Abstract Our purpose is to categorize palliative care development, country by country, throughout the world, showing changes over time. We adopt a multi-method approach. Development is categorized ...using a six-part typology: Group 1 (no known hospice-palliative care activity) and Group 2 (capacity-building activity) are the same as developed during a previous study (2006), but Groups 3 and 4 have been subdivided to produce two additional levels of categorization: 3a) Isolated palliative care provision, 3b) Generalized palliative care provision, 4a) Countries where hospice-palliative care services are at a stage of preliminary integration into mainstream service provision, and 4b) Countries where hospice-palliative care services are at a stage of advanced integration into mainstream service provision. In 2011, 136 of the world's 234 countries (58%) had at least one palliative care service—an increase of 21 (+9%) from 2006, with the most significant gains having been made in Africa. Advanced integration of palliative care has been achieved in only 20 countries (8.5%). Total countries in each category are as follows: Group 1, 75 (32%); Group 2, 23 (10%); Group 3a, 74 (31.6%); Group 3b, 17 (7.3%); Group 4a, 25 (10.7%); and Group 4b, 20 (8.5%). Ratio of services to population among Group 4a/4b countries ranges from 1:34,000 (in Austria) to 1:8.5 million (in China); among Group 3a/3b countries, from 1:1000 (in Niue) to 1:90 million (in Pakistan). Although more than half of the world's countries have a palliative care service, many countries still have no provision, and major increases are needed before palliative care is generally accessible worldwide.
The hexosamine biosynthetic pathway elevates posttranslational addition of O-linked β-N-acetylglucosamine (O-GlcNAc) on intracellular proteins. Cancer cells elevate total O-GlcNAcylation ...by increasing O-GlcNAc transferase (OGT) and/or decreasing O-GlcNAcase (OGA) levels. Reducing O-GlcNAcylation inhibits oncogenesis. Here, we demonstrate that O-GlcNAcylation regulates glycolysis in cancer cells via hypoxia-inducible factor 1 (HIF-1α) and its transcriptional target GLUT1. Reducing O-GlcNAcylation increases α-ketoglutarate, HIF-1 hydroxylation, and interaction with von Hippel-Lindau protein (pVHL), resulting in HIF-1α degradation. Reducing O-GlcNAcylation in cancer cells results in activation of endoplasmic reticulum (ER) stress and cancer cell apoptosis mediated through C/EBP homologous protein (CHOP). HIF-1α and GLUT1 are critical for OGT-mediated regulation of metabolic stress, as overexpression of stable HIF-1 or GLUT1 rescues metabolic defects. Human breast cancers with high levels of HIF-1α contain elevated OGT, and lower OGA levels correlate independently with poor patient outcome. Thus, O-GlcNAcylation regulates cancer cell metabolic reprograming and survival stress signaling via regulation of HIF-1α.
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•Reducing OGT and O-GlcNAcylation in cancer cells decreases cancer glycolysis•OGT regulates stability of HIF-1α via regulation of α-ketoglutarate levels•Reducing OGT levels or activity induces ER stress and apoptosis in cancer cells•Stable HIF-1α mutant or GLUT1 overexpression rescues OGT-mediated phenotypes
Multiple cancers contain elevated levels of O-GlcNAc transferase (OGT). Ferrer et al. show that OGT and O-GlcNAcylation play a critical role in cancer-driven glycolysis and stress survival signaling by regulating the degradation of the hypoxia-inducible factor 1 (HIF-1α).
Epidermal growth factor receptor inhibitors (EGFRIs) have demonstrated improved overall survival in patients with non‐small cell lung cancer, pancreatic cancer, and colorectal cancer; however, their ...use is associated with dermatologic reactions of varying severity. The similar spectrum of events observed with monoclonal antibodies and tyrosine kinase inhibitors suggests such toxicities are a class effect. While such reactions do not necessarily require any alteration in EGFRI treatment, being best addressed through symptomatic treatment, there is limited evidence on which to base such therapies. In October 2006, at an international and interdisciplinary EGFRI dermatologic toxicity forum, the underlying mechanisms of these toxicities were discussed and commonly used therapeutic interventions were evaluated. Our aim was to reach a current consensus on management strategies. A three‐tiered, EGFRI‐focused toxicity grading system is suggested for the purposes of therapeutic decision making, and as a framework on which to build a stepwise approach to intervention. This approach to successful management is specifically tailored to accurately categorize dermatologic toxicity associated with EGFRIs, and can be easily applied by all health care professionals. The goal is to maximize quality of life in patients who are being treated with these agents—many of whom will be on these drugs for several months or even years.
Disclosure of potential conflicts of interest is found at the end of this article.
IMPORTANCE: Growing consensus suggests that frailty-associated risks should inform shared surgical decision making. However, it is not clear how best to screen for frailty in preoperative surgical ...populations. OBJECTIVE: To develop and validate the Risk Analysis Index (RAI), a 14-item instrument used to measure surgical frailty. It can be calculated prospectively (RAI-C), using a clinical questionnaire, or retrospectively (RAI-A), using variables from the surgical quality improvement databases (Veterans Affairs or American College of Surgeons National Surgical Quality Improvement Projects). DESIGN, SETTING, AND PARTICIPANTS: Single-site, prospective cohort from July 2011 to September 2015 at the Veterans Affairs Nebraska-Western Iowa Heath Care System, a Level 1 Veterans Affairs Medical Center. The study included all patients presenting to the medical center for elective surgery. EXPOSURES: We assessed the RAI-C for all patients scheduled for surgery, linking these scores to administrative and quality improvement data to calculate the RAI-A and the modified Frailty Index. MAIN OUTCOMES AND MEASURES: Receiver operator characteristics and C statistics for each measure predicting postoperative mortality and morbidity. RESULTS: Of the participants, the mean (SD) age was 60.7 (13.9) years and 249 participants (3.6%) were women. We assessed the RAI-C 10 698 times, from which we linked 6856 unique patients to mortality data. The C statistic predicting 180-day mortality for the RAI-C was 0.772. Of these 6856 unique patients, we linked 2785 to local Veterans Affairs Surgeons National Surgical Quality Improvement Projects data and calculated the C statistic for both the RAI-A (0.823) and RAI-C (0.824), along with the correlation between the 2 scores (r = 0.478; P < .001). Of these 2785 patients, there was sufficient data to calculate the modified Frailty Index for 1021, in which the C statistics were 0.865 (RAI-A), 0.797 (RAI-C), and 0.811 (modified Frailty Index). The correlation between the RAI-A and RAI-C was 0.547, and the correlations of the modified Frailty Index to the RAI-A and RAI-C were 0.300 and 0.26, respectively (all P < .001). A cutoff of RAI-C of at least 21 classified 18.3% patients as “frail” with a sensitivity of 0.50 and specificity of 0.82, whereas the RAI-A was less sensitive (0.25) and more specific (0.97), classifying only 3.7% as “frail.” CONCLUSIONS AND RELEVANCE: The RAI-C and RAI-A represent effective tools for measuring frailty in surgical populations with predictive ability on par with other frailty tools. Moderate correlation between the measures suggests convergent validity. The RAI-C offers the advantage of prospective, preoperative assessment that is proved feasible for large-scale screening in clinical practice. However, further efforts should be directed at determining the optimal components of preoperative frailty assessment.
Ipilimumab, which is an anti-cytotoxic T-cell lymphocyte-4 monoclonal antibody, showed a survival benefit in melanoma with adverse events (AEs) managed by protocol-defined guidelines. A phase II ...study in lung cancer assessed the activity of ipilimumab plus paclitaxel and carboplatin.
Patients (N = 204) with chemotherapy-naive non-small-cell lung cancer (NSCLC) were randomly assigned 1:1:1 to receive paclitaxel (175 mg/m(2)) and carboplatin (area under the curve, 6) with either placebo (control) or ipilimumab in one of the following two regimens: concurrent ipilimumab (four doses of ipilimumab plus paclitaxel and carboplatin followed by two doses of placebo plus paclitaxel and carboplatin) or phased ipilimumab (two doses of placebo plus paclitaxel and carboplatin followed by four doses of ipilimumab plus paclitaxel and carboplatin).Treatment was administered intravenously every 3 weeks for ≤ 18 weeks (induction). Eligible patients continued ipilimumab or placebo every 12 weeks as maintenance therapy. Response was assessed by using immune-related response criteria and modified WHO criteria. The primary end point was immune-related progression-free survival (irPFS). Other end points were progression-free survival (PFS), best overall response rate (BORR), immune-related BORR (irBORR), overall survival (OS), and safety.
The study met its primary end point of improved irPFS for phased ipilimumab versus the control (hazard ratio HR, 0.72; P = .05), but not for concurrent ipilimumab (HR, 0.81; P = .13). Phased ipilimumab also improved PFS according to modified WHO criteria (HR, 0.69; P = .02). Phased ipilimumab, concurrent ipilimumab, and control treatments were associated with a median irPFS of 5.7, 5.5, and 4.6 months, respectively, a median PFS of 5.1, 4.1, and 4.2 months, respectively, an irBORR of 32%, 21% and 18%, respectively, a BORR of 32%, 21% and 14%, respectively, and a median OS of 12.2, 9.7, and 8.3 months. Overall rates of grade 3 and 4 immune-related AEs were 15%, 20%, and 6% for phased ipilimumab, concurrent ipilimumab, and the control, respectively. Two patients (concurrent, one patient; control, one patient) died from treatment-related toxicity.
Phased ipilimumab plus paclitaxel and carboplatin improved irPFS and PFS, which supports additional investigation of ipilimumab in NSCLC.
The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLC). To aid in identification and treatment of these patients, we examined the ...clinical characteristics and treatment outcomes of patients who had NSCLC with and without EML4-ALK.
Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. EML4-ALK was identified by using fluorescent in situ hybridization for ALK rearrangements and was confirmed by immunohistochemistry for ALK expression. EGFR and KRAS mutations were determined by DNA sequencing.
Of 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild type (WT/WT) for both ALK and EGFR. Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were significantly younger (P < .001 and P = .005) and were more likely to be men (P = .036 and P = .039). Patients with EML4-ALK-positive tumors, like patients who harbored EGFR mutations, also were more likely to be never/light smokers compared with patients in the WT/WT cohort (P < .001). Eighteen of the 19 EML4-ALK tumors were adenocarcinomas, predominantly the signet ring cell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in overall survival.
EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.
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