Pan-cancer analysis of genomic scar patterns caused by homologous repair deficiency (HRD).

Homologous repair deficiency (HRD) is present in many cancer types at variable prevalence and can indicate response to platinum-based chemotherapy and PARP inhibition. We developed a tumor classification system based on the loss of function of genes in the homologous recombination repair (HRR) pathway. To this end, somatic and germline alterations in BRCA1/2 and 140 other HRR genes were included and assessed for the impact on gene function. Additionally, information on the allelic hit type and on BRCA1 promoter hypermethylation was included. The HRDsum score including LOH, LST, and TAI was calculated for 8847 tumors of the TCGA cohort starting from genotyping data and for the subcohort of ovarian cancer also starting from WES data. Pan-cancer, deleterious BRCA1/2 alterations were detected in 4% of the tumors, while 18% of the tumors were HRD-positive (HRDsum ≥ 42). Across 33 cancer types, both BRCA1/2 alterations and HRD-positivity were most prevalent in ovarian cancer (20% and 69%). Pan-cancer, tumors with biallelic deleterious alterations in BRCA1/2 were separated strongly from tumors without relevant alterations (AUC = 0.89), while separation for tumors with monoallelic deleterious BRCA1/2 alterations was weak (AUC = 0.53). Tumors with biallelic deleterious alterations in other HHR genes were separated moderately from tumors without relevant alterations (AUC = 0.63), while separation for tumors with such monoallelic alterations was weaker (AUC = 0.57). In ovarian cancer, HRDsum scores calculated from WES data correlated strongly with HRDsum scores calculated from genotyping data (R = 0.87) and were slightly (4%) higher. We comprehensively analyzed HRD scores and their association with mutations in HRR genes in common cancer types. Our study identifies important parameters influencing HRD measurement and argues for an integration of HRDsum score with specific mutational profiles.

Intranasal fentanyl and inhaled nitrous oxide for fracture reduction: The FAN observational study.

INTRODUCTION: Procedural sedation and analgesia (PSA) are frequently used for fracture reduction in pediatric emergency departments (ED). Combining intranasal (IN) fentanyl with inhalation of nitrous oxide (N2O) allow for short recovery time and obviates painful and time-consuming IV access insertions. METHODS: We performed a bicentric, prospective, observational cohort study. Patients aged 4-18years were included if they received combined PSA with IN fentanyl and N2O for the reduction of mildly/moderately displaced fracture or of dislocation. Facial Pain Scale Revised (FPS-R) and Face, Leg, Activity, Cry, Consolability (FLACC) scores were used to evaluate pain and anxiety before, during and after procedure. University of Michigan Sedation Score (UMSS), adverse events, detailed side effects and satisfaction of patients, parents and medical staff were recorded at discharge. A follow up telephone call was made after 24-72h. RESULTS: 90 patients were included. There was no difference in FPS-R during the procedure (median score 2 versus 2), but the FLACC score was significantly higher as compared to before (median score 4 versus 0, Δ 2, 95% CI 0, 2). Median UMSS was 1 (95% CI 1, 2). We recorded no serious adverse events. Rate of vomiting was 12% (11/84). Satisfaction was high among participants responding to this question 85/88 (97%) of parents, 74/83 (89%) of patients and 82/85 (96%) of physicians would want the same sedation again. CONCLUSION: PSA with IN fentanyl and N2O is effective and safe for the reduction of mildly/moderately displaced fracture or dislocation, and has a high satisfaction rate.

[Ethical aspects of palliative medicine]. / Ethische Aspekte der Palliativmedizin.

BACKGROUND: The aim of palliative medicine is to adequately care for and attend to patients suffering from life-threatening and incurable medical conditions according to their needs. This implies that for these patients it is not a matter of dealing with diseases that can be treated separately but with their existence in the face of their approaching death. OBJECTIVE: This article investigates which ethical questions are currently prioritized for discussion in palliative medicine. METHOD: Review of the current medical and ethical literature and own reflections with a relational ethics approach that puts patient wishes at the centre of attention. RESULTS: Palliative medicine is not a "luxury medicine" but has to be considered as primary care to which every person is entitled. If there is a need for improvement of care, promoting it is an ethical obligation. In this respect the question of a "good death" is extremely complex. The term is connected to the ethics of a good life and includes the dimensions of happiness-suffering as well as meaning-futility; therefore, the best possible treatment of symptoms, most of all pain is just as important as recognizing subjective questions of meaning. Dealing with the wishes of patients, including possible wishes to die, are the starting point for elaborating palliative care measures. It is concerned with finding the right point in time for each patient individually, in their best interests and according to their wishes, at which dying should no longer be held back but for their own benefit the patient should be accompanied and supported during dying. CONCLUSION: In the current construction of palliative medicine, including its normative configuration within the law and medical ethics, the criteria which are essential for the quality of life up to death are being discussed.

Age-related differences in processing visual device and task characteristics when using technical devices.

With aging visual feedback becomes increasingly relevant in action control. Consequently, visual device and task characteristics should more and more affect tool use. Focussing on late working age, the present study aims to investigate age-related differences in processing task irrelevant (display size) and task relevant visual information (task difficulty). Young and middle-aged participants (20-35 and 36-64 years of age, respectively) sat in front of a touch screen with differently sized active touch areas (4″ to 12″) and performed pointing tasks with differing task difficulties (1.8-5 bits). Both display size and age affected pointing performance, but the two variables did not interact and aiming duration moderated both effects. Furthermore, task difficulty affected the pointing durations of middle-aged adults moreso than those of young adults. Again, aiming duration accounted for the variance in the data. The onset of an age-related decline in aiming duration can be clearly located in middle adulthood. Thus, the fine psychomotor ability "aiming" is a moderator and predictor for age-related differences in pointing tasks. The results support a user-specific design for small technical devices with touch interfaces.

Intentions in wishes to die: analysis and a typology--a report of 30 qualitative case studies of terminally ill cancer patients in palliative care.

OBJECTIVE: To investigate the variations in and intentions of wishes to die (WTD) of palliative care cancer patients. METHODS: Thirty terminally ill cancer patients, their caregivers and relatives in a hospice, an oncology palliative care ward of a general hospital, and an outpatient palliative care service. 116 semistructured qualitative interviews analyzed by a combined approach using Grounded Theory and Interpretive Phenomenological Analysis. RESULTS: A WTD is dynamic and interactive. Its subjective phenomenology can be described by three aspects: intentions, motivations, and interactions. In this article, we present a typology of the possible intentions. We identified nine different (ideal) types of intentions that WTD statements might have, other than wishing to live and accepting death. Many WTD statements do not imply a desire to hasten death. The intentions of statements differ according to whether a WTD is related to as imaginary or as an action. Often WTD statements contain several partial wishes, which can be in tension with each other and form a dynamic, sometimes unstable equilibrium. CONCLUSIONS: Terminally ill persons' WTD statements differ in their intention, and deeper knowledge about these differences is ethically relevant.

BRCA1/2 testing: uptake, phenocopies, and strategies to improve detection rates in initially negative families.

In families with clustering of breast and ovarian cancer, molecular testing of the major susceptibility genes BRCA1/2 helps to identify patients with disease mutations and healthy persons at high risk who can participate in targeted intervention programs. We investigated 5559 families from the German Consortium for Hereditary Breast and Ovarian Cancer included between 1997 and 2008 and treated under clinical routine conditions. In each family an index patient/person had been screened for deleterious mutations in BRCA1/2. Healthy relatives agreed to predictive testing in 888 of 1520 BRCA1/2 mutation-positive families (58%). Of 2646 eligible unaffected first-degree relatives 1143 decided to be tested (43%). In 325 families with BRCA1/2-positive index patients one related BC/OC patient was tested and 39 (12.0%; 95% confidence interval: 8.7-16.0%) discrepant cases found. A second related individual was screened in 163 of 3388 (4.9%) families with BRCA1/2-negative index patient and in eight families a BRCA1/2 mutation was found. In BRCA1/2 mutation-positive families, BC/OC patients lacking the familial mutation have to be expected at a rather high rate. In families with BRCA1/2-negative index patient we recommend a second screening if another patient with a high probability of carrying a BRCA1/2 mutation is available.

[Retrobulbar optic neuropathy and non-Hodgkin lymphoma]. / Neuropathie optique rétrobulbaire et lymphome malin non hodgkinien.

INTRODUCTION: Non-Hodgkin lymphomas (NHLs) constitute a group of heterogeneous diseases that can arise in lymphatic nodal or extranodal sites. Ocular lymphomas account for 1% of all NHLs. Tumor of the orbit, which can lead to compression of the optic nerve, is the most frequent presentation of the disease. Primary infiltration of the optic nerve and its sheath remains exceptional. OBSERVATION: We report the case of a 51-year-old female patient treated for a NHL. While she was considered to be in remission after four courses of chemotherapy, she presented a right visual loss with hand motion acuity. Her examination revealed a right afferent pupillary defect. Brain MRI emphasized an infiltration of her right optic nerve with no other orbit abnormality. Cerebrospinal fluid analysis showed lymphomatous meningitis. She was then considered to have lymphomatous optic neuropathy (LON). Despite initial improvement of the visual acuity with treatment, the patient died of bone marrow aplasia 6 weeks later. CONCLUSION: LON can be suspected in a painful and sudden visual loss in a context of neoplasia. The diagnosis is confirmed by MRI and cerebrospinal fluid analysis. LON may occur as the sole ocular manifestation of disease recurrence in a patient with systemic NHL, otherwise thought to be in clinical remission.

[Clinical and paraclinical course of melanocytoma of the optic disk. Contribution of spectral- and time-domain OCT in the study of 10 patients]. / Aspects cliniques et paracliniques évolutifs des mélanocytomes papillaires. Apport de la tomographe à cohérence optique de type spectral dans l'étude de dix cas.

INTRODUCTION: Melanocytoma of the optic disk is a rare, benign, slow-growing tumor. We analyzed the clinical and paraclinical features of melanocytomas followed at the Fort-de-France University Hospital to expose and compare characteristics from new clinical imaging. PATIENTS AND METHOD: This was a prospective study of 10 patients with a melanocytoma of the optic disk. The principal features studied were the ophthalmoscopic findings, the visual field defects, fluorescein angiography features, and the comparison between standard time-domain optical coherence tomography (OCT) characteristics and the latest spectral-domain OCT findings. RESULTS: The mean age of the patients at diagnosis was 49.2 years. All the patients were from the French West Indies. The lesion was discovered incidentally in 90% of the cases. Visual acuity was normal in 70% of the cases. Visual field defects were present at the first visit in 80% of the cases. Tumor growth was monitored in 50% of the cases during a mean follow up of 4.8 years. The in-depth extension into chorioretina and laterally into the retina were better visualized in spectral-domain OCT than in time-domain OCT as hyperreflective granular dots. CONCLUSION: Optic disk melanocytoma appears to be a singular benign tumor that is seen more frequently in dark-skinned patients. Most melanocytomas do not cause significant visual impairment but can show substantial growth in size for many years of follow-up. A malignant transformation is always to fear in case of atypical development. Spectral domain OCT seems to be an important tool in the assessment of extension and follow-up.

Practice and carryover effects when using small interaction devices.

The use of interaction devices in modern work often challenges the human motor system, especially when these devices introduce unfamiliar transformations to the user. In this paper we evaluated expert performance and skill differences between experts and novices when using small motion- and force-controlled interaction devices (touchpad and mini-joystick) in an applied text-editing task. Firstly, experts performed better with their familiar input device than with an unfamiliar one. Particularly touchpad experts operating the unfamiliar mini-joystick showed highly asymmetric carryover costs. Results showed that the efficient performance of experts depended on domain-specific skills, which were not transferable. Secondly, with considerable practice (more than observed for simple and short tasks) novices were brought up to higher levels of performance. The motion-transformation between hand and cursor action was easier in understanding and application than the force-transformation. Thus, the touchpad was used more efficiently than the mini-joystick. In conclusion, practice effects found so far are considerably underestimated when it comes to an applied task. The results give reason to develop and implement skill-sensitive training procedures, since the acquisition of domain-specific skills is critical for expert performance. As a consequence, training procedures might be essential for complex applications and/or unfamiliar device transformations.

Cerebellar stem cells act as medulloblastoma-initiating cells in a mouse model and a neural stem cell signature characterizes a subset of human medulloblastomas.

Cells with stem cell properties have been isolated from various areas of the postnatal mammalian brain, most recently from the postnatal mouse cerebellum. We show here that inactivation of the tumor suppressor genes Rb and p53 in these endogenous neural stem cells induced deregulated proliferation and resistance to apoptosis in vitro. Moreover, injection of these cells into mice formed medulloblastomas. Medulloblastomas are the most common malignant brain tumors of childhood, and despite recent advances in treatment they are associated with high morbidity and mortality. They are highly heterogeneous tumors characterized by a diverse genetic make-up and expression profile as well as variable prognosis. Here, we describe a novel ontogenetic pathway of medulloblastoma that significantly contributes to understanding their heterogeneity. Experimental medulloblastomas originating from neural stem cells preferentially expressed stem cell markers Nestin, Sox2 and Sox9, which were not expressed in medulloblastomas originating from granule-cell-restricted progenitors. Furthermore, the expression of these markers identified a subset of human medulloblastomas associated with a poorer clinical outcome.

Sensumotor transformation of input devices and the impact on practice and task difficulty.

In the present study, the usability of two laptop input devices, touchpad and trackpoint, is evaluated. The focus is set on the impact of sensumotor transformation of input devices on practice and task difficulty. Thirty novices and 14 experts operated either touchpad or trackpoint over a period of 1600 trials of a point-click task. As hypothesized, novices and experts operated the touchpad by 15% faster compared to the trackpoint. For novices, performance rose distinctly and levelled off after 960 trials. This consolidation occurred earlier than reported in literature (1400-1600 trials) and, contrary to the assumption, learning was similar for touchpad and trackpoint. The impact of task difficulty dropped remarkably by practice, which points at a more general than specific task learning. In conclusion, ergonomic guidelines can be derived for the user-specific optimization of the usage of touchpad and trackpoint. Actual and potential applications of this research include the user-specific optimization of laptop input devices. Within the theoretical framework of psychomotor models, a profound knowledge of user behaviour in human-computer interaction is provided. Ergonomic guidelines can be derived for the efficient usage of laptop input devices and an optimized hardware and software design.

Notebook input devices put to the age test: the usability of trackpoint and touchpad for middle-aged adults.

In two experiments, the usability of input devices integrated into computer notebooks was under study. The most common input devices, touchpad (experiment 1) and trackpoint (experiment 2) were examined. So far, the evaluation of mobile input devices has been restricted to younger users. However, due to ongoing demographic change, the main target group of mobile devices will be older users. Therefore, the present study focused on ageing effects. A total of 14 middle-aged (40-65 years) and 20 younger (20-32 years) users were compared regarding speed and accuracy of cursor control in a point-click and a point-drag-drop task. Moreover, the effects of training were addressed by examining the performance increase over time. In total, 640 trials per task and input device were executed. The results show that ageing is a central factor to be considered in input device design. Middle-aged users were significantly slower than younger users when executing the different tasks. Over time, a significant training effect was observed for both devices and both age groups, although the benefit of training was greater for the middle-aged group. Generally, the touchpad performance was higher than the trackpoint performance in both age groups, but the age-related performance decrements were less distinct when using the touchpad.

[Is informed consent actually possible?]. / Ist ein informed consent wirklich möglich?

In prenatal medicine, the doctrine of informed consent is subject to several restrictions: women are confronted with social expectations to accept screening and tests that entail a pressure to decide. Some authors criticise that the informed consent overstretches the patient, dislocates responsibility to the individual, and, in many cases, is nothing but an empty ritual. The article defends the idea of informed consent. It argues that we need to reinterpret informed consent on the basis of a dialogical principle: the aim is to recognise the subjectivity and vulnerability of the patient in her special situation, which implies a mutual culture of hearing.

A 'nonsense' mutation leads to aberrant splicing of hMLH1 in a German hereditary non-polyposis colorectal cancer family.

Hereditary Non-polyposis Colorectal Cancer (HNPCC) is an autosomal dominant cancer predisposition syndrome caused by germline mutations in at least four genes encoding integral components of the cellular DNA mismatch repair (MMR) system. The spectrum of genetic alterations encompasses missense- and nonsense mutations, intronic mutations affecting splice donor or acceptor sites as well as small-scale deletions and insertions. We have identified a 'nonsense' mutation that activates a cryptic splice site generating an in frame deletion of the last 17 codons of exon1 of the hMLH1 gene causing HNPCC in a German family. We present a comprehensive genetic analysis of this family that demonstrates important aspects of HNPCC pathogenesis.

[Glioblastoma multiforme as a manifestation of Turcot syndrome]. / Glioblastoma multiforme als Manifestation des Turcot-Syndroms.

Turcot's syndrome, clinically characterized by the coincident occurrence of primary tumors of the colon and the central nervous system, can genetically be divided into two syndromes: familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon carcinoma (HNPCC). In the present case, a 60-year-old patient with glioblastoma multiforme and a history of hereditary malignomas is described as an example of a HNPCC-associated Turcot's syndrome. New molecular biological methods and results give deeper insight into clinical syndromes, and the better understanding improves diagnostics, therapy, and outcome estimations, even in rare diseases. In the present case, a new germinal mutation could be identified.

Comprehensive genetic counseling for families at risk for HNPCC: impact on distress and perceptions.

The aim of the study was to explore distress and health beliefs before and after comprehensive interdisciplinary counseling in families at risk for hereditary non-polyposis colorectal cancer (HNPCC). Results reported here were derived from a consecutive sample of 65 counselees [31 patients with colorectal cancer (CRC) and 34 unaffected at-risk persons] who participated in interdisciplinary counseling provided by human geneticists, surgeons, and psycho-oncologists before genetic testing. Data were collected from self-administered questionnaires before, as well as 4-6 weeks after, counseling. Distress and perceptions specific to HNPCC were assessed at both timepoints using standardized as well as author-derived instruments. Distress declined after counseling, as did worries related to HNPCC. An increase was found in personal belief in control of cancer risk, for instance, in the perceived efficacy of early detection of CRC. We also observed a trend toward greater anticipated ability to cope with a positive gene test after counseling. Changes after counseling were generally more pronounced for persons at risk, as compared to patients with cancer. The decrease in distress was partly attributable to an increase in personal self-confidence. One-third of the sample reported enhanced communication specific to hereditary disease within the family after counseling. A substantial minority, however, said they experienced increased worry and physical symptoms after counseling. Overall, counselees demonstrated less stress and perceived cancer threat as well as enhanced beliefs regarding personal control over cancer, suggesting an overall beneficial impact of comprehensive counseling. Further research is needed to identify those individuals most at risk for increased fear and worry related to HNPCC so that they may be most appropriately counseled.

Evaluation of Bethesda guidelines in relation to microsatellite instability.

PURPOSE: The Bethesda guidelines were developed for selection of patients whose tumors should be tested for high microsatellite instability. This study examined the validity of the different Bethesda criteria in relation to microsatellite instability status to simplify their use in clinical practice. METHODS: A total of 164 patients with colorectal or hereditary nonpolyposis colorectal cancer-associated cancers were registered on the basis of the Amsterdam criteria without age limitations (11 cases), multiple tumors (2 cases), the accumulation of colorectal cancer in the family (no first-degree relatives affected or the index patient's age up to 50 years; 45 cases), an early age at onset up to 50 years (13 cases), morphologic and histopathologic manifestations (right-sided colorectal cancer, mucinous undifferentiated histology; 1 case), and the Bethesda criteria (92 cases). The microsatellite instability status of tumors was determined using the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer marker reference panel. RESULTS: When applying all Bethesda criteria, high microsatellite instability tumors were identified in our hereditary nonpolyposis colorectal cancer registry with a sensitivity of 87 percent. Twenty-nine percent (27/92) of the Bethesda-positive patients displayed high microsatellite instability compared with 6 percent of patients (4/72) not meeting these criteria (P < 0.001). Only Bethesda Criteria 1, 3, and 4 showed a significantly different distribution of the microsatellite instability status when compared with those of the remaining patients registered (P < or = 0.001). These three criteria detected high microsatellite instability tumors in 48 percent (10/21), 50 percent (18/36), and 31 percent (21/67) of patients, respectively. When applying these criteria only, a cumulative detection rate of 77 percent of all (24/31) high microsatellite instability cases was found, thereby identifying 89 percent of high microsatellite instability tumors among the Bethesda-positive patients. Patients matching Criteria 1, 3, and 4 frequently showed hMSH2 or hMLH1 germline mutations and tumor-specific loss of protein expression. CONCLUSION: In our hereditary nonpolyposis colorectal cancer registry the complete Bethesda criteria showed the highest sensitivity to identify patients with high microsatellite instability tumors. However, for general medical practice outside academic centers, three criteria are reasonably accurate for adequate high microsatellite instability tumor selection.

Systematic identification of genes with coding microsatellites mutated in DNA mismatch repair-deficient cancer cells.

Microsatellite instability (MSI) caused by deficient DNA mismatch-repair functions is a hallmark of cancers associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome but is also found in about 15% of all sporadic tumors. Most affected microsatellites reside in untranslated intergenic or intronic sequences. However, recently few genes with coding microsatellites were also shown to be mutational targets in MSI-positive cancers and might represent important mutation targets in their pathogenesis. The systematic identification of such genes and the analysis of their mutation frequency in MSI-positive cancers might thus reveal major clues to their functional role in MSI-associated carcinogenesis. We therefore initiated a systematic database search in 33,595 distinctly annotated human genes and identified 17,654 potentially coding mononucleotide repeats (cMNRs) and 2,028 coding dinucleotide repeats (cDNRs), which consist of n > or = 6 and n > or = 4 repeat units, respectively. Expression pattern and mutation frequency of 19 of these genes with the longest repeats were compared between DNA mismatch repair-deficient (MSI(+)) and proficient (MSS) cancer cells. Instability frequencies in these coding microsatellite genes ranged from 10% to 100% in MSI-H tumor cells, whereas MSS cancer cells did not show mutations. RT-PCR analysis further showed that most of the affected genes (10/15) were highly expressed in tumor cells. The approach outlined here identified a new set of genes frequently affected by mutations in MSI-positive tumor cells. It will lead to novel and highly specific diagnostic and therapeutic targets for microsatellite unstable cancers.

When norms normalize: the case of genetic "enhancement".

As the possibility of genetic intervention becomes more concrete, defining and regulating ethically permissible interventions must include a consideration of the implicit as well as explicit consequences. These include the moral implications of defining "enhancement" by reference to a standard of normality. Some authors have called into question the standard ethical concerns about genetic enhancement, but the distinction between enhancing and therapeutic interventions is still structured as relatively unproblematic. However, determining the boundary between therapy and enhancement will have feedback effects on the socially implemented definitions of what counts as normal in human embodiment. Positioning the interface between permissible and nonpermissible interventions at the same place as the boundaries between therapy and enhancement, and between normal and abnormal embodiment, (1) uses biology to justify a moral evaluation, (2) privileges the single standpoint of the genetically canonical person, and (3) enhances the dichotomy between "normal" and "not normal". Assuming that the limit of permissibility along the interventional continuum is coterminous with the definitions of enhancement and of normality, distracts from the work of uncovering the real grounds to setting limits to genetic manipulation.