Eine Kombination aus neoadjuvanter Chemotherapie und radikaler Trachelektomie erlaubt es auch Frauen mit größeren Zervikarzinomen (Tumordurchmesser > 2 cm) bei Metastasenfreiheit fertilitätserhaltend zu operieren

Objective: The aim of this study is to assess our results of treatment of women with stage I cervical cancer > 2cm in diameter seeking fertility preservation. Treatment consisted of Laparoscopic Pelvic and Paraaortic Lymphadenectomy (LPPLND), and when no nodal metastasis was detected, neoadjuvant chemotherapy (NACT) followed by radical vaginal trachelectomy (RVT). Patients with positive lymph nodes underwent primary chemoradiation. Furthermore, we aim to summarize the literature on this topic. Methods: A cohort of women younger than 40 years of age with stage I disease > 2 cm who underwent LPPLND and either NACT and RVT or chemoradiation. Oncological outcome was evaluated prospectively. In addition, a Pubmed search was performed and current literature is summarized. Results: eighteen women were eligible for this study. Twelve (67%) women were diagnosed with metastasis in one or more pelvic and/or paraaortic lymph nodes, and thus received primary chemoradiation. After a mean follow-up of 25.5 months, three out of these 12 women (25%) developed recurrence. Six women (33%) underwent NACT and RVT. Three patients experienced complete response to NACT and three patients showed more than 50% tumor size reduction. After a mean follow-up of 30.6 months all six women are free of recurrence. One patient delivered a healthy infant. Eight studies were included in the literature review and used NACT and uterus preservation, however lymph node staging was performed after NACT. Conclusions: Staging LPPLND allows separating patients in high or low recurrence risk groups. NACT and RVT seems to be safe for women with completely staged stage I cervical cancer > 2 cm in diameter, whereas even after primary chemoradiation, patients with positive lymph nodes experienced recurrence. Therefore, selection of patients with stage I cervical carcinoma > 2 cm, eligible for fertility preservation should include histopathologic evaluation of lymph node status before any further treatment.Die aktuellen Leitlinien empfehlen die Durchführung einer fertilitäserhaltenden Therapie bei Zervikarzinom durch radikale Trachelektomie (bei Metastasenfreiheit) nur bis zu einem Tumordurchmesser von 2 cm. Das Ziel dieser Studie war es die Prognose von Frauen zu untersuchen, die eine fertilitätserhaltende Therapie bei Vorliegen eines größeren Zervixkarzinom (Stadium IB, Tumor > 2 cm) wünschten. Dieses Protokoll sah bei Metastasenfreiheit zunächst die Durchführung einer neoadjuvanten Chemotherapie (zur Reduktion des Tumorvolumens) gefolgt von einer radikalen Trachelektomie vor. Methode: Bei allen Studienpatientinnen erfolgte zunächst ein Lymphknotenstaging durch komplette pelvine und paraaortale Lymphonodektomie. Bei Nachweis von einer oder mehrerer Lymphknotenmetastasen wurde die Durchführung einer kombinierten Radiochemotherapie indiziert. Bei Lymphknotenfreiheit erhielten die Patientinnen eine neoadjuvante Chemotherapie und im Anschluß eine radikale Tracheleketomie. Ergebnisse: 18 Frauen wurden in die Studie eingeschlossen. Bei 12 Patientinnen (67%) wurde im Rahmen des initialen pelvinen und paraaortalen Lymphnotenstagings das Vorliegen von einer oder mehrerer Lymphknotenmetastasen nachgewiesen und daher die Durchführung einer primären Radiochemotherapie indiziert. Bei den verbleibenden 6 Frauen (initialer Tumordurchmesser im Mittel ???) wurde keine Metastase nachgewiesen und bei diesen Frauen daher eine neoadjuvante Chemotherapie, gefolgt von einer radikalen Tracheleketomie, durchgeführt. Die neoadjuvante Chemotherapie führte bei 3 Frauen zu einer makroskopisch kompletten Tumorrückbildung und bei den verbleibenden 3 Frauen dieser Gruppe zu einer 50%igen Reduktion des Tumorvolumens. In der Nachbeobachtungszeit von bislang 30 Monaten blieben alle 6 Frauen der Trachelektomiegruppe rezidivfrei, während bei den Frauen mit nachgewiesenen Lymphknotenmetastasen (und nach Durchführung einer kombinierten Radiochemotherapie) in 25% der betroffenen Frauen (3/12 Frauen) ein Rezidiv auftrat. Schlussfolgerung: Die initiale Feststellung des Lymphknotenstatus erlaubt es das individuelle Rezidivrisiko genauer zu bestimmen und läßt es vertretbar erscheinen auch Frauen mit größeren Zervikarzinomen (> 2 cm) bei Kinderwunsch durch eine Kombination aus neoadjuvanter Chemotherapie und radikaler Trachelektomie fertilitätserhaltend zu operieren

miR-214 coordinates melanoma progression by upregulating ALCAM through TFAP2 and miR-148b downmodulation.

Malignant melanoma is one of the most aggressive human cancers, but the mechanisms governing its metastatic dissemination are not fully understood. Upregulation of miR-214 and ALCAM and the loss of TFAP2 expression have been implicated in this process, with TFAP2 a direct target of miR-214. Here, we link miR-214 and ALCAM as well as identify a core role for miR-214 in organizing melanoma metastasis. miR- 214 upregulated ALCAM, acting transcriptionally through TFAP2 and also posttranscriptionally through miR-148b (itself controlled by TFAP2), both negative regulators of ALCAM. We also identified several miR-214–mediated prometastatic functions directly promoted by ALCAM. Silencing ALCAM in miR-214–overexpressing melanoma cells reduced cell migration and invasion without affecting growth or anoikisin vitro, and it also impaired extravasation and metastasis formation in vivo. Conversely, cell migration and extravasation was reduced in miR-214–overexpressing cells by upregulation of either miR 148b or TFAP2. These findings were consistent with patterns of expression of miR-214, ALCAM, and miR-148b in human melanoma specimens. Overall, our results define a pathway involving miR-214, miR-148b, TFAP2, and ALCAM that is critical for establishing distant metastases in melanoma

Accelerating legacy applications with spatial computing devices

Heterogeneous computing is the major driving factor in designing new energy-efficient high-performance computing systems. Despite the broad adoption of GPUs and other specialized architectures, the interest in spatial architectures like field-programmable gate arrays (FPGAs) has grown. While combining high performance, low power consumption and high adaptability constitute an advantage, these devices still suffer from a weak software ecosystem, which forces application developers to use tools requiring deep knowledge of the underlying system, often leaving legacy code (e.g., Fortran applications) unsupported. By realizing this, we describe a methodology for porting Fortran (legacy) code on modern FPGA architectures, with the target of preserving performance/power ratios. Aimed as an experience report, we considered an industrial computational fluid dynamics application to demonstrate that our methodology produces synthesizable OpenCL codes targeting Intel Arria10 and Stratix10 devices. Although performance gain is not far beyond that of the original CPU code (we obtained a relative speedup of x 0.59 and x 0.63, respectively, for a single optimized main kernel, while only on the Stratix10 we achieved x 2.56 by replicating the main optimized kernel 4 times), our results are quite encouraging to drawn the path for further investigations. This paper also reports some major criticalities in porting Fortran code on FPGA architectures

Absence of system xc⁻ on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

Background: Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System x(c)- or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration. Methods: Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system x(c)-, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT(-/-)) mice and irradiated mice reconstituted in xCT(-/-) bone marrow (BM), to their proper wild type (xCT(+/+)) controls. Results: xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT(+/+) mice, xCT(-/-) mice were equally susceptible to EAE, whereas mice transplanted with xCT(-/-) BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected. Conclusions: Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system x(c)- on immune cells invading the CNS participates to EAE. Since a total loss of system x(c)- had no net beneficial effects, these results have important implications for targeting system x(c)- for treatment of MS

A Predictive Model for Corticosteroid Response in Individual Patients with MS Relapses

<div><p>Objectives</p><p>To derive a simple predictive model to guide the use of corticosteroids in patients with relapsing remitting MS suffering an acute relapse.</p><p>Materials and Methods</p><p>We analysed individual patient randomised controlled trial data (n=98) using a binary logistic regression model based on age, gender, baseline disability scores [physician-observed: expanded disability status scale (EDSS) and patient reported: multiple sclerosis impact scale 29 (MSIS-29)], and the time intervals between symptom onset or referral and treatment.</p><p>Results</p><p>Based on two a priori selected cut-off points (improvement in EDSS ≥ 0.5 and ≥ 1.0), we found that variables which predicted better response to corticosteroids after 6 weeks were younger age and lower MSIS-29 physical score at the time of relapse (model fit 71.2% - 73.1%).</p><p>Conclusions</p><p>This pilot study suggests two clinical variables which may predict the majority of the response to corticosteroid treatment in patients undergoing an MS relapse. The study is limited in being able to clearly distinguish factors associated with treatment response or spontaneous recovery and needs to be replicated in a larger prospective study.</p></div

Consensus protocol for EEG and amplitude-integrated EEG assessment and monitoring in neonates

The aim of this work is to establish inclusive guidelines on electroencephalography (EEG) applicable to all neonatal intensive care units (NICUs). Guidelines on ideal EEG monitoring for neonates are available, but there are significant barriers to their implementation in many centres around the world. These include barriers due to limited resources regarding the availability of equipment and technical and interpretive round-the-clock personnel. On the other hand, despite its limitations, amplitude-integrated EEG (aEEG) (previously called Cerebral Function Monitor [CFM]) is a common alternative used in NICUs. The Italian Neonatal Seizure Collaborative Network (INNESCO), working with all national scientific societies interested in the field of neonatal clinical neurophysiology, performed a systematic literature review and promoted interdisciplinary discussions among experts (neonatologists, paediatric neurologists, neurophysiologists, technicians) between 2017 and 2020 with the aim of elaborating shared recommendations. A consensus statement on videoEEG (vEEG) and aEEG for the principal neonatal indications was established. The authors propose a flexible frame of recommendations based on the complementary use of vEEG and aEEG applicable to the various neonatal units with different levels of complexity according to local resources and specific patient features. Suggestions for promoting cooperation between neonatologists, paediatric neurologists, and neurophysiologists, organisational restructuring, and teleneurophysiology implementation are provided

HLA-class I markers and multiple sclerosis susceptibility in the Italian population

Previous studies reported an association with multiple sclerosis (MS) of distinct HLA-class I markers, namely HLA-A*02, HLA-Cw*05 and MOG-142L. In this work, we tested the association with MS of A*02 and Cw*05 in 1273 Italian MS patients and 1075 matched controls, which were previously analyzed for MOG-142, and explored the relationship among these three markers in modulating MS risk. HLA-A*02 conferred a statistically robust MS protection (odds ratio, OR=0.61; 95% confidence intervals, CI=0.51–0.72, P<10−9), which was independent of DRB1*15 and of any other DRB1* allele and remained similar after accounting for the other two analyzed class I markers. Conversely, the protective effect we previously observed for MOG-142L was secondary to its linkage disequilibrium with A*02. Cw*05 was not associated considering the whole sample, but its presence significantly enhanced the protection in the HLA-A*02-positive group, independently of DRB1: the OR conferred by A*02 in Cw*05-positive individuals (0.22, 95% CI=0.13–0.38) was significantly lower than in Cw*05-negative individuals (0.69, 95% CI=0.58–0.83) with a significant (P=4.94 × 10−5) multiplicative interaction between the two markers. In the absence of A*02, Cw*05 behaved as a risk factor, particularly in combination with DRB1*03 (OR=3.89, P=0.0006), indicating that Cw*05 might be a marker of protective or risk haplotypes, respectively

Cortical injury in multiple sclerosis; the role of the immune system

The easily identifiable, ubiquitous demyelination and neuronal damage that occurs within the cerebral white matter of patients with multiple sclerosis (MS) has been the subject of extensive study. Accordingly, MS has historically been described as a disease of the white matter. Recently, the cerebral cortex (gray matter) of patients with MS has been recognized as an additional and major site of disease pathogenesis. This acknowledgement of cortical tissue damage is due, in part, to more powerful MRI that allows detection of such injury and to focused neuropathology-based investigations. Cortical tissue damage has been associated with inflammation that is less pronounced to that which is associated with damage in the white matter. There is, however, emerging evidence that suggests cortical damage can be closely associated with robust inflammation not only in the parenchyma, but also in the neighboring meninges. This manuscript will highlight the current knowledge of inflammation associated with cortical tissue injury. Historical literature along with contemporary work that focuses on both the absence and presence of inflammation in the cerebral cortex and in the cerebral meninges will be reviewed