The Intergroup 0116 and the MAGIC trials changed clinical practice for resectable gastric cancer in the Western world. In these trials, overall survival improved with post-operative chemoradiotherapy ...(CRT) and perioperative chemotherapy (CT). Intention-to-treat analysis in the CRITICS trial of post-operative CT or post-operative CRT did not show a survival difference. The current study reports on the per-protocol (PP) analysis of the CRITICS trial.
The CRITICS trial was a randomized, controlled trial in which 788 patients with stage Ib–Iva resectable gastric or esophagogastric adenocarcinoma were included. Before start of preoperative CT, patients from the Netherlands, Sweden and Denmark were randomly assigned to receive post-operative CT or CRT. For the current analysis, only patients who started their allocated post-operative treatment were included. Since it is uncertain that the two treatment arms are balanced in such PP analysis, adjusted proportional hazards regression analysis and inverse probability weighted analysis were used to minimize the risk of selection bias and to estimate and compare overall and event-free survival.
Of the 788 patients, 478 started post-operative treatment according to protocol, 233 (59%) patients in the CT group and 245 (62%) patients in the CRT group. Patient and tumor characteristics between the groups before start of the post-operative treatment were not different. After a median follow-up of 6.7 years since the start of post-operative treatment, the 5-year overall survival was 57.9% (95% confidence interval: 51.4% to 64.3%) in the CT group versus 45.5% (95% confidence interval: 39.2% to 51.8%) in the CRT group (adjusted hazard ratio CRT versus CT: 1.62 (1.24-2.12), P = 0.0004). Inverse probability weighted analysis resulted in similar hazard ratios.
After adjustment for all known confounding factors, the PP analysis of patients who started the allocated post-operative treatment in the CRITICS trial showed that the CT group had a significantly better 5-year overall survival than the CRT group (NCT00407186).
•Overall survival remained not significantly different between post-operative CT and CRT in the updated ITT analysis.•Post-operative compliance was poor; about 60% of the patients started the allocated post-operative treatment.•In the per-protocol analysis, the CT group had a better 5-year overall survival.•More peritoneal metastases were observed in the CRT group.
Vitamin C or ascorbic acid (AA) is implicated in many biological processes and has been proposed as a supplement for various conditions, including cancer. In this review, we discuss the effects of AA ...on the development and function of lymphocytes. This is important in the light of cancer treatment, as the immune system needs to regenerate following chemotherapy or stem cell transplantation, while cancer patients are often AA-deficient. We focus on lymphocytes, as these white blood cells are the slowest to restore, rendering patients susceptible to often lethal infections. T lymphocytes mediate cellular immunity and have been most extensively studied in the context of AA biology. In vitro studies demonstrate that T cell development requires AA, while AA also enhances T cell proliferation and may influence T cell function. There are limited and opposing data on the effects of AA on B lymphocytes that mediate humoral immunity. However, AA enhances the proliferation of NK cells, a group of cytotoxic innate lymphocytes. The influence of AA on natural killer (NK) cell function is less clear. In summary, an increasing body of evidence indicates that AA positively influences lymphocyte development and function. Since AA is a safe and cheap nutritional supplement, it is worthwhile to further explore its potential benefits for immune reconstitution of cancer patients treated with immunotoxic drugs.
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•PSMA PET/CT indicated a previously unnoticed paired nasopharyngeal macroscopic salivary gland.•Presence of paired mucous glands was confirmed in 100 consecutive patients and cadaver ...histology.•In 723 patients, the radiotherapy dose to this area was associated with xerostomia and dysphagia.•We propose to name these newly identified macroscopic glands the “tubarial glands”.•Sparing these glands in radiotherapy provides an opportunity to improve quality of life.
The presence of previously unnoticed bilateral macroscopic salivary gland locations in the human nasopharynx was suspected after visualization by positron emission tomography/computed tomography with prostate-specific membrane antigen ligands (PSMA PET/CT). We aimed to elucidate the characteristics of this unknown entity and its potential clinical implications for radiotherapy.
The presence and configuration of the PSMA-positive area was evaluated in a retrospective cohort of consecutively scanned patients with prostate or urethral gland cancer (n = 100). Morphological and histological characteristics were assessed in a human cadaver study (n = 2). The effect of radiotherapy (RT) on salivation and swallowing was retrospectively investigated using prospectively collected clinical data from a cohort of head-neck cancer patients (n = 723). With multivariable logistic regression analysis, the association between radiotherapy (RT) dose and xerostomia or dysphagia was evaluated.
All 100 patients demonstrated a demarcated bilateral PSMA-positive area (average length 4 cm). Histology and 3D reconstruction confirmed the presence of PSMA-expressing, predominantly mucous glands with multiple draining ducts, predominantly near the torus tubarius. In the head-neck cancer patients, the mean RT dose to the gland area was significantly associated with physician-rated post-treatment xerostomia and dysphagia ≥ grade 2 at 12 months (0.019/gy, 95%CI 0.005–0.033, p = .007; 0.016/gy, 95%CI 0.001–0.031, p = .036). Follow-up at 24 months had similar results.
The human body contains a pair of previously overlooked and clinically relevant macroscopic salivary gland locations, for which we propose the name tubarial glands. Sparing these glands in patients receiving RT may provide an opportunity to improve their quality of life.
Background
Vitamin B12 and folate function as co‐factors in pathways used during physical activity. Physical activity may therefore increase vitamin requirements, leading to a risk of deficient ...plasma concentrations. We aimed to investigate the relationship between intake and plasma concentrations of vitamin B12 and folate in physically active adults, as well as identify other determinants of vitamin B12 and folate plasma concentrations.
Methods
The study population consisted of 873 adults (528 men and 345 women), aged 19–78 years, who participated in a 4‐day walking event. The relationship between intake and plasma concentrations of vitamin B12 and folate was assessed using correlation and linear regression analyses. In addition, potential other determinants (sex, age, body mass index, energy intake and physical activity) of vitamin plasma concentrations were investigated.
Results
Significant positive correlations were observed between intake and plasma concentrations of vitamin B12 Pearson’s correlation coefficient = 0.15; 95% confidence interval (CI) = 0.08–0.21 and folate (Pearson’s correlation coefficient = 0.18; 95% CI = 0.12–0.25). In addition to vitamin intake, sex, age and energy intake were also determinants of both vitamin B12 and folate plasma concentrations in multivariable regression models.
Conclusions
The results suggest a positive association between intake and plasma concentrations for both vitamin B12 and folate in physically active people. By contrast to our hypothesis, physical activity was not a determinant of vitamin B12 and folate plasma concentrations. However, sex, age and energy intake were found to be determinants. Thus, when studying the relationship between intake and plasma concentrations of vitamin B12 or folate, these factors should be taken into account.
The combination of sucrose and starch in the presence of surface-adsorbed salivary α-amylase and bacterial glucosyltransferases increase the formation of a structurally and metabolically distinctive ...biofilm by Streptococcus mutans. This host-pathogen-diet interaction may modulate the formation of pathogenic biofilms related to dental caries disease. We conducted a comprehensive study to further investigate the influence of the dietary carbohydrates on S. mutans-transcriptome at distinct stages of biofilm development using whole genomic profiling with a new computational tool (MDV) for data mining. S. mutans UA159 biofilms were formed on amylase-active saliva coated hydroxyapatite discs in the presence of various concentrations of sucrose alone (ranging from 0.25 to 5% w/v) or in combination with starch (0.5 to 1% w/v). Overall, the presence of sucrose and starch (suc+st) influenced the dynamics of S. mutans transcriptome (vs. sucrose alone), which may be associated with gradual digestion of starch by surface-adsorbed amylase. At 21 h of biofilm formation, most of the differentially expressed genes were related to sugar metabolism, such as upregulation of genes involved in maltose/maltotriose uptake and glycogen synthesis. In addition, the groEL/groES chaperones were induced in the suc+st-biofilm, indicating that presence of starch hydrolysates may cause environmental stress. In contrast, at 30 h of biofilm development, multiple genes associated with sugar uptake/transport (e.g. maltose), two-component systems, fermentation/glycolysis and iron transport were differentially expressed in suc+st-biofilms (vs. sucrose-biofilms). Interestingly, lytT (bacteria autolysis) was upregulated, which was correlated with presence of extracellular DNA in the matrix of suc+st-biofilms. Specific genes related to carbohydrate uptake and glycogen metabolism were detected in suc+st-biofilms in more than one time point, indicating an association between presence of starch hydrolysates and intracellular polysaccharide storage. Our data show complex remodeling of S. mutans-transcriptome in response to changing environmental conditions in situ, which could modulate the dynamics of biofilm development and pathogenicity.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders marked in most cases by the nuclear exclusion and cytoplasmic deposition of the RNA ...binding protein TDP43. We previously demonstrated that ALS-associated mutant TDP43 accumulates within the cytoplasm, and that TDP43 mislocalization predicts neurodegeneration. Here, we sought to prevent neurodegeneration in ALS/FTD models using selective inhibitor of nuclear export (SINE) compounds that target exportin-1 (XPO1). SINE compounds modestly extend cellular survival in neuronal ALS/FTD models and mitigate motor symptoms in an in vivo rat ALS model. At high doses, SINE compounds block nuclear egress of an XPO1 cargo reporter, but not at lower concentrations that were associated with neuroprotection. Neither SINE compounds nor leptomycin B, a separate XPO1 inhibitor, enhanced nuclear TDP43 levels, while depletion of XPO1 or other exportins had little effect on TDP43 localization, suggesting that no single exporter is necessary for TDP43 export. Supporting this hypothesis, we find overexpression of XPO1, XPO7 and NXF1 are each sufficient to promote nuclear TDP43 egress. Taken together, our results indicate that redundant pathways regulate TDP43 nuclear export, and that therapeutic prevention of cytoplasmic TDP43 accumulation in ALS/FTD may be enhanced by targeting several overlapping mechanisms.
Short-term fasting protects tumor-bearing mice against the toxic effects of chemotherapy while enhancing therapeutic efficacy. We randomized 131 patients with HER2-negative stage II/III breast ...cancer, without diabetes and a BMI over 18 kg m
, to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and during neoadjuvant chemotherapy. Here we show that there was no difference in toxicity between both groups, despite the fact that dexamethasone was omitted in the FMD group. A radiologically complete or partial response occurs more often in patients using the FMD (OR 3.168, P = 0.039). Moreover, per-protocol analysis reveals that the Miller&Payne 4/5 pathological response, indicating 90-100% tumor-cell loss, is more likely to occur in patients using the FMD (OR 4.109, P = 0.016). Also, the FMD significantly curtails chemotherapy-induced DNA damage in T-lymphocytes. These positive findings encourage further exploration of the benefits of fasting/FMD in cancer therapy. Trial number: NCT02126449.
Abstract
STUDY QUESTION
What are suitable doses of the aromatase inhibitor anastrozole (ATZ) and the progestin levonorgestrel (LNG), when delivered to the systemic circulation by an intravaginal ring ...(IVR), for further clinical development as a potential new therapy for the treatment of endometriosis?
SUMMARY ANSWER
Anticipated targets for pharmacokinetics, pharmacodynamics and safety/tolerability were achieved for both drug components of the IVR at the doses investigated, supporting selection of the doses to be investigated in Phase 2 studies.
WHAT IS KNOWN ALREADY
Aromatase is a key enzyme in the biosynthesis of estrogens and is known to increase local levels of estradiol (E2) at extragonadal sites. Up-regulation of aromatase expression has been demonstrated in endometriotic lesions and the use of oral aromatase inhibitors has been shown to reduce endometriosis-associated pelvic pain in small-scale clinical trials.
STUDY DESIGN, SIZE, DURATION
This Phase 1, randomized, multicentre, parallel-group, three-arm, open-label study assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of various IVRs intended for systemic drug delivery. After screening, healthy, ovulating women aged 18–35 years were randomized to use IVRs releasing one of the three ATZ/LNG dose combinations (in vitro nominal daily drug release rates on Day 29: ATZ/LNG 500 µg/20 µg low dose, ATZ/LNG 1000 µg/30 µg mid dose or ATZ/LNG 1500 µg/40 µg high dose) for two consecutive 28-day wearing periods without a treatment break.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Sixty women were included in the per protocol set. The primary variables were plasma concentrations of ATZ and LNG at the end of each treatment period and the mean size of largest follicle-like structures (FLSs) over 56 days. Serum concentrations of several hormones were also evaluated, with emphasis on E2 levels.
MAIN RESULTS AND THE ROLE OF CHANCE
At the end of the first treatment period, geometric mean plasma concentrations of LNG and ATZ, respectively, were 0.228 and 12.5 µg/l for the low dose, 0.269 and 19.8 µg/l for the mid dose and 0.384 and 37.3 µg/l for the high dose; results were similar at the end of the second treatment period. Over the entire treatment period, mean FLS sizes were higher in all three treatment groups than during the pretreatment cycle; more women in the mid- and high-dose groups had FLSs of at least 30 mm (32–45%) than those in the low-dose group (14–24%). Changes in the mean size of FLSs were similar to those reported for low-dose progestin-only oral contraceptives and generally resolved during the 2-month treatment period. Serum E2 levels were decreased, but only one woman in each of the mid- and high-dose groups, and no woman in the low-dose group, had a serum E2 level below 20 pg/ml in both cycles. All ATZ and LNG combinations showed good tolerability.
LIMITATIONS, REASONS FOR CAUTION
This was an exploratory study; no formal power calculation was performed.
WIDER IMPLICATIONS OF THE FINDINGS
The results of this first-in-human study of the ATZ/LNG IVR facilitated the selection of ATZ and LNG doses to be investigated in the Phase 2 studies of patients with endometriosis.
STUDY FUNDING/COMPETING INTEREST
The study was funded by Bayer Pharma AG. T.R. is an employee of DINOX GmbH, which received funding from Bayer Pharma AG to perform this study. M.-H.S.-M., K.W., R.N., S.K., J.K., H.S. and B.R. are or have been employees of Bayer Pharma AG. H.S. is a named inventor on EP 2 552 404 B1, a patent application relating to this work.
TRIAL REGISTRATION NUMBER
EudraCT number: 2011-005620-18.
TRIAL REGISTRATION DATE
16 November 2011.
DATE OF FIRST PATIENT'S ENROLMENT
14 March 2012.
Summary
This guideline updates and replaces the 4th edition of the AAGBI Standards of Monitoring published in 2007. The aim of this document is to provide guidance on the minimum standards for ...physiological monitoring of any patient undergoing anaesthesia or sedation under the care of an anaesthetist. The recommendations are primarily aimed at anaesthetists practising in the United Kingdom and Ireland. Minimum standards for monitoring patients during anaesthesia and in the recovery phase are included. There is also guidance on monitoring patients undergoing sedation and also during transfer of anaesthetised or sedated patients. There are new sections discussing the role of monitoring depth of anaesthesia, neuromuscular blockade and cardiac output. The indications for end‐tidal carbon dioxide monitoring have been updated.
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