Immunohistochemistry (IHC) for MLH1, MSH2, MSH6, and PMS2 protein expression and microsatellite instability (MSI) are well-established tools to screen for Lynch syndrome (LS). Although many cancer ...centers have adopted these tools as reflex LS screening after a colorectal cancer diagnosis, the standard of care has not been established, and no formal studies have described this practice in the United States. The purpose of this study was to describe prevalent practices regarding IHC/MSI reflex testing for LS in the United States and the subsequent follow-up of abnormal results.
A 12-item survey was developed after interdisciplinary expert input. A letter of invitation, survey, and online-survey option were sent to a contact at each cancer program. A modified Dillman strategy was used to maximize the response rate. The sample included 39 National Cancer Institute-designated Comprehensive Cancer Centers (NCI-CCCs), 50 randomly selected American College of Surgeons-accredited Community Hospital Comprehensive Cancer Programs (COMPs), and 50 Community Hospital Cancer Programs (CHCPs).
The overall response rate was 50%. Seventy-one percent of NCI-CCCs, 36% of COMPs, and 15% of CHCPs were conducting reflex IHC/MSI for LS; 48% of the programs used IHC, 14% of the programs used MSI, and 38% of the programs used both IHC and MSI. One program used a presurgical information packet, four programs offered an opt-out option, and none of the programs required written consent.
Although most NCI-CCCs use reflex IHC/MSI to screen for LS, this practice is not well-adopted by community hospitals. These findings may indicate an emerging standard of care and diffusion from NCI-CCC to community cancer programs. Our findings also described an important trend away from requiring written patient consent for screening.
The field of genetics and genomics is rapidly expanding, particularly in oncology. Genetics and genomics can lead to ethical concerns. Oncology nurses must balance the need for evidence-based ...oncology care with that of ethical care for patients and their family members.
The purpose of this article is to provide an overview of cancer genetics and ethics and their impact on oncology nurses, patients, and families.
A case study of familial adenomatous polyposis (FAP) is offered to illustrate the impact of a hereditary cancer syndrome on several generations of a family and ethical issues surrounding cancer genetics. In addition, a brief review of FAP, gene and tissue biobanking, and genome editing is provided. .
Genetics, genomics, and pharmaco-genomics are ubiquitous in cancer diagnosis and management. Nurses must be knowledgeable about the ethical issues related to cancer genetics and oncology care to advocate for the needs of patients with cancer. Communication with and education of patients and their families before germline genetic testing may reduce the emergence of ethical dilemmas.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Little is known about the skin-related quality of life (QOL) among women receiving external radiotherapy (EBT) and who experience breast radiodermatitis. This pilot study aimed to describe the ...thoughts and experiences of women experiencing breast radiodermatitis of the breast at a comprehensive community cancer program.
A printed survey was used to solicit feedback on the Dermatology Life Quality Index (DLQI) during the 5th week of EBT. An open-ended question inquired which DLQI-related issue was most important and why. A directed qualitative content analysis was conducted on the narrative responses.
Twenty-eight women provided a response to the “most important” question. Sixty narratives led to the identification of 35 codes and six themes during content analysis. Themes included perspectives on having radiodermatitis, sensations caused by radiodermatitis, knowledge, and preparation for radiotherapy, prevention of radiodermatitis, emotions induced by skin changes, and physical appearance of the breast skin.
The study results provide a glimpse into the perceptions of skin-related QOL among community-dwelling women who experienced breast radiodermatitis. Some women expressed that radiodermatitis had a profound impact on their QOL while other were surprised that EBT was easy compared to chemotherapy. Our findings parallel those found in a previous study conducted in an urban setting. Results provide insight into the thoughts and needs of women undergoing breast EBT. Assessing individual differences in skin-related QOL can provide needed information for tailoring care to the unique needs of each woman. Additional studies focusing specifically on skin-related QOL are needed.
Routine MSI and IHC testing of CRC tumors is an emerging practice in the U.S. To date, no published studies were found that describe the practice of reflex testing for MSI and IHC abnormalities on ...colorectal tumors in the U.S. Methods and materials A study packet (i.e., letter of invitation, survey, $5.00 incentive, and postage-paid return envelope) will be mailed to the cancer program and tumor registry directors at the 40 NCI-designated Comprehensive Cancer Centers, 567 ACS-accredited Community Hospital Comprehensive Cancer Programs, and 521 ACS-accredited Community Hospital Cancer Programs in the U.S. Collaboration between the directors of the cancer program and tumor registry will be encouraged and only one set of survey responses per cancer program will be retained.
Objective
There is a major unmet need for a molecular biomarker of seizures or epilepsy that lends itself to fast, affordable detection in an easy‐to‐use point‐of‐care device. Purines such as ...adenosine triphosphate and adenosine are potent neuromodulators released during excessive neuronal activity that are also present in biofluids. Their biomarker potential for seizures and epilepsy in peripheral blood has, however, not yet been investigated. The aim of the present study was to determine whether blood purine nucleoside measurements can serve as a biomarker for the recent occurrence of seizures and to support the diagnosis of epilepsy.
Methods
Blood purine concentrations were measured via a point‐of‐care diagnostic technology based on the summated electrochemical detection of adenosine and adenosine breakdown products (inosine, hypoxanthine, and xanthine; SMARTChip). Measurements of blood purine concentrations were carried out using samples from mice subjected to intra‐amygdala kainic acid‐induced status epilepticus and in video‐electroencephalogram (EEG)‐monitored adult patients with epilepsy.
Results
In mice, blood purine concentrations were rapidly increased approximately two‐ to threefold after status epilepticus (2.32 ± .40 µmol·L–1 control vs. 8.93 ± 1.03 µmol·L–1 after status epilepticus), and levels correlated with seizure burden and postseizure neurodegeneration in the hippocampus. Blood purine concentrations were also elevated in patients with video‐EEG‐diagnosed epilepsy (2.39 ± .34 µmol·L–1 control, n = 13 vs. 4.35 ± .38 µmol·L–1 epilepsy, n = 26).
Significance
Our data provide proof of concept that the measurement of blood purine concentrations may offer a rapid, low‐volume bedside test to support the diagnosis of seizures and epilepsy.
Background and Purpose
Refractory status epilepticus is a clinical emergency associated with high mortality and morbidity. Increasing evidence suggests neuroinflammation contributes to the ...development of drug‐refractoriness during status epilepticus. Here, we have determined the contribution of the ATP‐gated P2X7 receptor, previously linked to inflammation and increased hyperexcitability, to drug‐refractory status epilepticus and its therapeutic potential.
Experimental Approach
Status epilepticus was induced via a unilateral microinjection of kainic acid into the amygdala in adult mice. Severity of status epilepticus was compared in animals with overexpressing or knock‐out of the P2X7 receptor, after inflammatory priming by pre‐injection of bacterial lipopolysaccharide (LPS) and in mice treated with P2X7 receptor‐targeting and anti‐inflammatory drugs.
Key Results
Mice overexpressing P2X7 receptors were unresponsive to several anticonvulsants (lorazepam, midazolam, phenytoin and carbamazepine) during status epilepticus. P2X7 receptor expression increased in microglia during status epilepticus, at times when responses to anticonvulsants were reduced. Overexpression of P2X7 receptors induced a pro‐inflammatory phenotype in microglia during status epilepticus and the anti‐inflammatory drug minocycline restored normal responses to anticonvulsants in mice overexpressing P2X7 receptors. Pretreatment of wild‐type mice with LPS increased P2X7 receptor levels in the brain and reduced responsiveness to anticonvulsants during status epilepticus, which was overcome by either genetic deletion of P2X7 receptors or treatment with the P2X7 receptor antagonists, AFC‐5128 or ITH15004.
Conclusion and Implications
Our results demonstrate that P2X7 receptor‐induced pro‐inflammatory effects contribute to resistance to pharmacotherapy during status epilepticus. Therapies targeting P2X7 receptors could be novel adjunctive treatments for drug‐refractory status epilepticus.
Objective
Pharmacoresistance and the lack of disease‐modifying actions of current antiseizure drugs persist as major challenges in the treatment of epilepsy. Experimental models of ...chemoconvulsant‐induced status epilepticus remain the models of choice to discover potential antiepileptogenic drugs, but doubts remain as to the extent to which they model human pathophysiology. The aim of the present study was to compare the molecular landscape of the intra‐amygdala kainic acid model of status epilepticus in mice with findings in resected brain tissue from patients with drug‐resistant temporal lobe epilepsy (TLE).
Methods
Status epilepticus was induced via intra‐amygdala microinjection of kainic acid in C57BL/6 mice, and gene expression was analyzed via microarrays in hippocampal tissue at acute and chronic time‐points. Results were compared to reference datasets in the intraperitoneal pilocarpine and intrahippocampal kainic acid model and to human resected brain tissue (hippocampus and cortex) from patients with drug‐resistant TLE.
Results
Intra‐amygdala kainic acid injection in mice triggered extensive dysregulation of gene expression that was ~3‐fold greater shortly after status epilepticus (2729 genes) when compared to epilepsy (412). Comparison to samples from patients with TLE revealed a particularly high correlation of gene dysregulation during established epilepsy. Pathway analysis found suppression of calcium signaling to be highly conserved across different models of epilepsy and patients. cAMP response element‐binding protein (CREB) was predicted as one of the main upstream transcription factors regulating gene expression during acute and chronic phases, and inhibition of CREB reduced seizure severity in the intra‐amygdala kainic acid model.
Significance
Our findings suggest the intra‐amygdala kainic acid model faithfully replicates key molecular features of human drug‐resistant TLE and provides potential rational target approaches for disease‐modification through new insights into the unique and shared gene expression landscape in experimental epilepsy.
•P2X7R signaling regulates both glial and neuronal genes during seizures.•P2X7R deficiency in microglia reduces seizure severity and leads to an anti-inflammatory phenotype in microglia during ...seizures.•P2X7R deficiency in neurons increases seizure severity.•Increased expression of P2X7Rs on GABAergic interneurons reduces seizure severity in acquired and genetic models of epilepsy.
The purinergic ATP-gated P2X7 receptor (P2X7R) is increasingly recognized to contribute to pathological neuroinflammation and brain hyperexcitability. P2X7R expression has been shown to be increased in the brain, including both microglia and neurons, in experimental models of epilepsy and patients. To date, the cell type-specific downstream effects of P2X7Rs during seizures remain, however, incompletely understood.
Effects of P2X7R signaling on seizures and epilepsy were analyzed in induced seizure models using male mice including the kainic acid model of status epilepticus and pentylenetetrazole model and in male and female mice in a genetic model of Dravet syndrome. RNA sequencing was used to analyze P2X7R downstream signaling during seizures. To investigate the cell type-specific role of the P2X7R during seizures and epilepsy, we generated mice lacking exon 2 of the P2rx7 gene in either microglia (P2rx7:Cx3cr1-Cre) or neurons (P2rx7:Thy-1-Cre). To investigate the protective potential of overexpressing P2X7R in GABAergic interneurons, P2X7Rs were overexpressed using adeno-associated virus transduction under the mDlx promoter.
RNA sequencing of hippocampal tissue from wild-type and P2X7R knock-out mice identified both glial and neuronal genes, in particular genes involved in GABAergic signaling, under the control of the P2X7R following seizures. Mice with deleted P2rx7 in microglia displayed less severe acute seizures and developed a milder form of epilepsy, and microglia displayed an anti-inflammatory molecular profile. In contrast, mice lacking P2rx7 in neurons showed a more severe seizure phenotype when compared to epileptic wild-type mice. Analysis of single-cell expression data revealed that human P2RX7 expression is elevated in the hippocampus of patients with temporal lobe epilepsy in excitatory and inhibitory neurons. Functional studies determined that GABAergic interneurons display increased responses to P2X7R activation in experimental epilepsy. Finally, we show that viral transduction of P2X7R in GABAergic interneurons protects against evoked and spontaneous seizures in experimental temporal lobe epilepsy and in mice lacking Scn1a, a model of Dravet syndrome.
Our results suggest a dual and opposing action of P2X7R in epilepsy and suggest P2X7R overexpression in GABAergic interneurons as a novel therapeutic strategy for acquired and, possibly, genetic forms of epilepsy.
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