Characteristics associated with quality of life among people with drug-resistant epilepsy

Quality of Life (QoL) is the preferred outcome in non-pharmacological trials, but there is little UK population evidence of QoL in epilepsy. In advance of evaluating an epilepsy self-management course we aimed to describe, among UK participants, what clinical and psycho-social characteristics are associated with QoL. We recruited 404 adults attending specialist clinics, with at least two seizures in the prior year and measured their self-reported seizure frequency, co-morbidity, psychological distress, social characteristics, including self-mastery and stigma, and epilepsy-specific QoL (QOLIE-31-P). Mean age was 42 years, 54% were female, and 75% white. Median time since diagnosis was 18 years, and 69% experienced ≥10 seizures in the prior year. Nearly half (46%) reported additional medical or psychiatric conditions, 54% reported current anxiety and 28% reported current depression symptoms at borderline or case level, with 63% reporting felt stigma. While a maximum QOLIE-31-P score is 100, participants’ mean score was 66, with a wide range (25–99). In order of large to small magnitude: depression, low self-mastery, anxiety, felt stigma, a history of medical and psychiatric comorbidity, low self-reported medication adherence, and greater seizure frequency were associated with low QOLIE-31-P scores. Despite specialist care, UK people with epilepsy and persistent seizures experience low QoL. If QoL is the main outcome in epilepsy trials, developing and evaluating ways to reduce psychological and social disadvantage are likely to be of primary importance. Educational courses may not change QoL, but be one component supporting self-management for people with long-term conditions, like epilepsy

A p53-regulated apoptotic gene signature predicts treatment response and outcome in pediatric acute lymphoblastic leukemia

Russell O Bainer,1 Matthew R Trendowski,2 Cheng Cheng,3 Deqing Pei,3 Wenjian Yang,3 Steven W Paugh,4 Kathleen H Goss,5 Andrew D Skol,6 Paul Pavlidis,7 Ching-Hon Pui,4,8 T Conrad Gilliam,1 William E Evans,4,9,* Kenan Onel10–13,* 1Department of Human Genetics, 2Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, IL, 3Department of Biostatistics, 4Hematological Malignancy Program, St Jude Children’s Research Hospital, Memphis, TN, 5University of Chicago Medicine Comprehensive Cancer Center, 6Department of Pediatrics, The University of Chicago, Chicago, IL, USA; 7Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada; 8Department of Oncology, 9Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN, 10Division of Human Genetics and Genomics, 11Division of Hematology/Oncology and Stem Cell Transplantation, Cohen Children’s Medical Center, New Hyde Park, 12The Feinstein Institute for Medical Research, Manhasset, NY, 13Hofstra Northwell School of Medicine, Hofstra University, Hempstead, NY, USA *These authors contributed equally to this work Abstract: Gene signatures have been associated with outcome in pediatric acute lymphoblastic leukemia (ALL) and other malignancies. However, determining the molecular drivers of these expression changes remains challenging. In ALL blasts, the p53 tumor suppressor is the primary regulator of the apoptotic response to genotoxic chemotherapy, which is predictive of outcome. Consequently, we hypothesized that the normal p53-regulated apoptotic response to DNA damage would be altered in ALL and that this alteration would influence drug response and treatment outcome. To test this, we first used global expression profiling in related human B-lineage lymphoblastoid cell lines with either wild type or mutant TP53 to characterize the normal p53-mediated transcriptional response to ionizing radiation (IR) and identified 747 p53-regulated apoptotic target genes. We then sorted these genes into six temporal expression clusters (TECs) based upon differences over time in their IR-induced p53-regulated gene expression patterns, and found that one cluster (TEC1) was associated with multidrug resistance in leukemic blasts in one cohort of children with ALL and was an independent predictor of survival in two others. Therefore, by investigating p53-mediated apoptosis in vitro, we identified a gene signature significantly associated with drug resistance and treatment outcome in ALL. These results suggest that intersecting pathway-derived and clinically derived expression data may be a powerful method to discover driver gene signatures with functional and clinical implications in pediatric ALL and perhaps other cancers as well. Keywords: pediatric acute lymphoblastic leukemia, p53, gene expression signature, outcomes analysi

What questions do patients undergoing lower extremity joint replacement surgery have?

BACKGROUND: The value of the Internet to deliver preoperative education would increase if there was variability in questions patients want answered. This study's goal was to have patients consulting an orthopedic surgeon about undergoing either a total hip arthroplasty (THA) or a total knee arthroplasty (TKA) rate the importance of different questions concerning their care. METHODS: We assembled questions patients might have about joint replacement surgery by analyzing the literature and querying a pilot group of patients and surgeons. Twenty-nine patients considering undergoing THA and 19 patients considering TKR completed a written survey asking them to rate 30 different questions, with a 5 point Likert scale from 1 (least important) – 5 (most important). RESULTS: For patients considering THA or TKR, the 4 highest rated questions were: Will the surgery affect my abilities to care for myself?, Am I going to need physical therapy?, How mobile will I be after my surgery?, When will I be able to walk normally again? The mean percentage disagreement was 42% for questions answered by TKR patients and 47% for the THA group. Some patients gave a high rating to questions lowly rated by the rest of the group. CONCLUSIONS: Although there was enough agreement to define a core set of questions that should be addressed with most patients considering THA or TKA, some of the remaining questions were also highly important to some patients. The Web may offer a flexible medium for accommodating this large variety of information needs

Progastrin Represses the Alternative Activation of Human Macrophages and Modulates Their Influence on Colon Cancer Epithelial Cells

Macrophage infiltration is a negative prognostic factor for most cancers but gastrointestinal tumors seem to be an exception. The effect of macrophages on cancer progression depends on their phenotype, which may vary between M1 (pro-inflammatory, defensive) to M2 (tolerogenic, pro-tumoral). Gastrointestinal cancers often become an ectopic source of gastrins and macrophages present receptors for these peptides. The aim of the present study is to analyze whether gastrins can affect the pattern of macrophage infiltration in colorectal tumors. We have evaluated the relationship between gastrin expression and the pattern of macrophage infiltration in samples from colorectal cancer and the influence of these peptides on the phenotype of macrophages differentiated from human peripheral monocytes in vitro. The total number of macrophages (CD68+ cells) was similar in tumoral and normal surrounding tissue, but the number of M2 macrophages (CD206+ cells) was significantly higher in the tumor. However, the number of these tumor-associated M2 macrophages correlated negatively with the immunoreactivity for gastrin peptides in tumor epithelial cells. Macrophages differentiated from human peripheral monocytes in the presence of progastrin showed lower levels of M2-markers (CD206, IL10) with normal amounts of M1-markers (CD86, IL12). Progastrin induced similar effects in mature macrophages treated with IL4 to obtain a M2-phenotype or with LPS plus IFNγ to generate M1-macrophages. Macrophages differentiated in the presence of progastrin presented a reduced expression of Wnt ligands and decreased the number and increased cell death of co-cultured colorectal cancer epithelial cells. Our results suggest that progastrin inhibits the acquisition of a M2-phenotype in human macrophages. This effect exerted on tumor associated macrophages may modulate cancer progression and should be taken into account when analyzing the therapeutic value of gastrin immunoneutralization

Combination immunotherapy and active-specific tumor cell vaccination augments anti-cancer immunity in a mouse model of gastric cancer

<p>Abstract</p> <p>Background</p> <p>Active-specific immunotherapy used as an adjuvant therapeutic strategy is rather unexplored for cancers with poorly characterized tumor antigens like gastric cancer. The aim of this study was to augment a therapeutic immune response to a low immunogenic tumor cell line derived from a spontaneous gastric tumor of a CEA424-SV40 large T antigen (CEA424-SV40 TAg) transgenic mouse.</p> <p>Methods</p> <p>Mice were treated with a lymphodepleting dose of cyclophosphamide prior to reconstitution with syngeneic spleen cells and vaccination with a whole tumor cell vaccine combined with GM-CSF (a treatment strategy abbreviated as LRAST). Anti-tumor activity to subcutaneous tumor challenge was examined in a prophylactic as well as a therapeutic setting and compared to corresponding controls.</p> <p>Results</p> <p>LRAST enhances tumor-specific T cell responses and efficiently inhibits growth of subsequent transplanted tumor cells. In addition, LRAST tended to slow down growth of established tumors. The improved anti-tumor immune response was accompanied by a transient decrease in the frequency and absolute number of CD4⁺CD25⁺FoxP3⁺T cells (Tregs).</p> <p>Conclusions</p> <p>Our data support the concept that whole tumor cell vaccination in a lymphodepleted and reconstituted host in combination with GM-CSF induces therapeutic tumor-specific T cells. However, the long-term efficacy of the treatment may be dampened by the recurrence of Tregs. Strategies to counteract suppressive immune mechanisms are required to further evaluate this therapeutic vaccination protocol.</p

Gastrazole (JB95008), a novel CCK2/gastrin receptor antagonist, in the treatment of advanced pancreatic cancer: results from two randomised controlled trials

Gastrin has been shown to be a growth stimulant in pancreatic cancer cells. Gastrazole is a potent and selective gastrin receptor antagonist. Two randomised blinded trials were conducted to assess the effect of gastrazole in advanced pancreatic cancer. Patients with biopsy-proven, inoperable pancreatic carcinoma were recruited. Trial A compared protracted venous infusion (PVI) gastrazole with PVI placebo, whereas trial B compared PVI gastrazole with PVI fluorouracil (5-FU). Eighteen patients were randomised in trial A. Gastrazole produced significantly better survival compared to placebo (median 7.9 months vs 4.5 months; 1-year survival: 33 vs 11%, respectively; log rank P=0.02). No difference in toxicity was seen between gastrazole and placebo, except central venous catheter and pump complications. Ninety-eight patients were randomised in trial B. No significant survival difference was detected between gastrazole and 5-FU (median: 3.6 vs 4.2 months; 1-year survival: 13.2 vs 26.2%, respectively; log rank P=0.42). Toxicity of gastrazole was mild with significantly less diarrhoea (P=0.03), stomatitis (P<0.001) and hand– foot syndrome (P<0.001) compared to 5-FU. Quality of life (QoL) assessment showed similar QoL between gastrazole and 5-FU at baseline and no significant differences occurred with treatment either between arms or within arms. Compared to placebo, patients with advanced pancreatic cancer treated with gastrazole appeared to live longer, albeit in a very small trial and will require confirmation with large-scale randomised data. However, it did not produce survival advantage over PVI 5-FU. Lack of toxicity for gastrazole may allow its combination with cytotoxic drugs

Benthic community structure and ecosystem functions in above- and below-waterfall pools in Borneo

Waterfalls are geomorphic features that often partition streams into discrete zones. Our study examined aquatic communities, litter decomposition and periphyton growth rates for above- and below-waterfall pools in Ulu Temburong National Park, Brunei. We observed higher fish densities in below-waterfall pools (0.24 fish m−2 vs. 0.02 fish m−2 in above-waterfall pools) and higher shrimp abundance in above-waterfall pools (eight shrimp/pool vs. less than one shrimp/pool in below-waterfall pools). However, macroinvertebrate densities (excluding shrimp) were similar among both pool types. Ambient periphyton was higher in below-waterfall pools in 2013 (4.3 vs. 2.8 g m−2 in above-waterfall pools) and 2014 (4.8 vs. 3.4 g m−2 in above-waterfall pools), while periphyton growth rates varied from 0.05 to 0.26 g m−2 days−1 and were significantly higher in below-waterfall pools in 2014. Leaf litter decomposition rates (0.001 to 0.024 days−1) did not differ between pool types, suggesting that neither shrimp nor fish densities had consistent impacts on this ecosystem function. Regardless, this research demonstrates the varied effects of biotic and abiotic factors on community structure and ecosystem function. Our results have highlighted the importance of discontinuities, such as waterfalls, in tropical streams.</p

The Ontario Mother and Infant Study (TOMIS) III: A multi-site cohort study of the impact of delivery method on health, service use, and costs of care in the first postpartum year

Abstract Background The caesarean section rate continues to rise globally. A caesarean section is inarguably the preferred method of delivery when there is good evidence that a vaginal delivery may unduly risk the health of a woman or her infant. Any decisions about delivery method in the absence of clear medical indication should be based on knowledge of outcomes associated with different childbirth methods. However, there is lack of sold evidence of the short-term and long-term risks and benefits of a planned caesarean delivery compared to a planned vaginal delivery. It also is important to consider the economic aspects of caesarean sections, but very little attention has been given to health care system costs that take into account services used by women for themselves and their infants following hospital discharge. Methods and design The Ontario Mother and Infant Study III is a prospective cohort study to examine relationships between method of delivery and maternal and infant health, service utilization, and cost of care at three time points during the year following postpartum hospital discharge. Over 2500 women were recruited from 11 hospitals across the province of Ontario, Canada, with data collection occurring between April 2006 and October 2008. Participants completed a self-report questionnaire in hospital and structured telephone interviews at 6 weeks, 6 months, and 12 months after discharge. Data will be analyzed using generalized estimating equation, a special generalized linear models technique. A qualitative descriptive component supplements the survey approach, with the goal of assisting in interpretation of data and providing explanations for trends in the findings. Discussion The findings can be incorporated into patient counselling and discussions about the advantages and disadvantages of different delivery methods, potentially leading to changes in preferences and practices. In addition, the findings will be useful to hospital- and community-based postpartum care providers, managers, and administrators in guiding risk assessment and early intervention strategies. Finally, the research findings can provide the basis for policy modification and implementation strategies to improve outcomes and reduce costs of care