AM Patients Research Articles

Landscapes of gut microbiome and blood metabolomic signatures in relapsing remitting multiple sclerosis.

Although disturbances in the gut microbiome have been implicated in multiple sclerosis (MS), little is known about the changes and interactions between the gut microbiome and blood metabolome, and how these changes affect disease-modifying therapy (DMT) in preventing the progression of MS. In this study, the structure and composition of the gut microbiota were evaluated using 16S rRNA gene sequencing and an untargeted metabolomics approach was used to compare the serum metabolite profiles from patients with relapsing-remitting MS (RRMS) and healthy controls (HCs). Results indicated that RRMS was characterized by phase-dependent α-phylogenetic diversity and significant disturbances in serum glycerophospholipid metabolism. Notably, α-phylogenetic diversity was significantly decreased in RRMS patients during the chronic phase (CMS) compared with those in the acute phase (AMS). A distinctive combination of two elevated genera (Slackia, Lactobacillus) and five glycerophospholipid metabolism-associated metabolites (four increased: GPCho(22:5/20:3), PC(18:2(9Z,12Z)/16:0), PE(16:0/18:2(9Z,12Z)), PE(18:1(11Z)/18:2(9Z,12Z)); one decreased: PS(15:0/22:1(13Z))) in RRMS patients when comparing to HCs. Moreover, a biomarker panel consisting of four microbial genera (three decreased: Lysinibacillus, Parabacteroides, UBA1819; one increased: Lachnoanaerobaculum) and two glycerophospholipid metabolism-associated metabolites (one increased: PE(P-16:0/22:6); one decreased: CL(i-12:0/i-16:0/i-17:0/i-12:0)) effectively discriminated CMS patients from AMS patients, which indicate correlation with higher disability. Additionally, DMTs appeared to attenuate MS progression by reducing UBA1819 and upregulating CL(i-12:0/i-16:0/i-17:0/i-12:0). These findings expand our understanding of the microbiome and metabolome roles in RRMS and may contribute to identifying novel diagnostic biomarkers and promising therapeutic targets.

Evaluating TAB2, IKBKB, and IKBKG Gene Polymorphisms and Serum Protein Levels and Their Association with Age-Related Macular Degeneration and Its Treatment Efficiency.

Background and Objectives: Age-related macular degeneration (AMD) is the leading cause of blindness, affecting millions worldwide. Its pathogenesis involves the death of the retinal pigment epithelium (RPE), followed by photoreceptor degeneration. Although AMD is multifactorial, various genetic markers are strongly associated with the disease and may serve as biomarkers for evaluating treatment efficacy. This study investigates TAB2 rs237025, IKBKB rs13278372, and IKBKG rs2472395 variants and their respective serum protein concentrations in relation to AMD occurrence and exudative AMD treatment response to anti-VEGF treatment. Materials and Methods: The case-control study involved 961 individuals, and they were divided into three groups: control, early AMD, and exudative AM patients. Genotyping of selected SNPs were conducted using a real-time polymerase chain reaction method (RT-PCR). Based on the clinical OCT and BCVA data, patients with exudative AMD were categorized into one of two groups: responders and non-responders. The data obtained were analyzed using the "IBM SPSS Statistics 29.0" software program. Results: Our study revealed that TAB2 rs237025 allele A was identified as a risk factor for early and exudative AMD development. The same associations remained only in females with exudative AMD but not in males, suggesting gender-specific pathogenetic pathways in exudative AMD. Analysis of IKBKB rs13278372 or serum IKBKB protein associations with early or exudative AMD occurrence in the Lithuanian population revealed no significant associations. On the other hand, we found that each A allele of IKBKB rs13278372 was associated with a worse response to anti-VEGF treatment (OR = 0.347; 95% CI: 0.145-0.961; p = 0.041). These results suggest a potential marker for future studies evaluating anti-VEGF treatment for exudative AMD patients. IKBKG rs2472395 was a protective variant for early AMD in males and for exudative AMD in females only. Also, IKBKG protein concentration was lower in exudative AMD relative to the control group (median (IQR): 0.442 (0.152) vs. 0.538 (0.337), p = 0.015). Moreover, exudative AMD patients who carry the GG genotype of IKBKG rs2472394 exhibited significantly reduced serum IKBKG concentrations compared to the controls (median (IQR): 0.434 (0.199) vs. 0.603 (0.335), p = 0.012), leading to the hypothesis that the IKBKG rs2472394 variant might play a role in protein concentration differences and exudative AMD development. Conclusions: Our study identified the TAB2 rs237025 allele A as a significant risk factor for both early and exudative AMD, with gender-specific associations observed in females with exudative AMD, suggesting distinct pathogenetic pathways. While IKBKB rs13278372 and serum IKBKB protein levels showed no significant association with AMD development, the A allele of IKBKB rs13278372 was associated with a worse response to anti-VEGF treatment, indicating its potential as a marker for treatment outcomes. Additionally, the IKBKG rs2472395 variant was found to be protective for early AMD in males and exudative AMD in females, and lower IKBKG protein levels were associated with exudative AMD, particularly in patients with the GG genotype of IKBKG rs2472394, suggesting its role in protein concentration and disease progression. These findings highlight genetic markers that may contribute to AMD pathogenesis and treatment response.

Impact of the COVID-19 pandemic on care-quality outcomes in older adults admitted to hospital with altered mental status.

During the coronavirus disease (COVID-19) pandemic, patients with altered mental status (AMS: dementia, delirium and delirium superimposed on dementia) were profoundly affected by an abrupt transformation in healthcare systems. Here, we evaluated quality-care outcomes, including length of stay (LOS), in-hospital mortality, early readmission and mortality after hospital discharge, in older adults admitted for AMS during the pandemic and compared them to patients admitted prior to the pandemic. Chi-squared and Fisher's exact tests were used to examine changes to admissions for AMS before and during the pandemic, and their outcomes. Logistic regression analyses, with reference to pre-pandemic data, were conducted to examine the impact of the pandemic on outcomes. Prospective data of 21,192 non-COVID admissions to an acute general medical department in a Surrey (UK) hospital were collected from patients admitted before (1st April 2019 to 29th February 2020) and during the pandemic (1st March 2020 to 31st March 2021). There were 10,173 (47.7% men) from the pre-pandemic and 11,019 (47.5% men) from the pandemic periods; overall mean age = 68.3yr. During the pandemic AMS patients had significantly higher admission rates (1.1% vs 0.6%, P < 0.001). However, median LOS in hospital was shorter (9.0 days [IQR=5.3-16.2] vs 15.5 days [IQR = 6.2-25.7], P < 0.001) and thus were less likely to stay in hospital >3 weeks: adjusted OR = 0.26 (95%CI = 0.12-0.57). In-hospital mortality and readmission within 28 days of discharge did not change during the pandemic, but were less likely to die within 30 days of discharge: adjusted OR=0.32 (95%CI=0.11-0.96). This combination of higher admission rate, shorter LOS, and an unchanging early readmission suggests a higher admission-discharge turnover of different patients with AMS and provides important insights into the potential impact of the COVID-19 pandemic on healthcare delivery to individuals with AMS.

Immune phenotype profiling based on anatomic origin of melanoma and impact on clinical outcomes of immune checkpoint inhibitor treatment.

9569 Background: The inflamed immune phenotype is associated with a favorable response to immunotherapy in metastatic malignant melanoma. Although variations in molecular features across melanoma subtypes and differing ethnic distributions have been well reported, studies investigating immune phenotypes across multiple institutions within the context of different melanoma subtypes are scarce. We examined the association of immune phenotypes with outcomes after immunotherapy, based on subtypes of malignant melanoma. Methods: Two institutional advanced melanoma cohortsrepresenting Asian and Western populations (YUHS, n = 123; Stanford University, n = 102) were included. H&amp;E-stained tumor slides were assessed using Lunit SCOPE IO, an AI-powered whole slide image analyzer, to define the inflamed score (IS, % of inflamed area) and the inflamed phenotype (&gt;33.3% IS). Clinical outcomes after immune checkpoint inhibitor (anti-PD-1/PD-L1) treatment, including progression-free survival (PFS) and overall-survival (OS), were assessed. Results: In the overall cohort (n = 225), the inflamed phenotype was associated with prolonged PFS (HR = 0.634, 95% CI: 0.453 – 0.887, p = 0.007) and OS (HR = 0.655, 95% CI: 0.432 – 0.992, p = 0.044). On analysis of melanoma subtypes, we identified non-acral cutaneous melanomas (CM, n = 94), acral melanomas (AM, n = 52), mucosal melanomas (n = 43), uveal melanomas (n = 16), and melanomas of unknown primary site (n = 20), with a disproportionate enrichment of AM (37.4%) and mucosal (29.3%) melanoma cases in the YUHS cohort and CM cases (68.6%) in the Stanford cohort. The IS varied across different melanoma subtypes, with the highest IS observed in CM (median, [IQR]; 34.0, [5.8–52.2]), and significantly lower scores in AM (22.3, [7.7–36.9]), mucosal (13.6, [0–31.4]), and uveal melanoma (5.5, [0–13.6]). Among CM patients, the inflamed phenotype was significantly associated with better post-immunotherapy PFS (HR = 0.476, 95% CI: 0.274 – 0.826, p = 0.007). In contrast, the inflamed phenotype did not correlate with survival in AM patients (p = 0.58), who exhibited universally poorer PFS compared to non-AM patients (HR = 2.124, 95% CI: 1.486 - 3.005). Conclusions: AI-powered immune phenotype assessment highlights a heterogeneity of immune phenotypes across specific melanoma subtypes, as well as differential association with outcomes after immune checkpoint inhibitor treatment. While CM patients were well-stratified by immune phenotype, the predictive value of immune phenotyping was less pronounced in acral melanomas, which demonstrated poorer outcomes following immunotherapy.

Occurrence and Prognosis of Mixed Subtype Adenocarcinoma and Adeno-Squamous Carcinoma in Esophageal Cancer.

Purpose: To gain a deeper understanding of the incidence and survival rates of rare esophageal mixed adenoacanthoma (EAM) and esophageal mixed adeno-squamous carcinoma (EASC) to promote a more comprehensive understanding of these two subtypes. Background: EAM and EASC are rare subtypes of esophageal cancer with limited literature available. Extensive research has been conducted on the clinical and pathological characteristics of gastric and colorectal mixed adenoacanthomas, but there is relatively little literature on esophageal mixed adenoacanthomas. Therefore, this study aims to investigate the incidence and survival rates of these two subtypes in depth. Methods: Patients diagnosed with EAM and EASC between 2000 and 2019 were selected from the SEER database for the study. Joinpoint software was used to calculate the incidence rates of esophageal AM and ASC patients, and differences in cancer overall survival (OS) and cancer-specific survival (CSS) based on Kaplan-Meier curves were compared. Multivariate Cox regression analysis was employed to identify independent prognostic factors for OS and CSS, and a prognostic model was established and validated for accuracy. Results: The study found that the incidence of EAM increased until 2014, followed by a decline, while the incidence of EASC decreased until 2017, followed by an increase. Both of these subtypes were more common in male patients and those over the age of 65. For EAM patients, preoperative chemoradiotherapy was associated with better survival rates, while for EASC patients, preoperative radiotherapy combined with adjuvant chemotherapy improved survival. Finally, we constructed nomograms for predicting the overall survival of EAM and EASC patients by incorporating identified risk factors, which demonstrated good sensitivity and specificity. Conclusion: EAM and EASC are rare subtypes of esophageal cancer, and an in-depth exploration of their incidence and survival rates provides valuable data and insights for understanding these rare esophageal cancer subtypes. This information can assist clinical decision-making for healthcare professionals.

Abstract A035: Comparing the clinical and genomic landscapes of acral, mucosal, and cutaneous metastatic melanomas treated with immune checkpoint inhibitors

Abstract Background: Melanoma is a melanocytic malignancy that is classified into different subtypes, including cutaneous (CM), acral (AM), and mucosal melanoma (MM). Immune checkpoint inhibitors (ICI) targeting PD-1 and/or CTLA-4 have emerged as the standard of care for advanced metastatic melanoma. We investigated responses to ICIs, genomic profiles, and molecular differences among these different subtypes of melanoma. Methods: We performed a multi-center retrospective cohort study including patients with metastatic melanoma who received anti-PD1 +/- CTLA4 inhibitor ICI for metastatic disease. We employed the AACR GENIE (v13.1) cancer database, DepMap portal, and Enrichr web tool with MSigDB Hallmark 2020 database to analyze the incidence and distribution of significant alterations, differentially expressed genes, and pathway enrichment within distinct melanoma subtypes. Results: We identified 337 patients with advanced melanoma who received anti-PD1 +/- anti-CTLA4 for metastatic disease. CM was the most frequent melanoma subtype (81%), followed by MM (12%), and AM (8%). Patients with AM had the shortest OS and PFS CM (OS 3.4 years, PFS of 1.1 years), AM median (OS 1.4 years, PFS 3.8 months), and MM (OS 1.7 years, PFS 6 months; OS, P= 0.028; PFS P=0.029). Patients with CM or MM experienced longer OS with anti-PD1 +/- CTLA4 vs. anti-PD1 monotherapy, but no survival advantage was observed in patients with AM. In the GENIE dataset, we identified 2015/374/177 samples with CM/MM/AM, respectively. AM and MM patients were significantly more likely to be Female, Black or Asian than CM patients. BRAF V600 mutations were most frequent in CM (40%), followed by MM (7%) and AM (14%). However, MM and AM had an increase in alterations in cell cycle regulator genes. The incidence of CDK4 and CCND1 amplification, respectively was highest in AM (17%, 16%), followed by MM (6%, 6%) and CM (2%, 3%). We compared the pathways represented by differentially altered genes in AM vs. CM: G2M-Checkpoint (Q&amp;lt;0.05) and E2F targets (Q&amp;lt;0.05) pathways were enriched in AM. We also compared RNAseq data from n=4) AM and n=20 CM cell lines, and found the same pathways enriched amongst genes that were differentially expressed between AM and CM: G2M-Checkpoint (Q&amp;lt;0.01) and E2F targets (Q&amp;lt;0.01) Conclusions: Our findings highlight comparatively poor outcomes with ICIs in Acral Melanoma. AM has lower rates of actionable BRAF mutations; as such, very few patients with metastatic AM have access to effective 1st or 2nd line therapies. Thus, there is an urgent need to explore alternative therapeutic targets. Our data implicate cell cycle inhibitors as potentially important components of novel treatment strategies that could augment immunotherapy efficacy for patients with metastatic AM. Citation Format: Sadaf Solati, April A. N. Rose, Anna Spreafico, Adrian Sacher, Denis Yahiaoui, Wilson H. Miller. Comparing the clinical and genomic landscapes of acral, mucosal, and cutaneous metastatic melanomas treated with immune checkpoint inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A035.

Kappa free light chains index in multiple sclerosis very long-term prognosis.

The role of the kappa-free light chain (kFLC) in the diagnosis of multiple sclerosis (MS) and, to a lesser extent, its role as a medium-term prognostic marker have been extensively studied. This study aimed to explore its potential as a long-term prognostic marker for MS. We performed an exploratory retrospective observational study by selecting patients systemically followed up in our MS unit with available cerebrospinal fluid and serum samples at the time of initial evaluation. Two groups were defined: benign MS (bMS), defined as patients with Expanded Disability Status Scale (EDSS) ≤ 3 at 10 years of follow-up, and aggressive MS (aMS), defined as patients with EDSS ≥ 6 at 15 years of follow-up. Clinical variables were collected, and the immunoglobulin G (IgG) index, kFLC index, and oligoclonal bands (OCB) were determined for all patients and compared between the groups. Twenty bMS and 15 aMS patients were included in this study. Sixty percent (21/35) were female, and the mean age at the time of the first symptom was 31.5 ± 9.45 years, with no statistical differences between groups. Median follow-up time was 19.8 years (Interquartile range, IQR 15.9-24.6). The median EDSS scores at the last follow-up were 1.5 and 7.5 in the bMS and the aMS group, respectively. No statistically significant differences were found in the kFLC index between the two groups (136.6 vs. 140.27, p=0.59). The IgG index was positive in 62.9% of patients (55% bMS vs. 73.3% aMS, p>0.05), and OCB was positive in 88.6% (90% bMS vs. 86.7% aMS, p>0.05). A significant positive correlation was found between IgG and kFLC indices (rs = 0.85, p<0.001). Given the absence of differences between the two groups with opposite disease courses, it is unlikely that the kFLC index is a reliable and powerful marker of long-term prognosis in MS.

Prognostic value of genetic aberrations and tumor immune microenvironment in primary acral melanoma

BackgroundAcral melanoma (AM) is the most common subtype in Chinese melanoma patients with a very poor prognosis. However, our understanding of the disease pathogenesis and molecular landscape is limited by the few studies that have been conducted. Here, we profiled the clinical characteristics, mutational landscapes and tumor immune microenvironment of AM patients to gain insights into disease characteristics and potential treatment strategies.MethodsA total of 90 AM patients were enrolled and their tissue samples were subjected to next-generation sequencing and multiplexed immunohistochemistry tests. Kaplan–Meier curves and log-rank tests were used to analyze the prognostic potential of various genetic aberrations and immune cell compositions in AM.ResultsThe median disease-free survival was 21.3 months and estimated median overall survival (OS) was 60 months. More advanced stages, older ages and thickness of greater than 4 mm were associated with worse prognosis in AM patients (HR = 2.57, 95% CI 1.25–5.29, p = 0.01; HR = 2.77, 95% CI 1.22–6.28, p = 0.02; HR = 3.43, 95% CI 1.51–7.82, p < 0.01, respectively), while patients who received post-surgical treatments had better survival (HR = 0.36, 95% CI 0.17–0.76, p = 0.01). The most frequently altered genes included BRAF (14.5%), KIT (16.9%), NRAS (12%), NF1 (10.8%), APC (7.2%), and ARID2 (6%). Copy number variations (CNV) were commonly found in CCND1 (19.3%), CDK4 (19.3%), MDM2 (14.5%) and FGF19 (12%). CDK4 amplifications was independently associated with shorter OS in AM patients (HR = 3.61, 95% CI 1.38–9.46, p = 0.01). CD8 + T cells (p < 0.001) and M1 macrophages (p = 0.05) were more highly enriched in the invasive margin than in the tumor center. Patients with higher levels of M1 macrophage infiltration in the invasive margin derived markedly longer OS (HR = 0.43, 95% CI 0.20–0.95, p = 0.03). Interestingly, in CDK4-amplified patients, there tended to be a low level of M1 macrophage infiltration in the invasive margin (p = 0.06), which likely explains the poor prognosis in such patients.ConclusionsOur study provided a comprehensive portrait of the clinicopathological features, genetic aberrations and tumor microenvironment profiles in AM patients and identified candidate prognostic factors, which may facilitate development of additional therapeutic options and better inform clinical management of AM patients. Based on these prognostic factors, further studies should focus on enhancing the infiltration of M1 macrophages, especially in CDK4-amplified AM patients.

P01.03.B A quantitative comparison of cognitive performance and patient-reported symptoms in preoperative lower-grade glioma patients from two Dutch Hospitals

Abstract Background Protocols for assessment of (neuro)psychological outcomes in lower-grade glioma patients vary between hospitals. This potentially complicates generalization of these outcomes. We compared standardized scores on tests of two frequently impaired cognitive domains (attention and executive functioning (EF)), and two relevant patient-reported outcomes (PROs; depression and fatigue) of two neuro-oncological hospitals that use different measurement instruments. Material and Methods Data were used from preoperative assessments of patients with (IDH-mut) WHO grade II/III glioma tested between 2007 and 2021 at Amsterdam UMC (AMS) or at Elisabeth-Tweesteden Hospital Tilburg (ETZ). AMS patients were referred for (neuro)psychological assessment based on physician and patient preference (paper and pencil tests), whereas all ETZ patients routinely undergo screening (computerized tests). To compare scores of the different attention and EF tests we converted patients’ performances to z-scores based on normative data. For cognitive performance, we compared scores of different cognitive flexibility tests (CST vs SAT), processing speed tests (SDC vs LDMT), and Stroop tests (Stroop I and Stroop III). PROs included the CES-D vs HADS-D and the CIS-fatigue vs MVI-general fatigue (AMS vs ETZ, resp.). Differences were tested using Fisher's, χ 2, and Mann-Whitney U tests. Results Assessments were done median 4 weeks (AMS, n=97, range 19-0 weeks) and 1 day (ETZ, n=106; range 14-0 days) preoperatively. Age, sex, tumor location and histology were comparable between cohorts (p&amp;gt;0.05), but the AMS cohort showed significantly more grade III tumors (36% vs 16%) and more awake surgeries (84% vs 46%). Z-scores measuring attention and EF (n=94 and n=95, AMS vs ETZ) were not significantly different (CST vs SAT, percentage with a disorder (z &amp;lt;-1.5SD) 15% vs 13%; SDC vs LDMT 13% vs 14%; Stroop I 11% vs 18%; Stroop III 13% vs 16% at AMS and ETZ, resp.). Percentages of patients with possible depression (CES-D≥16, n=88 and HADS-D≥8, n=106) did not differ significantly between hospitals (28% vs 26%), nor did percentages of patients with severe fatigue (CIS-fatigue≥35, n=88 and MVI-general fatigue (z &amp;lt;-1.5SD), n=38, 42% vs 24% at AMS and ETZ, resp.). Conclusion Standardized scores of glioma patients on cognitive domains (attention and EF) and PROs (depression and fatigue) did not differ between two centers with slightly different samples using different testing protocols. This cautiously suggests that study findings on cognitive functioning and symptoms could be generalized. For research purposes, conjoint use of pooled populations for outcome evaluation could be explored with different samples from other centers using different instruments.

Les enjeux de la transition dans l’anorexie mentale vus par les professionnels : une étude qualitative

IntroductionAnorexia nervosa (AN) is an eating disorder (ED) that emerges during adolescence and may be lasting several years, or even becoming chronic. For these patients, the transition to adult care is a period of high risk of instability, relapse, symptomatic re-aggravation and increased development of co-morbidities or eventually leading to care drop-out or medical nomadism. Professionals involved in the transition process with AN patients are often challenged with various difficulties, and confronted with the need to plan this care stage. This study sought to understand the pediatricians and (child) psychiatrists experience of this transition step and to identify national practices around the transition process for adolescents and young adults with anorexia nervosa. MethodA qualitative study was carried out on the basis of thirteen recorded individual interviews with physicians specialised in eating disorders working in hospital adolescent medicine units or in adult medicine units. The methodology used was IPA (Interpretative Phenomenological Analysis). ResultsVarious difficulties and obstacles to a successful transition emerged as well as perspectives to improve the transition to adulthood care: early identification of the target population, choice of the most adapted unit to the severity level of the disease, family support during the transition, identification of a coordinating physician and enhanced networking support. The opportunity of a transition program is discussed among physicians, who are consistent on the need for guidelines. ConclusionThis qualitative study allowed us to highlight the difficulties of specialized professionals faced to the transition period with AM patients but also to consider the need for specific tools and guidelines to promote continuity to adulthood care.

Assessing the Significance of the Circadian Time of Administration on the Effectiveness and Tolerability of OnabotulinumtoxinA for Chronic Migraine Prophylaxis.

We aimed to provide insights on the role of the circadian time of administration in influencing the efficacy and tolerability/safety profile of OnabotulinumtoxinA (BoNTA) for chronic migraine (CM) prophylaxis. Methods: We retrospectively reviewed the medical files of BoNTA-naïve patients with CM who completed three consecutive cycles of treatment, according to the standard PREEMPT paradigm. Participants were classified to those scheduled to be treated in the morning hours from 8:00 to 12:00 (AM) or afternoon hours from 13:00 to 18:00 (PM). We then assessed and compared between groups the changes from baseline (T0—trimester before BoNTA’s first administration) to the period after its third administration (T3) in the following efficacy outcomes: (i) mean number of headache days/month, (ii) mean number of days/month with peak headache intensity of >4/10, (iii) mean number of days/month with consumption of any abortive treatment. Safety–tolerability was also compared between groups. Results: A total of 50 AM and 50 PM-treated patients were evaluated. The within-group analysis in both groups showed a significant decrease in all efficacy variables between T0 and T3. However, the between-group comparisons of all BoNTA-related efficacy outcomes at T3 vs. T0 documented comparable improvements between AM vs. PM-treated patients. Safety/tolerability was also similar between groups. Conclusions: We were not able to identify significant differences between patients treated in the AM vs. PM, so as to demonstrate that the circadian time of administration should be considered before initiating BoNTA in CM patients.

A randomized feasibility study evaluating temozolomide circadian medicine in patients with glioma.

Gliomas are the most common primary brain tumor in adults. Current treatments involve surgery, radiation, and temozolomide (TMZ) chemotherapy; however, prognosis remains poor and new approaches are required. Circadian medicine aims to maximize treatment efficacy and/or minimize toxicity by timed delivery of medications in accordance with the daily rhythms of the patient. We published a retrospective study showing greater anti-tumor efficacy for the morning, relative to the evening, administration of TMZ in patients with glioblastoma. We conducted this prospective randomized trial to determine the feasibility, and potential clinical impact, of TMZ chronotherapy in patients with gliomas (NCT02781792). Adult patients with gliomas (WHO grade II-IV) were enrolled prior to initiation of monthly TMZ therapy and were randomized to receive TMZ either in the morning (AM) before 10 am or in the evening (PM) after 8 pm. Pill diaries were recorded to measure compliance and FACT-Br quality of life (QoL) surveys were completed throughout treatment. Study compliance, adverse events (AE), and overall survival were compared between the two arms. A total of 35 evaluable patients, including 21 with GBM, were analyzed (18 AM patients and 17 PM patients). Compliance data demonstrated the feasibility of timed TMZ dosing. There were no significant differences in AEs, QoL, or survival between the arms. Chronotherapy with TMZ is feasible. A larger study is needed to validate the effect of chronotherapy on clinical efficacy.

Hysterectomy Outcomes Associated with Surgical Time-of-Day

<h3>Study Objective</h3> Literature from various surgical specialties has demonstrated that procedural start time is associated with operative outcomes. Herein, we sought to examine these diurnal associations in benign hysterectomy cases. <h3>Design</h3> Retrospective cohort analysis. <h3>Setting</h3> Five hospital healthcare system. <h3>Patients or Participants</h3> Women undergoing hysterectomy for benign indications from 7/1/2014 to 2/28/2019. <h3>Interventions</h3> Patients were stratified into two cohorts based on time entering the operating room: AM (before noon) and PM (after noon) groups. Demographic, clinical, and perioperative characteristics were collected. We evaluated post-operative outcomes including estimated blood loss (EBL), length of stay (LOS), and adverse perioperative events (blood transfusion, organ injury, conversion to laparotomy, cuff dehiscence, surgical site infection, readmission, reoperation, and death). Additionally, we assessed hospital costs. Statistical analysis included descriptive statistics, t-tests, and multivariate regression models. <h3>Measurements and Main Results</h3> Study included 2894 patients, 1910 AM patients and 984 PM patients. EBL was significantly higher in the PM start time group (mean AM: 181 mL vs mean PM: 218 mL, p<.001) whereas same-day discharge was more prevalent in the AM start time group (24.4% vs 12.5%). Multivariate regression models were constructed to evaluate for possible confounding variables: year, age, BMI, race, comorbidities, uterine size, surgical indication, and surgeon subspecialty. These models continued to show significantly increased EBL and LOS in the PM group. There was no association with operative times or adverse perioperative events. Regarding cost, AM start time was associated with increased hospital costs (median AM: $14,055, median PM: $11,725). Multivariate regression models also demonstrated these findings. <h3>Conclusion</h3> Our data suggests surgical outcomes can be associated with surgical time-of-day. While the underlying mechanism remains unclear, utilization of this information can help with surgical planning to personalize risk reduction and increase same-day discharge. Further analysis is underway to elucidate the time-of-day cost discrepancies.

Aggressive multiple sclerosis in Argentina: Data from the nationwide registry RelevarEM

The objectives of the present study were to describe the frequency of aggressive multiple sclerosis (aMS) as well as to compare clinical and radiological characteristics in aMS and non-aMS patients included in RelevarEM (NCT 03375177). MethodsThe eligible study population and cohort selection included adult-onset patients (≥18 years) with definite MS. AMS were defined as those reaching confirmed EDSS ≥ 6 within 5 years from symptom onset. Confirmation was achieved when a subsequent EDSS ≥ 6 was recorded at least six months later but within 5 years of the first clinical presentation. AMS and non-aMS were compared using the χ2 test for categorical and the Mann-Whitney for continuous variables at MS onset and multivariable analysis was performed using forward stepwise logistic regression with baseline characteristics at disease onset. ResultsA total of 2158 patients with MS were included: 74 aMS and 2084 non-aMS. The prevalence of aMS in our cohort was 3.4% (95%CI 2.7–4.2). AMS were more likely to be male (p = 0.003), older at MS onset (p < 0.001), have primary progressive MS (PPMS) phenotype (p = 0.03), multifocal presentation (p < 0.001), and spinal cord as well as infratentorial lesions at MRI during disease onset (p = 0.004 and p = 0.002, respectively). Conclusion3.4% of our patient population could be considered aMS. Men, patients older at symptom onset, multifocal presentation, PPMS phenotype, and spinal cord as well as brainstem lesions on MRI at clinical presentation all had higher odds of having aMS.

Meta-analysis of adjuvant radiotherapy for intracranial atypical and malignant meningiomas.

Meningiomas comprise 33% of all CNS tumors. The World Health Organization (WHO) describes meningiomas as benign (BM), atypical (AM), and malignant/anaplastic (MM). High-grade meningiomas such as AMs and MMs are more aggressive, recur more frequently, and portend a worse prognosis than BMs. Currently, the standard treatment for high-grade meningiomas, especially AMs, is ill-defined. In particular, the benefit to survival outcomes of adjuvant radiotherapy post-surgical resection remains unclear. In this study, we investigated the effect of adjuvant radiotherapy (ART) post-surgery on survival outcomes compared to surgery alone for high-grade meningiomas. PRISMA guidelines were a foundation for our literature review. We screened the PubMed database for studies reporting overall survival (OS), progression free survival (PFS), and tumor recurrence for intracranial, primary AM and MMs treated with surgery+ART or surgery alone. Fixed and random effect models compared tumor control rate for AM aforementioned groups. Mean 5-year PFS was 76.9% for AM (surgery+ART) and 55.9% for AM (surgery alone) patients. Mean 5-year OS was 81.3% and 74% for AM (surgery+ART) and AM (surgery alone) groups, respectively. Overall, the mean 5-year PFS for aggregated high-grade meningiomas AM+MM (surgery+ART) was 67.6%. Fixed effect models revealed tumor control rate as 76% for AM (surgery+ART) and 69% for AM (surgery alone) groups. ART induced toxicity incidence ranged from 12.0% to 35.5% for AM and MM patients. Our analysis suggests that (surgery+ART) may increase PFS, OS, and tumor control rates in high-grade meningiomas. However, further studies involving surgery+ ART should be conducted to fully evaluate the ideal radiosurgical candidate, modality, and dosage.

Temozolomide chronotherapy in patients with glioblastoma: a retrospective single-institute study.

BackgroundChronotherapy is an innovative approach to improving survival through timed delivery of anti-cancer treatments according to patient daily rhythms. Temozolomide (TMZ) is a standard-of-care chemotherapeutic agent for glioblastoma (GBM). Whether timing of TMZ administration affects GBM patient outcome has not previously been studied. We sought to evaluate maintenance TMZ chronotherapy on GBM patient survival.MethodsThis retrospective study reviewed patients with newly diagnosed GBM from January 1, 2010 to December 31, 2018 at Washington University School of Medicine who had surgery, chemoradiation, and were prescribed TMZ to be taken in the morning or evening. The Kaplan–Meier method and Cox regression model were used for overall survival (OS) analyses. The propensity score method accounted for potential observational study biases. The restricted mean survival time (RMST) method was performed where the proportional hazard assumption was violated.ResultsWe analyzed 166 eligible GBM patients with a median follow-up of 5.07 years. Patients taking morning TMZ exhibited longer OS compared to evening (median OS, 95% confidence interval [CI] = 1.43, 1.12–1.92 vs 1.13, 0.84–1.58 years) with a significant year 1 RMST difference (−0.09, 95% CI: −0.16 to −0.018). Among MGMT-methylated patients, median OS was 6 months longer for AM patients with significant RMST differences at years 1 (−0.13, 95% CI = −0.24 to −0.019) to 2.5 (−0.43, 95% CI = −0.84 to −0.028). Superiority of morning TMZ at years 1, 2, and 5 (all P < .05) among all patients was supported by RMST difference regression after adjusting for confounders.ConclusionsOur study presents preliminary evidence for the benefit of TMZ chronotherapy to GBM patient survival. This impact is more pronounced in MGMT-methylated patients.

Effectiveness of preventive onabotulinumtoxin A injections for migraine headaches is dependent on the circadian time of administration

ABSTRACT We have previously shown that quarterly preventive onabotulinumtoxin A (BTA) injections administered to diurnally active patients for chronic migraines (CM) associate with increased discomfort when performed in the morning. The purpose of this study was to further examine if the effectiveness of preventive BTA injections depends on the procedure’s circadian timing. A total of 90 diurnally active patients with a medical history of CM and undergoing BTA injection therapy were enrolled in the study. One hundred and fifty-five units of BTA were administered according to the standardized PREEMPT protocol, either during the course of morning (AM) or afternoon (PM) clinic hours. Patients were asked to keep headache diaries, which were reviewed at the time of their follow-up BTA injections 3 months later. The number of headache days experienced during the first, second, and third month following BTA injection, and the number of headache days during the last 7 days prior to follow-up was collected, as was the self-rating of the effectiveness of BTA treatment. Fifty-five (61%) patients were injected during the AM clinic and 35 (39%) during the PM clinic. There was no difference in gender, race, and age variables between the AM and PM patients. The average total number of headache days during 3 months following injection was significantly higher for the AM-treated compared to the PM-treated patients (22.37 ± 18.85 vs. 10.54 ± 7.5, p =.0007). AM patients also reported a higher number of headache days during each of the 3 months following BTA injection. In contrast, PM patients reported higher effectiveness of preventive BTA treatment. The average number of headache days during the week prior to the follow up, as well as the presence of headache on the day of the follow-up was not significantly different between the AM and PM groups. Scheduling diurnally active CM patients with stable circadian sleep/wake routine for afternoon BTA injections appear to improve the effectiveness of BTA therapy as well as patients’ satisfaction with the treatment.

The tumor genetics of acral melanoma: What should a dermatologist know?

Dermatologists stand at the gateway of individualization of classification, treatment, and outcomes of acral melanoma patients. The acral melanoma genetic landscape differs in vital ways from that of other cutaneous melanomas. These differences have important implications in understanding pathogenesis, treatment, and prognosis. The selection of molecularly targeted therapy must be adapted for acral melanoma. It is also critical to recognize that tumor development is far more complex than an isolated event, reliably treated by a medication acting on a single target. Tumors exhibit intratumor genetic heterogeneity, metastasis may have different genetic or epigenetic features than primary tumors, and tumor resistance may develop because of the activation of alternative genetic pathways. Microenvironmental, immune, and epigenetic events contribute and sustain tumors in complex ways. Treatment strategies with multiple targets are required to effectively disrupt the tumor ecosystem. This review attempts to translate the current molecular understanding of acral melanoma into digestible concepts relevant to the practice of dermatology. The focus is tumor genetics defining potentially treatable cancer pathways, contextualized within the relevant pathologic and molecular features.

HSPA1A gene polymorphism rs1008438 is associated with susceptibility to acute mountain sickness in Han Chinese individuals.

BackgroundAcute mountain sickness (AMS) usually occurs among non‐acclimated individuals after rapid ascending to high‐altitude environments (generally ≥2,500 m). However, the precise molecular mechanism of AMS remains unclear. Our study aimed to investigate the relationship between several single nucleotide polymorphisms (SNPs) and AMS susceptibility.MethodsIn this work, sequencing data were obtained from 69 AMS patients and 95 matched acclimated Han Chinese individuals from southwest China. Five SNPs (rs1008438, rs150877473, rs1799983, rs2153364, and rs3025039) were systematically investigated in all the participants.ResultsIn our study, we found that allele frequencies of “A” (AMS 69.57% vs. non‐AMS 54.74%) and “C” (AMS 30.43% vs. non‐AMS 45.26%) in the HSPA1A gene rs1008438 were significantly different between the AMS and non‐AMS groups (p = .01). Genotypes “CC” and “CA” of the HSPA1A gene (rs1008438) were associated with lower risk of developing AMS than the genotype “AA.” Comparing the genotypes “CC + CA” and “AA,” we also observed that the “CC + CA” genotype of rs1008438 was associated with lower AMS risk.ConclusionsIn our case‐control study, there was a significant association between the rs1008348 polymorphism and AMS susceptibility, suggesting that this particular SNP might be a Han‐specific risk factor for AMS. We believe that this study establishes a foundation for further elucidation of the genetic mechanisms underlying AMS.

Daytime variation does not impact outcome of cardiac surgery: Results from a diverse, multi-institutional cardiac surgery network

ObjectiveRecent single-center and experimental data suggested greater adverse cardiac events for patients undergoing aortic valve replacement (AVR) in the morning (AM) versus the afternoon (PM). However, previous studies in patients undergoing coronary artery bypass grafting (CABG) have found no similar time-related difference. We examined the impact of AM versus PM operative time on surgical outcomes of CABG and AVR in a diverse, multi-institutional cardiac surgery network between January 2008 and September 2018. MethodsThe AM group included patients whose surgery start time was between 6:30 and 9 AM, whereas noon to 2:30 PM was considered PM (8901 AM/1962 PM) for CABG and (2598 AM/617 PM) for AVR. Because of imbalances in sample size, risk factors, and Society of Thoracic Surgeons predicted risk between groups, propensity score matching using all baseline characteristics was used to create 2 well-matched patient groups whose outcomes were compared. ResultsAfter propensity score matching, there was no difference in mortality, stroke, prolonged ventilation, renal failure, deep sternal wound infection, reoperation, myocardial injury, atrial fibrillation, or readmission between AM and PM groups for both isolated CABG and AVR. However, there were mixed differences noted in intensive care unit length of stay, postoperative length of stay, blood product use, and crossclamp time. Findings were stable when accounting for site and physician effects, whereas subgroup analyses showed similar findings in the elective, diabetic, Hispanic, and off-pump patient populations. ConclusionsThere were no differences in operative mortality nor in major morbidity between well-matched AM and PM patients undergoing either CABG or AVR.