Development and pilot-testing of an evidence-based quality indicator set for home mechanical ventilation care: the OVER-BEAS project.

BACKGROUND: The number of patients depending on home mechanical ventilation (HMV) has increased substantially in Germany in recent years. These patients receive long-term care in different nursing facilities (nursing home, shared living community, private home). However, there are limited data available on the quality of care of HMV patients. The aim of the OVER-BEAS project was to identify quality indicators (QIs) of HMV care using an evidence-based approach. METHODS: A multidisciplinary board consisting of professionals and experts of HMV provision compiled a set of QIs between March and September 2019. In a structured, transparent process a set of QIs covering structures, processes and outcome of HMV patient's care were proposed and evaluated based on the best available evidence. QIs were defined as relevant, reliable and valid measurements of the quality of HMV care and furthermore to be comprehensive and applicable in practice. RESULTS: The experts proposed 40 QIs and consented a final set of 26 QIs. Based on the final set, questionnaires to document the QIs were developed: (1) to assess the quality and describe the structure of the nursing facility; and (2) to gather information on patient-related processes and outcomes. The feasibility of the questionnaires was tested in 5 nursing facilities treating HMV patients. The remarks from the nursing specialists were categorised in three groups: (1) term missing accuracy, (2) problem of understanding, and (3) not documented or documented elsewhere. Mean documentation time by the nursing specialists for one patient was 15 min. Based on this feedback, the questionnaires were finalised. CONCLUSIONS: We proposed a set of QIs relating to long-term HMV care and developed two questionnaires to collect this information. In a pilot study, we found the set of questionnaires to be feasible in assessing the quality of HMV care according to current evidence. The development of standardised evidence-based QIs to evaluate HMV care is a step towards implementing a standardised quality assurance program to document the quality of care of HMV patients.

De novo KCNA6 variants with attenuated KV 1.6 channel deactivation in patients with epilepsy.

OBJECTIVE: Mutations in the genes encoding neuronal ion channels are a common cause of Mendelian neurological diseases. We sought to identify novel de novo sequence variants in cases with early infantile epileptic phenotypes and neurodevelopmental anomalies. METHODS: Following clinical diagnosis, we performed whole exome sequencing of the index cases and their parents. Identified channel variants were expressed in Xenopus oocytes and their functional properties assessed using two-electrode voltage clamp. RESULTS: We identified novel de novo variants in KCNA6 in four unrelated individuals variably affected with neurodevelopmental disorders and seizures with onset in the first year of life. Three of the four identified mutations affect the pore-lining S6 α-helix of KV 1.6. A prominent finding of functional characterization in Xenopus oocytes was that the channel variants showed only minor effects on channel activation but slowed channel closure and shifted the voltage dependence of deactivation in a hyperpolarizing direction. Channels with a mutation affecting the S6 helix display dominant effects on channel deactivation when co-expressed with wild-type KV 1.6 or KV 1.1 subunits. SIGNIFICANCE: This is the first report of de novo nonsynonymous variants in KCNA6 associated with neurological or any clinical features. Channel variants showed a consistent effect on channel deactivation, slowing the rate of channel closure following normal activation. This specific gain-of-function feature is likely to underlie the neurological phenotype in our patients. Our data highlight KCNA6 as a novel channelopathy gene associated with early infantile epileptic phenotypes and neurodevelopmental anomalies.

Early recognition of SGCE-myoclonus-dystonia in children.

AIM: To evaluate early dystonic features in children and adolescents with SGCE-myoclonus-dystonia. METHOD: In this cross-sectional study, 49 patients (26 females and 23 males) with SGCE-myoclonus-dystonia (aged 15y 2mo, SD 12y) with childhood-onset (2y 10mo, SD 1y 10mo) dystonia were examined using a standardized video recorded protocol. Dystonia was rated using the Writer's Cramp and Gait Dystonia Rating Scales. Disability and impairment for handwriting and walking were also rated. RESULTS: Dystonia was present at rest (n=1), posture (n=12), and during specific motor tasks (n=45) such as writing (n=35), walking (n=23), and running (n=20). Most children reported disability while performing these tasks. Early dystonic patterns were identified for writer's cramp and gait dystonia, the latter named the 'circular shaking leg', 'dragging leg', and 'hobby-horse gait' patterns. Sensory tricks were used by five and eight children to improve dystonia and myoclonus during writing and walking respectively. The rating scales accurately measured the severity of action dystonia and correlated with self-reported disability. INTERPRETATION: Children with SGCE-myoclonus-dystonia show recognizable dystonic patterns and sensory tricks that may lead to an early diagnosis and timely therapeutic approach. Isolated writer's cramp is a key feature in childhood and should prompt SCGE analysis. The proposed action dystonia scales could be used to monitor disease course and response to treatment. WHAT THIS PAPER ADDS: Most children with SGCE-myoclonus-dystonia got writer's cramp and had walking and running dystonia. Writer's cramp was a key feature and should prompt SGCE genetic investigation. 'Circular shaking leg', 'dragging leg', and 'hobby-horse gait' were recognized as early gait patterns. Children used sensory tricks to improve myoclonus and dystonia, suggesting common pathophysiological mechanisms. Action dystonia rating scales are valid tools to assess severity in children.

Half of the patients with subepithelial tumors present borderline or pathologic anxiety-distress and carcinophobia: a multicenter cohort study.

BACKGROUND AND AIMS: Minor nonspecific gastrointestinal subepithelial lesions (usually defined by the term 'tumor') are usually associated with a malignant illness and cancer. The aim of this study was to assess anxiety-distress and carcinophobia in patients referred to specialized monographic outpatient clinics for evaluation and treatment of this type of lesion. METHODS: Prospective, multicenter, cohort study. Specific self-reported questionnaires were used to report threatening life-experiences and to assess levels of distress (The Hospital Anxiety and Depression Scale) and cancer-related worries (The Cancer Worry Scale). RESULTS: Forty participants were included and analyzed at baseline. Pathologic and borderline anxiety were detected in 13% (5/40, 95%CI: 4-27%) and 35% (14/40, 95%CI: 21-52%) of participants, respectively, whereas, cancer-related worries (moderate to very high) were observed in 48% (19/40, 95%CI: 32-64%) of participants. Pathologic global distress was identified in 25% (10/40, 95%CI: 13-42%) of subjects. Higher educational level (university studies), a lack of lifetime psychiatric comorbidity and a lack of family history of cancer were associated with less anxiety, global distress and carcinophobia. CONCLUSIONS: Almost half of the patients diagnosed with a minor nonspecific gastrointestinal subepithelial lesion presented anxiety-distress and/or carcinophobia. Specific associations with anxiety-distress reaction and fears were detected.

Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment.

VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function.

The Genetic Landscape of Complex Childhood-Onset Hyperkinetic Movement Disorders.

BACKGROUND AND OBJECTIVE: The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders. METHODS: Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, clinical, and genetic data. Two pediatric movement disorder experts reviewed available video footage, classifying hyperkinetic movements according to published criteria. RESULTS: One hundred forty patients with pathogenic variants in 17 different genes (ADCY5, ATP1A3, DDC, DHPR, FOXG1, GCH1, GNAO1, KMT2B, MICU1, NKX2.1, PDE10A, PTPS, SGCE, SLC2A1, SLC6A3, SPR, and TH) were identified. In the majority, hyperkinetic movements were generalized (77%), with most patients (69%) manifesting combined motor semiologies. Parkinsonism-dystonia was characteristic of primary neurotransmitter disorders (DDC, DHPR, PTPS, SLC6A3, SPR, TH); chorea predominated in ADCY5-, ATP1A3-, FOXG1-, NKX2.1-, SLC2A1-, GNAO1-, and PDE10A-related disorders; and stereotypies were a prominent feature in FOXG1- and GNAO1-related disease. Those with generalized hyperkinetic movements had an earlier disease onset than those with focal/segmental distribution (2.5 ± 0.3 vs. 4.7 ± 0.7 years; P = 0.007). Patients with developmental delay also presented with hyperkinetic movements earlier than those with normal neurodevelopment (1.5 ± 2.9 vs. 4.7 ± 3.8 years; P < 0.001). Effective disease-specific therapies included dopaminergic agents for neurotransmitters disorders, ketogenic diet for glucose transporter deficiency, and deep brain stimulation for SGCE-, KMT2B-, and GNAO1-related hyperkinesia. CONCLUSIONS: This study highlights the complex phenotypes observed in children with genetic hyperkinetic movement disorders that can lead to diagnostic difficulty. We provide a comprehensive analysis of motor semiology to guide physicians in the genetic investigation of these patients, to facilitate early diagnosis, precision medicine treatments, and genetic counseling. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.

Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.

Genetic diagnosis of basal ganglia disease in childhood.

AIM: To correlate clinical, radiological, and biochemical features with genetic findings in children with bilateral basal ganglia lesions of unknown aetiology, and propose a diagnostic algorithm for early recognition. METHOD: Children with basal ganglia disease were recruited in a 2-year prospective multicentre study for clinical, biomarker, and genetic studies. Radiological pattern recognition was examined by hierarchical clustering analysis. RESULTS: We identified 22 genetic conditions in 30 out of 62 paediatric patients (37 males, 25 females; mean age at onset 2y, SD 3; range 0-10y; mean age at assessment 11y, range 1-25y) through gene panels (n=11), whole-exome sequencing (n=13), and mitochondrial DNA (mtDNA) sequencing (n=6). Genetic aetiologies included mitochondrial diseases (57%), Aicardi-Goutières syndrome (20%), and monogenic causes of dystonia and/or epilepsy (17%) mimicking Leigh syndrome. Radiological abnormalities included T2-hyperintense lesions (n=26) and lesions caused by calcium or manganese mineralization (n=9). Three clusters were identified: the pallidal, neostriatal, and striatal, plus the last including mtDNA defects in the oxidative phosphorylation system with prominent brain atrophy. Mitochondrial biomarkers showed poor sensitivity and specificity in children with mitochondrial disease, whereas interferon signature was observed in all patients with patients with Aicardi-Goutières syndrome. INTERPRETATION: Combined whole-exome and mtDNA sequencing allowed the identification of several genetic conditions affecting basal ganglia metabolism. We propose a diagnostic algorithm which prioritizes early use of next-generation sequencing on the basis of three clusters of basal ganglia lesions.

Muscarinic acetylcholine receptor M1 mutations causing neurodevelopmental disorder and epilepsy.

De novo rare damaging variants in genes involved in critical developmental pathways, notably regulation of synaptic transmission, have emerged as a frequent cause of neurodevelopmental disorders (NDD). NDD show great locus heterogeneity and for many of the associated genes, there is substantial phenotypic diversity, including epilepsy, intellectual disability, autism spectrum disorder, movement disorders, and combinations thereof. We report two unrelated patients, a young girl with early-onset refractory epilepsy, severe disability, and progressive cerebral and cerebellar atrophy, and a second girl with mild dysmorphism, global developmental delay, and moderate intellectual disability in whom trio-based whole-exome sequencing analysis uncovered de novo missense variants in CHRM1. Biochemical analyses of one of the NDD-associated variants proved that it caused a reduction in protein levels and impaired cellular trafficking. In addition, the mutated receptor showed defective activation of intracellular signaling pathways. Our data strengthen the concept that brain-reduced muscarinic signaling lowers the seizure threshold and severely impairs neurodevelopment.

Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene.

The neurological phenotype of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) and short-chain enoyl-CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11; HIBCH, n = 6) and paroxysmal dystonia (SCEH, n = 2). Basal ganglia lesions (18 patients) were associated with small cysts in the putamen/pallidum in half of the cases, a characteristic hallmark for diagnosis. Eighteen pathogenic variants were identified, 11 were novel. Among all 89 cases, we observed a longer survival in HIBCH compared to SCEH patients, and in HIBCH patients carrying homozygous mutations on the protein surface compared to those with variants inside/near the catalytic region. The SCEH p.(Ala173Val) change was associated with a milder form of paroxysmal dystonia triggered by increased energy demands. In a child harbouring SCEH p.(Ala173Val) and the novel p.(Leu123Phe) change, an 83.6% reduction of the protein was observed in fibroblasts. The SCEH and HIBCH defects in the catabolic valine pathway were a frequent cause of Leigh syndrome in our cohort. We identified phenotype and genotype associations that may help predict outcome and improve clinical management.

Video conference vs face-to-face group psychotherapy for distressed cancer survivors: A randomized controlled trial.

OBJECTIVE: This study assesses the effectiveness of face-to-face group positive psychotherapy for cancer survivors (PPC) compared to its online adaptation, online group positive psychotherapy for cancer survivors (OPPC), which is held via videoconference. A two-arm, pragmatic randomized controlled trial was conducted to examine the effects of both interventions on emotional distress, post-traumatic stress symptoms (PTSS), and post-traumatic growth (PTG) among cancer survivors and analyze attrition to treatment. METHODS: Adult women with a range of cancer diagnoses were invited to participate if they experienced emotional distress at the end of their primary oncological treatment. Emotional distress, PTSS, and PTG were assessed at baseline, immediately after treatment, and 3 months after treatment. Intention-to-treat analyses were carried out using general linear mixed models to test the effect of the interventions overtime. Logistic regressions were performed to test differential adherence to treatment and retention to follow-up. RESULTS: A total of 269 individuals participated. The observed treatment effect was significant in both modalities, PPC and OPPC. Emotional distress (b = -2.24, 95% confidence interval [CI] = -3.15 to -1.33) and PTSS (b = -3.25, 95% CI = -4.97 to -1.53) decreased significantly over time, and PTG (b = 3.08, 95% CI = 0.38-5.78) increased significantly. Treatment gains were sustained across outcomes and over time. Analyses revealed no significant differences between modalities of treatment, after adjusting for baseline differences, finding that OPPC is as effective and engaging as PPC. CONCLUSIONS: The OPPC treatment was found to be effective and engaging for female cancer early survivors. These results open the door for psycho-oncology interventions via videoconference, which are likely to lead to greater accessibility and availability of psychotherapy.

An exploratory study in breast cancer of factors involved in the use and communication with health professionals of Internet information.

OBJECTIVE: To study the impact of the spontaneous use of Internet on breast cancer patients and on their relationship with health professionals. METHODS: A mixed methodology was used. Two questionnaires were designed through three focus groups, and then administered to 186 patients and 59 professionals in order to assess: (1) patients' use of Internet for health-related information and (2) the impact of this information on patients' psychological outcomes and on their relationship with professionals. RESULTS: Patients spent more time looking for illness-related information after diagnosis, using interactive communities more than static information websites. Patients and professionals disagreed about the use of Internet in terms of the knowledge it provides, and its psychological impact. The main barrier reported by patients regarding the sharing of online information with their professionals was the belief that it would damage their relationship. CONCLUSIONS: Both professionals and patients have a protectionist conception of the therapeutic relationship. This attitude tends to dismiss the positive impact that the use of Internet and the new communication tools may have in cancer patients. New resources should provide an "Internet Prescription" and modes of interaction to facilitate a more open digital communication.

Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood.

AIM: To perform a deep phenotype characterisation in a pedigree of 3 siblings with Leigh syndrome and compound heterozygous NDUFAF6 mutations. METHOD: A multi-gene panel of childhood-onset basal ganglia neurodegeneration inherited conditions was analysed followed by functional studies in fibroblasts. RESULTS: Three siblings developed gait dystonia in infancy followed by rapid progression to generalised dystonia and psychomotor regression. Brain magnetic resonance showed symmetric and bilateral cytotoxic lesions in the putamen and proliferation of the lenticular-striate arteries, latter spreading to the caudate and progressing to cavitation and volume loss. We identified a frameshift novel change (c.554_558delTTCTT; p.Tyr187AsnfsTer65) and a pathogenic missense change (c.371T>C; p.Ile124Thr) in the NDUFAF6 gene, which segregated with an autosomal recessive inheritance within the family. Patient mutations were associated with the absence of the NDUFAF6 protein and reduced activity and assembly of mature complex I in fibroblasts. By functional complementation assay, the mutant phenotype was rescued by the canonical version of the NDUFAF6. A literature review of 14 NDUFAF6 patients showed a consistent phenotype of an early childhood insidious onset neurological regression with prominent dystonia associated with basal ganglia degeneration and long survival. INTERPRETATION: NDUFAF6-related Leigh syndrome is a relevant cause of childhood onset dystonia and isolated bilateral striatal necrosis. By genetic complementation, we could demonstrate the pathogenicity of novel genetic variants in NDUFAF6.

Homomeric Kv7.2 current suppression is a common feature in KCNQ2 epileptic encephalopathy.

OBJECTIVE: To gain insight into the mechanisms underlying KCNQ2 encephalopathy by examining the electrophysiologic properties of mutant Kv7.2 channels in different multimeric configurations. METHODS: We analyzed the genotype-phenotype relationship in 4 patients with KCNQ2 encephalopathy and performed electrophysiologic analysis of M-currents mediated by homomeric Kv7.2 or heteromeric Kv7.2/Kv7.3 channels. RESULTS: Negligible or no current was recorded in cells expressing homomeric E130K, W270R, or G281R de novo mutants, and it was reduced by more than 90% for the L243F maternally inherited mutant. The E130K and G281R mutants presented a marked dominant-negative behavior, whereas the current density was partially reduced (L243F) or not affected (W270R) when coexpressed with wild-type Kv7.2 subunits. In contrast, the extent of Kv7.3 "rescue," which yields negligible currents on its own, followed the sequence E130K > L243F > W270R, whereas no rescue was observed with the G281R mutant. No significant effects on current density were observed when subunits were expressed in a 0.5:0.5:1.0 (Kv7.2:mutant:Kv7.3) DNA ratio to mimic the genetic balance. There was an increase in sensitivity to phosphatidylinositol 4,5-bisphosphate (PIP2 ) depletion for W270R/Kv7.3, but no substantial differences were observed when the mutated subunits were coexpressed with Kv7.2 or both Kv7.2 and Kv7.3. SIGNIFICANCE: There was a marked disparity of the impact of these mutations on Kv7.2 function, which varied on association with Kv7.2 or Kv7.3 subunits. Current density of homomeric channels was the most reliable property relating Kv7.2 function to encephalopathy, but other factors are required to explain the milder phenotype for some individuals carrying the maternally inherited L243F mutation. We hypothesize that the role of homomeric Kv7.2 channels for fine-tuning neuronal connections during development is critical for the severity of the KCNQ2 encephalopathy.

Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies.

Thiamine is a crucial cofactor involved in the maintenance of carbohydrate metabolism and participates in multiple cellular metabolic processes within the cytosol, mitochondria, and peroxisomes. Currently, four genetic defects have been described causing impairment of thiamine transport and metabolism: SLC19A2 dysfunction leads to diabetes mellitus, megaloblastic anemia and sensory-neural hearing loss, whereas SLC19A3, SLC25A19, and TPK1-related disorders result in recurrent encephalopathy, basal ganglia necrosis, generalized dystonia, severe disability, and early death. In order to achieve early diagnosis and treatment, biomarkers play an important role. SLC19A3 patients present a profound decrease of free-thiamine in cerebrospinal fluid (CSF) and fibroblasts. TPK1 patients show decreased concentrations of thiamine pyrophosphate in blood and muscle. Thiamine supplementation has been shown to improve diabetes and anemia control in Rogers' syndrome patients due to SLC19A2 deficiency. In a significant number of patients with SLC19A3, thiamine improves clinical outcome and survival, and prevents further metabolic crisis. In SLC25A19 and TPK1 defects, thiamine has also led to clinical stabilization in single cases. Moreover, thiamine supplementation leads to normal concentrations of free-thiamine in the CSF of SLC19A3 patients. Herein, we present a literature review of the current knowledge of the disease including related clinical phenotypes, treatment approaches, update of pathogenic variants, as well as in vitro and in vivo functional models that provide pathogenic evidence and propose mechanisms for thiamine deficiency in humans.

Stroke prevention in patients with acute ischemic stroke and atrial fibrillation in Germany - a cross sectional survey.

BACKGROUND: Atrial fibrillation (AF) is present in 15-20% of patients with acute ischemic stroke. Oral anticoagulation reduces the risk of AF-related recurrent stroke but clinical guideline recommendations are rather vague regarding its use in the acute phase of stroke. We aimed to assess the current clinical practice of medical stroke prevention in AF patients during the acute phase of ischemic stroke. METHODS: In April 2017, a standardized anonymous questionnaire was sent to clinical leads of all 298 certified stroke units in Germany. RESULTS: Overall, 154 stroke unit leads participated (response rate 52%). Anticoagulation in the acute phase of stroke is considered feasible in more than 90% of AF patients with ischemic stroke. Clinicians assume that about two thirds of all AF patients (range 20-100%) are discharged on oral anticoagulation. According to local preferences, acetylsalicylic acid is given orally in the majority of patients with delayed initiation of oral anticoagulation. A non-vitamin K-dependent oral anticoagulant (NOAC) is more often prescribed than a vitamin K-dependent oral anticoagulant (VKA). VKA is more often chosen in patients with previous VKA intake than in VKA naive patients. In the minority of patients, stroke unit leads discuss the prescription of a specific oral anticoagulant with the treating general practitioner. Adherence to medical stroke prevention after hospital discharge is not assessed on a regular basis in any patient by the majority of participating stroke centers. CONCLUSIONS: Early secondary stroke prevention in AF patients in German stroke units is based on OAC use but prescription modalities vary in clinical practice.

GRP94 Is Involved in the Lipid Phenotype of Brain Metastatic Cells.

Metabolic adaptation may happen in response to the pressure exerted by the microenvironment and is a key step in survival of metastatic cells. Brain metastasis occurs as a consequence of the systemic dissemination of tumor cells, a fact that correlates with poor prognosis and high morbidity due to the difficulty in identifying biomarkers that allow a more targeted therapy. Previously, we performed transcriptomic analysis of human breast cancer patient samples and evaluated the differential expression of genes in brain metastasis (BrM) compared to lung, bone and liver metastasis. Our network approach identified upregulation of glucose-regulated protein 94 (GRP94) as well as proteins related to synthesis of fatty acids (FA) in BrM. Here we report that BrM cells show an increase in FA content and decreased saturation with regard to parental cells measured by Raman spectroscopy that differentiate BrM from other metastases. Moreover, BrM cells exerted a high ability to oxidize FA and compensate hypoglycemic stress due to an overexpression of proteins involved in FA synthesis and degradation (SREBP-1, LXRα, ACOT7). GRP94 ablation restored glucose dependence, down-regulated ACOT7 and SREBP-1 and decreased tumorigenicity in vivo. In conclusion, GRP94 is required for the metabolic stress survival of BrM cells, and it might act as a modulator of lipid metabolism to favor BrM progression.

Meaning-centered psychotherapy integrated with elements of compassion: A pilot study to assess feasibility and utility.

OBJECTIVE: The main objective of this study is to establish emotional benefits of promoting and maintaining meaning in palliative care patients in the final weeks of life and to assess the benefits of including the compassion and self-compassion constructs in the Meaning-Centered Psychotherapy Model (MCP). METHOD: Fifty-one cancer inpatients were randomly assigned to one of the three brief interventions for cancer patients in the end of life: the MCP-palliative care version, the MCP-compassionate palliative care (MCP-CPC), or standard counseling. Feasibility, acceptability, and utility were assessed in each condition. Likewise, patients' opinions about the effectiveness of interventions' elements were also collected.ResultOf the 51 patients that began one of the three interventions, 30 completed the three-session interventional program, as well as the pre- and posttreatment questionnaires. No significant differences were found between therapies in terms of the positive feedback of patients regarding the structure, focus, and length of the all three psychotherapeutic interventions. The most helpful elements or constructs reported by patients were meaning, self-compassion, compassion, legacy, and courage and commitment.Significance of resultsAn abbreviated version of MCP-CPC tailored to the needs of palliative care patients appears to be feasible, acceptable, and helps patients cope with the process of dying. Further research in bigger samples is needed to establish evidence for the feasibility, acceptability, and utility of a brief MCP-CPC for palliative care patients in their last weeks of life. More proposals of further elements are also needed to improve the results. Such research can create or refine previous treatment approaches which improve the quality of life and psychological distress in patients with advanced cancer.

Psychological and clinical correlates of posttraumatic growth in cancer: A systematic and critical review.

OBJECTIVE: The objective of this study is to describe major findings on posttraumatic growth (PTG) in cancer, by analyzing its various definitions, assessment tools, and examining its main psychological and clinical correlates. METHODS: A search in relevant databases (PsycINFO, Pubmed, ProQuest, Scopus, and Web of Science) was performed using descriptors related to the positive reactions in cancer. Articles were screened by title, abstract, and full text. RESULTS: Seventy-two met the inclusion criteria. Most articles (46%) focused on breast cancer, used the PTG inventory (76%), and had a cross-sectional design (68%). The PTG resulted inversely associated with depressive and anxious symptoms and directly related to hope, optimism, spirituality, and meaning. Illness-related variables have been poorly investigated compared to psychological ones. Articles found no relationship between cancer site, cancer surgery, cancer recurrence, and PTG. Some correlations emerged with the elapsed time since diagnosis, type of oncological treatment received, and cancer stage. Only few studies differentiated illness-related-life-threatening stressors from other forms of trauma, and the potentially different mechanisms connected with PTG outcome in cancer patients. CONCLUSIONS: The evaluation of PTG in cancer patients is worthy, because it may promote a better adaption to the illness. However, many investigations do not explicitly refer to the medical nature of the trauma, and they may have not completely captured the full spectrum of positive reactions in cancer patients. Future research should better investigate issues such as health attitudes; the risks of future recurrences; and the type, quality, and efficacy of medical treatments received and their influence on PTG in cancer patients.