Bone resorption measurement with unusual bone markers: Critical evaluation of the method in phosphorus-deficient and calcium-deficient growing rats

An in vivo method to evaluate bone resorption in rats, by using unusual bone seekers not dependent on renal tubular transfer, is described and a critical evaluation of the method is made. In our experimental conditions,⁸⁵Sr and¹⁷⁷Lu are virtually exclusively localized in bone whereas²³⁷Np remains unchanged in different soft organs, so that the concomitant use of these markers can be used for measuring bone resorption. If osteolysis occurs 21 days after the injection of these markers, under our experimental conditions, any increase in the urinary excretion of¹⁷⁷Lu and²³⁷Np represents a rise in bone resorption, whereas an increase in Sr excretion reflects both bone and renal tubular events. According to our bone localization studies, the enhancement of Lu and Np excretion reflects primarily an increase in cortical bone resorption localized at the endosteal (Lu) and at the periosteal (Np) surfaces respectively. In addition, strontium is considered to be the marker of mineral resorption whereas Lu and Np, under our experimental conditions, would reflect the organic bone resorption. This method is tested in phosphorus-deficient rats and in calcium-deficient rats which exhibit disturbances of calcium metabolism at both the bone and kidney levels. In agreement with previous investigations, the use of these bone markers to evaluate osteolysis shows: (a) after a 1-week phosphorus deficiency, a slight increase in cortical bone resorption with a simultaneous fall in calcium and strontium renal tubular reabsorption, and (b) after a 1-week calcium deficiency, a high rise in cortical bone resorption with a simultaneous increase in the renal tubular reabsorption of calcium and strontium.     

A Randomized,Double-Blind,Dose-Finding,Multicenter, Phase 2 Study of Radium Chloride (Ra 223) in Patients with Bone Metastases and Castration-Resistant Prostate Cancer

Background

Patients with castration-resistant prostate cancer (CRPC) and bone metastases have an unmet clinical need for effective treatments that improve quality of life and survival with a favorable safety profile.

Objective

To prospectively evaluate the efficacy and safety of three different doses of radium chloride (Ra 223) in patients with CRPC and bone metastases.

Design, setting, and participants

In this phase 2 double-blind multicenter study, 122 patients were randomized to receive three injections of Ra 223 at 6-wk intervals, at doses of 25 kBq/kg (n = 41), 50 kBq/kg (n = 39), or 80 kBq/kg (n = 42). The study compared the proportion of patients in each dose group who had a confirmed decrease of ≥50% in baseline prostate-specific antigen (PSA) levels.

Outcome measurements and statistical analysis

Efficacy was evaluated using blood samples to measure PSA and other tumor markers, recorded skeletal-related events, and pain assessments. Safety was evaluated using adverse events (AEs), physical examination, and clinical laboratory tests. The Jonckheere-Terpstra test assessed trends between groups.

Results and limitations

The study met its primary end point with a statistically significant dose–response relationship in confirmed ≥50% PSA declines for no patients (0%) in the 25-kBq/kg dose group, two patients (6%) in the 50-kBq/kg dose group, and five patients (13%) in the 80-kBq/kg dose group (p = 0.0297). A ≥50% decrease in bone alkaline phosphatase levels was identified in six patients (16%), 24 patients (67%), and 25 patients (66%) in the 25-, 50-, and 80-kBq/kg dose groups, respectively (p < 0.0001). The most common treatment-related AEs (≥10%) occurring up to week 24 across all dose groups were diarrhea (21%), nausea (16%), and anemia (14%). No difference in incidence of hematologic events was seen among dose groups. Potential limitations include small patient numbers and differences among dose groups at baseline.

Conclusions

Ra 223 had a dose-dependent effect on serum markers of CRPC activity, suggesting that control of bone disease with Ra 223 may affect cancer-related outcomes. Ra 223 was well tolerated at all doses.

Trial registration

ClinicalTrials.gov: NCT00337155.     

New and Emerging Therapies for Bone Metastases in Genitourinary Cancers

Context

Bone metastases are a common feature of advanced genitourinary malignancies and a prominent cause of morbidity and mortality.

Objective

The objective of this review is to discuss the incidence, pathophysiology, and management of bone metastases in the most prevalent genitourinary malignancies.

Evidence acquisition

We reviewed the relevant medical literature, with a particular emphasis on prospective randomized controlled trials. Much of the relevant clinical trial data focus on prostate cancer (PCa). We provide a nonsystematic review and our perspective on the available data.

Evidence synthesis

Clinical manifestations can include pain, hypercalcemia, pathologic fractures, and spinal cord compression. Optimal systemic therapy for skeletal metastases often features a combination of disease-specific therapy and bone-targeted therapy. Some agents, such as the radiopharmaceutical radium-223, blur the line between those categories. Osteoclast inhibition is a validated strategy in the management of selected patients with bone metastases. Zoledronic acid, a bisphosphonate, is approved for the prevention of skeletal events caused by solid tumors metastatic to bone. Denosumab is a fully human monoclonal antibody that inactivates receptor activator of nuclear factor-κB ligand and is approved for the same indication. Beta-emitting radiopharmaceuticals can be effective for the palliation of pain caused by bone metastases, but their use is often limited by marrow suppression. The alpha-emitting radiopharmaceutical radium-223 has recently been shown to improve overall survival and prevent skeletal events in select men with castration-resistant PCa metastatic to bone. Multiple ongoing clinical trials are designed to examine the potential for therapeutic inhibition of additional targets such as Src and hepatocyte growth factor (MET).

Conclusions

Bone metastases cause considerable morbidity and mortality among patients with genitourinary malignancies. Optimal management requires consideration of bone-targeted therapy as well as disease-specific therapy. Further research is needed to optimize the use of existing agents and to define the therapeutic potential of novel targets.     

Impact of Bone and Liver Metastases on Patients with Renal Cell Carcinoma Treated with Targeted Therapy

Background

The skeleton and liver are frequently involved sites of metastasis in patients with metastatic renal cell carcinoma (RCC).

Objective

To analyze outcomes based on the presence of bone metastases (BMs) and/or liver metastases (LMs) in patients with RCC treated with targeted therapy.

Design, setting, and participants

We conducted a review from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) of 2027 patients with metastatic RCC.

Outcome measurements and statistical analysis

We analyzed the impact of the site of metastasis on overall survival (OS) and time-to-treatment failure. Statistical analyses were performed using multivariable Cox regression.

Results and limitations

The presence of BMs was 34% overall, and when stratified by IMDC risk groups was 27%, 33%, and 43% in the favorable-, intermediate-, and poor-risk groups, respectively (p < 0.001). The presence of LMs was 19% overall and higher in the poor-risk patients (23%) compared with the favorable- or intermediate-risk groups (17%) (p = 0.003). When patients were classified into four groups based on the presence of BMs and/or LMs, the hazard ratio, adjusted for IMDC risk factors, was 1.4 (95% confidence interval [CI], 1.22–1.62) for BMs, 1.42 (95% CI, 1.17–1.73) for LMs, and 1.82 (95% CI, 1.47–2.26) for both BMs and LMs compared with other metastatic sites (p < 0.0001). The prediction model performance for OS was significantly improved when BMs and LMs were added to the IMDC prognostic model (likelihood ratio test p < 0.0001). Data in this analysis were collected retrospectively.

Conclusions

The presence of BMs and LMs in patients treated with targeted agents has a negative impact on survival. Patients with BMs and/or LMs may benefit from earlier inclusion on clinical trials of novel agents or combination-based therapies.     

Prognostic Significance of Bone Metastases and Bisphosphonate Therapy in Patients with Renal Cell Carcinoma

Background

Bone metastases (BMs) are frequently present in patients with metastatic renal cell carcinoma (mRCC) and cause significant morbidity.

Objective

The purpose of this analysis was to assess the impact of BMs and bisphosphonate therapy (BT) on outcomes in mRCC.

Design, setting, and participants

We conducted a pooled analysis of patients with mRCC treated from 2003 to 2011 in phase 2 and 3 trials.

Outcome measurements and statistical analysis

Statistical analyses were performed using Cox regression and the Kaplan-Meier method.

Results and limitations

We identified 2749 patients treated with sunitinib (n = 1059), sorafenib (n = 355), axitinib (n = 359), temsirolimus (n = 208), temsirolimus plus interferon-α (IFN-α) (n = 208), or IFN-α (n = 560), with 28% (n = 781) having BMs. A total of 285 patients (10.4%) received BT. The presence of BMs in patients was associated with shorter overall survival (OS) when compared with patients without BMs (13.2 vs 20.2 mo, respectively; p < 0.0001) and shorter progression-free survival (PFS) (5.1 vs 6.7 mo, respectively; p < 0.0008). When stratified by risk groups, the presence of BMs was associated with shorter OS in all risk groups. The use of BT in patients with BMs was not associated with improved OS compared with patients who did not receive BT (13.3 vs 13.1 mo, respectively; p = 0.3801) or improved PFS (5.1 vs 4.9 mo, respectively; p = 0.1785). Bisphosphonate users with BMs did not have a decreased rate of skeletal-related events (SREs) compared with nonusers (8.6% vs 5.8%, respectively; p = 0.191). In addition, BT was associated with increased rates of hypocalcemia, renal insufficiency, and osteonecrosis of the jaw (p < 0.0001). Data were analyzed retrospectively.

Conclusions

We confirm that the presence of BMs is associated with shorter survival in mRCC. BT did not affect survival or SRE prevention and was associated with increased toxicity.

Patient summary

In this analysis, we demonstrate that bone metastases are associated with shorter survival in patients with metastatic renal cell carcinoma. In addition, we call into question the utility of bisphosphonate therapy in this population.     

Measurement of Estrogen Effect on Bone Turnover by 2H2O Labeling

Estrogen loss has been known to increase bone turnover through accelerated bone resorption coupled by increased bone formation. In the present study, we measured estrogen effect on bone turnover by incorporation of ²H from ²H₂O into amino acids. At 6 weeks of age, rats were either sham-operated (sham) or ovariectomized (ovx). Two weeks after surgery, 17β-estradiol (est) was implanted subcutaneously to ovx rats. At 9 weeks of age, ²H₂O labeling started by administration of 4% ²H₂O to rats for 4 or 7 weeks in drinking water after a single intraperitonial bolus injection with 99.9% ²H₂O. Body ²H₂O enrichments were stable at approximately 3.0% over labeling period. Fractional replacements (f) of the midshaft femur were higher in the sham group (40.36 ± 4.89% vs 42.47 ± 11.22%) than the ovx (28.57 ± 9.67% vs 37.47 ± 8.34%) and est (26.57 ± 4.00% vs 30.35 ± 5.34%) groups 4 and 7 weeks after labeling, respectively. Ovariectomy-induced bone loss was observed in the trabecular bone along with a significantly increased number of osteoclasts, all of which were normalized after estradiol treatment. Taken together, our results indicate that estrogen deficiency significantly reduces the proportion of newly synthesized bone matrix as well as the total amount of bone matrix. The reduced portion of new matrix in ovx rats, presumably caused by activated osteoclastic degradation, was compensated rapidly with time. In addition, estradiol treatment protected the bone matrix by decreasing bone turnover rate.     

Temporal variations in iliac trabecular bone formation in vertebral osteoporosis

Summary The histologic heterogeneity of osteoporosis relative to normal controls has attracted great interest. There has been controversy as to whether patients with high turnover osteoporosis may convert to a normal or low turnover form, and vice versa. We have studied 44 patients over 12 years by dynamic histomorphometry and⁸⁵Sr kinetics + calcium balance performed within 60 days in 20 patients (Group 1) and 75–808 days apart in the remainder (Group 2). In the first group, the histologic tissue level bone formation rate (BFR/BV or BFR/BS) was predictive of the⁸⁵Sr measurements of bone formation (r=0.66P<0.01). There was no statistically significant correlation in Group 2 and the regression coefficients were significantly different (P=0.01). Periodic regression was used to determine if seasonal changes were responsible for this loss of correlation; none was found that was of statistical significance. No systematic changes with time in bone formation were found in Group 2 during the period of observation; nor were consistent secular changes detected when the data for both groups were examined according to procedure data. In conclusion, bone formation may change with time in postmenopausal osteoporosis. Evidence that these changes are systematic was not found and this has implications for the design of treatment studies.     

Seasonal variation of lumbar spine bone mineral content in normal women

Summary The seasonal influence on lumbar spine bone mineral was evaluated in a prospective study of 26 normal women aged 19–66 years. Bone mineral content of the second, third, and fourth lumbar vertebrae (lumbar BMC) was determined every 3 months during 1 year by using dual-photon (¹⁵³Gd) absorptiometry. Lumbar BMC was, on an average (mean±SE), 0.86±0.27 arbitrary units or 1.7±0.5% higher in July to September than in January to March (P<0.005), when other sources of variation were eliminated. It is hypothesized that the seasonal variation in lumbar spine bone mineral reflects differences of the mechanical loading on the vertebrae. The interpretation of longitudinal studies of lumbar BMC may be erroneous if the seasonal variations in bone mineral are not considered.     

Inhibition of bone cell metabolism increases strontium-85 uptake

Summary Experiments have been performed on the canine tibia to investigate whether perturbation of the energy metabolism of bone cells can influence the short-term exchange of bone mineral. Simultaneous injection of three radioactive tracers,¹²⁵I-albumin,⁸⁵Sr, and⁸⁶Rb, into the tibial nutrient artery was followed immediately by measurement of the concentration of these tracers in the venous outflow from the bone for a period of 5 minutes. This procedure was performed before and after the injection of potassium cyanide into the bone. From the measured concentrations, extraction ratios for⁸⁵Sr and⁸⁶Rb with respect to¹²⁵I-albumin were calculated. It was found that net extraction after 5 minutes of⁸⁵Sr was significantly increased. This result indicates that efflux of ions from exchangeable mineral is dependent to a significant extent on the metabolic activity of bone cells.     

Skeletal retention of45Ca and85Sr compared: Further studies on intravenously injected85Sr as a tracer for skeletal calcium

Summary The physical characteristics of⁴⁷Ca and⁴⁵Ca make them unsuitable for studying the long-term (>30 days) handling of skeletal calcium in patients. Therefore a study was conducted in 3 normal subjects in which the skeletal uptakes and subsequent retentions of simultaneously administered intravenous doses of⁴⁵Ca and⁸⁵Sr were compared. Specific activities of⁴⁵Ca (relative to⁴⁰Ca) were then observed in plasma and prolonged urine collections for up to 5 months. The whole-body retention of⁸⁵Sr was followed simultaneously in a whole-body counter. On the hypothesis that the single passage retention of both tracers in the skeleton was identical, after the effects of second and subsequent tracer recirculations the skeleton had been removed by deconvolution analysis, it was possible to calculate from the⁸⁵Sr data and the excretory clearance of⁴⁰Ca the predicted⁴⁵Ca specific activity for each subject as a function of time. Within the limits imposed by data scatter and measurement uncertainties, the predicted and observed long-term⁴⁵Ca specific activity curves appeared identical. However, in a separate study on approximately 40 patients,⁸⁵Sr was shown to underestimate the size of the exchangeable pools of bone calcium by about 20%. In the same group of patients, a close relationship was observed between the endogenous fecal calcium excretion rates, as calculated, respectively, from data obtained after simultaneous injections of⁸⁵Sr and⁴⁷Ca. Furthermore, the⁴⁷Ca accretion rate to bone could be predicted from the⁸⁵Sr data with a coefficient of variation of 15%.⁸⁵Sr is not the preferred tracer for studying the short-term handling of calcium by the skeleton. However, long-term “exchange” processes lead to prolonged (>30 days) tracer retention at surfaces where new bone is not being formed. When it is necessary to separate these processes from true bone formation,⁸⁵Sr is a practical and suitable tracer for patient studies.     

Nanostructuring of Biomaterials—A Pathway to Bone Grafting Substitute

Abstract Background: The bone substitute NanoBone^? consists of nanocrystalline hydroxyapatite embedded in a highly porous matrix of silica gel. It promotes the healing of bone defects and is degraded by osteoclasts during bone remodeling. The present study investigates the interactions of NanoBone^? with bone tissue. Methods: Granules of NanoBone^? were implanted in defects of critical size in the mandible of minipigs. Samples were taken after 5 and 10 weeks and demineralized. The composition of the implanted granules was analyzed by means of transmission and scanning electron microscopy and EDX. Enzymeand immunohistochemistry was used to investigate organic components of NanoBone^? granules that arised after implantation in the host. Results: EDX demonstrated that 5 weeks after implantation the silica gel was degraded and replaced by an organic matrix. Ultrastructurally, the matrix appeared amorphous with only single collagen fibrillae. PAS-staining indicated the presence of carbohydrates. Immunohistochemically, the bone proteins osteopontin, osteocalcin and BMP-2 were found as constituents of the new matrix. Alkalic phosphatase activity was located in osteoblasts and newly formed bone on NanoBone^? and focally in particles. Osteoclasts with ruffled borders, sealing zones, and acid phosphatase activity were situated in resorption lacunae at granule surfaces not covered by new bone. Conclusions: In vivo, the silica gel of NanoBone^? is replaced by bone matrix glycoproteins with known functions in attraction, adhesion, and differentation of bone cells as osteoblasts and osteoclasts. We assume that the deposition of these molecules supports the early phase of NanoBone^? degradation by osteoclasts and promotes the production of new bone tissue.     

Radionuclide Staging of Renal Function in Type 1 Diabetes Mellitus

Aim. The aim of this study was to assess renal function in different stages of type 1 diabetes mellitus by radionuclide methods. Additionally, glomerular and tubular functions were correlated with urinary albumin (UAER) and N-acetyl-β-D-glucosaminidase (NAGA) excretion rates. Patients and methods. Fifty-three patients with diabetes mellitus were classified into four groups: normoalbuminuric (NA, 18 patients), microalbuminuric (MiA, 12 patients), macroalbuminuric (MaA, 13 patients), and chronic renal failure group (CRF, 10 patients). Glomerular filtration rate (GFR) was estimated by diethylenetriamine pentaacetic acid-technetium 99m (^99mTc-DTPA) clearance rate while tubular function was calculated as a percentage of net injected activity fixed in both kidneys, 4 h after intravenous injection of dimercaptosuccinate acid-technetium 99m (^99mTc-DMSA). Additionally, ^99mTc-DTPA clearance was correlated with estimated GFR (eGFR) by using modified Modification of Diet in Renal Disease (MDRD) Study Group formula. Results. ^99mTc-DTPA clearance and ^99mTc-DMSA fixation were found significantly higher in normoalbuminuric group (p < 0.05 and p < 0.02, respectively), unchanged in microalbuminuric group (p > 0.05, p > 0.05), and decreased in both macroalbuminuric (p < 0.0001, p < 0.00001) and chronic renal failure group (p < 0.0001, p < 0.00001). Renal function was denoted as normal, increased (hyperfunction), or decreased (hypofunction). It was found normal in a high percentage of patients with normalbuminuria (filtration 44.4%, fixation 72.2% pts) and microalbuminuria (66.7% and 66.7%). Renal hyperfunction was not only found frequent in normalbuminuric group (55.6% and 27.8%), but was also recorded in microalbuminuric group (8.3% and 8.3%). Renal hypofunction was present in all macroalbuminuric patients and in one-quarter of those with microalbuminuria as well. Such distribution of renal function conditions indicated normalbuminuric and microalbuminiric groups functionally heterogeneous. Regression analysis showed a significant correlation between ^99mTc-DTPA clearance and eGFR in MaA and CRF groups only. Although urinary NAGA excretion rate was shown as a less sensitive staging parameter, being significantly increased when compared to control group only in MaA and CRF groups (p < 0.05), it significantly correlated with ^99mTc-DTPA clearance rate (r = ?0.485, p = 0.0004) and ^99mTc-DMSA tubular fixation (r = ?0.526, p = 0.0002). Conclusions. The results of this study favor the performance of radionuclide studies together with the determination of urinary albumin excretion rate in patients with type 1 diabetes mellitus in order to achieve more reliable staging of diabetic kidney disease. The demonstration of glomerular hyperfiltration and tubular hyperfunction by radiopharmaceuticals contributes to the early detection of diabetic kidney disease, while the quantification of renal function enables the follow-up of the progressive function loss in the later course of the disease.     

Evaluation of Quality of Life Using EORTC QLQ‐BM22 in Patients with Bone Metastases after Treatment with Magnetic Resonance Guided Focused Ultrasound

Objective

To reveal the alterations in quality of life (QOL) in bone metastases patients after magnetic resonance guided focused ultrasound (MRgFUS).

Methods

This retrospective study enrolled 26 patients diagnosed with bone metastases. Patients had various primary malignant tumors and tumor lesions in different locations. All patients received MRgFUS for bone metastasis. Each focal spot sonication pulse that was applied to create energy deposition lasted 20 s and was performed at a frequency of 1.05 MHz. The visual analog scale (VAS) was used to measure pain level and the EORTC QLQ‐BM22 was applied to evaluate QOL for 12 months. The lower the QLQ‐BM22 score, the better the QOL of patients.

Results

The painful site subscale of the EORTC QLQ‐BM22 was observed without significant change. Significant reductions in the functional subscales were observed after therapy compared with the baseline. The functional interference was reduced significantly during the first 12 months. From the 2‐month time point onwards, the pain characteristics subscale also decreased significantly. VAS scores had decreased by 40.8% 1 month after the operation and had decreased 10.9% compared with VAS scores preoperation. Scores for pain characteristics decreased by 28.8% after the operation and the scores were still down by 10.8% 1 year after the treatment. VAS scores indicated a significant reduction in pain over the course of the research until the 12‐month time point follow‐up compared with the baseline.

Conclusion

MRgFUS therapy improved the QOL of patients with bone metastasis by relieving bone pain.

     

Total body bone mineral and lean body mass by dual-photon absorptiometry

Summary A method was developed for measuring total body bone mineral (TBBM) and lean body mass in vivo using dual-photon absorptiometry. The entire body was scanned in a rectilinear raster (transverse speed of 1 cm/s and longitudinal steps of 2.5 cm) with a modified nuclear medicine scanner and conventional nuclear counting electronics. The source was¹⁵³Gd (1 Ci) with principal photopeaks at 44 and 100 keV. The scan time was about 70 min with an absorbed dose of under 1 mrem. The low dose allows measurements to be repeated at frequent intervals or used on children. Short-term (months) precision of TBBM was about 1.5% for isolated skeletons and about 2% on normal human subjects. Long-term (years) precision on skeletons was under 3%. The precision of percent fat was 0.9%, which would lead to an error of less than 1% in the TBBM. Geometry of measurements also had minimal (and correctable) influence on the accuracy of results. The accuracy (1 standard error of estimate) of TBBM on isolated skeletons (N=5) was 36 g (equivalent to about 13 g of Ca) with a correlation coefficient of 0.99; this error amounts to about 1–1.5% in normal adults, 2% in older women, and 2.5% in osteoporotic females. The dual-photon absorptiometry method could be implemented in many nuclear medicine departments to follow skeletal changes during growth and aging or to follow the course of a disease or treatment.     

Fetal rat bone in organ culture: Effect of bone growth and bone atrophy on the comparative losses of45Ca and3H-tetracycline

Summary Fetal rat bones were cultured in either growth-inducing or resorption-inducing media to study mineral losses during bone growth and atrophy in vitro. Whole radii and ulnae from 19-day-old fetal rats, prelabeled with⁴⁵Ca and/or³H-tetracycline, were cultured intact or cut, and then digested by collagenase to obtain the calcified portion of the bones. Three-to five-fold more³H-tetracycline than⁴⁵Ca was lost from the calcified portion when the bones were cultured for 4 days in growth-inducing media. Similar small amounts of⁴⁵Ca were lost from live and killed bones, but more³H-tetracycline was lost from live bones than from killed bones. More³H-tetracycline was released into the growth medium with a low concentration of calcium (0.5 mM) than when the calcium concentration was high (1.0 mM); no significant difference was seen in the release of⁴⁵Ca into the medium at different calcium concentrations. Larger amounts of both isotopes were lost when the prelabeled bones were cultured in resorption-inducing media than in growth-inducing media. When parathyroid hormone stimulated bone resorption in a resorption-inducing medium, equal proportions of both isotopes and bone collagen were lost. Greater losses of³H-tetracycline than of⁴⁵Ca suggest that⁴⁵Ca was conserved locally during the resorption that accompanies bone growth, but not during resorption that accompanies bone atrophy.     

Improved Outcomes for Lap-Banding Using the Insuflow? Device Compared with Heated-Only Gas

Background and Objectives:

Preconditioning gas by humidification and warming the pneumoperitoneum improves laparoscopic outcomes. This prevents peritoneal desiccation and detrimental events related to traditional cold-dry gas. Few comparisons have been done comparing traditional cold-dry, heated-only, and humidified-warmed carbon dioxide.

Methods:

A prospective, controlled, randomized, double-blind study of laparoscopic gastric banding included 113 patients and compared traditional dry-cold (n=35) versus dry-heated (n=40), versus humidified-warm gas (n=38). Pain medications were standardized for all groups. Endpoints were recovery room length of stay, pain location, pain intensity, and total pain medications used postoperatively for up to 10 days.

Results:

The humidified-warmed group had statistically significant differences from the other 2 groups with improvement in all end points. The dry-heated group had significantly more pain medication use and increased shoulder and chest pain than the other 2 groups had.

Conclusion:

Using warm-humidified gas for laparoscopic gastric banding reduces shoulder pain, shortens recovery room length of stay, and decreases pain medication requirements for up to 10 days postoperatively. Dry-heated gas may cause additional complications as is indicated by the increase in pain medication use and pain intensity.     

Phase I trial with a combination of docetaxel and Sm-lexidronam in patients with castration-resistant metastatic prostate cancer

Background

This study was designed to evaluate toxicity and preliminary efficacy of 2 cycles of concomitant standard dose/schedule of ¹⁵³Sm-lexidronam plus Q 3 weeks schedule escalating doses of docetaxel in metastatic castration-resistant prostate cancer (mCRPC).

Methods

mCRPC patients with progressive bone metastases were treated in 4 cohorts. Docetaxel doses were escalated from 50, 50, 0 mg/m² (on days 1, 22, 43, per 12-week cycle) to 75, 75, 75 mg/m². ¹⁵³Sm-lexidronam was administered on days 2 (Q 12 weeks) at dose of 1 mCi/kg/cycle (maximum of 2 cycles).

Results

Thirteen patients received an average of 3.6 doses of docetaxel (range, 2–6 doses, median 4) and 1.5 doses of ¹⁵³Sm-lexidronam (range, 1–2, median 2). Toxicity was primarily hematologic. There were total 35 episodes grade 3/4 neutropenia with a median 7 (range 7–14) days to recovery to ≤grade 1. One dose limiting grade 3 thrombocytopenia occurred on cohorts 3 and 4. Eight of 13 (62%) patients had PSA > 50% decrease as best response during the treatment. Median time to bone disease progression was 5.2 months (range 91 days–10 months+); 6/13 (46%) patients had stable/improved bone scans at 6 months and 6/6 (100%) symptomatic patients had improvement in pain.

Conclusions

Concurrent 6-month administration of 4 doses (75 mg/m²) of standard Q 3 weeks schedule of docetaxel with 2 Q 3 months infusions of 1 mCi/Kg ¹⁵³Sm-lexidronam is feasible with reversible bone marrow suppression, and deserves further testing in mCRPC patients with extensive bone metastasis.     

The distribution of cortical and trabecular bone mass along the lengths of the radius and ulna and the implications forin vivo bone mass measurements

The amounts of cortical and trabecular bone mineral mass were measured by means of microdissection and an ashing technique at approximately 2.5 mm intervals along the most distal 12 cm of radii and ulnae from four women aged 21, 43, 63, and 85. The data show that the distributions of mineral mass and percentage of trabecular bone are similar in both bones. At sites in the radius and ulna commonly used in the photon absorptiometric method of bone mineral mass measurement the percentage of trabecular bone varies between 10% and 50%. The percentage of trabecular bone in the most distal 10% of the length of the radius and ulna remains approximately constant with age but the percentage in the segment which lies between 30% and 40% of the length, measured from the styloid process, increases with age.