Effects of a Plant-Based High-Protein Diet on Fatigue in Breast Cancer Patients Undergoing Adjuvant Chemotherapy - a Randomized Controlled Trial.

BACKGROUND: Breast cancer patients undergoing chemotherapy (CT) experience fatigue and other side-effects. Studies exploring interventions with a plant-based, high-protein diet on fatigue and body composition are lacking. The effects of these interventions on fatigue, body mass index (BMI), and body composition were evaluated. METHOD: Newly diagnosed breast cancer patients who were scheduled for adjuvant CT (n = 103) were randomly assigned to the intervention or control group. Study outcomes included fatigue using fatigue symptom inventory and body composition using bioelectric impedance analyzer done at the start of CT, 3rd CT, and 3 weeks after CT. Linear mixed models were used to compare groups over time. RESULTS: Fatigue decreased from 57% to 28% in the intervention group and increased from 65% to 78% in the control group (p < 0.001). BMI decreased by 0.7 ± 0.8 kg/m2 in the intervention group, while the decrease was 0.4 ± 1.3 kg/m2 in the control group (p = 0.015). Fat mass decreased in the intervention group (p < 0.001) and muscle mass improved in the intervention group and decreased in the control group (p < 0.05). CONCLUSIONS: A plant-based, high-protein diet during CT resulted in positive changes in fatigue, BMI and body composition.

The clinical utility and safety of short-course immune checkpoint inhibitors in multiple tumours-A real-world multicentric study from India.

The real-world data on short course of immune checkpoint inhibitor (ICI) use are sparse and merit exploration. A multicentric observational study on the safety and efficacy of ICI in oncology patients between August 2014 and October 2020 involves 1011 patients across 13 centers in India. The median age was 59 (min 16-max 98) years with male preponderance (77.9%). The predominant cohort received short-course ICI therapy; the median number of cycles was 5 (95% confidence interval [CI] 1-27), and the median duration of therapy was 3 (95% CI 0.5-13) months. ICIs were used commonly in the second and third line setting in our study (66.4%, n = 671). Objective response rate (complete or partial response) was documented in 254 (25.1%) of the patients, 202 (20.0%) had stable disease, and 374 (37.0%) had progressive disease. The clinical benefit rate was present in 456 (45.1%). Among the patients whom ICI was stopped (n = 906), the most common reason for cessation of ICI was disease progression (616, 68.0%) followed by logistic reasons like financial constraints (234, 25.82%). With a median follow-up of 14.1 (95% CI 12.9-15.3) months, there were 616 events of progression and 443 events of death, and the median progression free survival and overall survival were 6.4 (95% CI 5.5-7.3) and 13.6 (95% CI 11.6-15.7) months, respectively, in the overall cohort. Among the immune-related adverse events, autoimmune pneumonitis (29, 3.8%) and thyroiditis (24, 2.4%) were common. Real-world multicentric Indian data predominantly with short-course ICI therapy have comparable efficacy/safety to international literature with standard ICI therapy.

Efficacy of scaffold-mediated localized chemotherapy in cancer: A systematic review of current research.

OBJECTIVE: To assess the efficacy of scaffold-mediated localized chemotherapy in cancer. METHODS: Databases including PubMed, Cochrane Library, and SCOPUS were searched for articles reporting the use of scaffold-mediated localized drug delivery in cancer. Essential data including scaffold fabrication material and methods, drug dosage and release duration and its effect on the cancer cells were extracted. RESULTS: 15 articles out of 60 screened, fulfilled the eligibility criteria. Among the 15 studies, 5 studies included only cell lines and 2 studies were on mouse models, while 8 studies involved a combination of cell lines and mouse models. Scaffold materials included both synthetic polymers such as poly-lactide, polycaprolactone and natural materials including d-periosteum and human micro-fragmented adipose tissueA wide number of other variables included the fabrication procedure, drugs used, and the methods used to assess the effects on cancer. As a result, it was not possible to make any direct comparison of the efficacy of the therapeutic strategy used in each of these studies. CONCLUSION: Irrespective of the many variables, a common consensus in all the included studies was that scaffold mediated localized drug delivery effectively reduced cancer cell viability by increasing drug bioavailability to the target tissue, while its localized effect reduced the risk of systemic toxicity.

Is toombak a risk factor for oral leukoplakia and oral squamous cell carcinoma ? A systematic review.

INTRODUCTION: Toombak is a form of smokeless tobacco that is not well known in Western Society but is widely used by the Sudanese population and many others in the sub-Sahara region. However, unlike other smokeless tobacco products, information on the carcinogenic potential of toombak is scarce. The present review explored any potential epidemiological association between the use of toombak and oral leukoplakia and oral squamous cell carcinoma (OSCC). METHODS: Databases including the Web of Science, SCOPUS, EMBASE and PubMed were searched for literature on the potential association between toombak and oral leukoplakia and OSCC. The search also included grey literature. The search period extended from 1990 to 2018. Following data mining, the study selection was conducted by two reviewers independently. RESULTS: Eight studies that satisfied the inclusion criteria were included. Based on these results, there was a threefoldto sevenfold increased risk of developing the oral leukoplakia and oral squamous cell carcinoma among toombak users compared with non-users. CONCLUSION: Based on the results of the systematic review, there is a strong epidemiological evidence to suggest toombak to be a major risk factor for both oral leukoplakia and OSCC. Further studies are necessary to evaluate the molecular pathway of toombak-induced oral carcinogenesis.

Ganglioglioma in children and young adults: single institution experience and review of the literature.

BACKGROUND: Ganglioglioma (GG) is a rare mixed glial-neuronal neoplasm accounting for 0.5-5% of all pediatric central nervous system (CNS) tumors. Rarity of this tumor has precluded defining robust treatment guidelines. This retrospective study evaluates the prognostic factors and outcomes of this rare neoplasm. PATIENTS AND METHODS: Retrospective analysis of 55 patients with GG was conducted to describe clinical findings, and outcomes. Kaplan-Meier survival and Cox-regression analyses were performed to assess the overall survival (OS) and progression-free survival (PFS). RESULTS: The mean age at diagnosis was 11.8 years (range 1-21 years) with a median follow-up period of 9.5 years. 53 patients (92.7%) had low grade GG and 2 patients had anaplastic GG. 25 patients had tumor progression, whose median PFS was 12 years. Six patients with low grade GG progressed to a higher grade, with median survival of 9.1 month after transformation. The 5 and 10 year PFS were 65 and 57%, respectively. The 5 and 10 year OS was 96 and 86% respectively. 8 of the 19 (42%) samples tested demonstrated positivity for the BRAF V600E mutation. Multivariate Cox regression analyses showed location and extent of resection were significant factors for PFS and presence of metastatsis attained significance for OS. CONCLUSION: This is the one of the largest retrospective study of pediatric GG. Identifying clinical variables, which could stratify these tumors into low- and high-risk groups might help to profile a risk-based therapeutic strategy. Collaborative multiinstitutional prospective studies are warranted to delineate treatment consensus and investigate prognostic factors.

Stiripentol efficacy and safety in Dravet syndrome: a 12-year observational study.

AIM: To assess long-term safety and efficacy of stiripentol as an antiepileptic medication for people with Dravet syndrome. METHOD: A prospective, observational open-label study (2003-2015) of the efficacy and long-term safety of stiripentol in patients with Dravet syndrome and ongoing seizures. Frequency of generalized tonic-clonic seizures, focal seizures, status epilepticus, and adverse events were recorded. RESULTS: Forty-one patients started stiripentol, with median age at enrolment 5 years 7 months (range 11mo-22y) and median duration of treatment 37 months (range 2-141mo). Twenty out of 41 patients had greater than or equal to 50% long-term reduction in frequency of generalized tonic-clonic seizures. Frequency of focal seizures was decreased by greater than or equal to 50% in 11 out of 23 patients over the long-term. Frequency of status epilepticus was decreased by 50% or more in 11 out of 26 patients. The most common adverse events were anorexia, weight loss, sedation, and behavioural changes. One patient had worsening of absence and myoclonic seizures. Another developed recurrent pancreatitis on concurrent valproate. INTERPRETATION: Stiripentol improves long-term seizure frequency in approximately 50% of patients with Dravet syndrome, when used as part of unrestricted polytherapy. Long-term use appears safe. In more than 40% of patients, episodes of status epilepticus markedly decrease after stiripentol initiation. What this paper adds Frequency of status epilepticus is reduced in 40% of patients with Dravet syndrome after stiripentol initiation. Stiripentol is effective for generalized tonic-clonic and focal seizures. Stiripentol can be safely used with a range of antiepileptic drugs.

HR+HER2- breast cancers with growth factor receptor-mediated EMT have a poor prognosis and lapatinib downregulates EMT in MCF-7 cells.

Despite an overall good prognosis, a significant proportion of patients with hormone receptor positive human epidermal growth factor receptor 2 negative breast cancers develop distant metastases. The metastatic potential of epithelial cells is known to be regulated by tumor-stromal interaction and mediated by epithelial-to-mesenchymal transition. Hormone receptor positive human epidermal growth factor receptor 2 negative tumors were used to estimate markers of epithelial-to-mesenchymal transition, and the luminal breast cancer cell line MCF-7 was used to examine the interactions between integrins and growth factor receptors in causation of epithelial-to-mesenchymal transition. A total of 140 primary tumors were sub-divided into groups enriched for the markers of epithelial-to-mesenchymal transition (snail family transcriptional repressor 2 and integrin ß6) versus those with low levels. Within the epithelial-to-mesenchymal transition+ tumors, there was a positive correlation between the transcripts of integrin ß6 and growth factor receptors-human epidermal growth factor receptor 2 and epidermal growth factor receptor. In tumors enriched for epithelial-to-mesenchymal transition markers, patients with tumors with the highest quartile of growth factor receptor transcripts had a shorter disease-free survival compared to patients with low growth factor receptor expression by Kaplan-Meier analysis (log rank, p = 0.03). Epithelial-to-mesenchymal transition was induced in MCF-7 cells by treatment with transforming growth factor beta 1 and confirmed by upregulation of SNAI1 and SNAI2 transcripts, increase of vimentin and integrin ß6 protein, and repression of E-cadherin. Treatment of these cells with the dual-specificity tyrosine-kinase inhibitor lapatinib led to downregulation of epithelial-to-mesenchymal transition as indicated by lower levels of SNAI1 and SNAI2 transcripts, integrin αvß6, and matrix metalloproteinase 9 protein. The results suggest that synergistic interactions between growth factor receptors and integrin ß6 could mediate epithelial-to-mesenchymal transition and migration in a subset of luminal breast cancers and lapatinib might be effective in disrupting this interaction.

Maturation of cortical circuits requires Semaphorin 7A.

Abnormal cortical circuits underlie some cognitive and psychiatric disorders, yet the molecular signals that generate normal cortical networks remain poorly understood. Semaphorin 7A (Sema7A) is an atypical member of the semaphorin family that is GPI-linked, expressed principally postnatally, and enriched in sensory cortex. Significantly, SEMA7A is deleted in individuals with 15q24 microdeletion syndrome, characterized by developmental delay, autism, and sensory perceptual deficits. We studied the role that Sema7A plays in establishing functional cortical circuitry in mouse somatosensory barrel cortex. We found that Sema7A is expressed in spiny stellate cells and GABAergic interneurons and that its absence disrupts barrel cytoarchitecture, reduces asymmetrical orientation of spiny stellate cell dendrites, and functionally impairs thalamocortically evoked synaptic responses, with reduced feed-forward GABAergic inhibition. These data identify Sema7A as a regulator of thalamocortical and local circuit development in layer 4 and provide a molecular handle that can be used to explore the coordinated generation of excitatory and inhibitory cortical circuits.

Effects of Yoga in Managing Fatigue in Breast Cancer Patients: A Randomized Controlled Trial.

BACKGROUND: Cancer-related fatigue is widely prevalent in cancer patients and affects quality of life in advanced cancer patients. Fatigue is caused due to both psychologic distress and physiological sequel following cancer progression and its treatment. In this study, we evaluate the effects of yogic intervention in managing fatigue in metastatic breast cancer patients. METHODS: Ninety-one patients with metastatic breast cancer were randomized to receive integrated yoga program (n = 46) or supportive therapy and education (n = 45) over a 3-month period. Assessments such as perceived stress, fatigue symptom inventory, diurnal salivary cortisol, and natural killer cell counts were carried out before and after intervention. Analysis was done using an intention-to-treat approach. Postmeasures for the above outcomes were assessed using ANCOVA with respective baseline measure as a covariate. RESULTS: The results suggest that yoga reduces perceived stress (P = 0.001), fatigue frequency (P < 0.001), fatigue severity (P < 0.001), interference (P < 0.001), and diurnal variation (P < 0.001) when compared to supportive therapy. There was a positive correlation of change in fatigue severity with 9 a.m. salivary cortisol levels. CONCLUSION: The results suggest that yoga reduces fatigue in advanced breast cancer patients.

Effect of Yoga on Sleep Quality and Neuroendocrine Immune Response in Metastatic Breast Cancer Patients.

BACKGROUND: Studies have shown that distress and accompanying neuroendocrine stress responses as important predictor of survival in advanced breast cancer patients. Some psychotherapeutic intervention studies have shown have modulation of neuroendocrine-immune responses in advanced breast cancer patients. In this study, we evaluate the effects of yoga on perceived stress, sleep, diurnal cortisol, and natural killer (NK) cell counts in patients with metastatic cancer. METHODS: In this study, 91 patients with metastatic breast cancer who satisfied selection criteria and consented to participate were recruited and randomized to receive "integrated yoga based stress reduction program" (n = 45) or standard "education and supportive therapy sessions" (n = 46) over a 3 month period. Psychometric assessments for sleep quality were done before and after intervention. Blood draws for NK cell counts were collected before and after the intervention. Saliva samples were collected for three consecutive days before and after intervention. Data were analyzed using the analysis of covariance on postmeasures using respective baseline measure as a covariate. RESULTS: There was a significant decrease in scales of symptom distress (P < 0.001), sleep parameters (P = 0.02), and improvement in quality of sleep (P = 0.001) and Insomnia Rating Scale sleep score (P = 0.001) following intervention. There was a decrease in morning waking cortisol in yoga group (P = 0.003) alone following intervention. There was a significant improvement in NK cell percent (P = 0.03) following intervention in yoga group compared to control group. CONCLUSION: The results suggest modulation of neuroendocrine responses and improvement in sleep in patients with advanced breast cancer following yoga intervention.

Effects of a Yoga Program on Mood States, Quality of Life, and Toxicity in Breast Cancer Patients Receiving Conventional Treatment: A Randomized Controlled Trial.

AIMS: The aim of this study is to compare the effects of yoga program with supportive therapy counseling on mood states, treatment-related symptoms, toxicity, and quality of life in Stage II and III breast cancer patients on conventional treatment. METHODS: Ninety-eight Stage II and III breast cancer patients underwent surgery followed by adjuvant radiotherapy (RT) or chemotherapy (CT) or both at a cancer center were randomly assigned to receive yoga (n = 45) and supportive therapy counseling (n = 53) over a 24-week period. Intervention consisted of 60-min yoga sessions, daily while the control group was imparted supportive therapy during their hospital visits. Assessments included state-trait anxiety inventory, Beck's depression inventory, symptom checklist, common toxicity criteria, and functional living index-cancer. Assessments were done at baseline, after surgery, before, during, and after RT and six cycles of CT. RESULTS: Both groups had similar baseline scores. There were 29 dropouts 12 (yoga) and 17 (controls) following surgery. Sixty-nine participants contributed data to the current analysis (33 in yoga, and 36 in controls). An ANCOVA, adjusting for baseline differences, showed a significant decrease for the yoga intervention as compared to the control group during RT (first result) and CT (second result), in (i) anxiety state by 4.72 and 7.7 points, (ii) depression by 5.74 and 7.25 points, (iii) treatment-related symptoms by 2.34 and 2.97 points, (iv) severity of symptoms by 6.43 and 8.83 points, (v) distress by 7.19 and 13.11 points, and (vi) and improved overall quality of life by 23.9 and 31.2 points as compared to controls. Toxicity was significantly less in the yoga group (P = 0.01) during CT. CONCLUSION: The results suggest a possible use for yoga as a psychotherapeutic intervention in breast cancer patients undergoing conventional treatment.

Paclitaxel injection concentrate for nanodispersion versus nab-paclitaxel in women with metastatic breast cancer: a multicenter, randomized, comparative phase II/III study.

Paclitaxel is widely used in the treatment of patients with metastatic breast cancer (MBC). Formulations of paclitaxel contain surfactants and solvents or albumin derived from human blood. The use of co-solvents such as polyoxyethylated castor oil is thought to contribute to toxicity profile and hypersensitivity reactions as well as leaching of plasticizers from polyvinyl chloride bags and infusion sets. Currently, nab-paclitaxel, an albumin-bound paclitaxel in nanometer range continues to be the preferred taxane formulation used in clinic. This study (CTRI/2010/091/001116) investigated the efficacy and tolerability of a polyoxyethylated castor oil- and albumin-free formulation of paclitaxel [paclitaxel injection concentrate for nanodispersion (PICN)] compared with nab-paclitaxel in women with refractory MBC. The current study was a multicenter, open-label, parallel-group, randomized, comparative phase II/III trial evaluating the efficacy and safety of PICN (260 mg/m(2) [n = 64] and 295 mg/m(2) [n = 58] every 3 weeks) compared with nab-paclitaxel (260 mg/m(2) every 3 weeks [n = 58]) in women 18 and 70 years old with confirmed MBC. Overall response rate (ORR) was assessed with imaging every 2 cycles. An independent analysis of radiologic data was performed for evaluable patients. Progression-free survival (PFS) was a secondary efficacy measure. Independent radiologist-assessed ORRs in the evaluable population of women aged ≥70 years were 35, 49, and 43 % in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Median PFS in the evaluable population was 23, 35, and 34 weeks in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Adverse events occurred in similar proportions of patients across treatment arms. Hypersensitivity reactions were not frequently observed with the clinical use of PICN across the treatment cohorts. In women with metastatic breast cancer, PICN at 260 and 295 mg/m(2) every 3 weeks was effective and well tolerated and showed similar tolerability compared with nab-paclitaxel 260 mg/m(2) every 3 weeks. Statistically, significant differences were not observed in the PICN and nab-paclitaxel treatment arms for radiologist-assessed ORR or median PFS. The novel paclitaxel formulation, PICN, offers apart from efficacy, potential safety advantage of decreased use of corticosteroid pretreatment and the absence of the risk of transmission of blood product-borne disease.

N-cadherin regulates molecular organization of excitatory and inhibitory synaptic circuits in adult hippocampus in vivo.

N-Cadherin and ß-catenin form a transsynaptic adhesion complex required for spine and synapse development. In adulthood, N-cadherin mediates persistent synaptic plasticity, but whether the role of N-cadherin at mature synapses is similar to that at developing synapses is unclear. To address this, we conditionally ablated N-cadherin from excitatory forebrain synapses in mice starting in late postnatal life and examined hippocampal structure and function in adulthood. In the absence of N-cadherin, ß-catenin levels were reduced, but numbers of excitatory synapses were unchanged, and there was no impact on number or shape of dendrites or spines. However, the composition of synaptic molecules was altered. Levels of GluA1 and its scaffolding protein PSD95 were diminished and the density of immunolabeled puncta was decreased, without effects on other glutamate receptors and their scaffolding proteins. Additionally, loss of N-cadherin at excitatory synapses triggered increases in the density of markers for inhibitory synapses and decreased severity of hippocampal seizures. Finally, adult mutant mice were profoundly impaired in hippocampal-dependent memory for spatial episodes. These results demonstrate a novel function for the N-cadherin/ß-catenin complex in regulating ionotropic receptor composition of excitatory synapses, an appropriate balance of excitatory and inhibitory synaptic proteins and the maintenance of neural circuitry necessary to generate flexible yet persistent cognitive and synaptic function.

Lung cancer imaging.

Lung cancer remains the leading cause of cancer-related deaths in the US. Imaging plays an important role in the diagnosis, staging, and follow-up evaluation of patients with lung cancer. With recent advances in technology, it is important to update and standardize the radiological practices in lung cancer evaluation. In this article, the authors review the main clinical applications of different imaging modalities and the most common radiological presentations of lung cancer.

Preliminary experience with diffusion tensor imaging before and after re-irradiation treatments in children with progressive diffuse pontine glioma.

PURPOSE: The purpose of this study is to evaluate quantitative changes in diffusion tensor imaging (DTI) tractography and fractional anisotropy (FA) of the pons along with clinical correlation, in patients who receive re-irradiation for progressive diffuse intrinsic pontine glioma (DIPG). METHODS: A retrospective case review of children with progressive DIPG who received re-irradiation at our institution from 2007 to 2011 after approval from the Institutional Review Board was performed. Tractography analysis and FA were analyzed pre and post-re-irradiation, and correlation with clinical features and MR imaging was performed. RESULTS: DTI analysis showed reduced values of FA on tumor progression. Increase in the FA values was noted after re-irradiation in these patients. This correlated with clinical improvement. These changes were concordant with the 3D tractography analysis which showed better visualization of the corticospinal tracts as they course through brainstem and posterior transverse pontine fibers following re-irradiation. CONCLUSION: Serial changes in the FA values using DTI could provide clinically more correlative information in patients with progressive DIPG, who receive re-irradiation. Though the use and results of this modality has been reported in the newly diagnosed DIPG before, evaluation of DTI in children who receive re-irradiation for progressive DIPG has not been reported earlier. Though limited by the small sample size and treatment variability, this study for the first time shows the preliminary experience, potential, and likely efficacy of complementing DTI analysis to routine neuroimaging also in patients re-irradiated for progressive DIPG to better assess treatment response.

Regeneration of axons in injured spinal cord by activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons.

Axon growth potential is highest in young neurons but diminishes with age, thus becoming a significant obstacle to axonal regeneration after injury in maturity. The mechanism for the decline is incompletely understood, and no effective clinical treatment is available to rekindle innate growth capability. Here, we show that Smad1-dependent bone morphogenetic protein (BMP) signaling is developmentally regulated and governs axonal growth in dorsal root ganglion (DRG) neurons. Down-regulation of the pathway contributes to the age-related decline of the axon growth potential. Reactivating Smad1 selectively in adult DRG neurons results in sensory axon regeneration in a mouse model of spinal cord injury (SCI). Smad1 signaling can be effectively manipulated by an adeno-associated virus (AAV) vector encoding BMP4 delivered by a clinically applicable and minimally invasive technique, an approach devoid of unwanted abnormalities in mechanosensation or pain perception. Importantly, transected axons are able to regenerate even when the AAV treatment is delivered after SCI, thus mimicking a clinically relevant scenario. Together, our results identify a therapeutic target to promote axonal regeneration after SCI.

Early developmental outcomes in children following convulsive status epilepticus: a longitudinal study.

PURPOSE: Convulsive status epilepticus (CSE) is the most common pediatric neurologic emergency and is often associated with unfavorable neurodevelopmental outcomes. The early developmental trajectory of children following CSE has not been previously investigated, leaving a gap in our understanding of how these adverse long-term outcomes emerge. METHODS: We prospectively recruited children aged between 1 and 42 months from a predefined geographic region of North London who had at least one episode of CSE and classified them as prolonged febrile seizures (PFS) or nonfebrile CSE. Neuropsychological and imaging investigations were conducted within 6 weeks of CSE (baseline) and were repeated a year later (follow-up). Neurodevelopment was assessed using the Bayley Scales of Infant Development III and compared to normally developing children. Predictors of neurodevelopmental scores at baseline and follow-up were investigated using regression analyses. KEY FINDINGS: Of the 54 children that underwent investigations a mean of 38 days following CSE, 27 had PFS (mean age 18.4 months) and 27 had nonfebrile CSE (mean age 15.5 months). In addition, 17 healthy controls were assessed (mean age 20.49 months). Children with nonfebrile CSE had a worse developmental outcome than children with PFS (p < 0.002), despite there being no differences in seizure characteristics. In contrast to expectations, the PFS group had a worse developmental outcome than controls (p = 0.002). There were no significant differences in performance from baseline to 1-year follow-up for the 70.4% of children who provided data. Seizure characteristics were not shown to be significant predictors of performance. SIGNIFICANCE: CSE is associated with developmental impairments within 6 weeks of the acute event that continue to be present a year onward. This is also true of PFS cases that under-perform relative to controls despite mean scores within the clinically normal range. The absence of a change in performance from baseline to follow-up as well as the lack of a relationship between seizure characteristics and developmental outcomes supports the notion that premorbid abilities may be overshadowing any direct effects of CSE itself on outcome.

Recognition memory is impaired in children after prolonged febrile seizures.

Children with a history of a prolonged febrile seizure show signs of acute hippocampal injury on magnetic resonance imaging. In addition, animal studies have shown that adult rats who suffered febrile seizures during development reveal memory impairments. Together, these lines of evidence suggest that memory impairments related to hippocampal injury may be evident in human children after prolonged febrile seizures. The current study addressed this question by investigating memory abilities in 26 children soon after a prolonged febrile seizure (median: 37.5 days) and compared their results to those of 37 normally developing children. Fifteen patients were reassessed at a mean of 12.5 months after their first assessment to determine the transiency of any observed effects. We used the visual paired comparison task to test memory abilities in our group, as this task does not depend on verbal abilities and also because successful performance on the task has been proven to depend on the presence of functional hippocampi. Our findings show that patients perform as well as controls in the absence of a delay between the learning phase and the memory test, suggesting that both groups are able to form representations of the presented stimulus. However, after a 5-min delay, patients' recognition memory is not different from chance, and comparison of patients and controls points to an accelerated forgetting rate in the prolonged febrile seizure group. The patients' performance was not related to the time elapsed from the acute event or the duration of the prolonged febrile seizure, suggesting that the observed effect is not a by-product of the seizure itself or a delayed effect of medication administered to terminate the seizure. By contrast, performance was related to hippocampal size; participants with the smallest mean hippocampal volumes revealed the biggest drop in performance from the immediate to the delayed paradigm. At follow-up, children were still showing deficiencies in recognizing a face after a 5-min delay. Similarly, this suggests that the observed memory impairments are not a transient effect of the prolonged febrile seizures. This is the first report of such impairments in humans, and it is clinically significant given the links between mesial temporal sclerosis and prolonged febrile seizures. The persistence of these impairments a year onwards signals the potential benefits of intervention in these children who run the risk of developing episodic memory deficits in later childhood.

Survival of Trial-Like and Non-Trial-Like Patients With Immunotherapy in Advanced Hepatocellular Carcinoma in Real World: A Collaborative Multicenter Indian Study (IMHEP).

PURPOSE: Immune checkpoint inhibitors (ICIs) is the initial line of management in advanced hepatocellular carcinoma (HCC), but survivals in the real world are not known. MATERIALS AND METHODS: A retrospective study of patients with advanced HCC receiving ICIs (as first-line therapy or as later lines of therapy) across 11 Indian institutions was conducted. Patients were divided into either cohort 1 (trial-like receiving ICI as first-line therapy), with a Child Pugh score (CTP) of ≤6, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1, and no VP4 (main portal vein thrombosis [MPVT]) or cohort 2 (trial unlike) who did not satisfy at least one of the above criteria. The primary end point was 12-month overall survival (OS). RESULTS: Between January 2017 and January 2022, 133 patient data were analyzed. The presence of MPVT was seen in 33 patients (25%). The ICIs used were atezolizumab-bevacizumab, nivolumab, and pembrolizumab in 89 (66%), 44 (33%), and one (1%) patients, respectively. With a median follow-up of 13.8 months, the 12-month OS for the entire cohort was 33.4% (95% CI, 23.6 to 43.2). Patients in cohort 1 (n = 31) had a significantly improved OS compared with patients in cohort 2 (n = 102; 12-month OS, 57.9% [95% CI, 38.5 to 77.3] v 24% [95% CI, 13.4 to 34.6]; P = .005). Patients with CTP A as compared with CTP B (9.7 v 4.3 months; P < .001) and an ECOG PS of 0/1 as compared with a PS of ≥2 (8.7 v 7.2 months; P = .04) and without MPVT (9.4 v 4.0; P < .001) had superior survivals. CONCLUSION: Patients with advanced HCC in the real world, trial-like have survivals in consonance with trial data, whereas patients with features excluding them from trials, such as main portal vein thrombosis, poor ECOG PS, and child Pugh B status, have markedly inferior survivals, despite good tolerance to immunotherapy.

Synaptic loss and retention of different classic cadherins with LTP-associated synaptic structural remodeling in vivo.

Cadherins are synaptic cell adhesion molecules that contribute to persistently enhanced synaptic strength characteristic of long-term potentiation (LTP). What is relatively unexplored is how synaptic activity of the kind that induces LTP-associated remodeling of synapse structure affects localization of cadherins, particularly in mature animals in vivo, details which could offer insight into how different cadherins contribute to synaptic plasticity. Here, we use a well-described in vivo LTP induction protocol that produces robust synaptic morphological remodeling in dentate gyrus of adult rats in combination with confocal and immunogold electron microscopy to localize cadherin-8 and N-cadherin at remodeled synapses. We find that the density and size of cadherin-8 puncta are significantly diminished in the potentiated middle molecular layer (MML) while concurrently, N-cadherin remains tightly clustered at remodeled synapses. These changes are specific to the potentiated MML, and occur without any change in density or size of synaptophysin puncta. Thus, the loss of cadherin-8 probably represents selective removal from synapses rather than overall loss of synaptic junctions. Together, these findings suggest that activity-regulated loss and retention of different synaptic cadherins could contribute to dual demands of both flexibility and stability in synapse structure that may be important for synaptic morphological remodeling that accompanies long-lasting plasticity.