A systematic review of the role of bisphosphonates in metastatic disease

Objectives: To identify evidence for the role of bisphosphonates in malignancy for the treatment of hypercalcaemia, prevention of skeletal morbidity and use in the adjuvant setting. To perform an economic review of current literature and model the cost effectiveness of bisphosphonates in the treatment of hypercalcaemia and prevention of skeletal morbidity Data sources: Electronic databases (1966-June 2001). Cochrane register. Pharmaceutical companies. Experts in the field. Handsearching of abstracts and leading oncology journals (1999-2001). Review methods: Two independent reviewers assessed studies for inclusion, according to predetermined criteria, and extracted relevant data. Overall event rates were pooled in a meta-analysis, odds ratios ( OR) were given with 95% confidence intervals (CI). Where data could not be combined, studies were reported individually and proportions compared using chi- squared analysis. Cost and cost-effectiveness were assessed by a decision analytic model comparing different bisphosphonate regimens for the treatment of hypercalcaemia; Markov models were employed to evaluate the use of bisphosphonates to prevent skeletal-related events (SRE) in patients with breast cancer and multiple myeloma. Results: For acute hypercalcaemia of malignancy, bisphosphonates normalised serum calcium in >70% of patients within 2-6 days. Pamidronate was more effective than control, etidronate, mithramycin and low-dose clodronate, but equal to high dose clodronate, in achieving normocalcaemia. Pamidronate prolongs ( doubles) the median time to relapse compared with clodronate or etidronate. For prevention of skeletal morbidity, bisphosphonates compared with placebo, significantly reduced the OR for fractures (OR [95% CI], vertebral, 0.69 [0.57-0.84], non-vertebral, 0.65 [0.54-0.79], combined, 0.65 [0.55-0.78]) radiotherapy 0.67 [0.57-0.79] and hypercalcaemia 0.54 [0.36-0.81] but not orthopaedic surgery 0.70 [0.46-1.05] or spinal cord compression 0.71 [0.47-1.08]. However, reduction in orthopaedic surgery was significant in studies that lasted over a year 0.59 [0.39-0.88]. Bisphosphonates significantly increased the time to first SRE but did not affect survival. Subanalyses were performed for disease groups, drugs and route of administration. Most evidence supports the use of intravenous aminobisphosphonates. For adjuvant use of bisphosphonates, Clodronate, given to patients with primary operable breast cancer and no metastatic disease, significantly reduced the number of patients developing bone metastases. This benefit was not maintained once regular administration had been discontinued. Two trials reported significant survival advantages in the treated groups. Bisphosphonates reduce the number of bone metastases in patients with both early and advanced breast cancer. Bisphosphonates are well tolerated with a low incidence of side-effects. Economic modelling showed that for acute hypercalcaemia, drugs with the longest cumulative duration of normocalcaemia were most cost-effective. Zoledronate 4 mg was the most costly, but most cost-effective treatment. For skeletal morbidity, Markov models estimated that the overall cost of bisphosphonate therapy to prevent an SRE was pound250 and pound1500 per event for patients with breast cancer and multiple myeloma, respectively. Bisphosphonate treatment is sometimes cost-saving in breast cancer patients where fractures are prevented. Conclusions: High dose aminobisphosphonates are most effective for the treatment of acute hypercalcaemia and delay time to relapse. Bisphosphonates significantly reduce SREs and delay the time to first SRE in patients with bony metastatic disease but do not affect survival. Benefit is demonstrated after administration for at least 6-12 months. The greatest body of evidence supports the use of intravenous aminobisphosphonates. Further evidence is required to support use in the adjuvant setting

Safety and efficacy of hot avulsion as an adjunct to endoscopic mucosal resection (with videos)

Background Excision of all visible neoplastic tissue is the goal of endoscopic mucosal resection (EMR) of colorectal laterally spreading tumors (LSTs). Flat and fibrotic tissue can resist snaring. Ablation of visible polyps is associated with high recurrence rates. Avulsion is a technique to continue resection when snaring fails. Methods We retrospectively analyzed colonic EMRs of 564 consecutive referred polyps between 2015 and 2017. Hot avulsion was used when snaring was unsuccessful. Polyps treated with and without avulsion were compared. Results Hot avulsion was used in 20.9% (n=112) of all resected lesions. The recurrence rates on follow up colonoscopy were 17.52% in avulsion group versus 16.02% in the non-avulsion group (p= 0.76). Hot avulsion was associated with a trend toward higher rates of delayed hemorrhage (5.35% vs 2.58%; p=0.15) and post-coagulation syndrome (1.8% vs 0.47%; p=0.15), but polyps treated with any avulsion were larger than those in which no avulsion was used (p=<0.001). There were an insufficient number of adverse events to perform a multivariable analysis testing the effects of avulsion, size, and location on the risk of overall adverse events. Conclusion Unlike previous reports of using argon plasma coagulation to treat visible polyp during EMR, hot avulsion of visible/fibrotic neoplasia was associated with similar EMR efficacy compared with cases that did not require hot avulsion. The safety profile of hot avulsion appears acceptable

Endoscopic management of large ileocecal valve lesions over an 18-year interval

Background and study aims Ileocecal valve (ICV) lesions are challenging to remove endoscopically. Patients and methods This was a retrospective cohort study, performed at an academic tertiary US hospital. Sessile polyps or flat ICV lesions ≥ 20 mm in size referred for endoscopic mucosal resection (EMR) were included. Successful resection rates, complication rates and recurrence were compared to lesions ≥ 20 mm in size not located on the ICV. Results During an 18-year interval, there were 118 ICV lesions ≥ 20 mm with mean size 28.6 mm (44.9 % females; mean age 71.6 years), comprising 9.03 % of all referred polyps. Ninety ICV lesions (76.3 %) were resected endoscopically, compared to 91.3 % of non-ICV lesions (P < 0.001). However, in the most recent 8 years, successful EMR of ICV lesions increased to 93 %. Conventional adenomas comprised 92.2 % of ICV lesions and 7.8 % were serrated. Delayed hemorrhage and perforation occurred in 3.3 % and 0 % of ICV lesions, respectively, compared to 4.8 % and 0.5 % in the non-ICV group. At first follow-up, rates of residual polyp in the ICV and non-ICV groups were 16.5 % and 13.6 %, respectively (P = 0.485). At second follow-up residual rates in the ICV and non-ICV lesion groups were 18.6 % and 6.7 %, respectively (P = .005). Conclusions Large ICV polyps are a common source of tertiary referrals. Over an 18-year experience, risk of EMR for ICV polyps was numerically lower, and risk of recurrence was numerically higher at first follow and significantly higher at second follow-up compared to non-ICV polyps

Endoscopic control of polyp burden and expansion of surveillance intervals in serrated polyposis syndrome

Introduction Serrated polyposis syndrome (SPS) increases colorectal cancer (CRC) risk. We describe the numbers of colonoscopies and polypectomies performed to achieve and maintain low polyp burdens, and the feasibility of expanding surveillance intervals in patients who achieve endoscopic control. Methods We retrospectively evaluated a prospectively collected database on 115 SPS patients undergoing surveillance at Indiana University Hospital between June 2005 and May 2018. The endoscopist provided surveillance interval recommendations based on polyp burden. Endoscopic control was considered successful if surveillance examinations exhibited fewer polyps and if no or only an occasional polyp ≥1 cm in size was present at follow-up. Initial control was designated the clearing phase and the maintenance phase was surveillance after control was established. Results In total, 87 patients (75.7%) achieved endoscopic control, with some others in the clearing phase at this writing. Achieving control required a mean of 2.84 colonoscopies (including the baseline) over 20.4 months and a mean total 27.9 polyp resections. After establishing control, 71 patients were recommended to receive ≥24-month follow-up. Of those, 60 patients (69.0% of patients with initial control) continued surveillance at our center. The mean interval between colonoscopies during maintenance was 19.3 months with 6.74 mean polypectomies per procedure on polyps primarily <1 cm. There were no incident cancers or colon surgeries during maintenance. Conclusion Most patients achieved control of polyp burden with 2 to 3 colonoscopies over 1 to 2 years. After reaching control, 60 patients returned at intervals up to 24 months with no incident cancers and no surgeries required. Expansion of surveillance intervals to 24 months is effective and safe for many SPS patients who reach control of polyp burden

Dietary selenium intake among Ethiopian children in areas known for selenium spatial variability

Introduction: There is spatial variability of selenium (Se) in soil and crops in Ethiopia. We assessed the Se content of food items, breast milk, and urine among infants in Ethiopia from two areas with contrasting Se concentrations in soils. Methods: Dietary Se intakes among children (6–23 months) were evaluated using a weighed food record on two non-consecutive days. Also, spot urine samples from children and breast milk samples from their mothers were collected to determine Se concentration. Selenium concentrations in the samples were analyzed using an inductively coupled plasma mass spectrometer (ICP-MS). Results: Injera (prepared from teff and mixtures of other cereals) with a legume-based stew were the most frequently consumed foods by the children in both areas, followed by pasta. Overall, the Se concentration (mean ± SD) of food items, breast milk (12.2 ± 3.9 μg/L vs. 3.39 ± 1.5 μg/L), and urine samples (22.5 ± 11.5 μg/L vs. 3.0 ± 1.9 μg/L) from East Amhara were significantly higher than the corresponding samples from West Amhara (p < 0.001). The total Se intakes by the study children from East Amhara and West Amhara were 30.2 [IQ 25%, 14.2; IQ 75%, 54.1] and 7.4 [IQR 25%, 4.2; IQ 75%, 10.6] μg day–1, respectively; 31.5% of children from East Amhara and 92% of children from West Amhara were at risk of inadequate Se intakes. Urinary Se excretion accounted for 53 and 39% of daily dietary Se intake in East Amhara and West Amhara, respectively. Dietary Se intake was positively correlated with urinary Se excretion in East Amhara (r = 0.56; p < 0.001) but not among samples from West Amhara (r = 0.16; p ≥ 0.05), suggesting greater physiological Se conservation in a state of deficiency. Conclusion: There is spatial variability of Se in foods, breast milk, and urine in Ethiopia, suggesting the need for implementation of targeted agronomic interventions that enhance Se concentrations in the edible portion of plant foods

Plant Available Zinc Is Influenced by Landscape Position in the Amhara Region, Ethiopia

Zinc (Zn) is an important element determining the grain quality of staple food crops and deficient in many Ethiopian soils. However, farming systems are highly variable in Ethiopia due to different soil types and landscape cropping positions. Zinc availability and uptake by plants from soil and fertilizer sources are governed by the retention and release potential of the soil, usually termed as adsorption and desorption, respectively. The aim of this study was to characterize the amount of plant available Zn at different landscape positions. During the 2018/19 cropping season, adsorption-desorption studies were carried out on soil samples collected from on-farm trials conducted at Aba Gerima, Debre Mewi and Markuma in the Amhara Region. In all locations and landscape positions, adsorption and desorption increased with increasing Zn additions. The amount of adsorption and desorption was highly associated with the soil pH, the soil organic carbon concentration and cation exchange capacity, and these factors are linked to landscape positions. The Freundlich isotherm fitted very well to Zn adsorption (r2 0.87–0.99) and desorption (r2 0.92–0.99), while the Langmuir isotherm only fitted to Zn desorption (r2 0.70–0.93). Multiple regression models developed by determining the most influential soil parameters for Zn availability could be used to inform Zn fertilizer management strategies for different locations and landscape positions in this region, and thereby improve plant Zn use efficienc

Xenon isotopes in Archean and Proterozoic insoluble organic matter: a robust indicator of syngenecity?

Insoluble organic materials (kerogens) isolated from ancient sedimentary rocks provide unique insights into the evolution of early life. However, establishing whether these kerogens are indeed syngenetic with the deposition of associated sedimentary host rocks, or contain contribution from episodes of secondary deposition, is not straightforward. Novel geochemical criterions are therefore required to test the syngenetic origin of Archean organic materials. On one hand, the occurrence of mass-independent fractionation of sulphur isotopes (MIF-S) provides a tool to test the Archean origin of ancient sedimentary rocks. Determining the isotope composition of sulphur within kerogens whilst limiting the contribution from associated minerals (e.g., nano-pyrites) is however challenging. On the other end, the Xe isotope composition of the Archean atmosphere has been shown to present enrichments in the light isotopes relative to its modern composition, together with a mono-isotopic deficit in ¹²⁹Xe. Given that the isotopic composition of atmospheric Xe evolved through time by mass dependent fractionation (MDF) until ∼2.5-2.0 Ga, the degree of MDF of Xe isotopes trapped in kerogens could provide a time stamp for the last chemical equilibration between organic matter and the atmosphere. However, the extent to which geological processes could affect the signature of Xe trapped in ancient kerogen remains unclear. In this contribution, we present new Ar, Kr and Xe isotopic data for four kerogens isolated from 3.4 to 1.8 Gy-old cherts and confirm that Xe isotopes from the Archean atmosphere can be retained within kerogens. However, new Xe-derived model ages are lower than expected from the ages of host rocks, indicating that initially trapped Xe components were at least partially lost and/or mixed together with some Xe carried out by younger generations of organic materials, therefore complicating the Xe-based dating method. Whilst non-null Δ³³S values and ¹²⁹Xe deficits relative to modern atmosphere constitute reliable imprints from the Archean atmosphere, using Xe isotopes to provide information on the syngenetic origin of ancient organic matter appears to be a promising - but not unequivocal - tool that calls for further analytical development

Faster colonoscope withdrawal time without impaired detection using EndoRings

Background and study aims:  Mucosal exposure devices on the colonoscope tip have improved detection. We evaluated detection and procedure times in colonoscopies performed with EndoRings. Patients and methods:  We had 14 endoscopists in a university practice trial EndoRings. We compared detection and procedure times to age- and indication-matched procedures by the same endoscopists. Results:  There were 137 procedures with EndoRings. The adenoma detection rate was 44 % with EndoRings vs. 39 % without ( P  = 0.39). Mean adenomas per colonoscopy (standard deviation) was 1.2 (2.3) with EndoRings vs. 0.9 (1.6) without ( P  = 0.055). Mean insertion time with EndoRings was 6.2 (3.2) minutes vs. 6.6 (6.7) minutes without ( P  = 0.81). Mean withdrawal time with EndoRings in all patients with or without polypectomy was 12.2 (5.3) minutes and 16.1 (10.3) minutes without ( P  = 0.0005). Conclusion:  EndoRings may allow faster withdrawal during colonoscopy without any reduction in detection. Prospective trials with mucosal exposure devices targeting procedure times as primary endpoints are warranted

Sub-sampling a large physical soil archive for additional analyses to support spatial mapping; a pre-registered experiment in the Southern Nations, Nationalities, and Peoples Region (SNNPR) of Ethiopia

The value of physical archives of soil material from field sampling activities has been widely recognized. If we want to use archive material for new destructive analyses to support a task, such as spatial mapping, then an efficient sub-sampling strategy is needed, both to manage analytical costs and to conserve the archive material. In this paper we present an approach to this problem when the objective is spatial mapping by ordinary kriging. Our objective was to subsample the physical archive from the Ethiopia Soil Information System (EthioSIS) survey of the Southern Nations, Nationalities and Peoples Region (SNNPR) for spatial mapping of two variables, concentrations of particular fractions of selenium and iodine in the soil, which had not been measured there. We used data from cognate parts of surrounding regions of Ethiopia to estimate variograms of these properties, and then computed prediction error variances for maps in SNNPR based on proposed subsets of the archive of different size, selected to optimize a spatial coverage criterion (with some close sample pairs included). On this basis a subsample was selected. This is a preregistered experiment in that we have proposed criteria for evaluating the success of our approach, and are publishing that in advance of receiving analytical data on the subsampled material from the laboratories where they are being processed. A subsequent short report will publish the outcome. The use of preregistered trials is widely recommended and used in areas of science including public health, and we believe that it is a sound strategy to promote reproducible research in soil science

Linking soil adsorption-desorption characteristics with grain zinc concentrations and uptake by teff, wheat and maize in different landscape positions in Ethiopia

AimZinc deficiencies are widespread in many soils, limiting crop growth and contributing to Zn deficiencies in human diets. This study aimed at understanding soil factors influencing grain Zn concentrations and uptake of crops grown in different landscape positions in West Amhara, Ethiopia.MethodsOn-farm experiments were conducted in three landscape positions, with five farmers’ fields as replicates in each landscape position, and at three sites. Available Zn from the soil (Mehlich 3, M3, Zn) and applied fertilizer (NET_FERT Zn, estimated based on adsorption/desorption characteristics and applied Zn) were related to the actual grain Zn concentration and uptake of teff, wheat, and maize. Zinc fertilizer treatments tested were Zn applied at planting (basal), basal plus side dressing and a control with no Zn applied.ResultsZn treatments had a significant effect on grain Zn concentration (increase by up to 10%) but the effect on grain yield was variable. Differences in crop Zn concentrations along the landscape positions were observed but not at all sites and crops. Trial results showed that soils with higher soil pH and Soil Organic Carbon (SOC) (typical of footslope landscape positions) tended to adsorb more applied Zn (reduce NET_FERT Zn) than soils with lower soil pH and SOC (typical of upslope landscape positions). Zn availability indicators (M3, NET_FERT Zn, clay%) explained 14-52% of the observed variation in grain Zn concentrations, whereas macronutrient indicators (Total N, exchangeable K) together with M3 Zn were better in predicting grain Zn uptake (16 to 32% explained variability). Maize had the lowest grain Zn concentrations but the highest grain Zn uptake due to high yields.ConclusionWe found that the sum of indigenous and fertilizer Zn significantly affects grain Zn loadings of cereals and that the associated soil parameters differ between and within landscape positions. Therefore, knowledge of soil properties and crop characteristics helps to understand where agronomic biofortification can be effective