A phase II study of cabozantinib and pembrolizumab in advanced gastric/gastroesophageal adenocarcinomas resistant or refractory to immune checkpoint inhibitors.

BACKGROUND: Most patients with metastatic gastroesophageal adenocarcinoma (mGEA) progress on immune checkpoint inhibitors (ICIs). Novel approaches to overcome resistance to ICI in mGEA are needed. Cabozantinib is a multi-tyrosine kinase inhibitor thought to enhance the immunomodulatory effects of ICI. This study evaluated the combination of cabozantinib and pembrolizumab in ICI refractory or resistant mGEA. METHODS: Investigator-initiated, single-arm, single institution, and phase II study in patients with mGEA. Patients had progressed on ICI and/or had PD-L1 CPS score ≤10%. Cabozantinib dose was 40 mg p.o. daily on days 1-21 of a 21-day cycle, with pembrolizumab 200 mg i.v. on day 1. The primary endpoint was progression-free survival at 6 months (PFS-6). RESULTS: Twenty-seven patients were enrolled. Median age 58 years (24-87), female (n = 14), ECOG 0/1 = 13/14, GC/GEJ = 16/11, and non-Hispanic White/Hispanic/Asian = 12/8/7. The primary endpoint was met. After a median follow-up of 31.4 months (range 3.3-42.5), PFS-6 was 22.2% (95% CI 9.0-39.0). The median PFS and OS are 2.3 months (95% CI 1.7-4.1) and 5.5 months (3.1-14.0), respectively. The most common mutations were TP53 (78.3%) and CDH1/PIK3CA/CTNNB1 (17.4% each). The most common grade (G) treatment-related adverse events (TRAE) were diarrhea (25.9%), fatigue (18.5%), hypertension, and muscle cramps (14.8% each). G3-4 TRAE were seen in n = 3 patients (hypertension, thromboembolic event, esophageal perforation; each n = 1). No G5 was observed. CONCLUSIONS: The addition of cabozantinib to pembrolizumab shows clinical benefit in ICI-resistant or refractory mGEA with a tolerable safety profile. (ClinicalTrials.gov Identifier: NCT04164979. IRB Approved: UCI 18-124, University of California Irvine IRB#20195426.).

Hereditary Cancer Clinics Improve Adherence to NCCN Germline Testing Guidelines for Pancreatic Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year overall survival rate of 10%. In November 2018, NCCN recommended that all patients with PDAC receive genetic counseling (GC) and germline testing regardless of family history. We hypothesized that patients with PDAC were more likely to be referred for testing after this change to the guidelines, regardless of presumed predictive factors, and that compliance would be further improved following the implementation of a hereditary cancer clinic (HCC). METHODS: We conducted a single-institution retrospective analysis of patients diagnosed with PDAC from June 2017 through December 2021 at University of California, Irvine. We compared rates of genetics referral among patients in different diagnostic eras: the 18-month period before the NCCN Guideline change (pre-NCCN era: June 2017 through November 2018), 14 months following the change (post-NCCN era: December 2018 through January 2020), and 18 months after the creation of an HCC (HCC era: June 2020 through December 2021). Family and personal cancer history, genetics referral patterns, and results of GC were recorded. Data were compared using chi-square, Fisher exact, and multivariate analyses. RESULTS: A total of 335 patients were treated for PDAC (123 pre-NCCN, 109 post-NCCN, and 103 HCC) at University of California, Irvine. Demographics across groups were comparable. Prior to the guideline changes, 30% were referred to GC compared with 54.7% in the post-NCCN era. After the implementation of the HCC, 77.4% were referred to GC (P<.0001). The odds ratio (OR) for referral to GC among patients with a positive family history of cancer progressively decreased following the change (pre-NCCN era: OR, 11.90 [95% CI, 3.00-80.14]; post-NCCN era: OR, 3.39 [95% CI, 1.13-10.76]; HCC era: OR, 3.11 [95% CI, 0.95-10.16]). CONCLUSIONS: The 2018 updates to the NCCN Guidelines for PDAC recommending germline testing for all patients with PDAC significantly increased GC referral rates at our academic medical center. Implementation of an HCC further boosted compliance with guidelines.

Transcriptome data from silica-preserved leaf tissue reveal gene flow patterns in a Caribbean bromeliad.

BACKGROUND AND AIMS: Transcriptome sequencing is a cost-effective approach that allows researchers to study a broad range of questions. However, to preserve RNA for transcriptome sequencing, tissue is often kept in special conditions, such as immediate ultracold freezing. Here, we demonstrate that RNA can be obtained from 6-month-old, field-collected samples stored in silica gel at room temperature. Using these transcriptomes, we explore the evolutionary relationships of the genus Pitcairnia (Bromeliaceae) in the Dominican Republic and infer barriers to gene flow. METHODS: We extracted RNA from silica-dried leaf tissue from 19 Pitcairnia individuals collected across the Dominican Republic. We used a series of macro- and micro-evolutionary approaches to examine the relationships and patterns of gene flow among individuals. KEY RESULTS: We produced high-quality transcriptomes from silica-dried material and demonstrated that evolutionary relationships on the island match geography more closely than species delimitation methods. A population genetic examination indicates that a combination of ecological and geographical features presents barriers to gene flow in Pitcairnia. CONCLUSIONS: Transcriptomes can be obtained from silica-preserved tissue. The genetic diversity among Pitcairnia populations does not warrant classification as separate species, but the Dominican Republic contains several barriers to gene flow, notably the Cordillera Central mountain range.

How did UK social distancing restrictions affect the lives of women experiencing intimate partner violence during the COVID-19 pandemic? A qualitative exploration of survivor views.

BACKGROUND: Increased numbers of domestic abuse cases were reported at the start of the COVID-19 pandemic. Many people experiencing abuse faced barriers to seeking support with service closures affecting the sector. Available evidence suggests women are overrepresented in the reported cases of intimate partner violence (IPV) and we aimed to learn more about how their lives were impacted by social distancing restrictions. METHODS: We conducted an online qualitative interview study, using reflexive thematic analysis. Interviews were conducted between April 2021 and March 2022. 18 women in the UK with past experiences of IPV provided informed consent and participated in this study. RESULTS: During the analysis, we identified five themes relating to the impact of lockdown restrictions on participants' lives, including: (1) Lockdown meant being confined to a place where abuse was escalating, (2) Barriers to accessing support, including "cancelled" services and missed opportunities to intervene during interactions in lockdown with frontline workers. (3) Increased feelings of fear, isolation, and loss of control, particularly during the early stages of the pandemic from the combination of abuse and pandemic-related changes to daily life. (4) Some forms of support were more accessible during the pandemic, such as provision of online psychological support and social groups. Participants also accessed new forms of support for the first time during the pandemic, in some cases sparked by posts and content on social media about abuse awareness. (5) For some, psychosocial wellbeing transformed during the pandemic, with several participants using the word "freedom" when reflecting on their experience of simultaneously escaping abuse and living through the COVID-19 pandemic. CONCLUSIONS: In this study, we explored the views of female survivors of IPV in the UK during the COVID-19 pandemic. Our results highlight the importance of combined public awareness campaigns and community intervention points for victims to safely seek help during social distancing restrictions. Having the time and space to reflect on healing after escaping abuse was described by women in our study as a benefit from their lives in lockdown, which is a factor that could be incorporated into future initiatives developed to support people subjected to violence and abuse.

The molecular and cellular basis of copper dysregulation and its relationship with human pathologies.

Copper (Cu) is an essential micronutrient required for the activity of redox-active enzymes involved in critical metabolic reactions, signaling pathways, and biological functions. Transporters and chaperones control Cu ion levels and bioavailability to ensure proper subcellular and systemic Cu distribution. Intensive research has focused on understanding how mammalian cells maintain Cu homeostasis, and how molecular signals coordinate Cu acquisition and storage within organs. In humans, mutations of genes that regulate Cu homeostasis or facilitate interactions with Cu ions lead to numerous pathologic conditions. Malfunctions of the Cu+ -transporting ATPases ATP7A and ATP7B cause Menkes disease and Wilson disease, respectively. Additionally, defects in the mitochondrial and cellular distributions and homeostasis of Cu lead to severe neurodegenerative conditions, mitochondrial myopathies, and metabolic diseases. Cu has a dual nature in carcinogenesis as a promotor of tumor growth and an inducer of redox stress in cancer cells. Cu also plays role in cancer treatment as a component of drugs and a regulator of drug sensitivity and uptake. In this review, we provide an overview of the current knowledge of Cu metabolism and transport and its relation to various human pathologies.

A phase Ib feasibility trial of response adapted neoadjuvant therapy in gastric cancer (RANT-GC).

Current guidelines recommend neoadjuvant (NAC) and/or adjuvant chemotherapy for locally advanced gastric cancers (LAGCs). However, the choice and duration of NAC regimen is standardized, rather than personalized to biologic response, despite the availability of several different classes of agents for the treatment of gastric cancer (GC). The current trial will use a tumor-informed ctDNA assay (Signatera™) and monitor response to NAC. Based on ctDNA kinetics, the treatment regimen is modified. This is a prospective single center, single-arm, open-label study in clinical stage IB-III GC. ctDNA is measured at baseline and repeated every 8 weeks. Imaging is performed at the same intervals. The primary end point is the feasibility of this approach, defined as percentage of patients completing gastrectomy.

Evaluation of a primary antifungal prophylaxis protocol for preventing invasive mold infections after allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Invasive mold infections contribute to morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation. The optimal strategy for primary antifungal prophylaxis in this patient population remains uncertain. METHODS: Medical records of patients who underwent allogeneic hematopoietic stem cell transplantation between 1 January 2013 and 31 December 2017 were retrospectively reviewed. Adult patients were included if they received micafungin followed by fluconazole, with the option to escalate to voriconazole, for antifungal prophylaxis. The primary outcome was the incidence rate of proven or probable invasive mold infection. Secondary outcomes were time to invasive mold infection diagnosis, invasive mold infection-related mortality, and risk factors associated with invasive mold infection. RESULTS: Two hundred patients were included in the study, a majority of whom underwent matched unrelated (46%) or matched related (33%) donor transplants. The incidence rate of proven or probable invasive mold infection was 18.4 cases per 100 patient-years, with a one-year cumulative incidence of 14%. Median time to proven or probable invasive mold infection was 94 days post-transplant (IQR 26-178), with invasive mold infection-related mortality occurring in 18 (64%) of 28 patients diagnosed with invasive mold infection. Comparison of invasive mold infection-free survival by potential risk factors failed to show any significant differences. CONCLUSIONS: In this real-life cohort of allogeneic hematopoietic stem cell transplantation recipients, the incidence of proven or probable invasive mold infection was higher than expected based on previous literature. In the absence of standard guidance on anti-mold prophylaxis in this patient population and given that unique risk factors for invasive mold infection may differ between institutions, it is essential that centers performing allogeneic hematopoietic stem cell transplantation routinely monitor their antifungal prophylaxis strategies for effectiveness.

Splice correction therapies for familial hypercholesterolemic patients with low-density lipoprotein receptor mutations.

PURPOSE OF REVIEW: Antisense oligomers (ASOs) have been available for decades: however, only recently have these molecules been applied clinically. This review aims to discuss the possible development of antisense-mediated splice correction therapies as precision medicines for familial hypercholesterolemic patients carrying mutations that compromise normal splicing of the low-density lipoprotein receptor (LDLR) gene transcript. RECENT FINDINGS: Three antisense drugs are currently being assessed in ongoing clinical trials for dyslipidemias, aiming to lower the plasma concentrations of lipoproteins that lead to end-organ damage, principally coronary artery disease. Although a handful of drugs may be applicable to many patients with familial hypercholesterolemia (FH), mutation-specific personalised antisense drugs may be even more effective in selected patients. Currently, there is no therapy that effectively addresses mutations in the LDLR, the major cause of FH. Many mutations in the LDLR that disrupt normal pre-mRNA processing could be applicable to splice correction therapy to restore receptor activity. SUMMARY: Precision medicine could provide long-term economic and social benefits if they can be implemented effectively and sustainably. Many mutations found in the LDLR gene could be amendable to therapeutic splice correction and we should consider developing a therapeutic ASO platform for these mutations.

Effects of classroom-based active breaks on cognition, sitting and on-task behaviour in children with intellectual disability: a pilot study.

BACKGROUND: Classroom-based active breaks can help typically developing children reduce sitting, increase physical activity and improve cognitive functions and on-task behaviour. Yet, this strategy has not been tested in children with intellectual disability (ID) - a population who are insufficiently active. This study aimed to investigate the effects of a 5-week active breaks intervention on cognitive functions and on-task behaviour in schoolchildren with ID. METHODS: Twenty-four children, aged between 8 and 12 years (37.5% girls), were recruited. Children's cognitive functions (response inhibition, lapses of attention, interference and working memory) were measured at baseline and end of trial using computer-based tests. Sitting, standing and movement patterns were assessed with inclinometers, and on-task behaviour was directly observed in the classroom before and after active breaks, at baseline, mid-trial and end of trial. Linear mixed models were used to investigate the intervention effects on cognitive functions and sedentary patterns; generalised linear mixed models were used to analyse on-task behaviour data. RESULTS: A significant time × group interaction was found for working memory favouring the intervention (B = 11.56, 95% confidence interval [1.92, 21.21]). No significant effects were found in relation to the other measures of children's cognition or on-task behaviour. Stepping time and bouts of sitting were positively affected. CONCLUSIONS: Classroom-based active breaks can increase physical activity and reduce sedentary behaviour in children with ID and might also benefit their working memory. Further research is required to clarify the effects on cognition and to investigate whether this strategy has other benefits in this population.

A Splice Intervention Therapy for Autosomal Recessive Juvenile Parkinson's Disease Arising from Parkin Mutations.

Parkin-type autosomal recessive juvenile-onset Parkinson's disease is caused by mutations in the PRKN gene and accounts for 50% of all autosomal recessive Parkinsonism cases. Parkin is a neuroprotective protein that has dual functions as an E3 ligase in the ubiquitin-proteasome system and as a transcriptional repressor of p53. While genomic deletions of PRKN exon 3 disrupt the mRNA reading frame and result in the loss of functional parkin protein, deletions of both exon 3 and 4 maintain the reading frame and are associated with a later onset, milder disease progression, indicating this particular isoform retains some function. Here, we describe in vitro evaluation of antisense oligomers that restore functional parkin expression in cells derived from a Parkinson's patient carrying a heterozygous PRKN exon 3 deletion, by inducing exon 4 skipping to correct the reading frame. We show that the induced PRKN transcript is translated into a shorter but semi-functional parkin isoform able to be recruited to depolarised mitochondria, and also transcriptionally represses p53 expression. These results support the potential use of antisense oligomers as a disease-modifying treatment for selected pathogenic PRKN mutations.

PD-1 Blockade in a Liver Transplant Recipient With Microsatellite Unstable Metastatic Colorectal Cancer and Hepatic Impairment.

Immune checkpoint inhibitors represent a newly established standard of care in patients with refractory metastatic colorectal cancer with mismatch repair deficiency and microsatellite instability. However, the use of immunotherapy is unclear in recipients of liver transplants with or without concurrent liver function abnormalities. Clinical trials investigating immunotherapy have mostly excluded liver transplant recipients and patients with abnormal liver function. This report presents the first case, to our knowledge, of a liver transplant patient with mismatch repair-deficient colon adenocarcinoma with liver metastases and concurrent abnormal liver function who safely responded to immunotherapy. We also review the literature on checkpoint inhibitor use in patients with other metastatic solid tumors after liver transplant and those with baseline liver function abnormalities. An increasing body of evidence supports the safety of checkpoint inhibition in patients with cancer and solid organ transplants, but further prospective studies are warranted. Use of immunotherapy in liver transplant recipients who have metastatic colorectal cancer with microsatellite instability is feasible but should be performed in a multidisciplinary team setting.

Usefulness of immunohistochemistry for mismatch repair protein and microsatellite instability examination in adenocarcinoma and background endometrium of sporadic endometrial cancer cases.

AIM: Microsatellite instability (MSI), which reflects loss of DNA mismatch repair (MMR) activity, and immunohistochemistry (IHC) for MMR proteins are employed as screening examinations for Lynch syndrome (LS). Recent studies revealed that there is a population of MSI-high tumors in sporadic endometrial cancer (EC). However, MSI data for Japanese EC patients are scarce. Furthermore, sporadic estrogen-dependent EC (type I) is generally considered to arise from hyperplasia. Because LS is usually associated with type I EC, we hypothesized that MSI might be involved in the oncogenic process in some sporadic EC. We conducted MSI testing to reveal MSI status in sporadic Japanese EC. IHC for MMR proteins was also performed. METHODS: Ninety-eight tissue samples of sporadic ECs from Japanese patients were used for IHC and MSI examinations. We also evaluated MMR protein expressions in the background normal endometrium. RESULTS: Microsatellite instability-high was observed in 10.2% of 98 cases with sporadic EC, a lower percentage than that in Western studies. Loss of some MMR proteins was observed in 23 cases (23.5%) and there was a significant correlation with MSI-high status (P < 0.001). Concerning the background endometrium, two cases showed partial loss of MLH1 and PMS2, corresponding to adjacent EC lesions, suggesting that MMR deficiency may already be present in the background endometrium. CONCLUSION: The MSI-high rate was low in our Japanese cohort. Our data confirmed the usefulness of MMR protein assessment for MSI screening in Japanese EC patients. Furthermore, IHC of the background endometrium might reveal the mechanism of MSI-high tumorigenesis.

Systematic Approach to Developing Splice Modulating Antisense Oligonucleotides.

The process of pre-mRNA splicing is a common and fundamental step in the expression of most human genes. Alternative splicing, whereby different splice motifs and sites are recognised in a developmental and/or tissue-specific manner, contributes to genetic plasticity and diversity of gene expression. Redirecting pre-mRNA processing of various genes has now been validated as a viable clinical therapeutic strategy, providing treatments for Duchenne muscular dystrophy (inducing specific exon skipping) and spinal muscular atrophy (promoting exon retention). We have designed and evaluated over 5000 different antisense oligonucleotides to alter splicing of a variety of pre-mRNAs, from the longest known human pre-mRNA to shorter, exon-dense primary gene transcripts. Here, we present our guidelines for designing, evaluating and optimising splice switching antisense oligomers in vitro. These systematic approaches assess several critical factors such as the selection of target splicing motifs, choice of cells, various delivery reagents and crucial aspects of validating assays for the screening of antisense oligonucleotides composed of 2'-O-methyl modified bases on a phosphorothioate backbone.

In Vitro Validation of Phosphorodiamidate Morpholino Oligomers.

One of the crucial aspects of screening antisense oligonucleotides destined for therapeutic application is confidence that the antisense oligomer is delivered efficiently into cultured cells. Efficient delivery is particularly vital for antisense phosphorodiamidate morpholino oligomers, which have a neutral backbone, and are known to show poor gymnotic uptake. Here, we report several methods to deliver these oligomers into cultured cells. Although 4D-Nucleofector™ or Neon™ electroporation systems provide efficient delivery and use lower amounts of phosphorodiamidate morpholino oligomer, both systems are costly. We show that some readily available transfection reagents can be used to deliver phosphorodiamidate morpholino oligomers as efficiently as the electroporation systems. Among the transfection reagents tested, we recommend Lipofectamine 3000™ for delivering phosphorodiamidate morpholino oligomers into fibroblasts and Lipofectamine 3000™ or Lipofectamine 2000™ for myoblasts/myotubes. We also provide optimal programs for nucleofection into various cell lines using the P3 Primary Cell 4D-Nucleofector™ X Kit (Lonza), as well as antisense oligomers that redirect expression of ubiquitously expressed genes that may be used as positive treatments for human and murine cell transfections.

Intercomparison of far-infrared transmittance measurements.

We present the results of the first systematic "round-robin" comparison of far-infrared transmittance spectra measurements, which was performed by five laboratories and piloted by Physikalisch-Technische (PTB). The transmittance spectra of four different samples were measured by the participating laboratories in the 600 cm-1 to 10 cm-1 range (16.67 µm to 1000 µm) in a blind comparison. Different types of instruments, Fourier transform infrared (FT-IR) spectrometers of Michelson type and a laser radiation-based system were used for the transmittance measurements. FT-IR spectrometers are the most popular and commonly used instruments for the spectral characterization of materials in the infrared spectral range, and are well established for quantitative measurements in the mid- and near-infrared spectral ranges. However, obtaining quantitative transmittance measurements in the far-infrared spectral range by means of these instruments is challenging, because it involves weaker radiation sources, stronger diffraction effects, significant radiation originating from the sample itself and temperature gradients inside the spectrometer that may not be given proper consideration. Therefore, this comparison was initiated to test the actual capability of and identify problems with FT-IR transmittance measurements in this spectral region. We discuss the results and the possible reasons for the observed discrepancies.

Defibrotide: An Oligonucleotide for Sinusoidal Obstruction Syndrome.

OBJECTIVE: To review the efficacy and safety of defibrotide as well as its pharmacology, mechanism of action, pharmacokinetics (PK), drug-drug interactions, dosing, cost considerations, and place in therapy. DATA SOURCES: A PubMed search was performed through August 2017 using the terms defibrotide, oligonucleotide, hepatic veno-occlusive disease (VOD), sinusoidal obstruction syndrome (SOS), and hematopoietic cell transplantation (HCT). Other data sources were from references of identified studies, review articles, and conference abstracts plus manufacturer product labeling and website, the Food and Drug Administration website, and clinicaltrials.gov. STUDY SELECTION AND DATA EXTRACTION: English-language trials that examined defibrotide's pharmacodynamics, mechanism, PK, efficacy, safety, dosing, and cost-effectiveness were included. DATA SYNTHESIS: Trials have confirmed the safety and efficacy of defibrotide for treatment of VOD/SOS in adult and pediatric HCT patients, with complete response rates and day +100 overall survival rates ranging from 25.5% to 76% and 35% to 64%, respectively. The British Committee for Standards in Haematology/British Society for Blood and Marrow Transplantation Guidelines recommend defibrotide prophylaxis in pediatric and adult HCT patients with risk factors for VOD/SOS; however, its prophylactic use in the United States is controversial. Although there are efficacy data to support this strategy, cost-effectiveness data have not shown it to be cost-effective. Defibrotide has manageable toxicities, with low rates of grade 3 to 4 adverse effects. CONCLUSIONS: Defibrotide is the first medication approved in the United States for the treatment of adults and children with hepatic VOD/SOS, with renal or pulmonary dysfunction following HCT. Data evaluating defibrotide for VOD/SOS prevention are conflicting and have not shown cost-effectiveness.

Comparison of biological and alloplastic meshes in ventral incisional hernia repair.

PURPOSE: The aim of our retrospective analysis was to compare the results of incisional hernia repair by porcine small intestinal submucosa-derived (SIS) meshes with those obtained by alloplastic polypropylene-based (PP) meshes in comparable surgical indications by matched-pair design. We hypothesized that in incisional hernia, SIS mesh repair is associated with fewer recurrences and SSO than PP mesh repair in incisional hernias. METHODS: Twenty-four matched pairs (SIS vs. PP mesh repair between 1 January 2005 and 31 December 2013) were identified by matching criteria: gender, age, comorbidities, body mass index, EHS hernia classification, mesh implantation technique, CDC wound classification, and source of contamination/primary surgery leading to incisional hernia. Minimal follow-up time was 24 months. Means and standard deviations were compared by paired t test; categorial data were compared by McNemar's test. Poisson's distribution and negative binominal distribution were employed to detect significant correlation. RESULTS: There were no statistically significant differences between both groups in the pre- and perioperative factors and the follow-up times. There were significantly more wound complications (19 vs. 12, p = 0.041), longer hospital stay (22.0 ± 6.3 vs. 12.0 ± 3.1 days, p = 0.010), and significantly more recurrent hernias (25 vs. 12.5%, p = 0.004) after SIS mesh repair. Both the Poisson's distribution and the negative binominal distribution unveiled significantly more complication points (3-6 vs. 1-2) per month after SIS mesh repair. CONCLUSION: There is no advantage of SIS meshes compared to PP meshes in incisional hernia repair with different degrees of wound contamination in this matched-pair analysis. Further prospective and randomized trials or at least registry studies such as the EHS register with standardized and defined conditions are warranted.

Amyloid-ß induces sleep fragmentation that is rescued by fatty acid binding proteins in Drosophila.

Disruption of sleep/wake activity in Alzheimer's disease (AD) patients significantly affects their quality of life and that of their caretakers and is a major contributing factor for institutionalization. Levels of amyloid-ß (Aß) have been shown to be regulated by neuronal activity and to correlate with the sleep/wake cycle. Whether consolidated sleep can be disrupted by Aß alone is not well understood. We hypothesize that Aß42 can increase wakefulness and disrupt consolidated sleep. Here we report that flies expressing the human Aß42 transgene in neurons have significantly reduced consolidated sleep compared with control flies. Fatty acid binding proteins (Fabp) are small hydrophobic ligand carriers that have been clinically implicated in AD. Aß42 flies that carry a transgene of either the Drosophila Fabp or the mammalian brain-type Fabp show a significant increase in nighttime sleep and long consolidated sleep bouts, rescuing the Aß42-induced sleep disruption. These studies suggest that alterations in Fabp levels and/or activity may be associated with sleep disturbances in AD. Future work to determine the molecular mechanisms that contribute to Fabp-mediated rescue of Aß42-induced sleep loss will be important for the development of therapeutics in the treatment of AD. © 2016 Wiley Periodicals, Inc.

Anti-contactin-associated protein-2 encephalitis: relevance of antibody titres, presentation and outcome.

BACKGROUND AND PURPOSE: To clarify the relevance of titres of IgG antibodies against contactin-associated protein-2 (CASPR2) in diagnosing anti-CASPR2 encephalitis and to describe features and outcomes. METHODS: This was a retrospective analysis of 64 patients with CASPR2 antibodies, categorized independently as 'autoimmune encephalitis' or 'other disease'. Logistic regression methods were performed to identify potential predictors of 'autoimmune encephalitis' in addition to CASPR2 antibodies. RESULTS: An upfront CASPR2 antibody serum titre cut-off at ≥1:200 had a diagnostic sensitivity of 85% and a specificity of 81%. Logistic regression analyses indicated that, in addition to titre, encephalitic magnetic resonance imaging (MRI) was a significant predictor of 'autoimmune encephalitis' (Nagelkerke's R2 = 0.81, P < 0.001) with high sensitivity (84%) and very high specificity (100%). Patients with CASPR2 antibodies and an estimated probability of >70% of having anti-CASPR2 encephalitis (n = 22) had limbic encephalitis (n = 18, one patient plus ataxia), Morvan syndrome (n = 2) or a hyperkinetic movement disorder (n = 2). Median modified Rankin score (mRS) at diagnosis was 3 (range 1-4). Twenty patients were male; median age was 64 (range 54-75) years; 5/15 patients with cerebrospinal fluid data had intrathecal CASPR2 antibody synthesis, and 12/19 with follow-ups >3 months (median 12 months, range 4-43 months) improved by ≥1 mRS point resulting in a median mRS of 2 (range 0-6; one death; all but one having received immunotherapy); and 2/15 patients with follow-up MRI developed hippocampal atrophy. CONCLUSIONS: Only higher CASPR2 serum antibody titres indicate anti-CASPR2 encephalitis, and diagnostic accuracy increases if MRI findings are considered. Anti-CASPR2 encephalitis has characteristic features and a favourable outcome with immunotherapy.

Detection of extra-regional tumour recurrence with 18F-FDG-PET/CT in patients with recurrent gynaecological malignancies being considered for radical salvage surgery.

AIM: To compare the detection rate of extra-regional metastases in patients with recurrent gynaecological malignancies being considered for radical salvage surgery with combined 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography (PET)/computed tomography (CT) compared to conventional imaging. MATERIALS AND METHODS: A retrospective review was performed of all patients in a provincial database with recurrent gynaecological malignancies being considered for pelvic exenteration that underwent restaging with CT/PET between March 2011 and October 2014. Findings on PET and conventional imaging (CT±pelvic MRI) were abstracted. Disease sites were classified according to the location (regional nodal metastases, extra-regional nodal metastases, peritoneum, or other distant sites) and diagnostic certainty (definitive or equivocal). The proportion of patients positive for extra-regional recurrence was calculated for PET and conventional imaging. In addition, the proportion of patients with indeterminate lesions only was calculated for each modality and the sites of indeterminate findings were tabulated. RESULTS: There were 85 patients (median age, 50 years; range: 30-81 years) with carcinoma of cervix (n=51), endometrium (n=18), vagina (n=6), or vulva (n=10). Extra-regional recurrence was detected in 8/85 (9.4%) and 24/85 (28.2%) patients on conventional imaging and PET, respectively (p=0.0017). The greatest impact of PET compared to conventional imaging was in the detection of extra-regional nodal metastases. PET had significantly fewer examinations equivocal for extra-regional recurrence versus conventional imaging (6/85 [7.1%] and 38/85 [44.7%], respectively, p<0.001). CONCLUSION: In patients with recurrent gynaecological malignancies being considered for radical salvage surgery, PET may identify significantly more extra-regional recurrence than conventional imaging. PET may also result in fewer equivocal lesions. The impact of these results on patient management and outcome should be confirmed in future prospective trials.