Response In Adult Patients Research Articles

Brain Stem Glioma Recurrence: Exploring the Therapeutic Frontiers.

Gliomas of the brainstem represent a small percentage of central nervous system gliomas in adults. Due to the proximity of the tumor to critical structures, radical surgery is highly challenging and limited to selected cases. In addition, postoperative treatments, which become exclusive to non-operable patients, do not guarantee satisfactory disease control, making the progression of the disease inevitable. Currently, there is a lack of therapeutic options to control tumor growth after the diagnosis of recurrence. The rarity of these tumors, their distinct behavioral characteristics, and the limited availability of tumor tissue necessary for the development of prognostic and predictive biomarkers contribute to the absence of a standardized approach for treating recurrent brainstem gliomas. A salvage radiotherapy (RT) retreatment could represent a promising approach for recurrent brainstem gliomas. However, to date, it has been mainly evaluated in pediatric cases, with few experiences available to assess the most appropriate RT dose, safety, and clinical responses in adult patients. This comprehensive review aims to identify instances of adult patients with recurrent brainstem gliomas subjected to a secondary course of RT, with a specific focus on the analysis of treatment-related toxicity and outcomes. Through this investigation, we endeavor to contribute valuable insights into the viability and efficacy of salvage RT retreatment in managing recurrent brainstem gliomas in the adult population.

Eculizumab for adult patients with atypical haemolytic-uraemic syndrome: full dataset analysis of Japanese post-marketing surveillance.

Eculizumab has been approved for atypical haemolytic-uraemic syndrome (aHUS) in Japan since 2013. Post-marketing surveillance enrolled patients with aHUS who received ≥ 1 dose of eculizumab to assess eculizumab safety and effectiveness. We evaluated serious adverse events and effectiveness endpoints, i.e., haematologic normalization, a decrease of ≥ 25% in serum creatinine (sCr) levels, and complete thrombotic microangiopathy (TMA) response in adult patients with aHUS without otherunderlying diseases. In addition, the difference of baseline characteristics between patients who did and did not meet effectiveness endpoints was examined. In this safety and effectiveness analysis, 79 adult patients were included; median age was 54.0years, median treatment duration was 30weeks. Total exposure time of eculizumab was 75.51 patient-years, and 94 serious adverse events were reported in 39 patients. No unexpected safety signals were identified in this population. Mean platelet count, lactate dehydrogenase and estimated glomerular filtration rate significantly improved after 7daysof treatment. Complete TMA response, haematologic normalization and the improvement of sCr levels were met by 35.3%, 40.4% and 51.3% of patients, respectively. Median treatment duration was shorter in patients who did not achieve complete TMA response (6weeks) than in patients who did (114weeks). Multivariate analysis suggested that the time from the most recent TMA episodeto start ofeculizumab treatment was negatively associated with kidney function improvement. No unexpected safety signals of eculizumab were identified in Japanese patients with aHUS in a real-world setting. Renal outcomes were negatively associated with the time from the most recent TMA episodeto the initiation of eculizumab treatment.

Comparison between dexmedetomidine and lidocaine for attenuation of cough response during tracheal extubation: A systematic review and meta-analysis.

Tracheal extubation often causes cardiovascular and airway responses, potentially resulting in hazardous consequences. It remains unknown whether dexmedetomidine or lidocaine is more effective for cough suppression. Hence, we conducted a systematic review and meta-analysis of randomised controlled trials to compare the effectiveness and safety of dexmedetomidine and lidocaine in reducing cough response after tracheal extubation in adult patients. A thorough search of electronic databases, including PubMed, Embase, Cochrane Library, and Web of Science, was conducted to identify relevant studies (from inception to 31 January 2023). Randomised controlled trials comparing intravenous (IV) dexmedetomidine versus IV lidocaine administration during emergence from anaesthesia to prevent tracheal extubation response in adult patients under general anaesthesia were included. The primary outcome was the incidence of post-extubation cough. Secondary outcomes included emergence time, extubation time, residual sedation, and incidences of bradycardia. Statistical analysis was conducted using RevMan software. The Cochrane risk of bias tool was used to evaluate the potential risk for bias. In total, seven studies with 450 participants were included. There was no statistically significant difference in the incidence of cough between dexmedetomidine and lidocaine groups [Risk Ratio = 0.76; 95% Confidence Interval: 0.46, 1.24]. Emergence and extubation times were not significantly different between the two groups. Meta-analysis revealed a higher incidence of bradycardia and residual sedation in dexmedetomidine compared to the lidocaine group. This meta-analysis found no difference in cough, emergence, and extubation time between dexmedetomidine and lidocaine after tracheal extubation. However, residual sedation and bradycardia were more significant in dexmedetomidine than in lidocaine.

493 - Lebrikizumab does not impact vaccine-induced immune responses: results from a phase 3 study in adult patients with moderate-to-severe atopic dermatitis

Abstract Introduction Lebrikizumab (LEB) is a monoclonal antibody (Ab) that has shown efficacy and safety in patients with moderate-to-severe atopic dermatitis (AD) in Phase 2/3 trials. LEB targets IL-13 and inhibits signaling of the IL-4Rα/IL-13Rα1 complex. The potential immunomodulator effect of LEB necessitates investigating its impact on immune responses. Objectives To report the seroresponses to the Tdap (Diphtheria/Tetanus Toxoids/Pertussis) and MCV (Meningococcal (Groups A, C, Y, and W-135)) vaccines in LEB-treated and placebo (PBO)-treated adult patients (aged 18-15 years) with moderate-to-severe AD; and to compare the efficacy of LEB vs PBO in the treatment of AD. Methods ADopt-VA was a US Phase 3, 16-week (W) randomized, double-blind, placebo-controlled study to assess LEB impact on vaccine immune responses in adult patients with moderate-to-severe AD. The primary endpoint was the immune response to 2 vaccines, the Tdap and MCV . LEB was given as a 500 mg loading dose at baseline and W2, followed by 250 mg LEB Q2W. At W12, both vaccines (Tdap and MCV) were administered to all patients, LEB group N=107, Placebo (PBO) group N=81. Immune responses were determined by Ab level differences between W12 and W16. Secondary efficacy endpoints at W16 were Investigator Global Assessment (IGA) and Eczema Area and Severity Index (EASI 75) scores. Results For Tdap, 73.6% of LEB patients had a positive Ab response vs 73.4% for PBO, 90% CI, 0.3 (-10.2, 11.2). For MCV, LEB patients had an 86.9% positive Ab response vs 75.0% for PBO, 90% CI, 12.2 (2.5, 22.0). IGA (0,1) was achieved by 40.6% of LEB patients vs 18.9% receiving PBO (p=<0.001); EASI 75 was achieved by 58.0% and 32.7% (p<0.001), respectively. The safety profile was consistent with previous LEB trials. Conclusions These data show that LEB does not negatively impact immune responses for Tdap or MCV vaccines in adults with moderate-to-severe AD.

A convenient and practical index for predicting the induction response in adult patients with hemophagocytic lymphohistiocytosis: ferritin/platelet ratio

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome with high mortality rate. The response to induction therapy is an important factor affecting survival. The purpose is to investigate laboratory predictors for induction response in adult patients with HLH, which are convenient, practical, and timeliness. Clinical data from January 2017 to December 2020 was retrospectively analyzed, and 269 patients were included. Patients were divided into remission and non-remission groups according to their induction response, 177 in the remission group, and 92 in the non-remission group. We reviewed general characteristics and analyzed the predictive value of serum ferritin, triglycerides, alanine aminotransferase (ALT), and blood cells before and 1–4 weeks after induction therapy for induction response by univariate analysis, ROC curves, etc. There was a correlation between serum ferritin, ALT, leukocytes, neutrophils, hemoglobin, platelets, and induction response (P < 0.05). Serum ferritin and platelets 1–4 weeks after induction therapy, respectively, might be a good predictor for induction response in adults with HLH, with AUC values close to or greater than 0.7. We established a new clinical model of the ferritin/platelet ratio. The results showed that the ferritin/platelet ratio at 1–4 weeks after induction therapy might be a practical index for predicting induction response, which significantly improved the area under the ROC curve (AUC > 0.75). Patients with a ferritin/platelet ratio > 16.08 at 2 weeks after induction therapy may have a relatively poor induction response. Ferritin/platelet ratio after induction therapy can be a good predictor for induction response in adult patients with HLH.

Impact of Oropharyngeal Stimulation during Laryngeal Mask Insertion on Cardiovascular Response in adult patients. A Double-blind Clinical Trial Study.

Laryngeal mask airway (LMA) insertion has been found to reduce cardiovascular responses when compared to laryngoscopy and intubation. This research aimed to examine the impact of various techniques employed for LMA insertion on cardiovascular response. This randomized, double-blind clinical trial included 90 elective surgery candidates divided into three groups of 30. All patients underwent similar anesthesia. The LMA was inserted using the classical technique, 180° rotation technique, and face-to-face triple maneuver technique (FFTMT). The cardiovascular responses, the success rate of LMA placement, and other outcomes were documented and compared among the three methods. The study revealed that the blood pressure of patients 10 minutes after LMA insertion using the rotational technique was higher than the standard technique (p=0.019). The pulse rate in the third (p=0.044, p=0.024) and fifth minutes (p=0.028, p=0.048) following the insertion of LMA demonstrated higher values when utilizing the FFTMT than the standard and rotational technique groups, respectively. Moreover, the incidence of sore throat following surgery in the FTFTM group was slightly greater than that observed with the standard and rotation techniques (p=0.389 and p=0.688, respectively). The findings of the present investigation indicated that implementing the classic technique for LMA placement resulted in a more consistent blood pressure (BP) and pulse rate (PR) response than the 180° rotation and FFTMT. Furthermore, the classical method exhibited a marginally lower success rate in terms of LMA insertion than the alternative methods.

Analyzing features of measles immune response in adult patients

Measles is a highly contagious, vaccine-preventable anthroponotic infection. Despite the policy of active measles vaccination for entire global population, measles has not completely disappeared, it wanes and waxes in outbreaks. It has been shown that not only the unvaccinated but also the vaccinated, which is quite understandable, subjects are involved in measles progression. The study was aimed at assessing features of the immune response in adult measles patients at rise in disease incidence upon its eradication. 1.158 blood sera from measles patients aged 18 to 70 living in Moscow and the Moscow region were studied by ELISA (Euroimmun, Germany). The vast majority of subjects were aged 1840 years comprising 72.36% cases. 69 sera collected at a later timepoint (1020 days from rash onset) were excluded and analyzed separately. According to anti-measles IgG and avidity level, the data were stratified as follows: group 1 with a primary type of immune response 582 sera (53.44%), not vaccinated in childhood; group 2 (secondary response) 446 sera (40.96%), vaccinated in childhood, but lost anti-measles antibodies; group 3 with intermediate level of parameters 61 sera. To clarify the type of immune response in group 3, an additional analysis of the spectrum of anti-measles antibody subclasses was carried out. It was shown that a mixed type of response was detected in this group: 31 subjects mainly had primary immune response, and 30 subjects secondary immune response. At the same time, 40 out of 61 subjects were vaccinated against measles 13 months prior to disease onset, i.e., it was overlapped on arising post-vaccination immunity. Thus, the previously identified trend towards the loss of post-vaccination immunity among older schoolchildren and young adults vaccinated in childhood who are involved in the epidemic process continues to worsen.

A prospective investigation of impacts of comorbid attention deficit hyperactivity disorder (ADHD) on clinical features and long-term treatment response in adult patients with obsessive-compulsive disorder (OCD)

BackgroundA close association between obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in children and adolescents has been investigated in previous studies. However, few studies examined the relationship between lifetime comorbidity of ADHD and OCD in adults. Therefore, we sought to investigate the clinical and psychopathological features related to comorbid ADHD in Japanese adult patients with OCD. MethodsWe assessed lifetime comorbidity of ADHD in 93 adult Japanese patients with OCD. Additionally, we used the Japanese version of Conners' Adult ADHD Rating Scales to assess the characteristics and severity of ADHD in each participant. According to the results, we excluded OCD patients that did not have ADHD but who exhibited elevated levels of ADHD traits. We compared OCD patients with ADHD (ADHD+ group) and those without ADHD or its trait (ADHD− group) in terms of background profiles and clinical features, such as OCD symptomatology and psychometric test results. Additionally, the 6-month treatment outcome was compared prospectively between groups. ResultsOf the 93 OCD participants, the prevalence of lifetime comorbidity of ADHD was estimated as 16.1%. Compared with the ADHD− group, participants in the ADHD+ group had an earlier age of onset of OCD, higher frequencies of hoarding symptoms, higher levels of depressive and anxiety symptoms and lower quality of life, more elevated levels of impulsivity, and higher rates of substance or behavioral addiction and major depression. Finally, the mean improvement rate on the Yale-Brown Obsessive Compulsive Scale after 6 months of standardized OCD treatment in the ADHD+ group (16.1%) was significantly lower than that in the ADHD− group (44.6%). ConclusionThe lifetime comorbidity of ADHD is likely to exert a significant effect on clinical features and treatment outcome in adult patients with OCD. It is important to consider that underlying ADHD pathology may function as a facilitator for increased severity of global clinical features and treatment refractory conditions in OCD patients. Further studies are required to examine treatment strategies for such patients.

Safety and efficacy of tisagenlecleucel in patients with relapsed or refractory B-cell lymphoma: the first real-world evidence in Japan.

Tisagenlecleucel, an autologous CD19-directed T-cell immunotherapy, can induce a durable response in adult patients with relapsed/refractory (r/r) B-cell lymphoma. To elucidate the outcome of chimeric antigen receptor (CAR) T-cell therapy in Japanese, we retrospectively analyzed the outcomes of 89 patients who received tisagenlecleucel for r/r diffuse large B-cell lymphoma (n = 71) or transformed follicular lymphoma (n = 18). With a median follow-up of 6.6-months, 65 (73.0%) patients achieved a clinical response. The overall survival (OS) and event-free survival (EFS) rates at 12months were 67.0% and 46.3%, respectively. Overall, 80 patients (89.9%) had cytokine release syndrome (CRS), and 6 patients (6.7%) had a grade ≥ 3 event. ICANS occurred in 5 patients (5.6%); only 1 patient had grade 4 ICANS. Representative infectious events of any grade were cytomegalovirus viremia, bacteremia and sepsis. The most common other adverse events were ALT elevation, AST elevation, diarrhea, edema, and creatinine elevation. No treatment-related mortality was observed. A Sub-analysis showed that a high metabolic tumor volume (MTV; ≥ 80ml) and stable disease /progressive disease before tisagenlecleucel infusion were both significantly associated with a poor EFS and OS in a multivariate analysis (P < 0.05). Notably, the combination of these 2 factors efficiently stratified the prognosis of these patients (HR 6.87 [95% CI 2.4-19.65; P < 0.05] into a high-risk group). We report the first real-world data on tisagenlecleucel for r/r B-cell lymphoma in Japan. Tisagenlecleucel is feasible and effective, even in late line treatment. In addition, our results support a new algorithm for predicting the outcomes of tisagenlecleucel.

Multisystem ALK-positive histiocytosis: a multi-case study and literature review

BackgroundAnaplastic lymphoma kinase (ALK)-positive histiocytosis, a novel rare histiocytic proliferation, was first described in 2008; it occurs in early infancy with liver and hematopoietic involvement. The spectrum was subsequently broadened to include localized diseases in older children and young adults. However, its full clinicopathological features and molecular lineage have not been fully elucidated.ResultsHere, we report four cases of multisystem ALK-positive histiocytosis without hematopoietic involvement. Clinically, three patients were adults aged between 32 and 51 years. Two patients’, whose main manifestations were intracranial mass and numerous micronodules in the thoracoabdominal cavity organs and skin papules respectively, had a partial response to ALK inhibitors after surgery. One patient presented with mediastinal neoplasm without surgical treatment, and progressive disease occurred after two years of ALK inhibitor therapy. The fourth patient was a 17-month-old male with a large intracranial mass and presented with a poor response to ALK inhibitor and chemoradiotherapy; he died eight months after surgery. Pathologically, the histiocytes were large, with abundant eosinophilic cytoplasm, and mixed with variable numbers of foamy cells and Touton giant cells. Interstitial fibrosis was also observed. Histiocytes were positive for macrophage markers (CD68 and CD163) and ALK. KIF5B-ALK fusions were detected in two cases, EML4-ALK in one, and both DCTN1-ALK and VRK2-ALK fusions were detected in one case.ConclusionsWe observed that ALK inhibitors present robust and durable responses in adult patients but a poor response in young children with central nervous system involvement. There is no consensus on the optimal treatment regimen and long-term prognosis requires further observation. Moreover, every unusual histiocytic proliferative lesion, especially unresectable and multisystem involvement, should be routinely tested for ALK immunohistochemical staining to identify this rare disease.

The Epidemiology of Pre-Hospital EMS Treatment of Geriatric Patients in the City of Vienna-An Overview.

Background: The city of Vienna, Austria, has a gradually aging population. Elderly people, over 65 years old and living at home or in nursing homes, frequently use Emergency Medical Services (EMS). However, there is no previous data comparing the EMS utilization of elderly- and non-elderly patients in Vienna. Methods: We retrospectively analyzed all EMS incidents in Vienna from 2012 to 2019. Transport- and emergency physician treatment rates, annual fluctuations, and the number of non-transports were compared between elderly (≥65 years) and non-elderly (18−64 years) patients. Results: Elderly people accounted for 42.6% of the total EMS responses in adult patients, representing an annual response rate of 223 per 1000 inhabitants ≥ 65 years. Compared to 76 per 1000 inhabitants in patients 18−64 years old, this results in an incidence rate ratio (IRR) of 2.93 [2.92−2.94]. Elderly people were more likely (OR 1.68 [1.65−1.70]) to need emergency physicians, compared to 18−64 year-olds. Nursing home residents were twice (OR 2.11 [2.06−2.17]) as likely to need emergency physicians than the rest of the study group. Non-transports were more likely to occur in patients over 65 years than in non-elderlies (14% vs. 12%, p < 0.001). Conclusions: The elderly population ≥ 65 years in Vienna shows higher EMS response rates than younger adults. They need emergency physicians more often, especially when residing in nursing homes. The economical and organizational strain this puts on the emergency response system should trigger further research and the development of solutions, such as specific response units dedicated to elderly people.

Long-term sialidase-specific immune responses after natural infection with cholera: Findings from a longitudinal cohort study in Bangladesh.

Immune responses that target sialidase occur following natural cholera and have been associated with protection against cholera. Sialidase is a neuraminidase that facilitates the binding of cholera toxin (CT) to intestinal epithelial cells. Despite this, little is known about age-related sialidase-specific immune responses and the impact of nutritional status and co-infection on sialidase-specific immunity. We enrolled 50 culture-confirmed Vibrio cholerae O1 cholera cases presenting to the icddr,b Dhaka hospital with moderate to severe dehydration. We evaluated antibody responses out to 18 months (day 540) following cholera. We assessed immune responses targeting sialidase, lipopolysaccharide (LPS), cholera toxin B subunit (CtxB), and vibriocidal responses. We also explored the association of sialidase-specific immune responses to nutritional parameters and parasitic co-infection of cases. This longitudinal cohort study showed age-dependent differences in anti-sialidase immune response after natural cholera infection. Adult patients developed plasma anti-sialidase IgA and IgG responses after acute infection (P<0.05), which gradually decreased from day 30 on. In children, no significant anti-sialidase IgA, IgM, and IgG response was seen with the exception of a late IgG response at study day 540 (p=0.05 compared to adults). There was a correlation between anti-sialidase IgA with vibriocidal titers, as well as anti-sialidase IgA and IgG with anti-LPS and anti-CtxB antibody responses in adult patients, whereas in children, a significant positive correlation was seen only between anti-sialidase IgA and CtxB IgA responses. Stunted children showed significantly lower anti-sialidase IgA, IgG, and IgM antibody responses and higher LPS IgG and IgM antibody responses than healthy children. The anti-sialidase IgA and IgG responses were significantly higher in cases with concomitant parasitic infection. Our data suggest that cholera patients develop age-distinct systemic and mucosal immune responses against sialidase. The stunted children have a lower anti-sialidase antibody response which may be associated with gut enteropathy and the neuraminidase plays an important role in augmented immune response in cholera patients infected with parasites.

Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia.

UCART19 is an "off-the-shelf" genome-edited anti-CD19 chimeric antigen receptor (CAR)-T cell product, manufactured from unrelated healthy donor cells. UCART19 was administered to 25 adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) in the CALM trial. All patients underwent lymphodepletion with fludarabine and cyclophosphamide ± alemtuzumab and received one of three ascending doses of UCART19. Given the allogeneic nature of UCART19, we analyzed the impact of lymphodepletion, HLA disparities, and host immune system reconstitution on its kinetics, along with other factors known to affect autologous CAR-T cell clinical pharmacology. Responder patients (12/25) had higher UCART19 expansion (C max) and exposure (AUCTlast) than nonresponders (13/25), as measured by transgene levels in peripheral blood. The persistence of CAR+ T cells did not exceed 28 days in 10/25 patients and lasted beyond 42 days in 4/25. No significant correlation was found between UCART19 kinetics and administered cell dose, patient and product characteristics or HLA disparities. However, the number of prior lines of therapy and absence of alemtuzumab negatively impacted UCART19 expansion and persistence. Alemtuzumab exposure positively affected IL7 and UCART19 kinetics, while negatively correlating with host T lymphocyte AUC0-28. UCART19 expansion is a driver of response in adult patients with R/R B-ALL. These results shed light on the factors associated with UCART19 kinetics, which remain highly affected by the impact of alemtuzumab on IL7 and host-versus-graft rejection. First description of the clinical pharmacology of a genome-edited allogeneic anti-CD19 CAR-T cell product showing the crucial role of an alemtuzumab-based regimen in sustaining UCART19 expansion and persistence through increased IL7 availability and decreased host T lymphocyte population.

Heterogeneity of neutrophils and inflammatory responses in patients with COVID-19 and healthy controls.

Severe respiratory viral infections, including SARS-CoV-2, have resulted in high mortality rates despite corticosteroids and other immunomodulatory therapies. Despite recognition of the pathogenic role of neutrophils, in-depth analyses of this cell population have been limited, due to technical challenges of working with neutrophils. We undertook an unbiased, detailed analysis of neutrophil responses in adult patients with COVID-19 and healthy controls, to determine whether distinct neutrophil phenotypes could be identified during infections compared to the healthy state. Single-cell RNA sequencing analysis of peripheral blood neutrophils from hospitalized patients with mild or severe COVID-19 disease and healthy controls revealed distinct mature neutrophil subpopulations, with relative proportions linked to disease severity. Disruption of predicted cell-cell interactions, activated oxidative phosphorylation genes, and downregulated antiviral and host defense pathway genes were observed in neutrophils obtained during severe compared to mild infections. Our findings suggest that during severe infections, there is a loss of normal regulatory neutrophil phenotypes seen in healthy subjects, coupled with the dropout of appropriate cellular interactions. Given that neutrophils are the most abundant circulating leukocytes with highly pathogenic potential, current immunotherapies for severe infections may be optimized by determining whether they aid in restoring an appropriate balance of neutrophil subpopulations.

Exploration of the induced cytokine responses in European Lyme neuroborreliosis: A longitudinal cohort study

Lyme neuroborreliosis (LNB) is a prevalent tick-borne disease in Europe caused by Borrelia burgdorferi sensu lato complex. Slightly suppressed induced Th1- and Th17-responses are seen at diagnosis. The induced immune response following antibiotic therapy is unknown. We hypothesized that the immune responses normalize after completing antibiotic treatment.An observational longitudinal cohort study investigating the induced immune response in adult patients with LNB at diagnosis, three and six months after treatment. Whole blood was added to three TruCulture® (Myriad RBM, Austin, USA) tubes each containing one stimulation. An additional TruCulture® tube was without stimulation representing the in vivo activation of blood immune cells. Nine cytokines were measured using Luminex (LX200, R&D Systems, BIO-Teche LTD). Changes in immune response were analyzed with linear mixed model including follow-up as categorical fixed effect.A total of 21 patients with 55 samples were included. All had clinical improvement, but 5/21 patients reported residual symptoms after six months. The non-induced release of IL-17A and IL-1β increased significantly from diagnosis to six month follow-up. Six months after treatment only IFN-α and TNF-α were below the reference range.Minor variations in the induced immune responses were seen during the study period. Th1- and Th17-responses continued to be low with low IFN-γ, IL-12p40, and IL-17A in multiple stimulations.Overall little dynamic was observed. The changes in the cytokine responses are most likely not linked to LNB pathogenesis and our results do not support the implementation of TruCulture® in the diagnostics or follow-up of LNB.

Efficacy of Dupilumab on Different Phenotypes of Adult with Moderate-to-Severe Atopic Dermatitis in Taiwan: A Real-World Study.

To determine phenotype-related dupilumab response in adult patients with atopic dermatitis (AD), this multicenter, retrospective study included 111 adults with moderate-to-severe AD in Taiwan, with median age of 31.5 years (18–87) and 71 (64.0%) males. Patients received dupilumab 300 mg per two to three weeks up to 12 months. We found a significant improvement after 4 and 16 weeks of treatment in all patients for all the assessed scores, including eczema area and severity index (EASI) improvement ≥50% (EASI-50) and 75% (EASI-75), EASI reaching minimal clinically important difference (MCID), and Investigator’s Global Assessment (IGA) improvement ≥2. Importantly, prior to asthma, early AD onset and 3-week drug intervals were significantly associated with a high proportion of EASI-75 at month 12, while prurigo and lichenoid phenotypes were associated with a lower proportion of EASI-75 at month 12. However, the majority of adverse events were mild in severity. In conclusion, our study results identify phenotype-related dupilumab response at month 12 in adults with moderate-to-severe AD, and we suggest that treatment should not be discontinued until reaching a satisfactory clinical response.

Amphiregulin/epidermal growth factor receptor/hypoxia-inducible factor-1α pathway regulates T helper 9 and T cytotoxic 9 cell response in adult patients with infectious mononucleosis.

Amphiregulin (AREG)/epidermal growth factor receptor (EGFR) signaling induces hypoxia-inducible factor-1α (HIF-1α), leading to promotion of T helper 9 (Th9) differentiation and anti-tumor functions. However, the role of the AREG/EGFR/HIF-1α pathway in regulating interleukin-9 (IL-9) production by T cells in adult patients with infectious mononucleosis (IM) has not been fully elucidated. Fifty IM patients and 20 controls were enrolled. The percentages of Th9 and T cytotoxic 9 (Tc9) cells, the mRNA relative expressions of the transcription factors of IL-9-secreting T cells, purine-rich nucleic acid binding protein 1 (PU.1) and forkhead box protein O1 (FOXO1), and the levels of IL-9, AREG, EGFR, and HIF-1α were measured. Peripheral blood mononuclear cells from IM patients were stimulated with EGFR inhibitor or exogenous AREG in the presence or absence of anti-HIF-1α. Regulation of the AREG/EGFR/HIF-1α pathway to IL-9 production by T cells was assessed. The percentages of Th9 and Tc9 cells, plasma IL-9 levels, and PU.1 and FOXO1 mRNA expressions were elevated in IM patients. Plasma levels of AREG and HIF-1α were also increased in IM patients. AREG levels correlated positively with the percentages of Th9 and Tc9 cells in IM patients. Inhibition of EGFR suppressed IL-9-producing T cell differentiation and HIF-1α production. Exogenous AREG stimulation not only induced EGFR and HIF-1α expression but also promoted IL-9-secreting T cell differentiation. Neutralization of HIF-1α abrogated AREG/EGFR-induced Th9 and Tc9 differentiation in IM patients. The current data suggested that the AREG/EGFR/HIF-1α pathway contributed to the elevation of Th9 and Tc9 differentiation in IM patients.

The first-in-class ERK inhibitor ulixertinib shows promising activity in mitogen-activated protein kinase (MAPK)-driven pediatric low-grade glioma models.

Pediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in the MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors. We investigated the antitumoral activity of ulixertinib monotherapy as well as in combination with MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy in pLGG. Patient-derived pLGG models reflecting the two most common alterations in the disease, KIAA1549:BRAF-fusion and BRAFV600E mutation (DKFZ-BT66 and BT40, respectively) were used for in vitro and in vivo (zebrafish embryos and mice) efficacy testing. Ulixertinib inhibited MAPK pathway activity in both models, and reduced cell viability in BT40 with clinically achievable concentrations in the low nanomolar range. Combination treatment of ulixertinib with MEKi or BH3-mimetics showed strong evidence of antiproliferative synergy in vitro. Ulixertinib showed on-target activity in all tested combinations. In vivo, sufficient penetrance of the drug into brain tumor tissue in concentrations above the in vitro IC50 and reduction of MAPK pathway activity was achieved. In a preclinical mouse trial, ulixertinib mono- and combined therapies slowed tumor growth and increased survival. These data indicate a high clinical potential of ulixertinib for the treatment of pLGG and strongly support its first clinical evaluation in pLGG as single agent and in combination therapy in a currently planned international phase I/II umbrella trial.

Immunogenicity induced by two and three doses of the BNT162b2 mRNA vaccine in patients with autoimmune inflammatory rheumatic diseases and immunocompetent controls: a longitudinal multicentre study

ObjectivesTo evaluate long-term kinetics of the BNT162b2 mRNA vaccine-induced immune response in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) and immunocompetent controls.MethodsA prospective multicentre study investigated serum anti-SARS-CoV-2 S1/S2...

Abstract 5221: The first-in-class ERK inhibitor ulixertinib (BVD-523) shows activity in MAPK-driven pediatric low-grade glioma models as single agent and in combination with MEK inhibitors or senolytics

Abstract Ulixertinib (BVD-523) is a well-tolerated, orally delivered, catalytic ERK1/2 inhibitor, which has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors. Pediatric low grade gliomas (pLGGs) are the most common pediatric brain tumors, with the most frequent driving alterations (KIAA:BRAF fusion, BRAF V600E mutation) occurring in the MAPK pathway. To investigate the anti-tumoral activity of ulixertinib in pLGG, cell lines recapitulating both main MAPK alterations were used: DKFZ-BT66 (pilocytic astrocytoma; KIAA:BRAF fusion) and BT40 (pleomorphic xanthoastrocytoma; BRAF V600E mutation and CDKN2A/B deletion). The potential synergism of combinations with MEK inhibitors, senolytics, and chemotherapy was investigated in vitro using metabolic activity and MAPK activity assays. The most promising combinations were validated in vitro by analysis of viable, dead, and apoptotic cells through high-content microscopy. The most clinically relevant combinations were further validated in vivo: 1) in two zebrafish embryo models (respectively, BT40 and DKFZ-BT66 yolk sac injection) and 2) in NSG mice (BT40 orthotopic PDX) including in vivo pharmacokinetic and -dynamic analyses. Our data demonstrate ulixertinib’s ability to inhibit MAPK pathway activity in all used models. Ulixertinib treatment reduced cell viability in the BRAF V600E mutated cell line at a remarkably low concentration of 62.7 nM (compared to other cell lines’ IC50 from the Genomics of Drug Sensitivity in Cancer database). In vivo pharmacokinetic and -dynamic analyses showed good penetrance of the drug into mouse brain tissue, with concentrations above the in vitro IC50 and reduction of MAPK activity as assessed by Western blot. Furthermore, ulixertinib treatment slowed tumor growth and significantly increased survival in NSG mice with orthotopic BT40 xenografts. Ulixertinib showed indications for anti-proliferative synergy in vitro, according to the Loewe and Bliss independence models, in combination with MEK inhibitors (trametinib, binimetinib) or senolytics (navitoclax, A1331852). Combinations with chemotherapy (carboplatin, vinblastine) were at most additive. Indications for synergy with binimetinib and navitoclax were confirmed in the zebrafish embryo xenograft models for both MAPK-altered backgrounds. The combination of ulixertinib with navitoclax was further investigated in the BT40 PDX mouse model, where tumor growth and survival were comparable to ulixertinib monotherapy. In conclusion, our data indicate a strong potential for ulixertinib as a clinically relevant therapeutic option for the treatment of pLGG to be further investigated in upcoming clinical trials. Potential synergism with MEK inhibitors and senolytics was noted and warrants further investigation. Citation Format: Romain Sigaud, Lisa Rösch, Charlotte Gatzweiler, Julia Benzel, Laura von Soosten, Heike Peterziel, Sara Najafi, Simay Ayhan, Nina Hofmann, Kathrin I. Förster, Jürgen Burhenne, Rémi Longuespée, Cornelis M. van Tilburg, David T. Jones, Stefan M. Pfister, Deborah Knoerzer, Brent Kreider, Max Sauter, Kristian W. Pajtler, Marc Zuckermann, Ina Oehme, Olaf Witt, Till Milde. The first-in-class ERK inhibitor ulixertinib (BVD-523) shows activity in MAPK-driven pediatric low-grade glioma models as single agent and in combination with MEK inhibitors or senolytics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5221.