Observations made during the TWP‐ICE campaign are used to drive and evaluate thirteen cloud‐resolving model simulations with periodic lateral boundary conditions. The simulations employ 2D and 3D ...dynamics, one‐ and two‐moment microphysics, several variations on large‐scale forcing, and the use of observationally derived aerosol properties to prognose droplet numbers. When domain means are averaged over a 6‐day active monsoon period, all simulations reproduce observed surface precipitation rate but not its structural distribution. Simulated fractional areas covered by convective and stratiform rain are uncorrelated with one another, and are both variably overpredicted by up to a factor of ∼2. Stratiform area fractions are strongly anticorrelated with outgoing longwave radiation (OLR) but are negligibly correlated with ice water path (IWP), indicating that ice spatial distribution controls OLR more than mean IWP. Overpredictions of OLR tend to be accompanied by underpredictions of reflected shortwave radiation (RSR). When there are two simulations differing only in microphysics scheme or large‐scale forcing, the one with smaller stratiform area tends to exhibit greater OLR and lesser RSR by similar amounts. After ∼10 days, simulations reach a suppressed monsoon period with a wide range of mean precipitable water vapor, attributable in part to varying overprediction of cloud‐modulated radiative flux divergence compared with observationally derived values. Differences across the simulation ensemble arise from multiple sources, including dynamics, microphysics, and radiation treatments. Close agreement of spatial and temporal averages with observations may not be expected, but the wide spreads of predicted stratiform fraction and anticorrelated OLR indicate a need for more rigorous observation‐based evaluation of the underlying micro‐ and macrophysical properties of convective and stratiform structures.
Key Points
CRMs reproduce domain‐mean precipitation but not its structural distribution
Simulated convective and stratiform fractional areas are variably overpredicted
Range of stratiform areas indicates a need for observation‐based evaluation
AbstractObjectiveLow-grade epithelial ovarian cancers (EOC), constitute the minority among all epithelial cancers. Our study objective was to focus on low-grade recurrent EOC and compare the survival ...with high-grade disease, as well as in regard to “platinum-sensitive” and “-resistant” recurrences according to platinum-free interval. MethodsThis is an exploratory analysis within the North-Eastern German Society of Gynecological Oncology (NOGGO) database including five randomized phase II/III trials comparing different chemotherapy regimens in recurrent EOC. We conducted survival analyses and cox-proportional regression models. ResultsOut of 1050 patients having the first recurrence, 42 (4%) patients had low-grade and 1008 (96%) patients had high-grade disease. In the subgroup of platinum-sensitive recurrences, progression-free survival (PFS) ( 8.7 m vs 9.7 m, p = 0.7) and overall survival (OS) (23.9 m vs 24.8 m, p = 0.9) did not differ between low-grade and high-grade diseases. In platinum-resistant recurrences, patients with low-grade ovarian cancer had significantly better PFS (7.6 m vs 3.6 m, p = 0.03) and OS (41.9 m vs 9.5 m p = 0.002) in comparison to those with high-grade cancer. At low-grade EOC, there were no significant PFS ( p = 0.91) and OS ( p = 0.25) differences between platinum-sensitive and –resistant recurrences. Patients with low-grade non-serous histology had lower PFS with compared to those with low-grade serous histology ( p = 0.004). At cox regression analysis presence of ascites and residual disease after secondary cytoreductive surgery were independently associated with poor PFS within low-grade recurrent EOC. ConclusionOur study indicates, platinum-free interval does not have any prognostic significance at recurrent low-grade EOC and non-serous histology is associated with poorer outcome in recurrence. Secondary surgical cytoreduction to no-gross residual disease and ascites are independently associated with disease progression.
Abstract Cytoreductive surgery is the backbone of the multimodal therapy in primary ovarian cancer patients. Despite the impact of various tumor biological factors, such as grading and histological ...subtype, the surgical outcome is the most important prognostic factor for both, progression free- and overall survival. In contrast, the management in recurrent situation remains since years a subject of an emotional international discussion. Only few prospective studies focused so far on the effect of surgery in relapsed ovarian cancer. Available retrospective data associate complete cytoreduction with prognosis improvement. However, the selection of patients eligible for surgery in recurrent situation is the essential issue. Establishment of predictive factors for complete tumor resection and define the patients group with recurrent disease who might profit from this approach is crucial. The available predictors of complete resection depend on results of primary surgery and current patients situation. Women, who underwent primary complete cytoreduction, are in good performance status and have only minimal ascites volume (less than 500ml) in recurrent situation have 76% likelihood of undergoing complete resection and survival prolongation. Moreover the complete cytoreduction in tertiary cytoreductive approach has been evaluated and showed also a potential positive influence on patients’ survival. This review concentrates on the recent data and highlights the need of further randomized trials in order to develop and incorporate operative standards in recurrent ovarian cancer.
Background
The aim of this study was to analyze the potential impact of chemotherapy-induced nausea and vomiting (CINV) on dose reductions, discontinuation of chemotherapy, and survival.
Patients and ...methods
This study was designed as individual participant data meta-analysis with the original study data of three phase II/III trials that were conducted by the North-Eastern German Society of Gynecological Oncology (NOGGO) including 1213 patients with recurrent ovarian cancer. Logistic and Cox regression analyses were used to estimate odds and hazard ratios after adjusting for age, ECOG, amount of delivered cycles, amount of recurrences, and amount of comedications and study.
Results
The majority of patients developed nausea (58.1%) and almost one third experienced vomiting (31.0%). CINV was not associated with FIGO stage, grading, histology, and number of recurrences. The necessity of dose reduction and discontinuation of chemotherapy did not correlate to nausea and vomiting (
p
= 0.88,
p
= 0.39 and
p
= 0.25,
p
= 0.54 respectively). Progression-free survival was shorter in patients with grade III/IV nausea and vomiting (
p
= 0.02; hazard ratio (HR) for grade III/IV nausea 1.58, 95% CI 1.14–2.20, and
p
= 0.02; HR for grade III/IV vomiting 1.67, 95% CI 1.15–2.42 respectively). CINV grade III/IV was also associated with poorer overall survival (
p
< 0.001; HR for grade III/IV nausea 2.35, 95% CI 1.64–3.37, and
p
< 0.001; HR for grade III/IV vomiting 1.67, 95% CI 1.15–2.42 respectively).
Conclusion
CINV is significantly associated with poorer prognosis in recurrent ovarian cancer patients while there was no correlation found with the necessity of dose reduction and prior discontinuation of treatment. This study underlines the importance of prevention and treatment of CINV as part of early best supportive care.
A decade of empirical work in brain imaging, genomics, and other areas of research has yielded new knowledge about the frequency of incidental findings, investigator responsibility, and risks and ...benefits of disclosure. Straightforward guidance for handling such findings of possible clinical significance, however, has been elusive. In early work focusing on imaging studies of the brain, we suggested that investigators and institutional review boards must anticipate and articulate plans for handling incidental findings. Here we provide a detailed analysis of different approaches to the problem and evaluate their merits in the context of the goals and setting of the research and the involvement of neurologists, radiologists, and other physicians. Protecting subject welfare and privacy, as well as ensuring scientific integrity, are the highest priorities in making choices about how to handle incidental findings. Forethought and clarity will enable these goals without overburdening research conducted within or outside the medical setting.
Tissue-specific alternative splicing profoundly effects animal physiology, development and disease, and this is nowhere more evident than in the nervous system. Alternative splicing is a versatile ...form of genetic control whereby a common pre-mRNA is processed into multiple mRNA isoforms differing in their precise combination of exon sequences. In the nervous system, thousands of alternatively spliced mRNAs are translated into their protein counterparts where specific isoforms play roles in learning and memory, neuronal cell recognition, neurotransmission, ion channel function, and receptor specificity. The essential nature of this process is underscored by the finding that its misregulation is a common characteristic of human disease. This review highlights the current views of the biological phenomenon of alternative splicing, and describes evidence for its intricate underlying biochemical mechanisms. The roles of RNA binding proteins and their tissue-specific properties are discussed. Why does alternative splicing occur in cosmic proportions in the nervous system? How does it affect integrated cellular functions? How are region-specific, cell-specific and developmental differences in splicing directed? How are the control mechanisms that operate in the nervous system distinct from those of other tissues? Although there are many unanswered questions, substantial progress has been made in showing that alternative splicing is of major importance in generating proteomic diversity, and in modulating protein activities in a temporal and spatial manner. The relevance of alternative splicing to diseases of the nervous system is also discussed.
The endometrial cancer (EC)‐specific Quality of Life module of the European Organization for Research and Treatment of Cancer (EORTC QLQ‐EN24), was developed and validated in one study. We ...independently validated and assessed the psychometric properties of the instrument. Two hundred and eight women with EC before surgery, during adjuvant treatment and follow‐up; in three different cancer centres completed the EORTC QLQ‐C30 and the EN24. The questionnaire's completion rate was 100%, except sexuality items, that were answered by 35% of patients. All item‐scale correlations for the multi‐item scales exceeded the .4 criterion and correlated well with their own scale, while correlations with the other scales were low. The internal consistency of all multi‐item scales were satisfactory (Cronbach's alpha coefficients ranging from .77 to .97). Discriminance for single‐item scales was low. The QLQ‐EN24 module discriminated well between clinically different patients, and there were no differences in quality of life questionnaire scales between patients with body mass index ≤30 when compared to those with >30. This validation study supports the reliability, as well as convergent and divergent validity of the EORTC QLQ‐EN24. The module is a useful instrument for the assessment of QOL in patients with EC. However, data concerning sexuality should be interpreted with caution.
Oliver-McFarlane syndrome is characterised by trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy. Laurence-Moon syndrome presents similarly, though with ...progressive spinocerebellar ataxia and spastic paraplegia and without trichomegaly. Both recessively inherited disorders have no known genetic cause.
Whole-exome sequencing was performed to identify the genetic causes of these disorders. Mutations were functionally validated in zebrafish pnpla6 morphants. Embryonic expression was evaluated via in situ hybridisation in human embryonic sections. Human neurohistopathology was performed to characterise cerebellar degeneration. Enzymatic activities were measured in patient-derived fibroblast cell lines.
Eight mutations in six families with Oliver-McFarlane or Laurence-Moon syndrome were identified in the PNPLA6 gene, which encodes neuropathy target esterase (NTE). PNPLA6 expression was found in the developing human eye, pituitary and brain. In zebrafish, the pnpla6 curly-tailed morphant phenotype was fully rescued by wild-type human PNPLA6 mRNA and not by mutation-harbouring mRNAs. NTE enzymatic activity was significantly reduced in fibroblast cells derived from individuals with Oliver-McFarlane syndrome. Intriguingly, adult brain histology from a patient with highly overlapping features of Oliver-McFarlane and Laurence-Moon syndromes revealed extensive cerebellar degeneration and atrophy.
Previously, PNPLA6 mutations have been associated with spastic paraplegia type 39, Gordon-Holmes syndrome and Boucher-Neuhäuser syndromes. Discovery of these additional PNPLA6-opathies further elucidates a spectrum of neurodevelopmental and neurodegenerative disorders associated with NTE impairment and suggests a unifying mechanism with diagnostic and prognostic importance.
PDF
