Prognostic Factors For Long-term Outcome Research Articles

Abstract PO2-25-03: Deciphering the immune molecular signature associated with pembrolizumab efficacy in the neoadjuvant setting of Triple-Negative Breast Cancer patients: a single-centre experience

Abstract Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancers and is characterized by a high rate of recurrence, despite the improvement of the therapeutic approaches in recent years. Neoadjuvant chemotherapy (NACT) is the standard treatment for early-stage TNBC. Achieving a pathological complete response (pCR) is considered an essential prognostic factor for long-term outcomes. However, the percentage of pCR patients after NACT is limited to 30-40%, thus requiring the implementation of novel therapeutic strategies. Recently, by applying a morphology-guided spatial transcriptomic approach on Tru-Cut biopsies, we showed that intratumoral infiltrating lymphocytes (iTILs) and stromal Natural Killer (NK) cells are major determinants of chemotherapy efficacy in TNBC. These data highlight a complex three-dimensional organization of the tumor landscape and underline how spatiality and molecular activation of immune cells are essential to enhance the efficacy of neoadjuvant NACT in TNBC. The fact that immune cells are important players in this setting is corroborated by the clinical success shown by the KEYNOTE-522 study. This trial paved the way for the use of immunotherapy in neoadjuvant settings, obtaining a significant improvement in the patient’s overall response compared to standard NACT. Still, the implementation of chemotherapy with immunotherapy in the TNBC neoadjuvant treatment implicates several compelling questions, including how to further increase the percentage of patients with a complete response, overcoming resistance mechanisms, and how to improve the personalization of treatment, evaluating which patients can benefit from a therapy de-scalation or another combined therapeutic strategy. In this prospective cohort study, we decided to define the relevance of different immune populations in affecting pembrolizumab efficacy in the neoadjuvant treatment of TNBC patients. We treated 40 patients with an early-TNBC diagnosis with the KEYNOTE-522 regimen that consists of four cycles of an intravenous infusion of pembrolizumab plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab plus epirubicin and cyclophosphamide. Only patients with evident side effects to immunotherapy administration were a priori excluded. Currently, 18 patients ended the neoadjuvant schedule and underwent surgical excision. Our data indicate that 15 patients displayed a pCR at the end of the therapy, whereas 3 patients displayed only partial response. To further clarify the immune dynamics that lead to a complete response to pembrolizumab in these patients, we collected peripheral blood before and after neoadjuvant treatment to isolate peripheral blood mononucleated cells (PBMCs). We applied a single-cell transcriptome analysis to shape any variations in circulating immune cells occurring during neoadjuvant treatment and associated with patient response. In addition, we collected residual tumors at surgery from partial responders and derived three-dimensional organoids that recapitulate the characteristics of the original patient tumor. These ex vivo organoid-based platforms are applied to clarify the molecular mechanisms driving neoadjuvant resistance. To this aim, we are performing co-cultures with autologous immune cells to identify novel combined therapeutic strategies to rescue pembrolizumab efficacy in these models. Overall, our study is defining the immune-related molecular mechanisms driving pembrolizumab and chemotherapy response in the neoadjuvant treatment of TNBC patients. Our findings can improve our understanding of which immune populations are determinant players in anti-TNBC immune response and can be proposed as novel biomarkers of pembrolizumab efficacy during the neoadjuvant treatment. Citation Format: Elisa Gasparini, Gloria Manzotti, Moira Ragazzi, Benedetta Donati, Federica Torricelli, Elisa Salviato, Alessandra Bisagni, Eleonora Zanetti, Alessandra Bologna, Saverio Coiro, Rita Vacondio, Guglielmo Ferrari, Giancarlo Bisagni, Carmine Pinto, Alessia Ciarrocchi, Francesca Reggiani. Deciphering the immune molecular signature associated with pembrolizumab efficacy in the neoadjuvant setting of Triple-Negative Breast Cancer patients: a single-centre experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-25-03.

Autism Spectrum Disorder in 2023: A Challenge Still Open.

In this paper, we provide an update on autism spectrum disorder (ASD), including epidemiology, etiopathogenesis, clinical presentation, instrumental investigations, early signs, onset patterns, neuropsychological hypotheses, treatments, and long-term outcome. The prevalence of this condition has increased enormously over the last few decades. This increase prompted a search for possible environmental factors whose effects would add up to a genetic predisposition leading to the development of autism. But the genetic and environmental variables involved are extremely numerous, and conclusive data regarding the etiopathogenesis are still far away. Assuming that a well-defined etiology is still found today only in a minority of cases, numerous pathogenetic mechanisms have been hypothesized. Among these, we mention oxidative stress, mitochondrial dysfunction, alteration of the intestinal microbiota, immune dysregulation, and neuroinflammation. These pathogenetic mechanisms could alter epigenetic status and gene expression, finally leading to ASD. Inherent in the term spectrum is the great clinical heterogeneity of this condition, mainly due to the frequent comorbidity that characterizes it. The earlier the diagnosis is made and the earlier psychoeducational treatment begins, the better the prognosis. In this sense, the role of pediatricians can be decisive in making children with signs suggestive of autism undergo a specialist diagnostic course. The development of increasingly advanced cognitive-behavioral educational techniques has considerably improved the prognosis of affected individuals, even though only a small minority of them come off the autistic spectrum. Pharmacological therapies are used to treat comorbidities. During childhood, the most important prognostic factor for long-term outcome seems to be intellectual functioning.

Prognostic factors of long-term outcomes after primary chemo-radiotherapy in non-metastatic anal squamous cell carcinoma: An international bicentric cohort.

e15501 Background: Anal squamous cell carcinoma (ASCC) is a rare malignancy with a rising incidence associated with Human papillomavirus (HPV) infection. Locally-advanced disease is associated with a 30% rate of treatment failure after standard chemoradiotherapy (CRT). We aimed to elucidate prognostic factors for ASCC after curative CRT. Methods: A retrospective multicenter study of 176 consecutive patients with ASCC having completed CRT treated between 2010 and 2017 at 2 centers. Complete response (CR), disease-free survival (DFS) and overall survival (OS) were analyzed by Kaplan–Meier estimates with log-rank tests. The hierarchical clustering on principal components (HCPC) method was employed in an unsupervised and multivariate approach. Results: CR rate was 68% and was predictive of DFS (p < 0.0001) and OS (p < 0.0001), where non-CR cases were associated shorter DFS (HR = 16.5, 95% CI 8.19-33.21) and OS (HR = 8.42, 95% CI 3.77–18.81) in univariate analysis. Median follow-up was 38 months, with 3-year DFS of 71%. Prognostic factors for DFS were cT1-T2 (p = 0.0001), N0 (p = 0.03), HIV-positive (p = 0.04), HIV-HPV coinfection (p = 0.02), and well-differentiated tumors (p = 0.03). Three-year OS was 81.6%. Female sex (p = 0.05), cT1-T2 (p = 0.019), and well-differentiated tumors (p = 0.003) were associated with better OS. This unsupervised analysis demonstrates clear segregation, identifying that poor prognosis clusters associated with shorter DFS (HR = 1.66, 95% CI = 1.21–2.27, p = 0.0012) were enriched with locally-advanced disease, anal canal location, HPV-HIV coinfection, and non-CR. Conclusions: In conclusion, our results reinforce the prognostic value of T stage, N stage, sex, differentiation status, tumor location, and HIV-HPV coinfection in ASCC after CRT.

Predictive value of high sensitivity C-reactive protein in three-vessel disease patients with and without type 2 diabetes

BackgroundDiabetes mellitus (DM) and atherosclerosis are multifactorial conditions and share a common inflammatory basis. Three-vessel disease (TVD) represents a major challenge for coronary intervention. Nonetheless, the predictive value of high-sensitivity C-reactive protein (hs-CRP) for TVD patients with or without type 2 DM remains unknown. Herein, we aimed to ascertain the long-term predictive value of hs-CRP in TVD patients according to type 2 DM status from a large cohort.MethodsA total of 2734 TVD patients with (n = 1040, 38%) and without (n = 1694, 62%) type 2 diabetes were stratified based on the hs-CRP (< 2 mg/L vs. ≥ 2 mg/L). Three multivariable analysis models were performed to evaluate the effect of potential confounders on the relationship between hs-CRP level and clinical outcomes. The Concordance index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were calculated to assess the added effect of hs-CRP and the baseline model with established risk factors on the discrimination of clinical outcomes. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE).ResultsThe median follow-up duration was 2.4 years. Multivariate Cox regression analyses showed that the incidence of MACCE (adjusted hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.01–1.35, p = 0.031) and all-cause death (HR 1.82, 95% CI 1.07–3.11, p = 0.026) were significantly higher in the diabetic group compared to the non-diabetic group. In the diabetic group, the incidence of MACCE (adjusted HR 1.51, 95% CI 1.09–2.10, p = 0.013) was significantly higher in the high hs-CRP group than in the low hs-CRP group; no significant difference was found for all-cause death (HR 1.63; 95% CI 0.58–4.58, p = 0.349). In the non-diabetic group, the prevalence of MACCE (adjusted HR 0.93, 95% CI 0.71–1.22, p = 0.613) was comparable between the two groups. Finally, the NRI (0.2074, p = 0.001) and IDI (0.0086, p = 0.003) for MACCE were also significantly increased after hs-CRP was added to the baseline model in the diabetic group.ConclusionsElevated hs-CRP is an independent prognostic factor for long-term outcomes of MACCE in TVD patients with type 2 diabetes but not in those without type 2 diabetes. Compared to traditional risk factors, hs-CRP improved the risk prediction of adverse cardiovascular events in TVD patients with type 2 diabetes.

Prognostic factors for long-term outcome in children with fetal alcohol spectrum disorders

IntroductionKnown protective factors for long-term outcome in children with fetal alcohol spectrum disorders (FASD) are early diagnosis and a stable, non-violent supportive environment. Which factors contribute to the stability of care is not yet known. Thus, the aim of our study was to evaluate whether the age at diagnosis and the complexity of brain dysfunction play a role for placement changes in children with FASD. Materials and methodsAn online survey was conducted among caregivers and professionals caring for children with FASD and seeking help at the German FASD Competence Centre Bavaria (N = 232). The survey collected information about diagnosis, brain dysfunctions, behavioural factors influencing everyday life and changes of placement. The association of timing of diagnosis, brain dysfunctions and neurobehavioral impairment with changes of placement (<2 vs. 2 or more changes) was evaluated via logistic regression models. ResultsAbout 50% of the children received their diagnosis of FASD after the age of 5 years. The complexity of brain dysfunctions in children with FASD affecting everyday life was high. 15% of the children experienced four or more changes of placement. Children with more neuropsychological impairments experienced more changes of placement (OR: 2.53, 95% CI: 1.36–4.71). ConclusionsEven though our results need to be interpreted with caution due to methodological limitations such as the use of a convenience sample and limited statistical power, they imply that severely affected children with FASD experience a less stable environment. These children may therefore be at high risk for a negative prognosis. To warrant a better prognosis for the affected children, professionals urgently need to pay attention to early recognition and the complexity of neuropsychological impairments in children with FASD as well as to the support that caregivers urgently need.

Prognostic Factors of Long-Term Outcomes after Primary Chemo-Radiotherapy in Non-Metastatic Anal Squamous Cell Carcinoma: An International Bicentric Cohort.

Anal squamous cell carcinoma (ASCC) is a rare malignancy with a rising incidence associated with human papillomavirus (HPV) infection. The locally advanced disease is associated with a 30% rate of treatment failure after standard chemoradiotherapy (CRT). We aimed to elucidate the prognostic factors for ASCC after curative CRT. A retrospective multicenter study of 176 consecutive patients with ASCC having completed CRT treated between 2010 and 2017 at two centers was performed. Complete response (CR), disease-free survival (DFS), and overall survival (OS) were analyzed by Kaplan-Meier estimates with log-rank tests. The hierarchical clustering on principal components (HCPC) method was employed in an unsupervised and multivariate approach. The CR rate was 70% and was predictive of DFS (p < 0.0001) and OS (p < 0.0001), where non-CR cases were associated with shorter DFS (HR = 16.5, 95% CI 8.19-33.21) and OS (HR = 8.42, 95% CI 3.77-18.81) in a univariate analysis. The median follow-up was 38 months, with a 3-year DFS of 71%. The prognostic factors for DFS were cT1-T2 (p = 0.0002), N0 (p = 0.035), HIV-positive (p = 0.047), HIV-HPV coinfection (p = 0.018), and well-differentiated tumors (p = 0.037). The three-year OS was 81.6%. Female sex (p = 0.05), cT1-T2 (p = 0.02) and well-differentiated tumors (p = 0.003) were associated with better OS. The unsupervised analysis demonstrated a clear segregation of patients in three clusters, identifying that poor prognosis clusters associated with shorter DFS (HR = 1.74 95% CI = 1.25-2.42, p = 0.0008) were enriched with the locally advanced disease, anal canal location, HIV-HPV coinfection, and non-CR. In conclusion, our results reinforce the prognostic value of T stage, N stage, sex, differentiation status, tumor location, and HIV-HPV coinfection in ASCC after CRT.

Prognostic value of the completeness of the metabolic response in patients with diffused large B-cell lymphoma

The currently used prognostic factors for long-term results of standard treatment of diffuse large B-cell lymphoma (DLBCL) are not clear enough to predict outcomes. The prognostic significance of interim PET/CT in DLBCL remains controversial. The aim of this study is to determine the predictive value of interim 18 F-FDG PET/CT after first-line treatment in patients with DLBCL. One hundred-eighty patients with DLBCL underwent baseline and interim 18 F-FDG PET/CT scans after 4 cycles of R-CHOP during the period of 2015–2020 at the N. N. Alexandrov National Cancer Centre of Belarus. Interim 18 F-FDG PET/ CT findings were retrospectively correlated to the progression-free survival (PFS) using the Kaplan–Meier analysis. The metabolic response was assessed according Deauville criteria: PET-negative – Deauville 1–2, PET-positive – Deauville 3–5. The International prognostic index (IPI) was used for risk stratification. After 4 cycles of chemotherapy, PET-positive lesions were found in 76 patients and negative scans – in 104 patients. Survival analyses showed highly significant relationships between early interim 18 F-FDG PET/CT imaging and PFS (p &lt; 0.001). For PET-negative patients, the 7-year PFS rate was 91.1 %, for PET-positive patients it is 41.2 %. 5-year PFS rates for PET-negative patients with IPI scores 0–1, 2–3 and 4–5 were 97.5, 93.4 and 66.7 %, respectively. For PET-positive patients, 5-year PFS rates in the same subgroups were 55.6, 50.6 and 23.1 %, respectively. Early interim 18 F-FDG PET/CT imaging is a predictor of PFS in DLBCL. An early assessment of chemotherapy response with 18 F-FDG PET/CT scans may provide useful information on selection of patients for escalated therapeutic strategies.

Prognostic factors for long-term outcome in bifocal hepatocellular carcinoma after resection.

This study aimed to evaluate whether the radiological similarity and clinicopathological factors determine the prognosis in bifocal hepatocellular carcinoma (bHCC) stratified by the Milan criteria. Consecutive patients with pathologically confirmed bHCC examined between January 2016 and December 2018 were retrospectively enrolled and grouped based on the Milan criteria. Two radiologists independently evaluated whether the imaging features of both tumors were consistent or not, which was defined as the radiological similarity. The clinicopathological data were also collected. The multivariable Cox regression was applied to separately identify the independent factors for recurrence-free survival (RFS) and overall survival (OS) in bHCC within and beyond the Milan criteria. A total of 193 patients were evaluated and divided into the within the Milan criteria group (n = 72) and the beyond the Milan criteria group (n = 121). bHCC within the Milan criteria showed a significantly better prognosis than those beyond the criteria. In the within the Milan criteria group, HBV-DNA load >104IU/mL, microvascular invasion (MVI), and different enhancement patterns were independently associated with poor RFS. MVI was an independent prognostic factor for poor OS. In the beyond the Milan criteria group, HBV infection, MVI, increased ratio of the larger to the smaller tumor diameter (RLSD) value, and low comprehensive similarity were associated with shorter RFS, whereas MVI and increased RLSD value were independent predictors for poor OS. Our study revealed that in addition to MVI- and HBV-related factors, similarity in imaging features between lesions of bHCC is associated with the long-term prognosis. • The prognosis of bifocal HCC patients within the Milan criteria is significantly better than those beyond the criteria. • The similarity in imaging features between lesions of bHCC was an independent prognostic factor. • The more similar the bifocal lesions are in imaging features, the better the prognosis is.

Systemic Immune-Inflammation Index Predicts Long-Term Outcomes in Patients with Three-Vessel Coronary Disease After Revascularization: Results from a Large Cohort of 3561 Patients.

ObjectiveThis study aimed to investigate the prognostic value of systemic immune inflammation index (SII) concerning long-term outcomes in patients with the three-vessel disease (TVD) after revascularization in a large cohort.MethodsIn total, 3561 TVD patients who had undergone revascularization between 2013 and 2018 were included in the study. Patients were divided into the low SII (<694.3 × 109/L) (n = 2556, 71.8%) and the high SII (≥694.3 × 109/L) group (n = 1005, 28.2%). The C-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were calculated to assess whether the addition of SII to a baseline model with traditional risk factors improved the accuracy of cardiac event prediction. The primary outcome was the frequency of major adverse and cerebrovascular events (MACCE). The secondary outcome was the incidence of all-cause death.ResultsAfter 2.4 years of follow-up, the Cox proportional hazard regression model analysis displayed that high SII was independently associated with an increased risk of developing future MACCE (hazard ratio [HR] 1.65, 95% confidence interval [CI] 1.23–2.21, p = 0.001) and all-cause death (HR: 2.96; 95% CI: 1.19–7.32, p = 0.019). The addition of SII significantly improved the reclassification beyond the baseline model with traditional risk factors (MACCE: NRI, 0.115; p = 0.0001; all-cause death: NRI, 0.369; p = 0.0001). Reclassification with the addition of SII also demonstrated an IDI of 0.0022 (p = 0.006) in MACCE and 0.0033 (p = 0.014) in all-cause death.ConclusionIn TVD patients after revascularization, increased SII is an independent prognostic factor for long-term outcomes of MACCE and death. Compared to traditional risk factors, SII improved the risk prediction of major cardiovascular events in TVD patients who underwent revascularization.

Prognostic factors for long-term outcomes of microvascular decompression in the treatment of glossopharyngeal neuralgia: a retrospective analysis of 97 patients.

The authors aimed to investigate predictors of postoperative outcomes of microvascular decompression (MVD) for the treatment of glossopharyngeal neuralgia (GPN). A cohort of 97 patients with medically refractory GPN who underwent MVD at the authors' institution between January 2010 and July 2019 was retrospectively reviewed. Univariate and multivariate regression models were used to identify predictors of long-term outcome in patients after MVD. Eighty-nine patients (91.8%) reported immediate and complete relief of pain after the procedure. Of the remaining 8 patients (8.2%), 6 achieved partial pain relief and pain gradually diminished within 2 weeks after surgery, and 2 did not experience postoperative pain relief. In univariate Cox regression analysis, venous compression of the glossopharyngeal nerve root entry zone (HR 3.591, 95% CI 1.660-7.767, p = 0.001) and lower degree of neurovascular conflict (HR 2.449, 95% CI 1.177-5.096, p = 0.017) were significantly associated with worse pain-free survival. In multivariate Cox regression analysis, venous compression (HR 8.192, 95% CI 2.960-22.669, p < 0.001) and lower degree of neurovascular conflict (HR 5.450, 95% CI 2.069-14.356, p = 0.001) remained independently associated with worse pain-free survival. Venous compression of the glossopharyngeal nerve root entry zone and lower degree of neurovascular conflict were significantly correlated with shorter pain-free survival in patients who underwent MVD for GPN. Microvascular decompression is a safe, feasible, and durable approach with a low complication rate for the treatment of GPN.

Current status of the association between malnutrition defined by the GLIM criteria and postoperative outcomes in gastrointestinal surgery for cancer: a narrative review.

In 2018, the Global Leadership Initiative on Malnutrition consortium published global consensus diagnostic criteria for malnutrition and highlighted the association between malnutrition and poor postoperative outcomes in patients with gastrointestinal cancer. The aforementioned criteria consist of phenotypic and etiologic criteria to diagnose malnutrition in individuals who undergo conventional screening to determine the at-risk population. Recent studies have reported the usefulness of prediction of postoperative outcomes using body mass index, weight loss, and reduced muscle mass as phenotypic criteria. Reduced muscle mass is an essential diagnostic criterion for sarcopenia, which is associated with poor outcomes in patients with cancer. The Global Leadership Initiative on Malnutrition criteria define reduced muscle mass as undernutrition. Malnutrition diagnosed based on the Global Leadership Initiative on Malnutrition criteria is an important risk factor for postoperative complications and also an independent poor prognostic factor for long-term outcomes; greater severity of malnutrition is associated with poorer outcomes. The current Global Leadership Initiative on Malnutrition criteria for malnutrition accurately predict outcomes, including postoperative complications and long-term prognosis; however, a revision may be warranted to ensure consistency with the diagnostic criteria for sarcopenia. Patients diagnosed with malnutrition based on the Global Leadership Initiative on Malnutrition criteria should be targeted for nutritional intervention. Further accumulation of evidence is necessary to conclusively establish the role of nutritional interventions in patients with malnutrition to improve postoperative complications and long-term outcomes.

Association of polygenic risk for schizophrenia with fast sleep spindle density depends on pro-cognitive variants

Cognitive impairment is a common feature in schizophrenia and the strongest prognostic factor for long-term outcome. Identifying a trait associated with the genetic background for cognitive outcome in schizophrenia may aid in a deeper understanding of clinical disease subtypes. Fast sleep spindles may represent such a biomarker as they are strongly genetically determined, associated with cognitive functioning and impaired in schizophrenia and unaffected relatives. We measured fast sleep spindle density in 150 healthy adults and investigated its association with a genome-wide polygenic score for schizophrenia (SCZ-PGS). The association between SCZ-PGS and fast spindle density was further characterized by stratifying it to the genetic background of intelligence. SCZ-PGS was positively associated with fast spindle density. This association mainly depended on pro-cognitive genetic variants. Our results strengthen the evidence for a genetic background of spindle abnormalities in schizophrenia. Spindle density might represent an easily accessible marker for a favourable cognitive outcome which should be further investigated in clinical samples.

Association between Sleep Disturbances at Subacute Stage of Mild Traumatic Brain Injury and Long-Term Outcomes.

Mild (mTBI) traumatic brain injury (TBI) accounts for the majority of all TBI cases. Evidence has suggested that patients with mTBI can suffer from long-lasting cognitive deficits, persistent symptoms, and decreased quality of life. Sleep disorders are commonly observed after TBI, with the prevalence rate of sleep disturbances in persons with TBI being much higher than that in the general population. Poor sleep quality can impair cognitive functions in the general population. This effect of sleep disturbances may impede the recovery processes in the population with TBI. The objective of this study is to add to our understanding of the relationship between self-reported sleep problems and other post-concussion symptoms and look at the association between early sleep problems and long-term outcomes in mTBI. Post-concussion symptoms, neurocognitive functions, level of global outcomes, and rating of satisfaction of life were assessed in 64 patients with mTBI. The results revealed that the presence of sleep disturbances co-occur with an increased level of overall post-concussion symptoms at the subacute stage of mTBI, particularly with symptoms including poor concentration, memory problems, and irritability. In addition, sleep disturbance at the subacute stage is associated with persistent poor concentration and memory problems, as well as worse neurocognitive function, slower overall recovery, and lower satisfactory of life at the long term. Our findings suggest that sleep disturbance can be a prognostic factor of long-term outcomes after mTBI. Early interventions to improve sleep quality can have potential benefits to facilitate the recovery process from mTBI.

Differing clinical features between Japanese siblings with cerebrotendinous xanthomatosis with a novel compound heterozygous CYP27A1 mutation: a case report

BackgroundCerebrotendinous xanthomatosis (CTX) is an autosomal-recessive lipid storage disorder caused by mutations in the CYP27A1 gene encoding the key enzyme in the bile acid synthesis, sterol 27-hydroxylase. Here, we report two Japanese CTX siblings with a novel compound heterozygous CYP27A1 mutation, showing different clinical phenotypes and responses to chenodeoxycholic acid (CDCA) therapy.Case presentationThe proband, a 32-year-old man, who had chronic diarrhea, bilateral cataracts, and xanthomas, demonstrated progressive neurological manifestations including ataxia, and spastic paraplegia during a 5-year follow-up period despite normalization of serum cholestanol after initiation of CDCA treatment. He also exhibited cognitive decline although improvement had been observed at the beginning of treatment. Follow-up brain magnetic resonance imaging (MRI) revealed pronounced progressive atrophy in the cerebellum, in addition to expanding hyperintense lesions in the dentate nuclei, posterior limb of the internal capsule, cerebral peduncles, and inferior olives on T2-weighted images. In contrast, the two-year-younger sister of the proband presented with chronic diarrhea, cataracts, xanthomas, and intellectual disability but no other neurological symptoms at the time of diagnosis. CDCA treatment lead to improvement of cognitive function and there were no characteristic CTX-related MRI features during the follow-up period. The siblings shared a paternally inherited c.1420C > T mutation (p.Arg474Trp) and a maternally inherited novel c.1176_1177delGA mutation, predicting p.(Glu392Asp*20).ConclusionsOur cases suggest that early diagnosis and subsequent initiation of CDCA treatment are crucial before the appearance of characteristic MRI findings and severe neurological manifestations related to CTX. Further studies are required to elucidate mechanisms responsible for the clinical diversity of CTX and prognostic factors for long-term outcomes following initiation of CDCA treatment.

A Prognostic and Carboplatin Response Predictive Model in Ovarian Cancer: A Mono-Institutional Retrospective Study Based on Clinics and Pharmacogenomics.

Carboplatin is the cornerstone of ovarian cancer (OC) treatment, while platinum-response, dependent on interindividual variability, is the major prognostic factor for long-term outcomes. This retrospective study was focused on explorative search of genetic polymorphisms in the Absorption, Distribution, Metabolism, Excretion (ADME) genes for the identification of biomarkers prognostic/predictive of platinum-response in OC patients. Ninety-two advanced OC patients treated with carboplatin-based therapy were enrolled at our institution. Of these, we showed that 72% of patients were platinum-sensitive, with a significant benefit in terms of OS (p = 0.001). We identified an inflammatory-score with a longer OS in patients with lower scores as compared to patients with the maximum score (p = 0.001). Thirty-two patients were genotyped for 1931 single nucleotide polymorphisms (SNPs) and five copy number variations (CNVs) by the DMET Plus array platform. Among prognostic polymorphisms, we found a potential role of UGT2A1 both as a predictor of platinum-response (p = 0.01) and as prognostic of survival (p = 0.05). Finally, we identified 24 SNPs related to OS. UGT2A1 correlates to an “inflammatory-score” and retains a potential prognostic role in advanced OC. These data provide a proof of concept that warrants further validation in follow-up studies for the definition of novel biomarkers in this aggressive disease.

FIB-4 index and liver fibrosis are risk factors for long-term outcomes in atrial fibrillation-related stroke

ObjectiveLiver fibrosis (LF) is associated with a poor prognosis in patients with ischemic stroke (IS). We aimed to assess whether LF affects long-term outcomes in patients with atrial fibrillation-related stroke or such effects vary according to sex. MethodsWe conducted a multicenter prospective cohort study of Korean patients with atrial fibrillation-related IS. We calculated the fibrosis-4 (FIB-4) index, and LF degree was categorized into two groups (non-advanced vs. advanced) based on the FIB-4 index. Recurrent IS, major adverse cardiac events (MACEs), and all-cause mortality were evaluated using Cox proportional hazard model. ResultsA total of 2897 patients were included; the median age was 75 (interquartile range 68–80) years, and 51.8% were men. The median follow-up period was 16.3 months. Of these patients, 23% had advanced LF indicated by FIB-4 index. Multivariable analysis in all populations demonstrated that the FIB-4 index and advanced LF were significantly associated with MACEs and all-cause mortality but not with recurrent IS. Furthermore, a sex disparity was observed in the outcomes of the patients. A high FIB-4 index in men was a significant predictor of recurrent IS [subdistribution hazard ratio (95% confidence interval): 1.08 (1.02–1.14)]. However, the significance of advanced LF disappeared in MACEs in women and in all-cause mortality in men. ConclusionThe FIB-4 index and advanced LF indicated by FIB-4 index are independent prognostic factors for long-term outcomes in Asian patients with atrial fibrillation-related IS. However, these predictors may contribute differently to patient outcomes depending on the sex.

Looking ahead: giant-cell arteritis in 10 years time.

Although great improvements have been achieved in the fields of diagnosing and treating patients with giant-cell arteritis (GCA) in the last decades, several questions remain unanswered. The progressive increase in the number of older people, together with growing awareness of the disease and use of advanced diagnostic tools by healthcare professionals, foretells a possible increase in both prevalence and number of newly diagnosed patients with GCA in the coming years. A thorough clarification of pathogenetic mechanisms and a better definition of clinical subsets are the first steps toward a better understanding of the disease and, subsequently, toward a better use of existing and future therapeutic options. Examination of the role of different imaging techniques for GCA diagnosing and monitoring, optimization, and personalization of glucocorticoids and other immunosuppressive agents, further development and introduction of novel drugs, identification of prognostic factors for long-term outcomes and management of treatment discontinuation will be the central topics of the research agenda in years to come.

Association of clinical characteristics, antidiabetic and cardiovascular agents with diabetes mellitus and COVID-19: a 7-month follow-up cohort study.

BackgroundThe prognostic factors of long-term outcomes in hospitalized patients with diabetes mellitus and COVID-19 are lacking.MethodsIn this retrospective cohort study, we evaluated patients aged ≥ 18-years-old with the COVID-19 diagnosis who were hospitalized between Feb 20 and Oct 29, 2020, in the Sina Hospital, Tehran, Iran. 1323 patients with COVID-19 entered in the final analysis, of whom 393 (29.7%) patients had diabetes. We followed up patients for incurring in-hospital death, severe COVID-19, in-hospital complications, and 7-month all-cause mortality. By doing univariate analysis, variables with unadjusted P-value < 0.1 in univariate analyses were regarded as the confounders to include in the logistic regression models. We made adjustments for possible clinical (model 1) and both clinical and laboratory (model 2) confounders. ResultsAfter multivariable regression, it was revealed that preadmission use of sulfonylureas was associated with a borderline increased risk of severity in both models [model 1, OR (95% CI):1.83 (0.91–3.71), P-value: 0.092; model 2, 2.05 (0.87–4.79), P-value: 0.099] and major adverse events (MAE: each of the severe COVID-19, multi-organ damage, or in-hospital mortality) in model 1 [OR (95% CI): 1.86 (0.90–3.87), P-value: 0.094]. Preadmission use of ACEIs/ARBs was associated with borderline increased risk of MAE in the only model 1 [OR (95% CI):1.83 (0.96–3.48), P-value: 0.066].ConclusionsPreadmission use of sulfonylureas and ACEIs/ARBs were associated with borderline increased risk of in-hospital adverse outcomes.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40200-021-00901-4.

Evaluation of the Anti-N-Methyl-D-Aspartate Receptor Encephalitis One-Year Functional Status Score in Predicting Functional Outcomes in Pediatric Patients with Anti-N-Methyl-D-Aspartate Receptor Encephalitis

Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is an autoimmune neurological condition associated with autoantibodies to the N-methyl-D-aspartate (NMDA) receptor; it is a common cause of pediatric encephalitis. 1 Gable M.S. Sheriff H. Dalmau J. Tilley D.H. Glaser C.A. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clin Infect Dis. 2012; 54: 899-904 Crossref PubMed Scopus (490) Google Scholar Presenting symptoms include behavioral disturbances, seizures, movement disorders, speech dysfunction, and altered consciousness and can lead to persistent neuropsychiatric deficits in children. 2 Titulaer M.J. McCracken L. Gabilondo I. et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013; 12: 157-165 Abstract Full Text Full Text PDF PubMed Scopus (1760) Google Scholar ,3 Wang Y. Zhang W. Yin J. et al. Anti-N-methyl-d-aspartate receptor encephalitis in children of Central South China: clinical features, treatment, influencing factors, and outcomes. J Neuroimmunol. 2017; 312: 59-65 Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Long-term outcomes are challenging to predict but are important for prognostication and guiding early management because early and aggressive immunotherapy may improve outcomes. 1 Gable M.S. Sheriff H. Dalmau J. Tilley D.H. Glaser C.A. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clin Infect Dis. 2012; 54: 899-904 Crossref PubMed Scopus (490) Google Scholar ,2 Titulaer M.J. McCracken L. Gabilondo I. et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013; 12: 157-165 Abstract Full Text Full Text PDF PubMed Scopus (1760) Google Scholar ,4 Gerstle K. Hur M.H. Moussa T. Pediatric anti-NMDA-R encephalitis: presentation, diagnosis, and management. Pediatr Ann. 2019; 48: e387-e390 Crossref PubMed Scopus (3) Google Scholar Developed to predict one-year outcomes in NMDARE, the NMDARE One-Year Functional Status (NEOS) score strongly predicts the probability of good functional outcomes. 5 Balu R. McCracken L. Lancaster E. Graus F. Dalmau J. Titulaer M.J. A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis. Neurology. 2019; 92: e244-e252 Crossref PubMed Scopus (100) Google Scholar However, the applicability of this tool has not yet been evaluated in a pediatric NMDARE cohort. This study aims to evaluate the NEOS score to predict one-year functional outcomes in patients with pediatric NMDARE.

Autoimmune Encephalitis–Related Seizures and Epilepsy: Diagnostic and Therapeutic Approaches

Autoimmune Encephalitis–Related Seizures and Epilepsy: Diagnostic and Therapeutic Approaches