Determining the pharmacologic window of bisphosphonates that mitigates severe injury-induced osteoporosis and muscle calcification, while preserving fracture repair.

Following severe injury, biomineralization is disrupted and limited therapeutic options exist to correct these pathologic changes. This study utilized a clinically relevant murine model of polytrauma including a severe injury with concomitant musculoskeletal injuries to identify when bisphosphonate administration can prevent the paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues, yet not interfere with musculoskeletal repair. INTRODUCTION: Systemic and intrinsic mechanisms in bone and soft tissues help promote biomineralization to the skeleton, while preventing it in soft tissues. However, severe injury can disrupt this homeostatic biomineralization tropism, leading to adverse patient outcomes due to a paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues. There remains a need for therapeutics that restore the natural tropism of biomineralization in severely injured patients. Bisphosphonates can elicit potent effects on biomineralization, though with variable impact on musculoskeletal repair. Thus, a critical clinical question remains as to the optimal time to initiate bisphosphonate therapy in patients following a polytrauma, in which bone and muscle are injured in combination with a severe injury, such as a burn. METHODS: To test the hypothesis that the dichotomous effects of bisphosphonates are dependent upon the time of administration relative to the ongoing biomineralization in reparative bone and soft tissues, this study utilized murine models of isolated injury or polytrauma with a severe injury, in conjunction with sensitive, longitudinal measure of musculoskeletal repair. RESULTS: This study demonstrated that if administered at the time of injury, bisphosphonates prevented severe injury-induced bone loss and soft tissue calcification, but did not interfere with bone repair or remodeling. However, if administered between 7 and 21 days post-injury, bisphosphonates temporally and spatially localized to sites of active biomineralization, leading to impaired fracture callus remodeling and permanence of soft tissue calcification. CONCLUSION: There is a specific pharmacologic window following polytrauma that bisphosphonates can prevent the consequences of dysregulated biomineralization, yet not impair musculoskeletal regeneration.

Cerebrospinal fluid markers of extracellular matrix remodelling, synaptic plasticity and neuroinflammation before and after cranial radiotherapy.

BACKGROUND: Advances in the treatment of brain tumours have increased the number of long-term survivors, but at the cost of side effects following cranial radiotherapy ranging from neurocognitive deficits to outright tissue necrosis. At present, there are no tools reflecting the molecular mechanisms underlying such side effects, and thus no means to evaluate interventional effects after cranial radiotherapy. Therefore, fluid biomarkers are of great clinical interest. OBJECTIVE: Cerebrospinal fluid (CSF) levels of proteins involved in inflammatory signalling, synaptic plasticity and extracellular matrix (ECM) integrity were investigated following radiotherapy to the brain. METHODS: Patients with small-cell lung cancer (SCLC) eligible for prophylactic cranial irradiation (PCI) were asked to participate in the study. PCI was prescribed either as 2 Gy/fraction to a total dose of 30 Gy (limited disease) or 4 Gy/fraction to 20 Gy (extensive disease). CSF was collected by lumbar puncture at baseline, 3 months and 1 year following PCI. Protein concentrations were measured using immunobased assays or mass spectrometry. RESULTS: The inflammatory markers IL-15, IL-16 and MCP-1/CCL2 were elevated in CSF 3 months following PCI compared to baseline. The plasticity marker GAP-43 was elevated 3 months following PCI, and the same trend was seen for SNAP-25, but not for SYT1. The investigated ECM proteins, brevican and neurocan, showed a decline following PCI. There was a strong correlation between the progressive decline of soluble APPα and brevican levels. CONCLUSION: To our knowledge, this is the first time ECM-related proteins have been shown to be affected by cranial radiotherapy in patients with cancer. These findings may help us to get a better understanding of the mechanisms behind side effects following radiotherapy.

The prognostic value of pre-treatment thrombocytosis in two cohorts of patients with non-small cell lung cancer treated with curatively intended chemoradiotherapy.

Chemoradiotherapy is the standard of care for inoperable stage III non-small cell lung cancer (NSCLC). This treatment, however, offers only a small chance of cure and is associated with many side effects. Little research has been made concerning which patients benefit most/least from the treatment. The present study evaluates the prognostic value of anemia, leukocytosis and thrombocytosis at diagnosis in this treatment setting. In the present study, data were collected retrospectively for 222 patients from two different phase II studies conducted between 2002-2007 in Sweden with patients treated with chemoradiotherapy for stage IIIA-IIIB NSCLC. Clinical data and the serum values of hemoglobin (Hgb), White blood cells (WBC) and Platelets (Plt) at enrollment were collected for all patients and studied in relation to overall survival using Kaplan-Meier product-limit estimates and a multivariate Cox proportional hazards regression model. The results showed that patients with thrombocytosis (Plt > 350 x 109/L) had a shorter median overall survival (14.5 months) than patients with normal Plt at baseline (23.7 months). Patients with leukocytosis (WBC > 9 x 109/L) had a shorter median survival (14.9 months) than patients with a normal WBC at baseline (22.5 months). However, in a multivariate model including all lab parameters and clinical factors, only thrombocytosis and performance status displayed a prognostic significance. In Conclusion, thrombocytosis showed to be an independent prognostic marker associated with shorter overall survival in stage III NSCLC treated with curatively intended chemoradiotherapy. This knowledge can potentially be used together with established prognostic factors, such as performance status when choosing the optimal therapy for the individual patient in this clinical setting.

Changes in skeletal collagen cross-links and matrix hydration in high- and low-turnover chronic kidney disease.

UNLABELLED: Chronic kidney disease (CKD) increases fracture risk. The results of this work point to changes in bone collagen and bone hydration as playing a role in bone fragility associated with CKD. INTRODUCTION: Clinical data have documented a clear increase in fracture risk associated with chronic kidney disease (CKD). Preclinical studies have shown reductions in bone mechanical properties although the tissue-level mechanisms for these differences remain unclear. The goal of this study was to assess collagen cross-links and matrix hydration, two variables known to affect mechanical properties, in animals with either high- or low-turnover CKD. METHODS: At 35 weeks of age (>75% reduction in kidney function), the femoral diaphysis of male Cy/+ rats with high or low bone turnover rates, along with normal littermate (NL) controls, were assessed for collagen cross-links (pyridinoline (Pyd), deoxypyridinoline (Dpd), and pentosidine (PE)) using a high-performance liquid chromatography (HPLC) assay as well as pore and bound water per volume (pw and bw) using a (1)H nuclear magnetic resonance (NMR) technique. Material-level biomechanical properties were calculated based on previously published whole bone mechanical tests. RESULTS: Cortical bone from animals with high-turnover disease had lower Pyd and Dpd cross-link levels (-21% each), lower bw (-10%), higher PE (+71%), and higher pw (+46%) compared to NL. Animals with low turnover had higher Dpd, PE (+71%), and bw (+7%) along with lower pw (-60%) compared to NL. Both high- and low-turnover animals had reduced material-level bone toughness compared to NL animals as determined by three-point bending. CONCLUSIONS: These data document an increase in skeletal PE with advanced CKD that is independent of bone turnover rate and inversely related to decline in kidney function. Although hydration changes occur in both high- and low-turnover disease, the data suggest that nonenzymatic collagen cross-links may be a key factor in compromised mechanical properties of CKD.

Olfactory loss after head and neck cancer radiation therapy.

BACKGROUND: A reduced sense of smell may be one explanation for why patients with cancer in the ear, nose and throat (ENT) region who are treated with radiation therapy lose weight. The purpose of this study was to investigate whether radiation therapy has a negative effect on olfactory function and, if so, whether this effect is dose-related. METHODOLOGY: Seventy-one patients were tested using odour-detection sensitivity and olfactory identification tests before radiation therapy and 20 months after it. RESULTS: Patients who received radiation close to the olfactory organ showed a reduced sense of smell, in both tests. A multiple regression analysis showed that the radiation dose was related to decline in the olfactory function, while age, sex, chemotherapy and interactions between these variables were not. CONCLUSION: Radiation therapy can damage olfactory cells.

Combined stent insertion and single high-dose brachytherapy in patients with advanced esophageal cancer--results of a prospective safety study.

Previous randomized studies comparing the two commonly used palliative treatments for incurable esophageal cancer, i.e. stent insertion and intraluminal brachytherapy, have revealed the pros and cons of each therapy. While stent treatment offers a more prompt effect, brachytherapy results in more long-lasting relief of dysphagia and a better health-related quality of life (HRQL) in those living longer. This prospective pilot study aimed to explore the feasibility and safety of combining these two regimes and incorporating a single high dose of internal radiation. Patients with newly diagnosed, incurable cancer of the esophagus and dysphagia were eligible for inclusion, and stent insertion followed by a single dose (12 Gy) of brachytherapy was performed as a two-stage procedure. Clinical parameters including HRQL and adverse events were registered at inclusion, and 1, 2, 3, 6, and 12 months later. Twelve patients (nine males) with a median age of 73 years (range 54-85) were included. Stent insertion followed by a single dose of brachytherapy was successfully performed in all but one patient who was treated with stent only. Relief of dysphagia was achieved in the majority of cases (10/11, P < 0.05), but HRQL did not improve except for dysphagia-related items. Only minor adverse events, including chest pain, reflux, and restenosis, were reported. The median survival time after inclusion was 6.6 months. Our conclusion is that the combination of stent insertion and single high-dose brachytherapy seems to be a feasible and safe palliative regime in patients with advanced esophageal cancer. Randomized trials comparing the efficacy of this strategy to stent insertion or brachytherapy alone are warranted.

Estuarine submerged aquatic vegetation habitat provides organic carbon storage across a shifting landscape.

Submerged aquatic vegetation (SAV) thrives across the estuarine salinity gradient providing valuable ecosystem services. Within the saline portion of estuaries, seagrass areas are frequently cited as hotspots for their role in capturing and retaining organic carbon (Corg). Non-seagrass SAV, located in the fresh to brackish estuarine areas, may also retain significant soil Corg, yet their role remains unquantified. Given rapidly occurring landscape and salinity changes due to human and natural disturbances, landscape level carbon pool estimates from estuarine SAV habitat blue carbon estimates are needed. We assessed Corg stocks in SAV habitat soils from estuarine freshwater to saline habitats (interior deltaic) to saline barrier islands (Chandeleur Island) within the Mississippi River Delta Plain (MRDP), Louisiana, USA. SAV habitats contain Corg stocks equivalent to those reported for other estuarine vegetation types (seagrass, salt marsh, mangrove). Interior deltaic SAV Corg stocks (231.6 ± 19.5 Mg Corg ha-1) were similar across the salinity gradient, and significantly higher than at barrier island sites (56.6 ± 10.4 Mg Corg ha-1). Within the MRDP, shallow water SAV habitat covers up to an estimated 28,000 ha, indicating that soil Corg storage is potentially 6.4 ± 0.1 Tg representing an unaccounted Corg pool. Extrapolated across Louisiana, and the Gulf of Mexico, this represents a major unaccounted pool of soil Corg. As marshes continue to erode, the ability of coastal SAV habitat to offset some of the lost carbon sequestration may be valuable. Our estimates of Corg sequestration rates indicated that conversion of eroding marsh to potential SAV habitat may help to offset the reduction of Corg sequestration rates. Across Louisiana, we estimated SAV to offset this loss by as much as 79,000 Mg C yr-1 between the 1960s and 2000s.

Does CO(2) flushing of the empty CPB circuit decrease the number of gaseous emboli in the prime?

Twenty (20) CPB-circuits were randomized to a CO(2) group or a control group. In the CO( 2) group, each circuit was flushed with CO(2) (10L/min) at the top of the venous reservoir for 5 minutes, after which priming fluid was added without interruption of the CO(2) inflow. Control group circuits were not flushed and contained air. A perfusionist, blinded to the study, started the pump (5L/min), ventilated the oxygenator (3L O(2)/min), and knocked on the oxygenator 20 times during the first and 14(th) minutes. Arterial line microemboli counts were registered with a Doppler for 15 minutes. In both groups, the median number of microemboli was highest during the first minute, 380.5 (288.75/422.25, 25(th)/75(th) percentile) counts in the control group versus 264.5 (171.75/422.25) counts in the CO( 2) group (p=0.01). Throughout the experiment, the median microembolic count minute by minute in the CO(2) group remained lower (p < or = 0 .004) than in the control group. Knocking on the reservoir (14(th) minute) increased the microemboli counts in both groups (p<0.01). The median values during the 15(th) minute were 15.5 and 0.5 in the control and the CO(2) groups, respectively, which were 9% (15.5/173) and 0.5% (0.5/87), respectively, of the values registered after 14 minutes. In conclusion, CO( 2) flushing of the empty circuit decreases the number of gaseous emboli in the prime compared with a conventional circuit that contains air before being primed with fluid. Knocking of the oxygenator releases gaseous emboli and the duration of re-circulating the circuit with prime influences the number of microemboli.

Inhibition of vascular endothelial growth factor in young adult mice causes low bone blood flow and bone strength with no effect on bone mass in trabecular regions.

OBJECTIVE: To determine the effect of an antibody to vascular endothelial growth factor (VEGF) on bone blood flow, bone strength, and bone mass in the young adult mouse. METHODS: Ten-week-old male BALB/cJ mice were body weight-randomized into either a rodent anti-VEGF monoclonal antibody (anti-VEGF, B20-4.1.1; 5 mg/kg 2×/wk.; n = 12) group or a vehicle (VEH; n = 12) group. After 42 days, mice were evaluated for bone blood flow at the distal femur by 18F-NaF-PET/CT and then necropsied. Samples from trabecular and cortical bone regions were evaluated for bone strength by mechanical testing, bone mass by peripheral quantitative computed tomography (pQCT), and micoarchitecture (MicroCT). Hydration of the whole femur was studied by proton nuclear magnetic resonance relaxometry (1H NMR). RESULTS: Distal femur blood flow was 43% lower in anti-VEGF mice than in VEH mice (p = 0.009). Ultimate load in the lumbar vertebral body was 25% lower in anti-VEGF than in VEH mice (p = 0.013). Bone mineral density (BMD) in the trabecular region of the proximal humeral metaphysis by pQCT, and bone volume fraction and volumetric BMD by MicroCT were the same in the two groups. Volume fraction of bound water (BW) of the whole femur was 14% lower in anti-VEGF than in VEH mice (p = 0.003). Finally, BW, but not cortical tissue mineral density, helped section modulus explain the variance in the ultimate moment experienced by the femur in three-point bending. CONCLUSION: Anti-VEGF caused low bone blood flow and bone strength in trabecular bone regions without influencing BMD and microarchitecture. Low bone strength was also associated with low bone hydration. These data suggest that bone blood flow is a novel bone property that affects bone quality.

Denitrification in cypress swamp within the Atchafalaya River Basin, Louisiana.

Nitrogen has been implicated as a major cause of hypoxia in shallow water along the Louisiana/Texas, USA coasts. Excess nitrogen (mainly nitrate) from Mississippi and Atchafalaya River drainage basins may drive the onset and duration of hypoxia in the northern Gulf of Mexico. Restoring and enhancing denitrification have been proposed to reduce and control coastal hypoxia and improve water quality in the Mississippi River Basin. Sediments were collected from six baldcypress restoration sites within the Atchafalaya River Basin, Louisiana, USA. The acetylene blockage technique was used to measure background and potential sediment denitrification rates. Denitrification fluxes were measured before nitrate addition (background rates) and after nitrate addition of 100mgNl(-1) (potential denitrification) at three seasonal temperatures. Background denitrification was low across all cypress swamp sites ranging from 0.9 to 8.8, 0.6 to 28.5 and 8.8 to 47.5g N evolved ha(-1)d(-1) at water/sediment column temperatures of 8, 22 and 30 degrees C, respectively. After nitrate addition, temperature had a significant effect on sediment denitrification potential. Maximum rates measured at 8, 22 and 30 degrees C were approximately 250-260, 550 and 970gNha(-1)d(-1), respectively. Most of the added nitrate in water columns, incubated at 8 degrees C, was removed after 65d compared to 32d and 17d at 22 and 30 degrees C, respectively. These results indicate cypress swamps have the potential to assimilate and process elevated levels of floodwater nitrate with denitrification being a major removal mechanism.

Locally delivered lovastatin nanoparticles enhance fracture healing in rats.

Statins stimulate bone formation in vitro and in vivo and, when given in large doses or by prolonged infusions, stimulate biomechanical strength of murine long bones with healing fractures. However, administration of statins by large oral doses or prolonged infusions to a fracture site is not a feasible therapeutic approach to hasten healing of human fractures. We administered lovastatin in biodegradable polymer nanobeads of poly(lactic-co-glycolide acid) to determine if lovastatin delivered in low doses in nanoparticles of a therapeutically acceptable scaffold could increase rates of healing in a standard preclinical model of femoral fracture. We found that these nanobeads: (1) stimulated bone formation in vitro at 5 ng/mL, (2) increased rates of healing in femoral fractures when administered as a single injection into the fracture site, and (3) decreased cortical fracture gap at 4 weeks as assessed by microcomputed tomography. These preclinical results suggest that lovastatin administered in a nanobead preparation may be therapeutically useful in hastening repair of human fractures.

Effects of chemical additives on hydrocarbon disappearance and biodegradation in freshwater marsh microcosms.

We determined how a cleaner and a dispersant affected hydrocarbon biodegradation in wetland soils dominated by the plant Panicum hemitomon, which occurs throughout North and South America. Microcosms received no hydrocarbons, South Louisiana crude, or diesel; and no additive, a dispersant, or a cleaner. We determined the concentration of four total petroleum hydrocarbon (TPH) measures and 43 target hydrocarbons in water and sediment fractions 1, 7, 31, and 186 days later. Disappearance was distinguished from biodegradation via hopane-normalization. After 186 days, TPH disappearance ranged from 24% to 97%. There was poor correlation among the four TPH measures, which indicated that each quantified a different suite of hydrocarbons. Hydrocarbon disappearance and biodegradation were unaltered by these additives under worse-case scenarios. Any use of these additives must generate benefits that outweigh the lack of effect on biodegradation demonstrated in this report, and the increase in toxicity that we reported earlier.

Low grandparental social support combined with low parental socioeconomic status is closely associated with obesity in preschool-aged children: a pilot study.

While the influence of parental socioeconomic status (SES) on children's weight status is well known, the impact of other family-related aspects such as parental and grandparental social support is less understood. This study investigates the importance of parents' SES and social support (functional and structural) for weight status in a clinical sample of preschoolers 4-6 years old with obesity (n = 39, 56% girls; 73% of parents were overweight/obese, 50% were of non-Swedish origin). Linear regression analyses, simple and multiple, were performed on SES and social support with child BMI SDS (body mass index standard deviation score) as the dependent variable. The results show that parents' income and low emotional support from paternal grandparents were significantly associated with more severe obesity. The association between parental income and the child's BMI SDS was stronger among parents who had low emotional support from their own parents. In conclusion, grandparental social support may be protective against childhood obesity.

Technical note: Recommendations for a standard procedure to assess cortical bone at the tissue-level in vivo using impact microindentation.

Impact microindentation is a novel method for measuring the resistance of cortical bone to indentation in patients. Clinical use of a handheld impact microindentation technique is expanding, highlighting the need to standardize the measurement technique. Here, we describe a detailed standard operation procedure to improve the consistency and comparability of the measurements across centers.

Prognostic factors for acute and late skin reactions in radiotherapy patients.

PURPOSE: Patients treated with identical radiotherapy schedules show a substantial variation in the degree of acute and late normal tissue reactions. To identify any possible contributing factors to this phenomenon, we have analyzed the treatments of 402 breast cancer patients. METHODS AND MATERIALS: The patients received adjuvant postoperative radiotherapy between 1972 and 1985 and have been followed up since then. Multivariate analyses were performed with peak reflectance erythema and peak acute reaction score as endpoints for the acute reactions, and with progression rate of telangiectasia as well as telangiectasia score as endpoints for the late reactions. Twenty patient- and treatment-related factors were tested such as age, menopausal status, hemoglobin level, serum calcium, smoking habits, hypothyroidism, diabetes, hypertension, blood pressure, cardiovascular and autoimmune disease, the influence of hormone therapy and chemotherapy, pretreatment reflectance value, acute skin reactions, radiation quality, individual dose, bilateral fields, and the total effect (TE) for the dose schedule applied. RESULTS: The TE was a strong prognostic factor for all endpoints. In addition to TE, blood pressure was prognostic for the peak erythema measured by reflectance spectrophotometry, and the pretreatment reflectance value was prognostic for the acute score. The only independent prognostic factors found for the progression of skin telangiectasia and telangiectasia score except for TE were the individual dose and the acute skin reactions. CONCLUSIONS: These factors explained at most about 30% of the variance describing the total patient-to-patient variability for each endpoint. The remaining variability is still unexplained but may be related to individual differences in cellular radiosensitivity, partly determined by genetic variations and partly by unknown epigenetic factors.

Fibroblast radiosensitivity versus acute and late normal skin responses in patients treated for breast cancer.

PURPOSE/OBJECTIVE: To determine if the radiosensitivity of normal human skin fibroblasts, measured in early passage cultures, is significantly correlated with the degree of acute or late normal skin damage in patients treated for breast cancer with radiotherapy. METHODS AND MATERIALS: In the 1970s, a series of breast cancer patients was treated at the Department of Oncology in Gothenburg, Sweden with postoperative irradiation to the parasternal region. Patients were treated bilaterally using different fractionation schedules and doses to the right and left fields. Peak acute reactions were scored on a six-point scale, and skin erythema was measured by reflectance spectrophotometry. Telangiectasia was graded over time on a six-point scale. In April 1992, two small skin biopsies were obtained from 22 patients in two treatment groups (i.e., four dose-fractionation schedules) and, using either delayed or immediate plating, fibroblast radiosensitivity was measured in early passage cultures by clonogenic survival, after high and low dose-rate irradiations. Survival at 2.0 Gy (SF2) was calculated from complete survival curves. RESULTS: To test assay reproducibility, SF2 values derived from paired biopsies of the same patient (12 cases) were compared. A reasonably good correlation (p = 0.075) was obtained for SF2s determined by high dose-rate irradiations with immediate plating, but not for delayed plating or low dose-rate treatments. The median coefficient of variation in the replicate SF2s after high dose-rate treatment and immediate plating was 13%, suggesting that the poor correlation in paired SF2 values is due to the magnitude of the uncertainty in SF2 relative to the overall spread in SF2 values between patients (CV = 28%). Individual SF2 values and averaged values from patients with data from two biopsies were compared with the acute and late clinical reactions. A significant negative correlation was found between SF2 and relative clinical response, but only when averaged high dose-rate SF2 values and telangiectasia scores were compared. There was no significant correlation between average SF2 values and acute responses or between individual SF2 measurements and either the acute or late clinical response. CONCLUSION: The results of this study suggest that the degree of late telangiectasia is at least partially dependent upon the intrinsic cellular radiosensitivity of normal fibroblasts, but the relationship is not clear cut. Multiple replicate assays are necessary to obtain reliable estimates of fibroblast SF2 values using current techniques.

Basal cell density in human skin for various fractionation schedules in radiotherapy.

Changes in the epidermal basal cell density (BCD) in human skin were determined during and immediately after fractionate radiotherapy. The basal cells are one of the target cell types responsible for acute skin reactions and measuring the BCD is a histological method for studying the time course and degree of reaction. Thirty-two patients with breast cancer participated in this study. They received postmastectomy radiotherapy to the thoracic wall. A 3-mm punch biopsy was taken from the irradiation field once a week for 6-10 weeks and the linear basal cell density was determined. Standard fractionation at two different dose levels (40 and 50 Gy) as well as hypofractionation and accelerated treatment have been investigated. For the first 3 weeks we found a constant decline in the BCD (about 0.8%/day), independent of dose and fractionation schedule. Using the nadir value as endpoint we found a dose-response relationship between 40 and 50 Gy, and for total effect (TE)-values in the range 430-1015. Compared to standard fractionation, hypofractionation showed somewhat less effect and accelerated fractionation showed significantly less effect. The reduced effect of accelerated fractionation is interpreted as a result of lack of cell cycle redistribution of cells between the two daily fractions in this type of tissue. The removal rate of dead or doomed cells could also affect the results for schedules with different overall time. The results of BCD were also compared to erythema.(ABSTRACT TRUNCATED AT 250 WORDS)

Does the interval between fractions matter in the range of 4-8 h in radiotherapy? A study of acute and late human skin reactions.

Accelerated radiotherapy has the potential to increase local control of rapidly growing tumours. To determine the necessary time interval for complete repair of sublethal damage in normal tissue in a clinical situation, we have compared the acute and late skin reactions with 8 and 24 h between fractions, using the same dose per fraction and total dose. Forty-nine breast cancer patients participated in this study, and received bilateral parasternal irradiation to 50 Gy with 2 Gy per fraction as part of their adjuvant postoperative radiotherapy. The time interval between daily fractions was always 8 h on the left field and 24 h on the right, and the total treatment time was 2.5 and 5 weeks, respectively. The acute endpoint was erythema, measured by reflectance spectrophotometry and an acute reaction score for erythema and desquamation. The late endpoint was telangiectasia, scored on an arbitrary scale. The results have also been compared with those in a previously treated group of patients with 4 and 24 h between fractions. The degree of acute reactions was decreased with an 8-h interval compared with 24 h between fractions with the peak acute score as endpoint; no difference was seen with the peak reflectance measurements. The maximal expression occurs approximately 1 week earlier with the accelerated schedule, possibly as a consequence of the reduction of the treatment time. The pattern of the acute reaction for 8 h between fractions is similar to that for 4 h.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between cellular radiation sensitivity and tissue response may provide the basis for individualising radiotherapy schedules.

There is a wide variation in normal tissue reactions to radiotherapy and in many situations the severity of these reactions limits radiotherapy dose. Clinical fractionation studies carried out in Gothenburg have demonstrated that a large part of the spectrum of normal tissue reactions is due to differences in individual normal tissue sensitivity. If this variation in normal tissue reactions is due to differences in intrinsic cellular radiosensitivity, it should be possible to predict tissue response based on measurement of cellular sensitivity. Here we report the initial results of a study aimed at establishing whether a direct relationship exists between cellular radiosensitivity and tissue response. Ten fibroblasts strains, including four duplicates, were established from a group of patients in the Gothenburg fractionation trials who had received radiotherapy following mastectomy. Skin doses were measured and both acute and late skin changes were observed following radiotherapy. Right and left parasternal areas were treated with different dose fractionation schedules. Clonogenic assays were used to assess intrinsic cellular radiosensitivity, and all experiments were carried out without prior knowledge of the clinical response, or which strains were duplicates. Irradiation was carried out using 60Co gamma-rays at high dose-rate (HDR) of 1-2 Gy/min and low dose-rate (LDR) of 1 cGy/min. A spectrum of sensitivity was seen, with SF2 values of 0.17-0.28 at HDR and 0.25-0.34 at LDR, and values of D0.01 of 5.07-6.38 Gy at HDR and 6.43-8.12 Gy at LDR. Comparison of the in vitro results with the clinical normal tissue effects shows a correlation between cellular sensitivity and late tissue reactions, which is highly significant with p = 0.02. A correlation between cellular sensitivity and acute effects was noted in the left-sided parasternal fields, but not the right. This is thought to be coincidental, and without biological significance. Our results suggest that cellular sensitivity might form the basis for the development of an assay system capable of predicting late normal tissue effects to curative radiotherapy, which might allow dose escalation in some patients. Increased local control and cure, with unchanged or improved normal tissue complications, could result from such individualised radiotherapy prescriptions.

The apparent fracture toughness of acrylic bone cement: effect of three variables.

In cemented arthroplasties, pores are almost invariably present at one or more of the so-called 'weak-link' zones (namely, the bone-cement interface, the cement mantle and the cement-implant interface). In the clinical milieu, arthroplasties are frequently subjected to cyclical loading. These conditions underscore the significance of the apparent fracture toughness (KISR) of the cement. The present work is an investigation of the effect of three variables on KISR of three commercial formulations of bone cement (namely, CMW3, PalacosR and Osteopal) measured using straight-sided chevron notched short rod specimens. For CMW3, the effect of mixing method was studied, with all cement constituents having been stored at ambient laboratory environment prior to being mixed. The highest KISR was obtained from material that was obtained from exposing the cement constituents to a passive vacuum for 20 s and then mixing them in a machine that subjected them to simultaneous mechanical mixing and centrifugation. For Palacos R, the effects of two variables [storage temperature of the cement constituents prior to being mixed (4 degrees C versus 21 degrees C) and mixing method (hand mixing versus vacuum mixing)] (taken individually) were studied. It was found that only mixing method exerts a significant effect on KISR. When room-temperature stored constituents were vacuum mixed, the KISR values for a low-viscosity cement (Osteopal) and a medium-viscosity cement of very similar composition (Palacos R) are not significantly different, indicating that the fracture resistance of bone cement is influenced more by its composition than its viscosity.