Is age a barrier to chemotherapy? Rates of treatment in older patients with breast, colon or lung cancer in England in 2014: A national registry study

Background Survival from cancer in older patients is poorer in the UK than other countries with similar health systems and wealth possibly due to undertreatment and increased toxicities in this specific population. This population-based observational study describes factors affecting systemic anticancer treatment (SACT) use in older patients in England. Methods We identified patients aged ≥70 with stage II-III breast cancer, stage III colon cancer and stage IIIB-IV non-small cell lung cancer (NSCLC) diagnosed in 2014 from a dataset collected by the National Health Service in England. We used logistic regression to estimate factors affecting likelihood of receiving SACT and performed separate regression analyses for each disease, adjusting for age, gender, stage at diagnosis, pathological features, performance status, Charlson comorbidity index, ethnicity and socioeconomic group. We assessed 2-year overall survival (OS) using Kaplan-Meier method. Case mix adjusted treatment rates and workload volume were calculated at hospital level and presented using funnel plots, stratified by age groups (<70 and ≥70) to allow for assessment of variation between centres. Results 36892 patients were identified: 19879 with stage II-III breast cancer, 5292 with stage III colon cancer and 11721 with stage IIIB-IV NSCLC. Patients over 70 were less likely to receive SACT compared to those aged under 70: breast 11.7% vs 64.6%, p < 0.001; colon 37.4% vs 79%, p < 0.001; NSCLC 33.5% vs 60.2%, p < 0.001. 2-year OS for patients receiving SACT was similar for patients aged ≥70 and <70: breast 91.5% (95% CI: 89.3%-93.2%) vs 96.4% (95% CI: 95.9%-96.7%); colon 84.8% (95% CI: 82.6%-86.8%) vs 88.3% (95% CI: 86.7%-89.8%); NSCLC 16.7% (95% CI: 15.1%-18.4%) vs 19.8% (95%CI: 18.5%-21.1%). Patients receiving SACT had better OS than those untreated. SACT rates varied widely between hospitals after adjusting for case-mix across all ages. Conclusions Our study suggests that several factors affect the likelihood of receiving SACT but after adjusting for these, age remains determinant. Identifying hospitals with significantly lower SACT rates should prompt local review of multidisciplinary team practice

Arterial hypertension in the Japanese /

"Subject Category, Health and Safety.""June 30, 1953.""This study was sponsored by the National Academy of Sciences--National Research Council, with funds supplied by the United States Atomic Energy Commission under Contract AT-49-1-Gen-72."Includes bibliographical references (page 10).Mode of access: Internet

Sphingosine Kinase 1 Serves as a Pro-Viral Factor by Regulating Viral RNA Synthesis and Nuclear Export of Viral Ribonucleoprotein Complex upon Influenza Virus Infection

<div><p>Influenza continues to pose a threat to humans by causing significant morbidity and mortality. Thus, it is imperative to investigate mechanisms by which influenza virus manipulates the function of host factors and cellular signal pathways. In this study, we demonstrate that influenza virus increases the expression and activation of sphingosine kinase (SK) 1, which in turn regulates diverse cellular signaling pathways. Inhibition of SK suppressed virus-induced NF-κB activation and markedly reduced the synthesis of viral RNAs and proteins. Further, SK blockade interfered with activation of Ran-binding protein 3 (RanBP3), a cofactor of chromosome region maintenance 1 (CRM1), to inhibit CRM1-mediated nuclear export of the influenza viral ribonucleoprotein complex. In support of this observation, SK inhibition altered the phosphorylation of ERK, p90RSK, and AKT, which is the upstream signal of RanBP3/CRM1 activation. Collectively, these results indicate that SK is a key pro-viral factor regulating multiple cellular signal pathways triggered by influenza virus infection. </p> </div

30-day mortality after systemic anticancer treatment for breast and lung cancer in England: a population-based, observational study

30-day mortality might be a useful indicator of avoidable harm to patients from systemic anticancer treatments, but data for this indicator are limited. The Systemic Anti-Cancer Therapy (SACT) dataset collated by Public Health England allows the assessment of factors affecting 30-day mortality in a national patient population. The aim of this first study based on the SACT dataset was to establish national 30-day mortality benchmarks for breast and lung cancer patients receiving SACT in England, and to start to identify where patient care could be improved.In this population-based study, we included all women with breast cancer and all men and women with lung cancer residing in England, who were 24 years or older and who started a cycle of SACT in 2014 irrespective of the number of previous treatment cycles or programmes, and irrespective of their position within the disease trajectory. We calculated 30-day mortality after the most recent cycle of SACT for those patients. We did logistic regression analyses, adjusting for relevant factors, to examine whether patient, tumour, or treatment-related factors were associated with the risk of 30-day mortality. For each cancer type and intent, we calculated 30-day mortality rates and patient volume at the hospital trust level, and contrasted these in a funnel plot.Between Jan 1, and Dec, 31, 2014, we included 23 228 patients with breast cancer and 9634 patients with non-small cell lung cancer (NSCLC) in our regression and trust-level analyses. 30-day mortality increased with age for both patients with breast cancer and patients with NSCLC treated with curative intent, and decreased with age for patients receiving palliative SACT (breast curative: odds ratio [OR] 1·085, 99% CI 1·040-1·132; p&lt;0·0001; NSCLC curative: 1·045, 1·013-1·079; p=0·00033; breast palliative: 0·987, 0·977-0·996; p=0·00034; NSCLC palliative: 0·987, 0·976-0·998; p=0·0015). 30-day mortality was also significantly higher for patients receiving their first reported curative or palliative SACT versus those who received SACT previously (breast palliative: OR 2·326 99% CI 1·634-3·312; p&lt;0·0001; NSCLC curative: 3·371, 1·554-7·316; p&lt;0·0001; NSCLC palliative: 2·667, 2·109-3·373; p&lt;0·0001), and for patients with worse general wellbeing (performance status 2-4) versus those who were generally well (breast curative: 6·057, 1·333-27·513; p=0·0021; breast palliative: 6·241, 4·180-9·319; p&lt;0·0001; NSCLC palliative: 3·384, 2·276-5·032; p&lt;0·0001). We identified trusts with mortality rates in excess of the 95% control limits; this included seven for curative breast cancer, four for palliative breast cancer, five for curative NSCLC, and seven for palliative NSCLC.Our findings show that several factors affect the risk of early mortality of breast and lung cancer patients in England and that some groups are at a substantially increased risk of 30-day mortality. The identification of hospitals with significantly higher 30-day mortality rates should promote review of clinical decision making in these hospitals. Furthermore, our results highlight the importance of collecting routine data beyond clinical trials to better understand the factors placing patients at higher risk of 30-day mortality, and ultimately improve clinical decision making. Our insights into the factors affecting risk of 30-day mortality will help treating clinicians and their patients predict the balance of harms and benefits associated with SACT.Public Health England

SK inhibition does not interfere with the viral entry step.

<p>(A and B) MDCK cells were infected with influenza virus (1 MOI) for 1 hr, followed by washing with PBS. Cells were then treated with SKI-II (10 µM) (A) or DMS (5 µM) (B) at 1, 2, 3, or 4 hpi. The expression of viral proteins M1 and M2 was detected by Western blot analysis at 8 hpi. (C and D) MDCK cells were treated with solvent or SKI-II (10 µM) upon influenza virus infection at an MOI of 1. The synthesis of (+) or (-) viral PB2 (C) or NP (D) RNA was analyzed by qPCR at 1 or 2 hpi. The RNA level at 1 hpi was set as 1.0. Values are means ± SEM of three reactions per sample. (E) A549 cells were treated with solvent, DMS (5 µM), or SKI-II (10 µM) and infected with influenza virus at an MOI of 10. The virus was allowed to attach to the cells at 4^°C for 1 hr and the cells were incubated at 37^°C for an additional 1 hr. Western blot analysis was performed to detect internalized viral M1 and GAPDH. The relative intensities for each band of viral M1 are shown.</p

SK inhibition suppresses influenza virus replication by impairing activation of the NF-κB signaling pathway.

<p>(A) MDCK cells were left untreated or treated with BAY11-7082 (2.5 µM) and infected with influenza virus at an MOI of 1. The expression of viral proteins M1, NS1, NS2, and actin was assessed by Western blotting at 7 hpi. (B) MDCK cells were treated with solvent or SKI-II (10 µM) and uninfected (Mock) or infected with influenza virus at an MOI of 3. At 0.5, 1, 2, or 4 hpi, Western blot analysis was performed to detect pIKKαβ, IKKαβ, and α-tubulin. (C) MDCK cells were treated with solvent alone or SKI-II (10 µM) and uninfected (Mock) or infected with influenza virus (3 MOI). At 3, 4, 5, or 6 hpi, Western blotting was performed to detect p-p65, p65, and viral M1. (D) MDCK cells were mock-infected or infected with influenza virus at an MOI of 3. They were fixed, permeabilized, and stained with antibodies against NF-κB subunit p65 (red) at 4 hpi and DRAQ5 dye to detect nuclei (blue). Representative confocal images are shown. Scale bar = 50 µm. (E) MDCK cells were co-transfected with NF-κB luciferase reporter plasmid and control Renilla luciferase plasmid. After 12 hrs, cells were treated with solvent alone or SKI-II (10 µM) upon influenza A/Hong Kong/8/68 virus infection at 5 MOI for 7 hrs or were transfected with influenza viral RNA (100 ng) for 7 hrs. Cell lysates were analyzed for luciferase activity with a luminometer. Relative luciferase activities are shown. Values are means ± SEM (n=3). *p<0.05.</p

SK inhibition impairs virus-induced activation of ERK/p90RSK/AKT to inhibit RanBP3-mediated nuclear export of viral NP.

<p>(A and B) HEK293 cells were transfected with scramble siRNA (siCTR) or siRNA targeting RanBP3 (siRanBP3); then the cells were infected with influenza virus at an MOI of 0.01 (A) or 1 (B). RanBP3, pRanBP3, viral M1, and α-tubulin were detected by Western blotting at 30 hpi (A). Viral NP (green) and nuclei (DRAQ5 dye, red) were visualized by confocal microscopy at 12 hpi (B). (C and D) MDCK cells were treated with solvent, DMS (5 µM), or SKI-II (10 µM) and infected with influenza virus at an MOI of 5 for the indicated times (C) or 6 hrs (D). Cell lysates were used for Western blot analysis to detect pRanBP3, RanBP3, α-tubulin, or actin. (E) MDCK cells were left untreated or treated with U0126 (10 µM) or LY294002 (10 µM) and infected with influenza virus at 3 MOI for 6 hrs. Western blot analysis was performed to detect pRanBP3, RanBP3, and GAPDH. (F) MDCK cells were treated with solvent alone or SKI-II (10 µM) and infected with influenza virus at an MOI of 1. Western blot analysis was performed to detect pERK, ERK, p-p90RSK, p90RSK, pRANBP3, or α-tubulin at 12 hpi. (G) MDCK cells were treated with solvent or SKI-II (10 µM) and mock-infected or infected with influenza virus at an MOI of 3. At 8 hpi, pAKT, AKT, and α-tubulin were detected by Western blot analysis.</p

Influenza virus increases SK1 activation, which is critical for viral replication.

<p>(A and B) HEK293 (A) or A549 (B) cells were infected with influenza A/WSN/33 virus (FLU) at an MOI of 3 for the indicated times. The levels of pSK1 or SK1 were analyzed by Western blotting. GAPDH or α-tubulin was used as internal loading control. The relative intensities for each band of pSK1 and SK1 were determined based on the control protein expression by densitometery and depicted below each blot. The relative level of protein at 0 hr was set as 1.0. (C and D) MDCK (C) or A549 (D) cells were treated with solvent (DMSO; -), DMS (5 µM), or SKI-II (10 µM) upon influenza virus infection at an MOI of 1. Cell lysates were used for Western blot analysis to detect viral proteins M1, M2, NS1, NS2, NP, and α-tubulin at 12 hpi. (E and F) MDCK cells were treated with solvent (-) or SKI-II upon influenza virus infection at an MOI of 5. The expression of (+) or (-) RNA of viral RNA polymerase subunit PB2 (E) or viral NP (F) was analyzed by real-time quantitative PCR (qPCR) at 5 hpi. Three reactions per sample were carried out. Values are means ± SEM of three reactions per sample. ***p<0.001. (G) MDCK cells were treated with solvent or SKI-II (3, 10, or 30 µM) and infected with influenza virus at an MOI of 0.01. At 24 hpi, a plaque assay was performed to determine virus titer (plaque forming unit, PFU/mL) at each condition. Values are means ± SEM. N = 3/group. ***p<0.001. (H) A549 cells were treated with solvent or SKI-II (10 µM) and infected with influenza virus at an MOI of 0.1. At 12, 36, or 60 hpi, viral titers (PFU/mL) were determined by a plaque assay. Values are means ± SEM (n=3). ***p<0.001. (I and J) SK1-overexpressing HEK293 (I) or A549 (J) cells were transfected with scramble siRNA control (siCTR) or siRNA targeting SK1 (siSK1). After 3 days, the cells were infected with influenza virus at an MOI of 1 (I) or 3 (I and J). At 12 hpi, Western blot analysis was performed to detect pSK1, SK1, viral proteins M2, NS1, NS2, NP, and α-tubulin.</p