Prostate-specific Antigen Bounce After Stereotactic Body Radiotherapy for Prostate Cancer: A Pooled Analysis of Four Prospective Trials.

AIMS: We conducted a pooled analysis of four prospective stereotactic body radiotherapy (SBRT) trials of low- and intermediate-risk prostate cancer to evaluate the incidence of prostate-specific antigen (PSA) bounce and its correlation with the time-dose-fraction schedule. The correlation between bounce with PSA response at 4 years (nadir PSA < 0.4 ng/ml) and biochemical failure-free survival (BFFS) was also explored. MATERIALS AND METHODS: The study included four treatment groups: 35 Gy/five fractions once per week (QW) (TG-1; n = 84); 40 Gy/five fractions QW (TG-2; n = 100); 40 Gy/five fractions every other day (TG-3; n = 73); and 26 Gy/two fractions QW (TG-4; n = 30). PSA bounce was defined as a rise in PSA by 0.2 ng/ml (nadir + 0.2) or 2 ng/ml (nadir + 2.0) above nadir followed by a decrease back to nadir. Patients with fewer than three follow-up PSA tests were excluded from the pooled analysis. RESULTS: In total, 287 patients were included, with a median follow-up of 5.0 years. The pooled 5-year cumulative incidence of bounce by nadir + 2.0 was 8%. The 2-year cumulative incidences of PSA bounce by nadir + 0.2 were 28.9, 21, 19.6 and 16.7% (P = 0.12) and by nadir + 2.0 were 7.2, 8, 2.7 and 6.7% (P = 0.32) for TG-1 to TG-4, respectively. Multivariable analysis revealed that for nadir + 2.0, pre-treatment PSA (odds ratio 0.49; 95% confidence interval 0.26-0.97) correlated with PSA bounce. Although PSA bounce by nadir + 0.2 (odds ratio 0.10; 95% confidence interval 0.04-0.24) and nadir + 2.0 (odds ratio 0.29; 95% confidence interval 0.09-0.93) was associated with a lower probability of PSA response at 4 years, there was no association between bounce by nadir + 0.2 (hazard ratio 0.36; 95% confidence interval 0.08-1.74) or nadir + 2 (hazard ratio 1.77; 95% confidence interval 0.28-11.07) with BFFS. CONCLUSION: The incidence of PSA bounce was independent of time-dose-fraction schedule for prostate SBRT. One in 13 patients experienced a bounce high enough to be misinterpreted as biochemical failure, and clinicians should avoid early salvage interventions in these patients. There was no association between PSA bounce and BFFS.

Low bone mineral density and fractures in stages 3-5 CKD: an updated systematic review and meta-analysis.

SUMMARY: The utility of bone mineral density (BMD) testing in chronic kidney disease (CKD) is not known. We performed a meta-analysis of studies reporting on BMD and fracture in CKD. All but one study was cross-sectional. BMD was lower in those with CKD and fractures compared to those without fractures. INTRODUCTION: CKD is associated with an increased risk of fracture. The utility of dual energy X-ray absorptiometry (DXA) to assess fracture risk in CKD is unknown. METHODS: We performed an updated meta-analysis and systematic review of published studies that reported on the association between DXA and fracture (morphometric spine or clinical nonspine) in predialysis and dialysis CKD. We identified 2,894 potential publications, retrieved 292 for detailed review, and included 13. All but one study was cross-sectional and three reported on the ability of DXA to discriminate fracture status in predialysis CKD. Results were pooled using a random effects model and statistical heterogeneity was assessed using the I2 statistic. RESULTS: BMD was statistically significantly lower at the femoral neck, lumbar spine, the 1/3 and ultradistal radius in subjects with fractures compared to those without regardless of dialysis status. For example, femoral neck BMD was 0.06 g/cm2 lower in dialysis subjects and 0.102 g/cm2 lower in predialysis subjects with fractures compared to those without. Lumbar spine BMD was 0.05 g/cm2 lower in dialysis subjects and 0.108 g/cm2 lower in predialysis subjects with fractures compared to those without. Our meta-analysis was limited to studies with small numbers of subjects and even smaller numbers of fractures. All of the studies were observational and only one was prospective. There was statistical heterogeneity at the lumbar spine, 1/3 and ultradistal radius. CONCLUSIONS: Our findings suggest that BMD can discriminate fracture status in predialysis and dialysis CKD. Larger, prospective studies are needed.

Evaluation of daily online set-up errors and organ displacement uncertainty during conformal radiation treatment of the prostate.

We have studied and analysed the magnitude of interfraction set-up errors and gold seed marker and prostate displacement in 118 patients using three gold seeds implanted within the prostate. Set-up errors and gold seed marker displacements were determined from bony anatomy and gold seed marker mismatch between the electronic portal image and the simulation digitally reconstructed radiograph (DRR), respectively. Prostate displacement relative to bony anatomy was determined from the difference between gold seed marker and bony anatomy displacement. Daily online repositioning of patients was accomplished through image matching using Varian Portal-Vision software. A total of 4878 electronic portal images and 236 DRRs from 118 patients were acquired over the course of the study. The means and standard deviations of the systematic error of gold seed marker displacement of 118 patients were 2.1+/-2.7 mm for anteroposterior (AP), -0.5+/-1.7 mm for left-right (L-R), and 1.0+/-1.9 mm for superoinferior (SI) directions; the random errors were 3.2 mm (0.9-4.9 mm) for AP, 1.9 mm (0.7-5.3 mm) for L-R, and 2.1 mm (0.7-4.5 mm) for SI directions. The mean and standard deviation of the isocentre set-up systematic error of 20 patients was 1.2+/-2.2 mm for AP, -0.1+/-1.4 mm for L-R, and -0.8+/-2.6 mm for SI directions. The isocentre set-up random errors were 1.6 mm (1.2-4.8 mm) for AP, 1.3 mm (0.6-2.5 mm) for L-R and 1.3 mm (1.0-2.6 mm) for SI directions. The mean and standard deviation of the prostate displacement systematic error relative to bony anatomy was 0.0+/-1.4 mm for AP, 0.0+/-1.1 mm for L-R and -0.2+/-2.4 mm for SI directions. Prostate displacement random errors were 1.5 mm (1.2-3.3 mm) for AP, 0.9 mm (0.4-1.5 mm) for L-R and 1.4 mm (1.2-2.4 mm) for SI directions.

Virological and serological diagnosis of cytomegalovirus infection in bone marrow allograft recipients.

To detect cytomegalovirus (CMV) infections, a total of 1,074 cultures of urine, saliva, or blood were collected weekly from 43 consecutive patients undergoing allogeneic bone marrow transplantation. Twenty-three patients were seronegative before transplant and primary infection occurred in 2 (9%). Twenty patients were initially seropositive and recurrent infections occurred in 5 (25%). Three patients in the recurrent group had proven CMV pneumonitis; viraemia was detected in two recipients, while the third had CMV isolated only from bronchial lavage fluid. The serological response of the 43 patients was defined by testing 559 serial sera for specific IgG and IgM antibodies by radioimmunoassay. Passive acquisition of IgG antibodies from blood products was found in 78% of initially seronegative recipients. One patient with primary infection responded in a pattern typical of immunocompetent individuals with long-term production of specific IgG and transient production of specific IgM antibodies. The second patient also had a typical response, but this was delayed until several weeks after the start of virus excretion. In patients with recurrent infections, specific IgM production did not correlate with episodes of virus excretion. Three of five such patients failed to mount a specific IgM response, and these were the only patients in the study to develop CMV pneumonitis. We conclude that CMV infection in bone marrow recipients can only be diagnosed by detection of virus; therefore, the ability of these patients to mount humoral immune responses should not be relied upon for diagnostic purposes.

Rapid diagnosis of cytomegalovirus infection in immunocompromised patients by detection of early antigen fluorescent foci.

Cell-cultures of cytomegalovirus (CMV) were fixed after 24 hours' incubation and examined by a monoclonal antibody based immunofluorescence method for the detection of CMV-specific early antigens. 385 urine, saliva, or blood samples from 63 immunocompromised patients were inoculated onto cell-cultures. Comparison with the results of conventional cell-cultures in patients who remained uninfected showed that the new technique had a specificity of 100%. The sensitivity was 80%. This immunofluorescence method gave positive results 27h after inoculation of the specimens instead of the mean of 17 X 5 days with the conventional method based on detection of cytopathic effect. 3 saliva samples, from patients who had previously excreted CMV, reacted in the immunofluorescence method but CMV, reacted in the cell-cultures-perhaps because the assay identified defective, interfering particles in these samples. The monoclonal antibodies were also used successfully in another immunofluorescence system to diagnose cytomegalovirus pneumonitis in 3 patients by testing material obtained by bronchoalveolar lavage.

Depletion of T lymphocytes in donor marrow prevents significant graft-versus-host disease in matched allogeneic leukaemic marrow transplant recipients.

For more than 15 years preclinical studies have suggested that acute graft-versus-host disease (aGvHD) might be prevented by the removal of immunocompetent T lymphocytes from the donor marrow inoculum. To test this observation in man 14 patients were given marrows virtually (greater than 99%) depleted of identifiable donor marrow T lymphocytes by the use of a "cocktail" of specific anti-T-cell monoclonal antibodies (MBG6 and RFT8) and rabbit complement. Patients were not given immunosuppressive prophylaxis after bone-marrow transplantation. Moderate to severe (grades II-IV) GvHD was totally prevented. 2 of 13 evaluable patients showed mild (grade I) skin GvHD only. Although peripheral blood recovery was slower than that obtained with other forms of GvHD prophylaxis, no fatal infections occurred. All patients survived the early post-transplant period.

Electrophysiologic abnormalities of heart in iron deficiency anemia. Effect of iron therapy.

55 patients with iron deficiency anemia (IDA) and 55 age- and sex-matched control subjects were given exercise test on a treadmill to observe the effect on ST segment of the electrocardiogram. 14 IDA patients showed significant ST segment depression compared to only 1 in the control group, the difference being highly significant (p less than 0.001). Test was repeated 2-3 days later in 12 IDA cases and it showed significant ST depression as on previous occasions showing the reproducibility of the results. 11 of these patients received total dose i.v. iron-dextran and the exercise test was repeated 2-3 days later before any significant rise in the hemoglobin level; in 10 cases there was no significant ST segment depression. Response to iron therapy was highly significant (p less than 0.003). Correction of electrophysiological abnormalities of the heart in IDA patients by iron therapy, before the rise of hemoglobin, may be the result of the effect of iron at the tissue level.

Cross-cultural study of a biochemical abnormality in paranoid schizophrenia.

We studied 24-hour urinary excretion of phenylethylamine (PEA) and creatinine in 50 schizophrenic (39 paranoid and 11 nonparanoid) and 19 nonpsychiatric patients from Bombay, India. Methods for diagnosis, clinical assessment, and 24-hour urine collection were identical to those used in an earlier study done in a Washington, D.C. hospital. Clinical evaluations were done in Bombay, while urinary PEA and creatinine estimations were performed at NIMH, Washington, without knowledge of the subjects' identify. Paranoid schizophrenic patients had significantly greater 24-hour urinary excretion of PEA than both nonparanoid schizophrenic patients and nonpsychiatric controls. The mean amount of PEA per g creatinine in urine was also highest of paranoid schizophrenic patients. Our findings provide cross-cultural support to the possibility of abnormal PEA metabolism in at least some patients with paranoid schizophrenia.