Relapse in medulloblastoma: what can be done after abandoning high-dose chemotherapy? A mono-institutional experience

Purpose

We retrospectively report strategies used for medulloblastoma patients progressing after craniospinal irradiation where we aimed for: symptom control, a satisfactory quality of life, accrual in phase 1–2 trials, when available, and the first two conditions could no longer be satisfied by already experienced second-line strategies.

Methods

Surgery was used in cases of doubtful relapse or when only one site was affected. Radiotherapy was given whenever possible, especially to relieve symptoms. The main chemotherapy regimens were oral temozolomide/etoposide, intravenous (iv.) cisplatin/etoposide, iv. gemcitabine/oxaliplatin, an oral sonic hedgehog pathway inhibitor and oral melphalan.

Results

Between 1998 and 2011, we treated 18 patients relapsed after median 20 months. Nine had relapsed locally, four had dissemination, three single metastases, and two had one synchronous local and metastatic recurrence. Responses to chemotherapy were seen in 32 % of cases. The median hospital stay for treatments/complications was 19 days. The 1- and 3-year progression-free survival (PFS) rates were 28?±?10 % and 0 %, respectively, for OS, they were 44?±?12 % and 22?±?10 % but no patient was cured. The median PFS after a first relapse was 7 months (range 1–29); the median OS was 7 months (range 4–44). No patients died due to treatment toxicity. Late recurrence (more than 1–2 years after diagnosis) and involvement of single sites were favorable prognostic factors.

Conclusions

Without succeeding in patients cure, we ensured them further treatment with short hospital stay thus affording low personal and social costs. The chances of cure may emerge from tailored therapies according to genetic stratification.     

Molecular biology of the voltage-gated sodium channel

The integral membrane protein composing the voltage-sensitive sodium channel is a bagel-like structure (Fig. 1) with a central pore that is highly selective for sodium ions. When the electric field across a cell's membrane becomes depolarized, the pore of the channel opens to allow sodium ions to flow down their electrochemical gradient into the cell¹. Voltage-gating, a common feature of all voltage-activated channels, is an essential functional property that is only now being understood in terms of the structural features of the protein.     

Prostaglandin synthesis in bovine coronary endothelial cells: comparison with other commonly studied endothelial cells

Comparison of arachidonic acid metabolism by bovine coronary artery endothelial cells, bovine aortic endothelial cells and human umbilical endothelial cells indicated potentially important differences in relative amounts of the different prostaglandins produced. Bovine coronary endothelial cells converted ¹⁴C-arachidonic acid to radioactive 6-keto PGF₁ (the stable metabolite of PGI₂) and to a lesser extent PGE₂. Bovine aortic cells synthesized 6-keto PGF₁ and 6,15-diketo PGF₁ as the major products. PGE₂, 6-keto PGE₁, PGE₂, and PGD₂ were minor metabolites. By comparison, endothelia cells isolated from human umbilical artery or vein formed mainly 6-keto PGF₁ and substantial amounts of PGF₂, PGE₂ and PGD₂. Basal concentrations of 6-keto PGF₁ were two-fold higher in bovine coronary cells than in bovine aortic endothelial cells, but seven-fold less than in endothelial cells cultured from human umbilical vessels. Histamine, bradykinin and thrombin stimulated PGI₂ synthesis in both coronary endothelial cells and human umbilical cells, but only bradykinin stimulated PGI₂ synthesis in bovine aortic cells. This comparative study indicates that endothelial cells vary in the metabolites of arachidonic acid that they produce depending upon the vascular origin of the cells. Also, endothelial cells from different vascular beds respond differently to specific vasoactive agents.     

Characterization of Healthcare-Associated and Community-Associated Clostridioides difficile Infections among Adults,Canada, 2015–2019

We investigated epidemiologic and molecular characteristics of healthcare-associated (HA) and community-associated (CA) Clostridioides difficile infection (CDI) among adult patients in Canadian Nosocomial Infection Surveillance Program hospitals during 2015–2019. The study encompassed 18,455 CDI cases, 13,735 (74.4%) HA and 4,720 (25.6%) CA. During 2015–2019, HA CDI rates decreased by 23.8%, whereas CA decreased by 18.8%. HA CDI was significantly associated with increased 30-day all-cause mortality as compared with CA CDI (p<0.01). Of 2,506 isolates analyzed, the most common ribotypes (RTs) were RT027, RT106, RT014, and RT020. RT027 was more often associated with CDI-attributable death than was non-RT027, regardless of acquisition type. Overall resistance C. difficile rates were similar for all drugs tested except moxifloxacin. Adult HA and CA CDI rates have declined, coinciding with changes in prevalence of RT027 and RT106. Infection prevention and control and continued national surveillance are integral to clarifying CDI epidemiology, investigation, and control.     

Frequency‐dependent modulation of neural oscillations across the gait cycle

Balance and walking are fundamental to support common daily activities. Relatively accurate characterizations of normal and impaired gait features were attained at the kinematic and muscular levels. Conversely, the neural processes underlying gait dynamics still need to be elucidated. To shed light on gait‐related modulations of neural activity, we collected high‐density electroencephalography (hdEEG) signals and ankle acceleration data in young healthy participants during treadmill walking. We used the ankle acceleration data to segment each gait cycle in four phases: initial double support, right leg swing, final double support, left leg swing. Then, we processed hdEEG signals to extract neural oscillations in alpha, beta, and gamma bands, and examined event‐related desynchronization/synchronization (ERD/ERS) across gait phases. Our results showed that ERD/ERS modulations for alpha, beta, and gamma bands were strongest in the primary sensorimotor cortex (M1), but were also found in premotor cortex, thalamus and cerebellum. We observed a modulation of neural oscillations across gait phases in M1 and cerebellum, and an interaction between frequency band and gait phase in premotor cortex and thalamus. Furthermore, an ERD/ERS lateralization effect was present in M1 for the alpha and beta bands, and in the cerebellum for the beta and gamma bands. Overall, our findings demonstrate that an electrophysiological source imaging approach based on hdEEG can be used to investigate dynamic neural processes of gait control. Future work on the development of mobile hdEEG‐based brain–body imaging platforms may enable overground walking investigations, with potential applications in the study of gait disorders.     

Vaccination with BNT162b2 and ChAdOx1 nCoV-19 Induces Cross-Reactive Anti-RBD IgG against SARS-CoV-2 Variants including Omicron

SARS-CoV-2 variants of concern (VOCs) have caused a significant increase in infections worldwide. Despite high vaccination rates in industrialized countries, the fourth VOC, Omicron, has outpaced the Delta variant and is causing breakthrough infections in individuals with two booster vaccinations. While the magnitude of morbidity and lethality is lower in Omicron, the infection rate and global spread are rapid. Using a specific IgG multipanel-ELISA with the spike protein’s receptor-binding domain (RBD) from recombinant Alpha, Gamma, Delta, and Omicron variants, sera from health-care workers from the Medical University of Vienna were tested pre-pandemic and post-vaccination (BNT162b2; ChAdOx1 nCoV-19). The cohort was continuously monitored by SARS-CoV-2 testing and commercial nucleocapsid IgG ELISA. RBD IgG ELISA showed significantly lower reactivity against the Omicron-RBD compared to the Alpha variant in all individuals (p < 0.001). IgG levels were independent of sex, but were significantly higher in BNT162b2 recipients <45 years of age for Alpha, Gamma, and Delta (p < 0.001; p = 0.040; p = 0.004, respectively). Pre-pandemic cross-reactive anti-Omicron IgG was detected in 31 individuals and was increased 8.78-fold after vaccination, regardless of vaccine type. The low anti-RBD Omicron IgG level could explain the breakthrough infections and their presence could also contribute to a milder COVID-19 course by cross-reactivity and broadening the adaptive immunity.     

Perceived stigma and quality of life in Parkinson’s disease with additional health conditions

BackgroundParkinson’s disease (PD) is associated with perceived stigma and affects quality of life (QoL). Additional health conditions may influence these consequences of PD.AimsThis study assessed the impact of health conditions on perceived stigma and QoL in persons with PD. We hypothesised that individuals with more health conditions would report more stigma and poorer QoL. We also examined the contributions of demographic and clinical characteristics to the correlations between health conditions and perceived stigma/QoL.MethodsWe identified 196 eligible participants from the Boston University Online Survey Study of Parkinson’s Disease and examined their health history, performance on multiple stigma measures, and scores on the 39-item Parkinson’s Disease Questionnaire assessing QoL.ResultsAt least one health condition was reported by 79% of the sample, with a median of 2 and a range of 0–7 health conditions. More perceived stigma and poorer QoL were associated with thyroid disease, depression, anxiety, and the total number of health conditions. These correlations were related to younger age, less education, and earlier disease onset. Other health conditions (high blood pressure, back/leg surgery, headache, cancer/tumours, and heart disease) were not significantly correlated with stigma or QoL.ConclusionsHaving more health conditions, or thyroid disease, depression, or anxiety, was associated with more perceived stigma and poorer QoL, with younger age, less education, and earlier disease onset affecting the associations. It is important to consider the burden of health conditions and how they affect persons with PD with specific clinical characteristics.     

Validation of the Italian Version of the SARC-F Questionnaire to Assess Sarcopenia in Older Adults

Background: SARC-F is a simple sarcopenia screening tool. This study aimed to examine the validity of the Italian version of SARC-F. Methods: A total of 97 elderly individuals (37/60 males/females, 65 years and older) who met the study’s selection criteria were included. SARC-F was translated into the Italian language in a culturally responsive manner. The total score was calculated by adding the scores on the five items. The participants were divided into two groups according to the total score (SARC-F < 4 vs. SARC-F ≥ 4), and their associations with various factors (handgrip test, chair stand test, and Skeletal Muscle Index assessed by DXA) have been examined by gender. In addition, the tool’s validity was analyzed by comparing it with different international working group diagnostic criteria for sarcopenia. Results: The total prevalence of sarcopenia according to the SARC-F was 14.2% and, specifically, 12.8% among men and 14.3% in women. The sensitivity of the SARC-F was (male (M): 11–50% and female (F): 22–36%) medium-low compared with the European, international, and Asian criteria of sarcopenia; however, SARC-F showed a high specificity (M: 77.3–100% and F: 79.5–100%) and a moderate Cronbach’s alpha coefficient of (0.669 (CI95%: 0.358–0.830). The participants in the SARC-F ≥ 4 group had poorer handgrip for EWGSOP2 (p < 0.001) and chair stand (p < 0.001) than the participants in the SARC-F < 4 group. Conclusions: The Italian language version of SARC-F showed high specificity, moderate reliability, and good associations with other predictive tests. The Italian version of SARC-F appears to be a useful screening tool for the diagnosis of sarcopenia in Italian elderly populations.     

Immunometabolic Reprogramming in Response to HIV Infection Is Not Fully Normalized by Suppressive Antiretroviral Therapy

Background: HIV infection results in immunometabolic reprogramming. While we are beginning to understand how this metabolic reprogramming regulates the immune response to HIV infection, we do not currently understand the impact of ART on immunometabolism in people with HIV (PWH). Methods: Serum obtained from HIV-infected (n = 278) and geographically matched HIV seronegative control subjects (n = 300) from Rakai Uganda were used in this study. Serum was obtained before and ~2 years following the initiation of ART from HIV-infected individuals. We conducted metabolomics profiling of the serum and focused our analysis on metabolic substrates and pathways assocaited with immunometabolism. Results: HIV infection was associated with metabolic adaptations that implicated hyperactive glycolysis, enhanced formation of lactate, increased activity of the pentose phosphate pathway (PPP), decreased β-oxidation of long-chain fatty acids, increased utilization of medium-chain fatty acids, and enhanced amino acid catabolism. Following ART, serum levels of ketone bodies, carnitine, and amino acid metabolism were normalized, however glycolysis, PPP, lactate production, and β-oxidation of long-chain fatty acids remained abnormal. Conclusion: Our findings suggest that HIV infection is associated with an increased immunometabolic demand that is satisfied through the utilization of alternative energetic substrates, including fatty acids and amino acids. ART alone was insufficient to completely restore this metabolic reprogramming to HIV infection, suggesting that a sustained impairment of immunometabolism may contribute to chronic immune activation and comorbid conditions in virally suppressed PWH.