Cancer Trial Impact: Understanding Implementation of the Short Course Oncology Treatment (SCOT) Trial Findings in colorectal cancer at a National Level.

AIMS: The Short Course Oncology Treatment (SCOT) trial indicated that 3 months of adjuvant doublet chemotherapy was non-inferior to 6 months of treatment for patients with colorectal cancer, with considerably less toxicity. The SCOT trial results were disseminated in June 2017. The aim of this study was to understand if SCOT trial findings were implemented in Scotland. MATERIALS AND METHODS: A retrospective analysis was carried out on a dataset derived from a source population of 5.4 million people. Eligible patients were those with stage II or III colorectal cancer who received adjuvant chemotherapy. Logistic regression was applied to understand the extent of practice change to a 3-month adjuvant chemotherapy duration after the SCOT trial results were disseminated. Interrupted time series analysis was used to visualise differences in prescribing trends before and after June 2017 for the overall cohort, and by SCOT trial eligibility. RESULTS: In total, 2310 patients were included in the study; 1957 and 353 treated pre- and post-June 2017, respectively. The median treatment duration decreased from 21 weeks (interquartile range 14-24) prior to June 2017 to 12 weeks (interquartile range 12-21 weeks) after June 2017 (P < 0.001). The proportion of patients receiving over 3 months of adjuvant treatment decreased from 75% to 42% (P < 0.001). This change was most noticeable for patients who met the SCOT trial eligibility criteria, and specifically for those with low-risk stage III disease and those treated with capecitabine and oxaliplatin (CAPOX). Although practice change occurred in all locations, there were differences between regions that could be explained by pre-SCOT trial prescribing trends. DISCUSSION: A significant change in chemotherapy prescribing occurred after dissemination of the SCOT trial results. National, real-world data can be used to capture the extent of implementation of clinical trial results. In this case, implementation was aligned with clinical trial subgroup findings. This type of analysis could be conducted to evaluate the impact of other clinical trials.

Posterolateral or direct lateral approach for hemiarthroplasty after femoral neck fractures: a systematic review.

BACKGROUND: The posterolateral approach (PLA) and direct lateral approach (DLA) are the most commonly used approaches for inserting a hemiarthroplasty in the treatment of femoral neck fractures. A recent review concluded that the routine use of PLA should be questioned, but this conclusion itself can be questioned. The aim of this study is to provide an updated overview and critical appraisal of the available evidence, focussing on outcomes most relevant for patients. METHODS: We conducted a comprehensive search of literature in the MEDLINE and EMBASE databases and Cochrane Library. Studies (till June 2018) to identify hip fracture clinical trials/comparative studies comparing alternative surgical approaches (PLA and DLA). We explored sources of heterogeneity and conducted pooled analyses when appropriate. RESULTS: 264 potentially eligible studies were identified of which 1 RCT, 3 prospective, 3 registry data and 5 retrospective studies were included. The RCT consisted performance and attrition bias. The mean MINORS score of the prospective/register studies was 17.3 (SD 3.5) and 13.8 (SD 1.9) of the 5 retrospective studies. The GRADE score for all the outcomes was very low. Due to the high and various types of biases across the included studies, we did not pool the data. None of studies assessed the activities of daily living functionality. 6 studies reported significantly more dislocations or reoperations due to dislocation in the PLA group, 6 other studies found no differences. DLA patients were more likely to develop abductor insufficiency leading to limping and more need for walking aids. The PLA patients tended to have better quality of life, less pain and more satisfaction compared to the DLA patients. CONCLUSION: Based on low-quality studies, PLA may be associated with more dislocations, but patients had less walking problems and a lower tendency to abductor insufficiency compared with DLA. Further clinical trials with methodology rigor are needed to determine which approach is more effective in terms of outcomes relevant to patients.

Research Note: Phosphorus digestibility in conventional canola meal determined using different balance assays.

Three experiments were conducted to determine ileal P digestibility and excreta P retention values for canola meal (CM) using 3 different types of balance assays. The first experiment was an ad libitum-fed chick experiment which evaluated the effect of phytase on ileal P digestibility and excreta P retention values. Chicks were fed a P-deficient cornstarch-dextrose-45% CM basal diet (0.13% nonphytate P) as diet 1 or that diet plus 125 or 250 FTU/kg of phytase, respectively, from 8 to 21 D of age. The digestibility/retention of P was 38% and phytase linearly increased both ileal digestibility and excreta retention of P (P < 0.05). The second experiment was a precision-fed chick assay conducted to determine ileal digestibility of P in CM at 21 D. Mean ileal P digestibility was determined to be 47.5% in chicks fed 6 g and 40.0% in chicks fed 9 g of CM and the values were not significantly different. Experiment 3 was an ad libitum-fed chick assay to determine ileal P digestibility and excreta P retention for CM with and without increasing levels of dietary supplemental Ca. The chicks were fed P-deficient - dextrose - CM diets containing increasing levels of 13.5, 27, 40.5, or 54% CM, respectively, with Ca:nonphytate P ratio maintained at 2:1 in diets 1-4 and 6:1 in diets 5-8. Based on regression analysis of ileal digesta or excreta P output on dietary P concentration, digestibility/retention of P in CM was 30%. Ileal P digestibility (and to a lesser extent excreta P retention) at 21 D was reduced by increased Ca:P ratio. The results of this study indicated that the 3 balance assays yielded reasonably consistent values of 30-40% for P digestibility/retention and ileal P digestibility was greatly affected by Ca:P ratio.

Increased Maternal Prenatal Adiposity, Inflammation, and Lower Omega-3 Fatty Acid Levels Influence Child Negative Affect.

OBJECTIVE: Increased maternal adiposity during pregnancy is associated with offspring risk for psychiatric disorders. Inflammation secondary to adiposity is believed to be an important mechanism through which this effect occurs. Although increased adiposity introduces risk, not all children of overweight mothers develop these problems. Gestational factors that modify this risk are not well-understood. If maternal increased adiposity exerts its effects on offspring outcomes by increasing inflammation in the gestational environment, then anti-inflammatory inputs such as omega-3 fatty acids may be one protective factor. The goal of this study was to investigate whether maternal pre-pregnancy body mass index (BMI) and omega-3 fatty acid levels independently and/or interactively predicted offspring infant negative affect, an early life marker of risk for psychopathology. METHODS: Data came from a prospective study of women recruited during pregnancy and their 6 month old infants (N = 62; 40% female). Maternal pre-pregnancy BMI was pulled from medical charts and third trimester omega-3 fatty acid concentrations were assessed in plasma. Child negative affect was assessed using observer- and maternal-ratings at 6 months of age. Maternal inflammation was indexed by third trimester plasma levels of interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1. RESULTS: Maternal pre-pregnancy BMI was associated with increased infant negative affect whereas eicosapentaenoic acid was associated with less infant negative affect. Maternal omega-3 fatty acid levels moderated the effect of BMI on infant negative affect, such that omega-3 fatty acids buffered children against the negative consequences of increased adiposity. Supporting the role of maternal inflammation in these associations, maternal BMI and omega-3 fatty acid levels interacted to predict maternal third trimester inflammation. Further, maternal inflammation was associated with increased infant negative affect. CONCLUSION: Results suggest that omega-3 supplementation during pregnancy may protect against offspring behavioral risk associated with increased maternal adiposity.

Phosphorus retention in corn, spray dried plasma protein, soybean meal, meat and bone meal, and canola meal using a precision-fed rooster assay.

Four experiments were conducted to evaluate the precision-fed rooster assay for determining excreta phosphorus retention values for 5 feed ingredients in which roosters were precision-fed the ingredients and excreta were collected quantitatively for 48 h. The first rooster assay determined the effects of increasing P intakes on excreta P retention values for corn. This assay involved feeding either 20 g of corn or 20 g of corn supplemented with increasing amounts of KH2PO4 to provide total P intakes of 51 to 351 mg and non-phytate P intakes of 16 to 316 mg. The excreta P retention value for corn fed alone was 75% but decreased greatly when non-phytate P intakes were 76 mg or higher for the corn diets containing added KH2PO4. The second precision-fed rooster assay involved feeding increasing amounts of spray dried plasma protein (SDPP) (5 to 20 g) which provided non-phytate P intakes of 61 to 242 mg. Excretion of P increased and excreta P retention values decreased from 94 to 60% as SDPP intake increased from 5 to 20 g. Experiment 3 determined excreta P retention values for solvent extracted dehulled soybean meal (SBM) (24 g intake) and also the effect of increasing intakes of SDPP (5 to 10 g) and meat and bone meal (MBM) (1.5 to 10 g) on their excreta P retention values. The excreta P retention value for SBM was 41%. Excreta P retention values for SDPP again decreased as P intake increased. Excreta P retention values for MBM were low (27 to 35%) at all intakes. In Experiment 4, roosters were tube-fed 8, 16, or 24 g of canola meal and excreta P retention values varied from 23 to 35% among intake levels. The results of this study indicated that excreta P retention values often varied greatly among different levels of ingredient and non-phytate phosphorus intake and suggest that the precision-fed assay may be useful for determining bioavailability of P only if non-phytate P intakes are low. In addition, the assay may not be accurate for ingredients which contain high Ca levels such as MBM.

Phosphorus bioavailability in increased-protein, reduced-fiber canola meal, conventional canola meal, and soybean meal fed to crossbred chicks.

Three experiments were conducted to evaluate 3 increased-protein, reduced-fiber canola meals (CM) (CMA, CMB, and Test CM), 2 conventional CM (CCM), and 2 soybean meals (SBM). For determination of P bioavailability in CM and SBM, a P-deficient cornstarch-dextrose-SBM basal diet was fed as Diet 1. The latter basal diet was then supplemented with 0.05 and 0.10% P from KH2PO4 or 12.5 and 25% of a CM or SBM. In addition, the effect of phytase enzyme on bioavailability of the P in CMA, Test CM, and one of the CCM was determined using P-deficient 45% CM-cornstarch-dextrose diets (0.11 to 0.15% non-phytate P), with a CM as the only source of dietary P. Additional diets contained 0.05 and 0.10% added P from KH2PO4 or 125 to 500 units phytase added per kg of diet. Crossbred chicks (New Hampshire X Columbian) were fed the experimental diets from 8 to 21 d post hatch in all experiments, and bioavailability of P was estimated using the slope ratio method in which tibia ash was regressed on supplemental P intake. A linear increase in tibia ash was observed as the P level increased by the addition of KH2PO4, CMA, CMB, or SBM. Based on the mean values of tibia ash in mg/tibia and tibia ash %, the mean bioavailabilities of P in the 3 increased-protein, reduced-fiber CM, 3 CCM, and 2 SBM relative to KH2PO4 were 18, 15, and 39%, respectively. A linear increase in weight gain and tibia ash was observed with addition of KH2PO4 or phytase to the P-deficient CM diets. It was estimated that 125 or 250 units/kg microbial phytase resulted in approximately 0.05 and 0.10% P being released from CM, respectively. In conclusion, the bioavailablity of the P in the new increased-protein, reduced-fiber CM was similar to that of CCM. Furthermore, phytase substantially and similarly increased the bioavailability of P in both types of CM.

Estrogen promotes the brain metastatic colonization of triple negative breast cancer cells via an astrocyte-mediated paracrine mechanism.

Brain metastases (BM) are a devastating consequence of breast cancer. BM occur more frequently in patients with estrogen receptor-negative (ER-) breast cancer subtypes; HER2 overexpressing (HER2+) tumors and triple-negative (TN) (ER-, progesterone receptor-negative (PR-) and normal HER2) tumors. Young age is an independent risk factor for the development of BM, thus we speculated that higher circulating estrogens in young, pre-menopausal women could exert paracrine effects through the highly estrogen-responsive brain microenvironment. Using a TN experimental metastases model, we demonstrate that ovariectomy decreased the frequency of magnetic resonance imaging-detectable lesions by 56% as compared with estrogen supplementation, and that the combination of ovariectomy and letrozole further reduced the frequency of large lesions to 14.4% of the estrogen control. Human BM expressed 4.2-48.4% ER+ stromal area, particularly ER+ astrocytes. In vitro, E2-treated astrocytes increased proliferation, migration and invasion of 231BR-EGFP cells in an ER-dependent manner. E2 upregulated epidermal growth factor receptor (EGFR) ligands Egf, Ereg and Tgfa mRNA and protein levels in astrocytes, and activated EGFR in brain metastatic cells. Co-culture of 231BR-EGFP cells with E2-treated astrocytes led to the upregulation of the metastatic mediator S100 Calcium-binding protein A4 (S100A4) (1.78-fold, P<0.05). Exogenous EGF increased S100A4 mRNA levels in 231BR-EGFP cells (1.40±0.02-fold, P<0.01 compared with vehicle control) and an EGFR/HER2 inhibitor blocked this effect, suggesting that S100A4 is a downstream effector of EGFR activation. Short hairpin RNA-mediated S100A4 silencing in 231BR-EGFP cells decreased their migration and invasion in response to E2-CM, abolished their increased proliferation in co-cultures with E2-treated astrocytes and decreased brain metastatic colonization. Thus, S100A4 is one effector of the paracrine action of E2 in brain metastatic cells. These studies provide a novel mechanism by which estrogens, acting through ER+ astrocytes in the brain microenvironment, can promote BM of TN breast cancers, and suggests existing endocrine agents may provide some clinical benefit towards reducing and managing BM.

Hypnotherapy in radiotherapy patients: a randomized trial.

PURPOSE: To determine whether hypnotherapy reduces anxiety and improves the quality of life in cancer patients undergoing curative radiotherapy (RT). METHODS AND MATERIALS: After providing written informed consent, 69 patients were randomized between standard curative RT alone (36 controls) and RT plus hypnotherapy (33 patients). Patients in the hypnotherapy group received hypnotherapy at the intake, before RT simulation, before the first RT session, and halfway between the RT course. Anxiety was evaluated by the State-Trait Anxiety Inventory DY-1 form at six points. Quality of life was measured by the Rand Medical Outcomes Study 36-item Health Survey (SF-36) at five points. Additionally, patients answered a questionnaire to evaluate their experience and the possible benefits of this research project. RESULTS: No statistically significant difference was found in anxiety or quality of life between the hypnotherapy and control groups. However, significantly more patients in the hypnotherapy group indicated an improvement in mental (p <0.05) and overall (p <0.05) well-being. CONCLUSION: Hypnotherapy did not reduce anxiety or improve the quality of life in cancer patients undergoing curative RT. The absence of statistically significant differences between the two groups contrasts with the hypnotherapy patients' own sense of mental and overall well-being, which was significantly greater after hypnotherapy. It cannot be excluded that the extra attention by the hypnotherapist was responsible for this beneficial effect in the hypnotherapy group. An attention-only control group would be necessary to control for this effect.

High-dose folinic acid and 5-fluorouracil bolus and continuous infusion in advanced colorectal cancer: poor response rate in unselected patients.

We have conducted a retrospective study of high-dose folinic acid and 5-fluorouracil in 96 patients with advanced colorectal cancer. Patients received 200 mg m-2 (maximum 300-350 mg) folinic acid by infusion over 2 h followed by an i.v. bolus of 5-fluorouracil 400 mg m-2 then an infusion of 5-fluorouracil 600 mg m-2 over 22 h. This was repeated over the next 24 h. The schedule was given every 2 weeks for four cycles; thereafter patients with objective response continued to a maximum of eight cycles. The overall response rate was 10.6% in 85 evaluable patients. The median duration of response was 11 months. The median survival was 6 months. Toxicity was low, only one patient experiencing toxicity greater than WHO grade II (grade IV platelet toxicity). Diarrhoea, nausea, vomiting and mucositis also occurred but were mild and infrequent. Our low response rate may be related to factors such as patient characteristics or duration of treatment.

Hypothalamic pituitary adrenal function in the extremely low birth weight infant.

Extremely premature infants manifest clinical features suggestive of adrenal insufficiency. Yet, serum cortisol levels are similar in ill and well preterm infants in a setting where one would expect high stress levels in the ill infants. We investigated the hypothalamic-pituitary-adrenal axis in 17 extremely low birth weight stressed premature infants, mean birth weight 739 g, gestational age, 26.1 weeks, using ovine CRH (oCRH) and ACTH stimulation. oCRH (1 microgram/kg) was administered at 2-7 days of life (mean = 4.1). ACTH rose from a basal value 6.0 +/- 0.8 pmol/L (mean +/- SEM) to 9.6 +/- 1.8 pmol/L (P < 0.01) at 15 min and 9.5 +/- 1.7 pmol/L (P < 0.01) at 60 min. Basal cortisol rose from 349.3 +/- 58.1 nmol/L to 422.3 +/- 57.9 nmol/L (P < 0.01) at 15 min and 568.7 +/- 60.2 nmol/L (P < 0.01) at 60 min. Cortisol values remained significantly (P < 0.05) elevated 24 h after oCRH. An ACTH stimulation test performed 24 h after the oCRH test demonstrated a significant cortisol rise from 603.5 +/- 130.5 nmol/L to 882.7 +/- 136.6 nmol/L (P < 0.05) at 60 min. Plasma CRH immunoactivity was also measured before oCRH testing and was detectable in 10 of 15 infants. The mean CRH immunoactivity was 21.8 +/- 4.4 pmol/L in the infants, significantly higher than 8 adult male controls (P < 0.04). Our results show a normal pituitary response to ovine CRH and a normal adrenal response to ACTH. We hypothesize that cortisol levels are inappropriately low in some ill preterm infants because of the inability of the extremely premature brain to recognize the stress of the illness or because of inadequate hypothalamic secretion of CRH. The significance of the measurable plasma CRH in the first week of life is unknown.

Detection of congenital hypopituitary hypothyroidism: ten-year experience in the Northwest Regional Screening Program.

We examined the results of the Northwest Regional Screening Program (NWRSP) over its first 10 years to determine whether the detection of hypopituitary hypothyroidism is a justified advantage of the primary thyroxine (T4)-supplemental thyroid-stimulating hormone (TSH) screening strategy, and to determine whether all such infants will be detected by this screening approach. Between May 1975 and May 1985, the NWRSP screened 850,431 infants, detecting 192 infants with primary hypothyroidism (1:4429) and eight with hypopituitary hypothyroidism (1:106,304). In 11 additional infants, TSH deficiency, not detected by the screening program, was diagnosed on recognition of clinical features over the same period. Thyroid hormone treatment was begun in seven of the 11 infants prior to obtaining the screening sample results because of clinical symptoms of hypopituitarism, including hypoglycemia, persistent jaundice, microgenitalia, diabetes insipidus, midface hypoplasia, cleft lip or palate, or abnormalities of vision. The other four infants were not detected despite clinical features of hypopituitarism (in retrospect) and low serum T4 with TSH concentration below assay sensitivity on at least one screening sample. The most accurate assessment of total cases comes from Oregon, where all cases of congenital hypopituitarism are referred to our center; we estimate a frequency of 1:29,000. In our experience, a combination of newborn T4-supplemental TSH screening measurements and recognition of clinical features of hypopituitarism is the optimal strategy for detecting infants with congenital hypopituitary hypothyroidism.

Adverse effects of iron supplementation: a comparative trial of a wax-matrix iron preparation and conventional ferrous sulfate tablets.

The acceptability of supplemental iron delivered from a wax-matrix tablet of ferrous sulfate was compared with that of a conventional ferrous sulfate tablet in a single-blind, parallel-group study. Both tablets were formulated to deliver 50 mg of elemental iron. The incidence of adverse effects was found to be significantly greater among 272 subjects taking the conventional tablets than among 271 subjects taking the wax-matrix preparation. Eighty-one percent of the subjects taking the wax-matrix preparation experienced no severe or moderate side effects as compared with only 50% of those taking the conventional tablets.