Clinical utility of comprehensive circulating tumor DNA genotyping compared with standard of care tissue testing in patients with newly diagnosed metastatic colorectal cancer.

BACKGROUND: Comprehensive biomarker testing is essential in selecting optimal treatment for patients with metastatic colorectal cancer (mCRC); however, incomplete genotyping is widespread, with most patients not receiving testing for all guideline-recommended biomarkers, in part due to reliance on burdensome sequential tissue-based single-biomarker tests with long waiting times or availability of only archival tissue samples. We aimed to demonstrate that liquid biopsy, associated with rapid turnaround time (TAT) and lower patient burden, effectively identifies guideline-recommended biomarkers in mCRC relative to standard of care (SOC) tissue testing. PATIENTS AND METHODS: Prospectively enrolled patients with previously untreated mCRC undergoing physician discretion SOC tissue genotyping submitted pretreatment blood samples for comprehensive circulating tumor DNA (ctDNA) analysis with Guardant360 and targeted RAS and BRAF analysis with OncoBEAM. RESULTS: Among 155 patients, physician discretion SOC tissue genotyping identified a guideline-recommended biomarker in 82 patients, versus 88 identified with comprehensive ctDNA (52.9% versus 56.8%, noninferiority demonstrated down to α = 0.005) and 69 identified with targeted PCR ctDNA analysis (52.9% versus 44.5%, noninferiority rejected at α = 0.05). Utilizing ctDNA in addition to tissue increased patient identification for a guideline-recommended biomarker by 19.5% by rescuing those without tissue results either due to tissue insufficiency, test failure, or false negatives. ctDNA median TAT was significantly faster than tissue testing when the complete process from sample acquisition to results was considered (median 10 versus 27 days, P < 0.0001), resulting in accelerated biomarker discovery, with 52.0% biomarker-positive patients identified by ctDNA versus 10.2% by SOC tissue 10 days after sample collection (P < 0.0001). CONCLUSIONS: Comprehensive ctDNA genotyping accurately identifies guideline-recommended biomarkers in patients with mCRC at a rate at least as high as SOC tissue genotyping, in a much shorter time. Based on these findings, the addition of ctDNA genotyping to clinical practice has significant potential to improve the care of patients with mCRC.

The efficacy of different vitamin D supplementation delivery methods on serum 25(OH)D: A randomised double-blind placebo trial.

BACKGROUND: The use of vitamin D supplementation has increased due to greater recognition of widespread deficiency. AIMS: There has been little research on the effectiveness of different delivery methods and therefore the aim of was to test the efficacy of different delivery methods on serum 25(OH)D. METHODS: Using a randomised repeated measures double-blind placebo design (registered under ClinicalTrials.gov Identifier no. NCT03463642), changes in serum 25(OH)D over a 4-week period using a capillary spot method were monitored. 62 female participants blindly chose a number related to a supplementation delivery method: pill placebo, pill, oral liquid, oral liquid placebo, Skin oil application (SOA) placebo, SOA plus vitamin D3 suspension, or SOA plus vitamin D3 suspension with essential oil enhancer; active vitamin D supplements contained 100,000IU. Participants took their allocated supplements over a 24-hr period with serum 25(OH)D retested 4 weeks later. Liquid chromatography-tandem mass spectrometry method was applied to dried blood spot samples by an independent laboratory. RESULTS: ANCOVA reported a significant difference between the groups (F1,6 = 146.68; p < 0.001, eta2 = 0.51). Separate analysis within the delivery methods (pill, SOA, oral liquid) indicated significant differences between the active and placebo supplementation groups (p < 0.01). Post hoc analysis of absolute changes indicated vit D pill and SOA + vit D + essential oil had significant increases (p < 0.05) in serum 25(OH)D compared to all other interventions with no significant difference between them. CONCLUSIONS: In human participants vitamin D oral pill has the greatest effect on serum 25(OH)D levels. Skin oil application delivery of vitamin D using a penetrator enhancer has also been shown to be an effective method of delivery.

Eccentric exercises; why do they work, what are the problems and how can we improve them?

Eccentric exercises (EE) have proved successful in the management of chronic tendinopathy, particularly of the Achilles and patellar tendons, where they have been shown to be effective in controlled trials. However, numerous questions regarding EE remain. The standard protocols are time-consuming and require very motivated patients. EE are effective in some tendinopathies but not others. Furthermore, the location of the lesion can have a profound effect on efficacy; for example, standard EE in insertional lesions of the Achilles are ineffective. Until recently little was known of the effect of EE on tendinopathic tendons, although a greater understanding of this process is emerging. Additionally, recent in vivo evidence directly comparing eccentric and concentric exercises provides a possible explanation for the therapeutic benefit of EE. The challenge now is to make EE more effective. Suggestions on areas of future research are made.

The mechanism for efficacy of eccentric loading in Achilles tendon injury; an in vivo study in humans.

OBJECTIVE: Degenerative disorders of tendons present an enormous clinical challenge. They are extremely common, prone to recur and existing medical and surgical treatments are generally unsatisfactory. Recently eccentric, but not concentric, exercises have been shown to be highly effective in managing tendinopathy of the Achilles (and other) tendons. The mechanism for the efficacy of these exercises is unknown although it has been speculated that forces generated during eccentric loading are of a greater magnitude. Our objective was to determine the mechanism for the beneficial effect of eccentric exercise in Achilles tendinopathy. METHODS: Seven healthy volunteers performed eccentric and concentric loading exercises for the Achilles tendon. Tendon force and length changes were determined using a combination of motion analysis, force plate data and real-time ultrasound. RESULTS: There was no significant difference in peak tendon force or tendon length change when comparing eccentric with concentric exercises. However, high-frequency oscillations in tendon force occurred in all subjects during eccentric exercises but were rare in concentric exercises (P < 0.0001). CONCLUSION: These oscillations provide a mechanism to explain the therapeutic benefit of eccentric loading in Achilles tendinopathy and parallels recent evidence from bone remodelling, where the frequency of the loading cycles is of more significance than the absolute magnitude of the force.

The effect of weight-bearing exercise on bone mineral density: a study of female ex-elite athletes and the general population.

The aim of this retrospective cohort study was to estimate the changes in bone mineral density (BMD) as a consequence of exercise in female ex-athletes and age-matched controls. Eighty-three ex-elite female athletes (67 middle and long distance runners, 16 tennis players, currently aged 40-65) were recruited from the original records of their sporting associations. Controls were 585 age-matched females. The main outcome measures were BMD of lumbar spine (LS), femoral neck (FN), and forearm, estimated by dual-energy X-ray absorptiometry (DXA) scan. Levels of physical activity were assessed using a modified Allied Dunbar Fitness Survey scale and classified as (a) ex-athletes, (b) active controls (> or = 1 h of vigorous physical activity currently and in the past), (c) low activity controls with inconsistent or intermediate levels of activity, and (d) inactive controls (< 15 minutes of exercise per week). After adjustment for differences in age, weight, height, and smoking, athletes had greater BMDs than controls: 8.7% at the LS (95% confidence interval [CI] 5.4-12.0; p < 0.001) and 12.1% at FN (CI 9.0-15.3; p < 0.001). The benefits of exercise appeared to persist after cessation of sporting activity. Active controls (n = 22) had greater BMDs than the inactive group (n = 347): 7.9% LS (CI 2.0-13.8; p = 0.009) and 8.3% FN (CI 2.7-13.8; p = 0.004). The low activity controls (n = 216) had an intermediate BMD. Tennis players had greater BMDs compared with runners: 12.0% LS (CI 5.7-18.2; p = 0.0004) and 6.5% FN (CI -0.2-13.2; p = 0.066). The BMD of tennis players' dominant forearms were greater than their nondominant forearms. In conclusion, regular vigorous weight-bearing exercise of 1 h or more per week is associated with an increase in BMD within a normal population. This study confirms long-term weight-bearing exercise as an important factor in the regulation of bone mass and fracture prevention.

Determinants of the first decade of bone loss after menopause at spine, hip and radius.

This study documented bone loss at three different sites in the early postmenopausal period, and examined potential predictors. Forty-three women underwent repeated measurements of bone density at the lumbar spine, proximal femur and distal radius for up to 14 years. Individual rates of bone loss were calculated for the spine and hip; for radial trabecular bone, rates were calculated separately for two time periods, earlier and later after menopause. In the spine and radius, initially high rates of loss diminished with time after menopause. No positive correlations for bone loss were found between the three sites, suggesting that faster than average bone loss was specific to individual bones. High body mass index (BMI) was significantly protective against fast bone loss at the spine and radius; in the spine, each unit increase in BMI was associated with a approximately 5% reduction in the rate of bone loss. Of the other variables measured (maximum oxygen consumption, lean body mass, fat mass, mean psoas muscle area at the L3 level, hand grip strength as well as anthropometry) only bone densitometry was sufficiently predictive to help guidance on hormone replacement or other prophylactic therapy. The data suggest that the known relationship between excessive leanness and risk of osteoporosis and vertebral fracture after menopause might in part be due to fast post-menopausal bone loss. Because bulk of psoas muscle was associated with low spine loss rates, the data also support a role for applied muscular loading in local maintenance of bone density.

Early diagnosis of myocardial infarction by timed sequential enzyme measurements.

Serum samples from patients admitted to a coronary care unit with a history of acute chest pain suggestive of myocardial infarction in the previous 12 h were obtained on admission and at 6 and 12 h, thereafter. Creatine kinase (CK), CK-MB isoenzyme, CK-MM sub-bands, myoglobin, and lactate dehydrogenase (LD) isoenzymes were examined. Changes were evaluated in relation to the diagnosis obtained from clinical examination, serial electrocardiography and 'routine' cardiac enzymes (CK, aspartate transaminase and alpha-hydroxy butyrate dehydrogenase daily for 3 days following admission). The slope of the logarithms of CK, CK-MB activity and CK-MB concentration in the early post infarct period fully distinguished between infarct and non-infarct patients. Measurement of myoglobin and lactate dehydrogenase isoenzymes was less sensitive. Serial estimation of CK-MM sub-band patterns allowed the time from infarction to be estimated. Serial estimation of CK in the 12 h following admission can be substituted for conventional daily enzyme estimations for the diagnosis of acute myocardial infarction in patients with onset of chest pain within the previous 12 h. This could reduce laboratory and in-patient costs.

Use of morphine sulfate (MS Contin) in patients with burns: a pilot study.

Morphine sulfate (MS Contin), a proven analgesic in the treatment of cancer pain and chronic benign pain, seems to be a good analgesic for the treatment of burn pain. MS Contin is morphine sulfate incorporated in a wax cellulose matrix delivery system. This wax cellulose delivery system gives MS Contin its duration of action. Ten patients were enrolled in an open-labeled, nonrandomized study. The study was designed to examine the analgesic efficacy of MS Contin in the burn population. Each patient remained in the study for 6 days. The efficacy of the analgesic regimen was subjectively measured by the visual pain scale. The MS Contin group was retrospectively compared with a group of patients who were given continuous intravenous infusions of morphine. The two groups were matched according to age, burn size, surgical procedures, and hospital stay. The analgesic qualities of MS Contin were comparable to those of continuous intravenous morphine sulfate infusions. MS Contin is a possible candidate for the treatment of patients with burn pain because of its analgesic qualities, oral dosing, and duration of action.

Menstrual state and exercise as determinants of spinal trabecular bone density in female athletes.

OBJECTIVE: To study the effects of amenorrhoea and intensive back exercise on the bone mineral density of the lumbar spine in female athletes. DESIGN: Cross sectional study comparing amenorrhoeic with eumenorrhoeic athletes and rowers with non-rowers. SETTING: The British Olympic Medical Centre, Northwick Park Hospital. PATIENTS: 46 Elite female athletes comprising 19 rowers, 18 runners, and nine dancers, of whom 25 were amenorrhoeic and 21 eumenorrhoeic. MAIN OUTCOME MEASURE: Trabecular bone mineral density of the lumbar spine measured by computed tomography. RESULTS: Mean trabecular bone mineral density was 42 mg/cm3 (95% confidence interval 22 to 62 mg/cm3) lower in the amenorrhoeic than the eumenorrhoeic athletes; this difference was highly significant (p = 0.0002). Mean trabecular bone mineral density was 21 mg/cm3 (1 to 41 mg/cm3) lower in the non-rowers than the rowers; this was also significant (p = 0.05). There was no interaction between these two effects (p = 0.28). CONCLUSION: The effect of intensive exercise on the lumbar spine partially compensates for the adverse effect of amenorrhoea on spinal trabecular bone density.

Esmolol and beta-adrenergic blockade.

Tachycardia often presents difficult management problems in anesthesia. Because it increases myocardial oxygen demand so sharply, tachycardia can quickly place patients at risk of myocardial ischemia. It can occur for any number of reasons. Deepening the anesthetic, either with inhalation agent or opioids, will ablate increases in heart rate, but changes in heart rate are often transient and changes in anesthetic depth are often not. Esmolol (Brevibloc) is a unique, short-acting beta blocker that is strongly beta 1 selective at usual clinical doses. As with other beta blockers, esmolol becomes less selective for the beta 1 receptor as its dose is increased. It is metabolized by red blood cell esterases resulting in a half-life of 9 minutes. Fifteen minutes after a bolus dose, esmolol is difficult to detect in the plasma. Its metabolites have clinically undetectable activity and are eliminated renally. Esmolol may be administered by intermittent, intravenous bolus doses or by continuous infusion. Infusions should be preceded by loading doses. Dose range varies with the patient's status, clinical situation, concomitant medications, and desired result. Patients receiving esmolol should be monitored because of its bradycardic and hypotensive effects.