimise the risk of recurrence.

[Long-Term Outcomes after Surgery of the Neurogenic Thoracic-Outlet Syndrome in Adolescents]. / Langzeitergebnisse nach Operation des neurogenen Thoracic-Outlet-Syndroms bei Jugendlichen.

BACKGROUND: Neurogenic Thoracic Outlet Syndrome (nTOS) describes a complex of symptoms caused by the compression of neural structures at the upper thoracic outlet. Typical symptoms include pain, numbness and motor weakness of the affected extremity. The incidence of nTOS is 2-3 per 100,000 and is highest between the ages of 25 and 40. There are only a few studies evaluating the surgical outcomes of nTOS in adolescent patients. In particular, there is a lack of long-term data. MATERIALS AND METHODS: In a retrospective study of nTOS cases receiving surgical treatment in our clinic between 2002 and 2021, eight patients between 15 and 18 years of age were included. Demographic data, risk factors, clinical symptoms, clinical functional tests, neurophysiological, radiological and intraoperative findings were evaluated. Postoperative data were recorded using a standardised questionnaire. Decompression of the inferior truncus and the C8 and Th1 nerve roots was performed via a supraclavicular approach. RESULTS: The average duration of symptoms before surgery was two years. Of the eight patients who underwent surgery, six answered the written questionnaire and could be analysed for the study. The average follow-up was nine years (1-18 years). After surgery, all patients experienced pain reduction; three were pain-free in the long run and five no longer required pain medication. Strength improved in all patients, but two patients still had mild motor deficits. Sensory disturbances were reduced in all patients, but residual hypoesthesia persisted in five. With regard to overhead work, half of the patients had no impairment after surgery. All patients were able to work at the time of the survey. Half of the patients pursued their sports activities without impairment, while mild impairment was reported by the other half. CONCLUSION: nTOS in adolescents is a rare compression syndrome. Decompression of the lower parts of the brachial plexus using a supraclavicular approach without resection of the first rib is an adequate treatment. This retrospective study showed that a reduction in pain was achieved in all patients. In some patients, slight sensory and motor disturbances as well as a certain restriction in overhead work persisted. Patients were able to return to sports.

The Potential Role of the Extracellular Matrix Glycoprotein Reelin in Glioblastoma Biology.

Glioblastoma, the most common and lethal primary adult brain tumor, cannot be successfully removed surgically due to its highly invasive nature. Therapeutically, approaches must be aimed at a systemic brain disease and not merely at a tumor located within the brain, unless a successful containment strategy can be found. Reelin, an extracellular matrix glycoprotein, plays an important role in neuronal migration and serves here as a natural stop signal. Interestingly, the expression of reelin is negatively associated with tumor grade and, within glioblastoma, correlates with increased overall survival. To further elucidate a potential biological reason for these findings, we looked at the cellular behavior of glioblastoma cell lines grown on a pure fibronectin matrix or a matrix with reelin inserts. While reelin had no significant effects on cellular metabolism, proliferation, or resistance to chemotherapeutic agents, it did significantly affect the cells' interaction with fibronectin. Both matrix attachment and detachment were modulated by reelin, and thus, the invasion and motility of cells interacting with a reelin-containing matrix were altered. The data presented in this work strongly suggest that reelin might be a potential modulator of underlying molecular mechanisms that contribute to glioblastoma invasion.

Mapping Motor Neuroplasticity after Successful Surgical Brachial Plexus Reconstruction Using Navigated Transcranial Magnetic Stimulation (nTMS).

Brachial plexus reconstruction (BPR) consists of the complex surgical restoration of nerve structures. To further understand the underlying motor cortex changes and evaluate neuroplasticity after a successful surgery, we performed a navigated transcranial magnetic stimulation (nTMS) study mapping the postoperative motor representation of the formerly plegic arm. We conducted a prospective nTMS study mapping the musculocutaneous nerve as a representative, prominent target of BPR including a patient (n = 8) and a control group (n = 10). Measurements like resting motor threshold (RMT), cortical motor area location, and size were taken. Mathematical analysis was performed using MATLAB 2022, statistical analysis was performed using SPSS 26, and nTMS mapping was performed using the Nexstim NBS 5.1 system. Mapping was feasible in seven out of eight patients. Median RMT on the affected hemisphere was 41% compared to 50% on the unaffected hemisphere and they were 37% and 36% on the left and right hemispheres of the control group. The motor area location showed a relocation of bicep brachii representation at the middle precentral gyrus of the corresponding contralateral hemisphere. Motor area size was increased compared to the control group and the patient's unaffected, ipsilateral hemisphere. Understanding cortical reorganization is important for potential future treatments like therapeutic nTMS. The issue of motor neuroplasticity in patients with brachial plexus lesions is worth exploring in further studies.

Health-related quality of life in patients with peripheral nerve tumors: results from the German multicentric Peripheral Nerve Tumor Registry.

Objective: Peripheral nerve tumors (PNTs) are rare diseases. So far, no multicenter data on diagnostics, the efficacy of treatment, long-term outcomes, and health-related quality of life (HRQoL) exist. The establishment of the Peripheral Nerve Tumor Registry (PNTR) in 2015 allows for the systematic analysis of patients with tumors associated with peripheral nerves. The present study aims to investigate the impact of PNT on an individual's HRQoL and the effect of surgery. Methods: HRQoL was pre- and postoperatively assessed by the Euro-Qol-5D-5L (EQ-5D-5L) and Euro-Qol visual analog scale (EQ-VAS) survey in the retrospective and prospective study arm in three active participating study centers. An index was calculated based on the EQ-5D-5L for the quantification of health state (0: worst possible state of health, 1: best possible state of health). The EQ-VAS ranges from 0% (worst imaginable health status) to 100% (best possible health status). Patient characteristics (age, sex), as well as disease (histopathological entity) and treatment (pre- and postoperative symptoms, type of treatment)-specific data, were analyzed. Results: Data from 171 patients from three high-volume centers were included, with schwannoma (70.8%, n = 121) and neurofibroma (15.8%, n = 27) being the most prevalent histopathological diagnoses. Both the median health index value (preoperative: 0.887, n = 167; postoperative: 0.910, n = 166) and the median EQ-VAS (preoperative: 75%, n = 167; postoperative: 85%, n = 166) of the entire cohort regarding all histopathological diagnosis improved significantly after surgical therapy (p < 0.001). Preoperatively, 12.3% (n = 21) reached the highest index score of 1.0 in EQ-5D-5L and 100% in the EQ-VAS score in 5.3% (n = 9) of all patients. Postoperatively, the highest index score of 1.0 and 100% in the EQ-VAS score increased significantly and were achieved in 33.3% (n = 57) and 11.1% (n = 19) of the patients, respectively (p < 0.001). Conclusion: For the first time, our study presents multicenter data on life quality and the effect of surgery in primarily benign peripheral nerve tumors. Early surgery at a specialized center could improve neurological outcomes and, in conclusion, better QoL. In summary, surgical therapy significantly improved the entire cohort's QoL, VAS, and analgesia.

The impact of SARS-Covid-19 pandemic on peripheral nerve surgery - A single centre report.

OBJECTIVE: SARS-Cov-19 pandemic totally changed daily routine work in German hospitals. As hospital capacity was reduced, many surgeries were postponed or even cancelled. On March 25th 2020 the German Society of Neurosurgery (DGNC) published a statement in which urgent non-elective surgeries were defined for each neurosurgical domain, whereas elective interventions were deferred. The present work examines the impact of these Covid strategies focusing on patients with peripheral lesions who were conducted to our department during this period of time. METHODS: All patients who underwent any peripheral nerve surgery at our department from January 2018 until December 2022, were included. The complete range of surgeries including peripheral nerve lesions was examined encompassing compression syndromes, traumatic lesions of brachial plexus, traumatic lesions and tumors of single peripheral nerves. The numbers of surgical procedures were compared before, during and after pandemic. Pearson correlation coefficient was analysed. RESULTS: From 2018 to 2022 the total number of surgical procedures involving peripheral nerves included 2422 procedures. Compression syndromes made up the largest proportion (1433 operations, 59%), followed by peripheral nerve lesions (445 operations, 18%), peripheral nerve tumors (344 operations, 14%) and lesions of the brachial plexus (142 operations, 6%). The average was 40,5 interventions per month, the range was 7-63. Two declines in the number of peripheral nerve surgeries were noted during this period. The first was in April and May 2020 with an average drop of 65% and 41% respectively. In these months the average number of operations was 37. The second decrease was from October 2021 until January 2022, where number of surgeries was reduced by 16%, 36%, 83% and 18% with an average number of 50 operations. Both declines showed a significant and strong correlation with the lower number of compression syndrome treatments (r = 0.952, p < 0.001 and r = 0.968, p < 0.001), while no drop and no significant correlation was found in the treatment of traumatic peripheral nerve injuries (p = 0.769, r = 0.095 and p = 0.243, r = 0.366) and traumatic brachial plexus injuries (p = 0.787, r = 0.088 and p = 0.780, r = 0.09). A weak significant correlation was seen in the treatment numbers of peripheral nerve tumors (p = 0.017, r = 0.672 and p = 0.015, r = 0.67). CONCLUSION: Covid-19 pandemic lead to a significant decrease in the number of nerve decompressions, since, according to the German Society of Neurosurgery, those were considered as elective surgeries.

Case report: Atypical neurofibromatous neoplasm with uncertain biological potential of the sciatic nerve and a widespread arteriovenous fistula mimicking a malignant peripheral nerve tumor in a young patient with neurofibromatosis type 1.

We report an unusual constellation of diseases in a 32-year-old woman with neurofibromatosis type 1 (NF1) diagnosed with the recently described precursor entity of malignant peripheral nerve sheath tumor (MPNST), the so-called atypical neurofibromatous neoplasm with unknown biological potential (ANNUBP) and a large symptomatic cervical arteriovenous fistula. An [18F] 2-Fluoro-2-deoxy-D-glucose PET/CT (FDG-PET/CT) was performed to detect and stage a conspicuous symptomatic cervical tumor. The FDG-PET/CT showed high FDG uptake in one of the multiple known tumorous lesions associated with peripheral nerves. However, no relevant FDP uptake was observed in this affected cervical area. After digital subtraction angiography, the cervical mass turned out to be a widespread arteriovenous fistula of the vertebral artery. This was successfully treated using endovascular embolization. Subsequently, magnet resonance imaging (MRI) of the FDG-positive tumor revealed a well-enhanced homogeneous mass of the sciatic nerve measuring 5.2×2.4×2.8 cm. Microsurgical gross total tumor resection was performed using ultrasound. The final histopathological diagnosis was ANNUBP transformed from neurofibroma. The patient benefited excellently from the surgery; no recurrence or metastasis has been observed since resection. According to imaging, ANNUBP can be characterized as a well-enhanced homogeneous mass on MRI, displaying high uptake on FDG-PET/CT and hypoechogenic in ultrasound.

Collection of Rare Peripheral Nerve Tumors-Insights from the German Registry.

The most common peripheral nerve tumors are of a benign nature and include schwannoma or neurofibroma. In rare cases, other tumors or non-tumorous lesions can mimic peripheral nerve tumors clinically or radiologically. Based on data from the multicentric German Peripheral Nerve Tumor Registry (PNTR), which encompasses current information on 315 surgically treated patients from three high-volume centers, we present 61 cases of rare tumors and lesions that mimic tumors associated with peripheral nerves. This cohort displays considerable heterogeneity, featuring a broad spectrum of morphological features and biological potentials. Histopathological diagnoses include various intrinsic peripheral nerve tumors such as malignant peripheral nerve tumors (MPNSTs) (n = 13), perineurioma (n = 17), and hybrid nerve sheath tumors (HPNSTs, comprising schwannoma/perineurioma and schwannoma/neurofibroma) (n = 14), as well as atypical neurofibromatous neoplasm with unknown biological potential (ANNUBP) (n = 1). Additionally, the cohort encompasses extrinsic tumorous lesions like lymphoma (n = 3), lymphangioma (n = 2), hemangioma (n = 2), solitary fibrous tumor (n = 2), metastatic disease (n = 1), and single cases of other rare tumor entities (n = 6). An overview of the underlying pathology, imaging features, and clinical presentation is provided, with a brief description of each entity. A definitive preoperative differentiation between benign peripheral nerve tumors and rare intrinsic and extrinsic tumors is often not possible. Clinical examination and subtle imaging clues can at least indicate the possibility of a rare entity. The basic requirement is close cooperation between radiologists, neurologists, neuropathologists, and neurosurgeons at a specialized center to develop a multidisciplinary concept and offer the patient the best therapeutic approaches.