Real-world evidence on siponimod treatment in patients with secondary progressive multiple sclerosis.

BACKGROUND: Therapeutic options targeting inflammation in multiple sclerosis (MS) have evolved rapidly for relapsing-remitting MS, whereas few therapies are available for progressive forms of MS, in particular secondary progressive MS (SPMS). The approval of siponimod for SPMS has allowed for optimism in the otherwise discouraging therapeutic landscape. METHODS: We conducted a retrospective, multicenter, non-interventional study analyzing the efficacy and safety of siponimod under real-world conditions in 227 SPMS patients. According to the retrospective study framework, data was acquired at prespecified time points. Clinical readouts were assessed every three months. Disease progression was determined as increase in expanded disability status scale (EDSS), radiological progression, or the occurrence of new relapses under treatment. For safety analyses, adverse events (AE) and reasons for discontinuation were documented. The collected data points were analyzed at baseline and after 6, 12 and 18 months. However, data were predominately collected at the 6- and 12-month time points as many patients were lost to follow-up. In a group consisting of 41 patients, a more detailed investigation regarding disease progression was conducted, including data from measurement of cognitive and motoric functions. RESULTS: Under siponimod therapy, 64.8% of patients experienced sustained clinical disease stability at 12 months. Out of the stable patients 21.4% of patients improved. Of the remaining patients, 31.5% experienced EDSS progression, 3.7% worsened without meeting the threshold for progression. Relapses occurred in 7.4%. Radiological disease activity was detected in 24.1% of patients after six months of treatment and in 29.6% of patients at 12 months follow-up. The in-depth cohort consisting of 41 patients demonstrated no substantial changes in cognitive abilities measured by Paced Auditory Serial Addition Test and Symbol Digit Modalities Test or motoric functions measured with Timed 25-Foot Walk, 100-m timed test, and 9-Hole Peg Test throughout the 12-month study period. Radiological assessment showed a stable volume of white and grey matter, as well as a stable lesion count at 12 months follow-up. AE were observed in nearly half of the included patients, with lymphopenia being the most common. Due to disease progression or AE, 31.2% of patients discontinued therapy. CONCLUSION: Treatment with siponimod had an overall stabilizing effect regarding clinical and radiological outcome measures. However, there is a need for more intensive treatment management and monitoring to identify disease progression and AE.

[Surgical treatment of primary leiomyosarcoma of the inferior vena cava]. / Primer vena cava inferior leiomyosarcoma (VCI-LMS) sebészi kezelése.

CASE REPORT: pLMS in the wall of the inferior vena cava is an extremely rare form of retroperitoneal malignancies. A case in a young female patient is presented; clinical symptoms, pre- and postoperative diagnosis and surgical treatment are discussed. A retroperitoneal mass detected by imaging was found to be a large tumor mass located at the middle segment of the IVC on exploration. The tumour was successfully excised and the IVC was reconstructed with a synthetic graft. Eight years later, this patient needed a repeat surgery due to local recurrence. This time tumour was attached to the left renal vein. A re-resection of the IVC was performed with subsequent synthetic graft reconstruction and the distal end of the left renal vein was reimplanted into a lower segment of IVC. DISCUSSION: Primary leiomyosarcoma of the inferior vena cava (pLMS-IVC) is an extremely rare form of retroperitoneal malignancies. The tumour arises from the medial layer of the venous wall and can grow either intraluminally, or extraluminally or in both directions, as well. It can be localized in the first segment of IVC (above the hepatic veins), in the second segment between hepatic and renal veins and finally in the third segment between the right common iliac vein and renal veins. Therefore, the tumour can infiltrate both hepatic and/or renal vessels. Upper segment tumours can cause Budd-Chiari syndrome (hepatomegaly, abdominal pain, jaundice and ascites) with a bad prognosis. Middle segment tumours usually present with right upper quadrant pain, or may mimic biliary tract disease with a much better prognosis. Accumulating experience suggests that radio-chemotherapy alone seems to be less effective than "en bloc" resection with clear margins including loco-regional lymph nodes. Therefore, our choice of treatment was the latter. Although radical resection can be carried out in most of cases, 50% of patients develop a late recurrence yet.

The activity of spinal commissural interneurons during fictive locomotion in the lamprey.

Commissural interneurons in the lamprey coordinate activity of the hemisegmental oscillators to ensure proper left-right alternation during swimming. The activity of interneuronal axons at the ventral commissure was studied together with potential target motoneurons during fictive locomotion in the isolated lamprey spinal cord. To estimate the unperturbed activity of the interneurons, axonal recordings were chosen because soma recordings inevitably will affect the level of membrane depolarization and thereby spike initiation. Of 227 commissural axons recorded during locomotor activity, 14 produced inhibitory and 3 produced excitatory postsynaptic potentials (PSPs) in target motoneurons. The axons typically fired multiple spikes per locomotor cycle, with approximately 10 Hz sustained frequency. The average shortest spike interval in a burst corresponded to an instantaneous frequency of approximately 50 Hz for both the excitatory and inhibitory axons. The maximum number of spikes per locomotor cycle was inversely related to the locomotor frequency, in accordance with previous observations in the spinal hemicord preparation. In axons that fired multiple spikes per cycle, the mean interspike intervals were in the range in which the amplitude of the slow afterhyperpolarization (sAHP) is large, providing further support for the role of the sAHP in spike timing. One hundred ninety-five axons (86%) fired rhythmically during fictive locomotion, with preferred phase of firing distributed over either the segmental locomotor burst phase (40% of axons) or the transitional phase (between bursts; 60%). Thus in lamprey commissural interneurons, we found a broad distribution of firing rates and phases during fictive locomotion.

[Clinical symptoms and treatment of cervicofacial actinomycosis. Literature survey and case report]. / Az actinomycosis cervicofacialis klinikai jellemzoi es korszeru terápiája. Irodalmi osszefoglaldó es esetközlés.

Actinomycosis is a chronic, specific inflammation which is characterized by suppuration, abscess formation, tissue fibrosis and granuloma formation. Actinomycosis has three main forms (cervicofacial, which is the most frequent, approximately 60%, pulmonary and abdominal), but other regions of the body can be involved, too (e.g. neck, ovaries, bones), that is why its differential diagnosis becomes more and more relevant. Regarding its treatment, the majority of authors recommends the combination of surgical and antibiotic treatment. The authors of this article present a typical case of cervicofacial actinomycosis, in which the authors used the combination of surgical and antibiotic treatment. As a result of the treatment the healing process was completed successfully and without complications.

5-HT Modulation of identified segmental premotor interneurons in the lamprey spinal cord.

Ipsilaterally projecting spinal excitatory interneurons (EINs) generate the hemisegmental rhythmic locomotor activity in lamprey, while the commissural interneurons ensure proper left-right alternation. 5-HT is a potent modulator of the locomotor rhythm and is endogenously released from the spinal cord during fictive locomotion. The effect of 5-HT was investigated for three segmental premotor interneuron types: EINs, commissural excitatory and commissural inhibitory interneurons. All three types of interneurons produced chemical postsynaptic potentials in motoneurons, but only those from EINs had an electrical component. The effect of 5-HT was studied on the slow afterhyperpolarization, involved in spike frequency regulation, and on the segmental synaptic transmission to motoneurons. 5-HT induced a reduction in the slow afterhyperpolarization and a depression of synaptic transmission in all three types of segmental interneurons. Thus 5-HT is a very potent modulator of membrane properties and synaptic transmission of last-order segmental premotor interneurons. Such modulation of locomotor network interneurons can partially account for the observed effects of 5-HT on the swimming pattern in lamprey.

Intracellular QX-314 causes depression of membrane potential oscillations in lamprey spinal neurons during fictive locomotion.

Spinal neurons undergo large cyclic membrane potential oscillations during fictive locomotion in lamprey. It was investigated whether these oscillations were due only to synaptically driven excitatory and inhibitory potentials or if voltage-dependent inward conductances also contribute to the depolarizing phase by using N-(2,6-dimethylphenyl carbamoylmethyl)triethylammonium bromide (QX-314) administered intracellularly during fictive locomotion. QX-314 intracellularly blocks inactivating and persistent Na+ channels, and in some neurons, effects on certain other types of channels have been reported. To detail the effects of QX-314 on Na+ and Ca2+ channels, we used dissociated lamprey neurons recorded under whole cell voltage clamp. At low intracellular concentrations of QX-314 (0.2 mM), inactivating Na+ channels were blocked and no effects were exerted on Ca2+ channels (also at 0.5 mM). At 10 mM QX-314, there was, however a marked reduction of I(Ca). In the isolated spinal cord of the lamprey, fictive locomotion was induced by superfusing the spinal cord with Ringer's solution containing N-methyl-D-aspartate (NMDA), while recording the locomotor activity from the ventral roots. Simultaneously, identified spinal neurons were recorded intracellularly, while infusing QX-314 from the microelectrode. Patch electrodes cannot be used in the intact spinal cord, and therefore "sharp" electrodes were used. The amplitude of the oscillations was consistently reduced by 20-25% in motoneurons (P < 0.05) and unidentified spinal neurons (P < 0.005). The onset of the effect started a few minutes after impalement and reached a stable level within 30 min. These effects thus show that QX-314 causes a reduction in the amplitude of membrane potential oscillations during fictive locomotion. We also investigated whether QX-314 could affect glutamate currents by applying short pulses of glutamate from an extracellular pipette. No changes were observed. We also found no evidence for a persistent Na+ current in dissociated neurons, but these cells have a much-reduced dendritic tree. The results indicate that there is an inward conductance, which is sensitive to QX-314, during membrane potential oscillations that "boosts" the synaptic drive during fictive locomotion. Taken together, the results suggest that inactivating Na+ channels contribute to this inward conductance although persistent Na+ channels, if present on dendrites, could possibly also contribute to shaping the membrane potential oscillations.