Mortality after radiotherapy or surgery in the treatment of early stage non-small-cell lung cancer: a population-based study on recent developments.

BACKGROUND: Stereotactic body radiotherapy (SBRT) can achieve high tumour control with limited toxicity for inoperable early stage non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: The German Epidemiologic Cancer Registries from the Robert-Koch Institute were assessed. Periods according to the availability of SBRT were: (1) 2000-2003 (pre-SBRT); (2) 2004-2007 (interim); and (3) 2007-2014 (broad availability of SBRT). To assess the association of cancer-related parameters with mortality, hazard ratios (HR) from Cox proportional hazards models were computed. To evaluate the change of treatment-related mortality, we performed interaction analyses and the relative excess risk due to interaction (RERI, additive scale) was computed. RESULTS: A total of 16,292 patients with UICC stage I NSCLC diagnosed between 2000 and 2014 were analysed. Radiotherapy utilization increased from 5% in pre-SBRT era to 8.8% after 2007. In univariate analyses, survival in the whole cohort improved only marginally when 2000-2003 is compared to 2004-2007 (HR 0.92, 95% CI 0.85-1.01) or 2008-2014 (HR 0.93, 95% CI 0.86-1.01). Comparing surgery/radiotherapy, mortality in the radiotherapy group started from a 3.5-fold risk in 2000-2003 to 2.6 after 2007. The interaction analysis revealed a stronger improvement for radiotherapy (multiplicative scale for 2000-2003 vs. > 2007: 0.74, 95% CI 0.58-0.94). On an additive scale, treatment × period interaction revealed an RERI for 2000-2003 vs. > 2007 of - 1.18 (95% CI - 1.8, - 0.55). CONCLUSIONS: Using population-based data, we observed a survival improvement in stage I lung cancer over time. With an increasing utilization of radiotherapy, a stronger improvement occurred in patients treated with radiotherapy when compared to surgery.

[Scleral melting after cyclophotocoagulation]. / Skleraeinschmelzung nach Zyklophotokoagulation.

We report on a case of a scleral melting as a rare but severe complication of transscleral cyclophotocoagulation. The tissue defect was successfully repaired by tectonic keratoplasty.

Citizen approval of nudging interventions promoting healthy eating: the role of intrusiveness and trustworthiness.

BACKGROUND: Nudging interventions have lately been widely adopted by policy makers to increase the welfare of society and to help citizens make better choices. Hence, it has become important to understand the conditions under which they are approved. While most research has looked into whether professionals approve of nudging interventions, surprisingly the opinion of the target group has been widely ignored. This study investigated citizens' level of approval of nudging in the realm of healthy eating promotion, as well as its boundary conditions. METHODS: Participants (N = 1441) from the US and seven European countries were probed for their level of approval of nudges. Moreover, we investigated whether these levels of approval were dependent on the level of intrusiveness of the nudge and on the type and trustworthiness of the source (policy makers, experts, industry) implementing the nudge. RESULTS: People revealed moderate to high levels of approval with nudging across all countries. Intrusiveness and nudging approval were negatively associated. Nudges implemented by experts received more approval than those by policy makers. In general, approval increased with the trustworthiness of the source. CONCLUSIONS: These results provide information for European and American policy makers considering using nudging in their policy repertoire.

Prognostic implications of the co-detection of the urokinase plasminogen activator system and osteopontin in patients with non-small-cell lung cancer undergoing radiotherapy and correlation with gross tumor volume.

BACKGROUND: The urokinase plasminogen activator system (uPA, uPAR, PAI­1) is upregulated in cancer and high plasma levels are associated with poor prognosis. Their interaction with hypoxia-related osteopontin (OPN) which is also overexpressed in malignant tumors suggests potential clinical relevance. However, the prognostic role of the uPA system in the radiotherapy (RT) of non-small-cell lung cancer (NSCLC), particularly in combination with OPN, has not been investigated so far. METHODS: uPA, uPAR, PAI­1 and OPN plasma levels of 81 patients with locally advanced or metastasized NSCLC were prospectively analyzed by ELISA before RT and were correlated to clinical patient/tumor data and prognosis after RT. RESULTS: uPAR plasma levels were higher in M1; uPA and PAI­1 levels were higher in M0 NSCLC patients. uPAR correlated with uPA (p < 0.001) which also correlated with PAI­1 (p < 0.001). The prognostic impact of OPN plasma levels in the RT of NSCLC was previously reported by our group. PAI­I plasma levels significantly impacted overall (OS) and progression-free survival (PFS). Low PAI­1 levels were associated with a significantly reduced OS and PFS with a nearly 2­fold increased risk of death (p = 0.029) and tumor progression (p = 0.029). In multivariate analysis, PAI­1 levels remained an independent prognostic factor for OS and PFS with a 3­fold increased risk of death (p = 0.001). If PAI­1 plasma levels were combined with OPN or tumor volume, we found an additive prognostic impact on OS and PFS with a 2.5- to 3­fold increased risk of death (p = 0.01). CONCLUSION: Our results suggest that PAI-1 but not uPA and uPAR might add prognostic information in patients with advanced NSCLC undergoing RT. High pretreatment PAI-1 plasma levels were found predominantly in M0-stage patients and indicate a favorable prognosis as opposed to OPN where high plasma levels are associated with poor survival and metastasis. In combination, PAI-1 and OPN levels successfully predicted outcome and additively correlated with prognosis. These findings support the notion of an antidromic prognostic impact of OPN and PAI-1 plasma levels in the RT of advanced NSCLC.

[Optical Coherence Tomography Angiography in Diagnosis and Post-Treatment Assessment of Hemangioblastomas in Hippel-Lindau Disease]. / Möglichkeiten der optischen Kohärenztomografie-Angiografie bei Diagnostik und postoperativer Verlaufskontrolle von Hämangioblastomen bei Von-Hippel-Lindau-Syndrom.

Background Optical coherence tomography angiography (OCTA) offers the possibility to visualize, non-invasively, blood vessels of the retina. In vascular tumors, especially hemangioblastomas in Hippel-Lindau disease, new information can be obtained with OCTA concerning structure of the tumor, tumor activity and treatment success. Patients Ten eyes of 10 patients with retinal hemangioblastoma in Hippel-Lindau disease were included. The age of the patients ranged from 19 years to 65 years (median 44 years). Results A total of 10 active and one inactive hemangioblastomas were examined with OCTA. In larger tumors, only the superficial blood flow could be visualized. Four hemangioblastomas were not treated due to their location near the optic nerve head. Six hemangioblastomas in the peripheral retina were treated with laser photocoagulation. In 4 eyes, a reduced blood flow could be shown directly after the treatment. The visualization of the perfusion was partially blocked after laser treatment. Conclusion OCTA enables innovative methods of pre- and postoperative assessment of retinal hemangioblastomas. It has the potential to give new information about the morphology, activity and effects of treatment. Prospective studies with longer follow-up are needed to evaluate the therapeutic relevance of this new imaging method.

Loss of function of PGAP1 as a cause of severe encephalopathy identified by Whole Exome Sequencing: Lessons of the bioinformatics pipeline.

We evaluated a multiple consanguineous Turkish family with two children, a boy and a girl, affected by severe encephalopathy, hypotonia, microcephaly and retinal dystrophy by a combination of linkage analysis and Whole Exome Sequencing (WES). We analyzed the sequence data by two different bioinformatics pipelines which did not differ in overall processing strategy but involved differences in software used, minor allele frequency (MAF) thresholds and reference data sets, the usage of in-house control exomes and filter settings to prioritize called variants. Assuming autosomal recessive mode of inheritance, only homozygous variants present in both children were considered. The resulting variant lists differed partially (nine variants identified by both pipelines, ten variants by only one pipeline). Major reasons for this discrepancy were different filters for MAF and different variant prioritizations. Combining the variant lists with the results of linkage analysis and further prioritization by expression data and prediction tools, an intronic homozygous splice variant (c.1090-2A>G; IVS9-2A>G; p.?) in PGAP1 (Post-GPI Attachment To Proteins 1) was identified and validated by cDNA analysis. PGAP1 ensures the first step of maturation of GPI (glycosylphosphatidylinositol)-anchor proteins. Recently, a homozygous loss-of-function mutation in PGAP1 has been reported in one family with two children affected by a similar phenotype. The present report not only illustrates the possible influence of specific filtering settings on the results of WES but also confirms PGAP1 as a cause of severe encephalopathy.

Craniofrontonasal syndrome in a male due to chromosomal mosaicism involving EFNB1: further insights into a genetic paradox.

Craniofrontonasal syndrome (CFNS) is an X-linked disorder caused by inactivating mutations in the gene for ephrin-B1 (EFNB1). Paradoxically it shows a more severe phenotype in females than in males. As a result of X inactivation cell populations with and without EFNB1 expression are found in EFNB1+/- females. This is thought to initiate a process termed cellular interference which may be responsible for the phenotype in females. We present a boy with severe clinical features of CFNS. In ∼42% of his blood cells we found a supernumerary ring X chromosome containing EFNB1 but lacking XIST. Mosaicism for cell populations with different levels of EFNB1 expression can explain the severe phenotype of this patient. In vitro experiments in Xenopus tissue showed that cells overexpress ephrinB1 cluster and sort out from wild-type cells. Our report provides further evidence that cellular interference contributes to the paradoxical inheritance pattern of CFNS.

Comprehensive array CGH of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance.

About 40% of patients with myelodysplastic syndromes (MDSs) present with a normal karyotype, and they are facing different courses of disease. To advance the biological understanding and to find molecular prognostic markers, we performed a high-resolution oligonucleotide array study of 107 MDS patients (French American British) with a normal karyotype and clinical follow-up through the Duesseldorf MDS registry. Recurrent hidden deletions overlapping with known cytogenetic aberrations or sites of known tumor-associated genes were identified in 4q24 (TET2, 2x), 5q31.2 (2x), 7q22.1 (3x) and 21q22.12 (RUNX1, 2x). One patient with a 7q22.1 deletion had an additional 5q31.2 deletion of the acute myeloid leukemia/MDS region, the smallest deletion identified so far and including the putative tumor suppressor (ts) genes, EGR1 and CTNNA1. One TET2 deletion was homozygous and one heterozygous, with a missense mutation in the remaining allele, further supporting its role as a ts gene. Besides these recurrent alterations, additional individual imbalances were found in 34 cases; in total, 42/107 (39%) cases had genomic imbalances. These patients had an inferior survival as compared with the rest of the patients (P=0.002). This study emphasizes the heterogeneity of MDS, but points to interesting genes that may have diagnostic and prognostic impact.

Pseudoautosomal inheritance of Léri-Weill syndrome: what does it mean?

The short stature homeobox (SHOX) gene is located in the pseudoautosomal region 1 of both sex chromosomes. Haploinsufficiency of SHOX leads to different phenotypes ranging from isolated short stature to Léri-Weill syndrome characterized by short stature, mesomelia and Madelung deformity. We describe a family with a SHOX deletion originally located on the Y chromosome and transmitted from father to daughter by crossover during meiosis. The male index patient presented with short stature, mesomelia and mild Madelung deformity. His father had a normal height but slightly disproportionate short legs. The sister of the index patient presented with marked Madelung deformity and normal height. A deletion of the SHOX gene was identified in the male index patient, his father and his sister. Metaphase fluorescence in situ hybridization (FISH) analyses showed a deletion of the SHOX gene on the Y chromosomes of the index patient and his father, and on the X chromosome of his sister, indicating that a meiotic crossover of the SHOX gene region between the X and Y chromosomes had occurred. The pseudoautosomal region 1 is a known recombination 'hot spot' in male meiosis. Published genetic maps indicate high recombination frequency of ∼40% for SHOX in male meiosis leading to pseudoautosomal inheritance.

Prediction of aggression on a locked psychiatric admissions ward.

OBJECTIVE: The present study evaluates the accuracy of clinical and archival predictors of patients' aggressive behaviour on a locked admissions ward. METHOD: Over a 9-month period, staff members estimated the likelihood that patients would become aggressive during their stay in the ward. These unaided clinical assessments were obtained with Visual Analogue Scales (VASs) administered before the end of the first full day of admission. Archival predictions were based on demographic variables (e.g. gender, number of previous admissions, diagnosis) derived from patients' admission forms. Aggressive behaviour was recorded with the Staff Observation Aggression Scale-Revised (SOAS-R). RESULTS: Clinical predictions of aggression were found to be moderately accurate. On the basis of clinical estimates, 75% of the patients were correctly classified as becoming aggressive or not. CONCLUSION: Although a body of evidence indicates that unaided clinical prediction of violent recidivism after hospital discharge does not perform well, it may be quite accurate in estimating short-term aggression risks during acute psychiatric admission.

[Gender identity disorders as a symptom of psychosis, schizophrenia in particular]. / Genderidentiteitsstoornissen als bijverschijnsel van psychose, in het bijzonder schizofrenie.

In the Netherlands it has recently become possible for transsexual patients to receive hormonal treatment from the onset of puberty. Until the age of 16, pubertal development can be prevented with luteinizing hormone-releasing hormone (LHRH) agonists. From 16 years of age onwards, gender adjustment can be initiated by administration of hormones of the opposite sex. Surgical treatment can be offered once the patient reaches 18 years of age. Although such treatment will only be initiated with reticence and after a long phase of intense diagnostic screening, the question arises whether a clear differentiation can be made between pure gender identity disorders and secondary transsexual feelings that are part of an ongoing psychopathological development, such as schizophrenia. The potential diagnostic confusion is illustrated by a case history of a male schizophrenic patient. This patient had been treated hormonally for transsexualism for years before acute psychotic decompensation occurred. Neuroleptic treatment of the psychosis rapidly reduced the psychotic symptoms. In retrospect, the patient regards his transsexual period as a 'mistake'. Delusions about one's physical appearance and the urge to drastically change the way one looks appear to be relatively common in patients suffering from schizophrenia.

Redefinition: coping with normal results from predictive gene testing for neurodegenerative disorders.

The purpose of this qualitative study was to describe the psychosocial impact and coping processes of normal (negative) results from predictive testing for an inherited neurodegenerative disease. Ten adults with normal results of predictive testing for the Huntington disease (HD) or the Pallido-Ponto-Nigral Degeneration (PPND) gene mutation participated in semi-structured interviews 1 month after receiving results, and seven of these participants were interviewed 6 months later. The major theme of Redefinition was derived using Knafl and Webster's analysis method (1988). People who received normal gene results experienced loss of former beliefs about themselves and developed new self definitions, relationships with family, and roles in society. This coping process evolved from a personal focus at 1 month to a broader future perspective at 6 months after testing. Identifying components of the redefinition process may be an important consideration in planning interventions to promote coping with normal gene results in persons within at-risk families.

Psychosocial impact of predictive testing for Huntington disease on support persons.

Although a support person is required by many centers during the predictive testing protocol for Huntington disease (HD), little is known about the psychosocial impact of predictive testing on persons serving in this role. Eighteen adults who were support persons during predictive HD testing in one HD testing center completed a semi-structured interview to describe their experiences. Participants also completed the Impact of Events Scale (IES) to assess perceptions of emotional distress regarding predictive testing and the State Anxiety Scale of the State Trait Anxiety Inventory (STAI) to assess anxiety regarding the interview. State anxiety scores were similar to normative values for working adults. Although support persons for individuals with a positive gene test scored higher on all measures of the IES than those who were support persons for persons with negative gene mutation results, these differences were not statistically significant. Support persons identified aspects of the protocol that did not fit their needs, perceived the testing process as extending into subsequent caregiving responsibilities when the test was positive, and were uninformed regarding specific caregiving issues for family members with the gene mutation. The impact of the testing experience appeared to be most intense for those support persons who were at-risk offspring of probands. Findings suggest that individual assessment of support person needs may allow more focused counseling of support persons during predictive genetic HD testing. Collaboration with health care providers may facilitate symptom management following testing.

The DIAL-log study. 2: Support in the early stages of dementia.

In the previous article (Vol 8(6): 387-93) the background information and study aims/limitations of the Dementia Information and Advice Lines (DIAL-log) project were outlined. This article introduces the main findings of the project and suggests that the transition into dementia is experienced through rising degrees of uncertainty and anxiety. People with the early experience of dementia also requested strategies for coping with memory loss and uncertainty over the meaning and purpose of memory testing. Building on the main findings of the project, the article concludes with a five-stage framework to help shape future research and service support.

The DIAL-log study 1: Profiling the experience of people with dementia.

Between July 1996 and December 1997 telephone helpline staff from the Alzheimer's Disease Society (ADS) in London, and six participating ADS regions in England and one in Northern Ireland, documented calls from people with dementia who contacted the service. Each call was recorded as soon as practicable after its completion on a Dementia Information and Advice Line (DIAL) log form (DIAL-log). Sixty-four calls were recorded in this way and 62 completed DIAL-logs were included in the study findings. Analysis of the data was undertaken via SPSS 6.1 for Windows. This article, the first of two, introduces the background to the study and notes that callers reported memory loss and forgetfulness as the most frequently noticed first signs of dementia. The study aims and limitations are also outlined in this first article. The second article will detail the main findings and the challenges that the DIAL-log study may provide for future dementia care practice and research.

Adults seeking presymptomatic gene testing for Huntington disease.

PURPOSE: To describe the expectations of those seeking presymptomatic gene testing for Huntington disease (HD). Identification of the gene for HD makes it possible to conduct testing to determine if a healthy person with a family history of HD has a mutation in this gene. Presymptomatic gene testing reveals the likelihood that a person will develop an inherited disease in the future. Understanding expectations allows for more complete assessment and counseling before presymptomatic gene testing for genetic diseases. DESIGN: Descriptive qualitative. The population was people with a family history of HD. The sample was 17 asymptomatic adults with a positive family history of HD who requested presymptomatic gene identification at one tertiary genetic counseling program, 1995 to 1996. METHODS: Semi-structured interviews concerning expectations of adults seeking presymptomatic genetic testing were conducted by telephone. Interviews occurred after the individuals had requested presymptomatic gene identification but before results were reported. Content analysis was used to identify the expectations and questions of those who had decided to seek presymptomatic testing. FINDINGS: Common expectations included anticipating relief from uncertainty, hoping to plan for their future health care and life decisions, wanting to know if their children were at risk of developing HD, anticipating loss of family support from relatives, expecting relief from self monitoring, venturing into the unknown, and planning for disclosure. Participants attempted to avoid their loss of genetic privacy by withholding the decision to seek testing from their primary care providers. CONCLUSIONS: Participants seeking presymptomatic HD gene testing consider the effect of gene identification on themselves and their families. A desire to limit insurance or employment discrimination contributes to subjects not seeking input from health care providers in their decision making.

Empower children to develop healthful eating habits.

Controlling a child's eating habits is counterproductive. By allowing children to make decisions about what and how much to eat, parents empower children to self-regulate their eating. The parent's role is to offer a variety of healthful foods, oversee the planning and assembly of meals, and set the schedule for meals and snacks. The child's responsibility is to decide what, how much, and even whether to eat.