Code status communication training in postgraduate oncology programs: a needs assessment.

Background: Discussions with patients with cancer about cardiopulmonary resuscitation directives (code status) are often led by residents. This study was carried out in Canada to identify current educational practices and gaps in training for this communication skill. Methods: Canadian medical and radiation oncology residents and program directors (pds) were surveyed about teaching practices, satisfaction with current education, and barriers to teaching code status discussion skills. Relative frequencies of categorical and ordinal responses were calculated. Results: Between November 2016 and February 2017, 95 (58.6%) of 162 residents and 17 (63%) of 27 pds completed surveys. Only 54.1% and 48.3% of medical and radiation oncology residents, respectively, had received any code status communication training before entering an oncology program. While 41% of residents expected to receive formal teaching on this topic during residency, 47.1% of pds endorsed inclusion of this topic in curricula. Only 20% of residents reported receiving formal evaluation of this skill while 41.2% of pds indicated that evaluations are provided. The importance of this communication skill in oncology was strongly supported. Among residents, 88% desired more training, and 82.3% of pds identified the need for new educational resources. Lack of time, resources, and evaluation tools were among the most commonly identified barriers to teaching. Conclusions: Oncology residency pds and trainees feel that code status communication is important, but teaching and evaluation of this skill are limited. Barriers to teaching and skill-building have been identified. Further work is underway to develop novel educational resources for code status communication training.

Thyroid hormone receptor beta-1 expression in early breast cancer: a validation study.

PURPOSE: Preliminary data suggest that high expression of the TRß1 tumor suppressor is associated with longer survival among women with early breast cancer. We undertook this study to validate these findings. METHODS: In this prospective cohort study, we analyzed the prognostic significance of TRß1 protein expression in the breast tumors of 796 women who had undergone breast surgery in the Henrietta Banting Breast Cancer database. All women were recruited after undergoing primary surgical therapy at Women's College Hospital (Toronto, ON, Canada) between January 1987 and December 2000. Details regarding patient age at diagnosis, systemic, and local therapies, as well as pathological features of their tumor have been systematically recorded. Clinical outcomes including breast cancer recurrence and death have been updated at least once each year with a median follow-up of 9.6 years (range 0.1-21 years). RESULTS: High TRß1 expression (> 4 on the Allred score) was associated with a longer breast cancer-specific survival with a HR 0.45 (95% CI 0.33-0.61), p < 0.0001 in a univariable Cox regression model. This was maintained in a multivariable model adjusted for age, tumor size, nodal status, chemotherapy, hormone therapy, radiotherapy, surgery, and ER status with a HR of 0.61 (95% CI 0.44-0.85), p = 0.004. CONCLUSIONS: High expression of TRß1 is associated with longer breast cancer-specific survival independent of other prognostic factors. Given that low TRß expression is associated with chemotherapy resistance in-vitro, TRß1 may also serve as a predictive biomarker or even a therapeutic target given the availability of TRß agonists.

A randomized phase II study of weekly paclitaxel with or without pelareorep in patients with metastatic breast cancer: final analysis of Canadian Cancer Trials Group IND.213.

BACKGROUND: Pelareorep, a serotype 3 reovirus, has demonstrated preclinical and early clinical activity in breast cancer and synergistic cytotoxic activity with microtubule targeting agents. This multicentre, randomized, phase II trial was undertaken to evaluate the efficacy and safety of adding pelareorep to paclitaxel for patients with metastatic breast cancer (mBC). METHODS: Following a safety run-in of 7 patients, 74 women with previously treated mBC were randomized either to paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 every 4 weeks plus pelareorep 3 × 1010 TCID50 intravenously on days 1, 2, 8, 9, 15, and 16 every 4 weeks (Arm A) or to paclitaxel alone (Arm B). Primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate, overall survival (OS), circulating tumour cell counts, safety, and exploratory correlative analyses. All comparisons used a two-sided test at an alpha level of 20%. Survival analyses were adjusted for prior paclitaxel. RESULTS: Final analysis was performed after a median follow-up of 29.5 months. Pelareorep was well tolerated. Patients in Arm A had more favourable baseline prognostic variables. Median adjusted PFS (Arm A vs B) was 3.78 mo vs 3.38 mo (HR 1.04, 80% CI 0.76-1.43, P = 0.87). There was no difference in response rate between arms (P = 0.87). Median OS (Arm A vs B) was 17.4 mo vs 10.4 mo (HR 0.65, 80% CI 0.46-0.91, P = 0.1). CONCLUSIONS: This first, phase II, randomized study of pelareorep and paclitaxel in previously treated mBC did not show a difference in PFS (the primary endpoint) or RR. However, there was a significantly longer OS for the combination. Further exploration of this regimen in mBC may be of interest.

(18)F-fluorodeoxyglucose positron-emission tomography-computed tomography to diagnose recurrent cancer.

BACKGROUND: Sometimes the diagnosis of recurrent cancer in patients with a previous malignancy can be challenging. This prospective cohort study assessed the clinical utility of (18)F-fluorodeoxyglucose positron-emission tomography-computed tomography ((18)F-FDG PET-CT) in the diagnosis of clinically suspected recurrence of cancer. METHODS: Patients were eligible if cancer recurrence (non-small-cell lung (NSCL), breast, head and neck, ovarian, oesophageal, Hodgkin's or non-Hodgkin's lymphoma) was suspected clinically, and if conventional imaging was non-diagnostic. Clinicians were asked to indicate their management plan before and after (18)F-FDG PET-CT scanning. The primary outcome was change in planned management after (18)F-FDG PET-CT. RESULTS: Between April 2009 and June 2011, 101 patients (age, median 65 years; 55% female) were enroled from four cancer centres in Ontario, Canada. Distribution by primary tumour type was: NSCL (55%), breast (19%), ovarian (10%), oesophageal (6%), lymphoma (6%), and head and neck (4%). Of the 99 subjects who underwent (18)F-FDG PET-CT, planned management changed after (18)F-FDG PET-CT in 52 subjects (53%, 95% confidence interval (CI), 42-63%); a major change in plan from no treatment to treatment was observed in 38 subjects (38%, 95% CI, 29-49%), and was typically associated with (18)F-FDG PET-CT findings that were positive for recurrent cancer (37 subjects). After 3 months, the stated post-(18)F-FDG PET-CT management plan was actually completed in 88 subjects (89%, 95% CI, 81-94%). CONCLUSION: In patients with suspected cancer recurrence and conventional imaging that is non-diagnostic, (18)F-FDG PET-CT often provides new information that leads to important changes in patient management.

Calibration and algorithm development for estimation of nitrogen in wheat crop using tractor mounted N-sensor.

The experiment was planned to investigate the tractor mounted N-sensor (Make Yara International) to predict nitrogen (N) for wheat crop under different nitrogen levels. It was observed that, for tractor mounted N-sensor, spectrometers can scan about 32% of total area of crop under consideration. An algorithm was developed using a linear relationship between sensor sufficiency index (SIsensor) and SISPAD to calculate the N app as a function of SISPAD. There was a strong correlation among sensor attributes (sensor value, sensor biomass, and sensor NDVI) and different N-levels. It was concluded that tillering stage is most prominent stage to predict crop yield as compared to the other stages by using sensor attributes. The algorithms developed for tillering and booting stages are useful for the prediction of N-application rates for wheat crop. N-application rates predicted by algorithm developed and sensor value were almost the same for plots with different levels of N applied.

Vitamin B6 deficiency and galactose induced alterations in morphology and osmotic fragility of rat erythrocytes.

Recently, red blood cells have been investigated mainly for alterations in ion transporting capacity, membrane bound enzymes or modifications in the structure of its individual constituents in clinical and experimental urolithiasis. However, the implication of such modifications on the physical state or morphology of cells has not been investigated. Scanning electron microscopic studies performed in vitamin B6 deficient and/or galactose fed rat (established hyperoxaluric models) erythrocytes, showed the presence of large number of stomatocytes, spherocytes and other variously deformed cells as compared to discocytic cells seen in normal control group. These changes in shape were in concurrence with red cell osmotic fragility, which decreased both in vitamin B6 deficient and vitamin B6 deficient + galactose fed group (19 % and 33 % hemolysis at 4 g/l NaCl, respectively) while it increased in galactose control group (73 % hemolysis at 4 g/l NaCl) as compared to normal control group (55 % hemolysis at 4 g/l NaCl). These morphological and physical state alterations could be correlated with red blood cells' membrane cholesterol and phospholipid sub-class distribution. These findings suggest that some structural membrane changes occur due to vitamin B6 deficiency and/or galactose feeding, which may be responsible for the altered membrane functions known to be associated with pathogenesis of urolithiasis.

Calcium and oxalate uptake by the renal brush border membrane vesicles in magnesium-deficient rats.

Calcium and oxalate uptake by renal brush border membrane vesicles (BBMV) was examined in magnesium-deficient and pair-fed control rats. Uptake studies were carried out by rapid filtration technique and rate of influx of calcium and oxalate as a function of extravesicular concentration (0.1 nM--1.0 mM) examined. Calcium uptake by renal BBMV exhibited saturable kinetics while oxalate uptake followed a biphasic transport mechanism showing saturable kinetics at low oxalate concentrations and passive diffusion at higher concentrations. In magnesium deficiency the kinetics of calcium and oxalate uptake by renal BBMV remained unaltered but the rate of uptake was significantly enhanced at all the extravesicular concentrations studied. Double reciprocal plot for calcium uptake showed no change in Vmax but a decrease in Km (2.08 mM) in magnesium--deficient rats as compared to pair-fed controls (Km = 5.00 mM). Similar plot for oxalate uptake showed an increase in Vmax (7.69 nmoles/8 min/mg protein) in magnesium deficient group as compared to pair-fed controls (5.55 nmoles/8 min/mg protein), while Km remained unchanged. The results of the present study indicate high risk of calcium oxalate stone formation in magnesium--deficient rats due to hyperabsorption and retention of calcium and oxalate by the renal tubular brush border membrane.

Effect of Tribulus terrestris on oxalate metabolism in rats.

This study concerns the effect of an aqueous extract of Tribulus terrestris on the metabolism of oxalate in male rats fed sodium glycolate. Glycolate feeding resulted in hyperoxaluria as well as increased activities of oxalate synthesizing enzymes of the liver i.e. glycolate oxidase (GAO), glycolate dehydrogenase (GAD) and lactate dehydrogenase (LDH), and decreased kidney LDH activity. T. terrestris administration to sodium glycolate fed rats produced a significant decrease in urinary oxalate excretion, and a significant increase in urinary glyoxylate excretion, as compared to sodium glycolate fed animals. The supplementation of T. terrestris with sodium glycolate also caused a reduction in liver GAO and GAD activities, whereas liver LDH activity remained unaltered. The isoenzyme pattern of kidney LDH revealed that normalization of kidney LDH by T. terrestris feeding was mainly due to an increase in the LDH 5 fraction. The LDH 1 isoenzyme remained unchanged in all the groups.

Study of urinary calcium excretion after oral calcium load in stone formers, their spouses and first-degree blood relatives.

Hypercalciuria has long been considered a common abnormality in stone formers, and familial predisposition to renal stone formation has also been reported. Renal stone formers, their spouses and first-degree blood relatives (the latter two groups of subjects had no previous or present history of stone disease) were investigated for their response to an oral load of 2 g calcium (as di-calcium phosphate). Serum calcium, phosphorus, uric acid, creatinine and urea were within the normal range in all the subjects initially as well as 4 h after the load. After the oral calcium load, 66.6% of the stone formers, 25% of the first-degree relatives and none of the spouses were hypercalciuric. Administration of 2 g calcium produced a significantly greater urinary excretion of calcium in stone formers (123.8 +/- 43 mg/8 h, p < 0.001) and their first-degree blood relatives (89.8 +/- 26 mg/8 h, p < 0.01) as compared to the spouses of stone formers (65.5 +/- 12.8 mg/8 h). A significant increase in urinary calcium excretion after calcium loading was also found among the stone formers (p < 0.01) as compared to their first-degree blood relatives. A significantly higher mean rise in calcium excretion (over the basal excretion) in calcium stone formers (p < 0.001) and their first-degree blood relatives (p < 0.01), as compared to the spouses of stone formers suggests a greater predisposition to renal stone disease in first-degree blood relatives than the spouses of the stone patients.

Effect of combined supplementation of magnesium oxide and pyridoxine in calcium-oxalate stone formers.

A combined supplement of magnesium oxide (300 mg/day) and pyridoxine.HCl (10 mg/day) was given p.o. to 16 recurrent calcium oxalate (CaOx) stone formers, and its therapeutic efficacy was biochemically evaluated by measuring various parameters of blood (Na, K, Mg, urea, creatinine, calcium, phosphate, uric acid, alanine transaminase, aspartate transaminase and alkaline phosphatase) and urine (volume, pH, creatinine, Na, K, Mg, uric acid, calcium, phosphate, oxalate and citrate) at 0, 30, 60, 90 and 120 days of treatment. Serum Mg significantly (P < 0.01) increased after 30 days of treatment and remained constant thereafter while other blood parameters were unaltered. Combined treatment led to a significant increase in the urinary excretion of Mg and citrate over pretreatment values while oxalate excretion showed a gradual and significant decline during the therapy. The results confirmed the efficacy of MgO-pyridoxine supplementation in terms of changes in urinary excretion of lithogenic and inhibitory components, leading to a significant (P < 0.01) decrease in CaOx risk index from 0.09 +/- 0.04 at 0 day to 0.05 +/- 0.02 after 120 days of treatment.

A comparative study of erythrocyte oxalate flux rate and urinary oxalate excretion in hyperoxaluric rats.

The present study was carried out to investigate the relation between erythrocyte oxalate flux rate and the pathogenesis of calcium oxalate renal stone disease having hyperoxaluria as the main risk factor. Male albino rats were made hyperoxaluric by feeding them diets viz. vitamin B6 deficient, vitamin B6 deficient + 51.7% galactose or fructose (serving as a sole source of carbohydrate), along with their respective pair-fed controls for 4 weeks. After 28 days of feeding, oxalate excretion was in the order of vitamin B6 deficient + galactose > galactose control > vitamin B6 deficient + fructose > vitamin B6 deficient > fructose control/vitamin B6 control. Whereas, transmembrane oxalate flux rate was in the order of vitamin B6 deficient > vitamin B6 deficient + galactose > vitamin B6 deficient + fructose > vitamin B6 control > galactose control > fructose control. No significant correlation (r = 0.304) was found between the urinary oxalate excretion and erythrocyte oxalate flux rates of various groups of rats. The study indicates that increase in oxalate excretion does not concomitantly increase the transmembrane oxalate flux in red blood cells.

Oxalate metabolism in magnesium-deficient rats.

Male weanling rats were maintained on magnesium-deficient diet for 30 d and compared with pair-fed control rats fed magnesium-supplemented diet. Magnesium deficiency led to slow growth and finally to a significant decrease in body weight (P < 0.001) accompanied by a significant hypomagnesaemia, hypomagnesuria and hyperoxaluria (P < 0.001 in each case) in experimental rats as compared to the control rats. Magnesium deficiency altered the glyoxylate metabolism in the liver and kidney mitochondria by significantly decreasing glyoxylate oxidation (by 26 per cent in liver and 17 per cent in kidney) and activity of alpha-ketoglutarate:glyoxylate carboligase enzyme (by 35 per cent in liver and 27 per cent in kidney) in the experimental animals. A significant increase in the specific activities of glycolic acid oxidase (P < 0.001) and glycolic acid dehydrogenase (P < 0.01) and a significant decrease in alanine transaminase (P < 0.01) was also observed in magnesium-deficient rats. No change in liver and kidney lactate dehydrogenase was observed. Thus magnesium deficiency in rats leads to accumulation of glyoxylate in the tissues, a part of which is converted into oxalate, thereby promoting hyperoxaluria.

Intestinal absorption of calcium and oxalate in magnesium-deficient rats.

To examine the contribution of exogenous calcium and oxalate in magnesium deficiency, intestinal absorption of both calcium and oxalate was studied by preparing brush border membrane vesicles (BBMV). Purity of the BBMV was ascertained biochemically by enrichment of the marker enzyme alkaline phosphatase by 14-fold with a concomitant 90 per cent decrease in the basolateral marker enzyme Na+/K(+)-ATPase in the purified membrane preparation as compared to the respective homogenate in both the groups. Uptake studies were carried out by a rapid filtration technique. The kinetics were studied by measuring the rate of influx as a function of concentration (0.1-1.0 mM). BBMV from both the groups showed a linear positive relationship between the uptake rate and the concentration for both calcium and oxalate, thereby demonstrating that calcium and oxalate are transported through intestinal microvillus membrane by a simple passive diffusion process. However, the rate of uptake of calcium and oxalate was significantly higher in the magnesium-deficient group as compared to the pair-fed control group, as shown by the increase in the slope line for both calcium and oxalate (for calcium, control = 3.88, deficient = 5.86; for oxalate, control = 4.41, deficient = 7.20). Analysis of the lipid composition of the BBM revealed a significant decrease in the cholesterol content (P < 0.01) with a concomitant increase in the triglycerides (P < 0.01) and total fatty acid content (P < 0.001) in the magnesium-deficient group. Thus the results indicate that, although the mechanism of translocation of calcium and oxalate in the intestine is similar in the two groups, magnesium deficiency leads to hyperabsorption of both the ligands through alterations in the lipid composition of the membrane, thereby increasing the risk of stone formation.

Recent advances in measurement of oxalate in biological materials.

Hyperoxaluria is the predominant risk factor in urinary stone disease. A specific, accurate and reliable oxalate assay for urine and plasma is very important for both the diagnosis and efficient management of patients. A review of the advantages and disadvantages of various methods of oxalate determination is presented and is followed by the authors' recommendations.

Urinary excretion of inorganic pyrophosphate by normal subjects and patients with renal calculi in north-western India and the effect of diclofenac sodium upon urinary excretion of pyrophosphate in stone formers.

24 h urinary pyrophosphate excretion was studied in 20 normal healthy subjects and 75 idiopathic stone formers from north-western regions of India. The mean 24-hour urinary excretion of pyrophosphate was significantly low in stone formers (50.67 +/- 2.16 mumol/24 h) as compared to that of normal subjects (71.46 +/- 5.46 mumol/24 h) (p less than 0.01). Diclofenac sodium, a non-steroidal anti-inflammatory agent, was administered 50 mg thrice daily for 1 week to 18 stone formers and 24-hour urinary pyrophosphate excretion was studied before and after drug therapy. The 24-hour urinary excretion of pyrophosphate increased from 54.32 +/- 21.40 to 78.31 +/- 28.03 mumol subsequent to diclofenac sodium therapy (p less than 0.01).

The effect of diclofenac sodium on urinary concentration of calcium, uric acid and glycosaminoglycans in traumatic paraplegics.

Non-steroidal anti-inflammatory drugs (NSAID) have been shown to decrease calcium excretion in the experimental animal, in human volunteers and in calcium stone formers. Paraplegics tend to be hypercalciuric during the first 2 years after their injury and this is said to be a predisposing factor for stone formation in these patients. The effect of the NSAID diclofenac sodium was studied in 12 traumatic paraplegics who had sustained their injury 1 to 6 months previously; 24-h urine samples collected before and 2 weeks and 4 weeks after oral diclofenac sodium 50 mg tds were analysed for calcium, uric acid, glycosaminoglycans (GAGs) and volume. There were no significant changes in urinary volume, uric acid and GAGs excretion. However, urinary calcium concentration and 24-h calcium excretion decreased significantly following 2 weeks' and 4 weeks' treatment with diclofenac sodium.

Oxalate binding to rat intestinal brush-border membrane in pyridoxine deficiency: a kinetic study.

Oxalate bound specifically to the intestinal brush-border membrane (BBM) of pyridoxine-deficient rats, but not to BBM of control rats. The binding of oxalate to intestinal BBM of pyridoxine-deficient rats was rapid, reversible, dependent on concentration of oxalate, temperature sensitive and competitively inhibited by oxalate analogues. Kinetic analysis of the oxalate binding data revealed induction of two distinct classes of receptor site for oxalate. The high-affinity oxalate binding sites, reached saturation at 60-70 nM oxalate, had a Kd of 24.29 nM and the number of binding sites were 30 pmoles (i.e., 1.8.10(13) molecules). The low-affinity oxalate binding sites, could not be saturated under experimental conditions upto 1 microM oxalate. It had a Kd of 487.5 nM and the number of binding sites were 156 pmoles (i.e., 9.4.10(13) molecules). The apparent energy of activation was 19 kcal/mol. The half-saturation concentration of inhibitor (IC50) of oxalate was 0.4.10(-5) M, while all other structural analogues of oxalate had higher IC50 values. Among the competitive inhibitors tested IC50 was in the following order, pyruvate greater than maleate greater than oxaloacetate greater than glyoxylate greater than parabonate greater than oxalate. These kinetic characteristics indicate involvement of a membrane protein in oxalate binding and transport in rat intestinal brush-border membrane in pyridoxine deficiency.

Chronobiology of urinary citrate excretion amongst stone-formers and healthy males from north western India.

Urinary citrate excretion was estimated colorimetrically from urine samples collected every 3 h for 24 h from 25 healthy adult males (non-stone formers; mean age 39 +/- 7 years) and 25 male patients suffering from calcium nephrolithiasis (stone formers; mean age 41 +/- 6 years). The 24 h citrate excretion was 2.47 +/- 0.65 mmol in non-stone formers and 2.02 +/- 0.71 mmol in stone formers. This difference was not significant. However, cosinor rhythmometry revealed a significant circadian rhythmicity in urinary citrate excretion in the healthy males which was absent in the stone formers; the amplitude was 0.06 mmol in non-stone formers and 0.017 mmol in stone formers. The acrophase was located at 14:25 h in non-stone formers and at 23:30 h in stone formers.

Effect of vitamin A deficiency on oxalate uptake by rat intestinal brush border membrane vesicles (BBMV) and its contribution towards urolithiasis.

The intestinal uptake of [14C]oxalate, [14C]glyoxylate, and [14C]glycolate are studied in brush border membrane vesicles (BBMV) isolated from vitamin A-deficient and pair-fed control rats. The data obtained indicate that oxalate and its precursors are transported across the BBMV by passive diffusion. The intestinal uptake of glyoxylate and glycolate remains unaltered in vitamin A deficiency, while uptake rate of oxalate was significantly increased (p less than 0.01) in vitamin A-deficient rats as compared to pair-fed controls. In conclusion, the results indicate that vitamin A deficiency leads to hyperabsorption of oxalate through the gut.