Standard versus hypofractionated intensity-modulated radiotherapy for prostate cancer: assessing the impact on dose modulation and normal tissue effects when using patient-specific cancer biology.

Hypofractionation of prostate cancer radiotherapy achieves tumour control at lower total radiation doses, however, increased rectal and bladder toxicities have been observed. To realise the radiobiological advantage of hypofractionation whilst minimising harm, the potential reduction in dose to organs at risk was investigated for biofocused radiotherapy. Patient-specific tumour location and cell density information were derived from multiparametric imaging. Uniform-dose plans and biologically-optimised plans were generated for a standard schedule (78 Gy/39 fractions) and hypofractionated schedules (60 Gy/20 fractions and 36.25 Gy/5 fractions). Results showed that biologically-optimised plans yielded statistically lower doses to the rectum and bladder compared to isoeffective uniform-dose plans for all fractionation schedules. A reduction in the number of fractions increased the target dose modulation required to achieve equal tumour control. On average, biologically-optimised, moderately-hypofractionated plans demonstrated 15.3% (p-value: <0.01) and 23.8% (p-value: 0.02) reduction in rectal and bladder dose compared with standard fractionation. The tissue-sparing effect was more pronounced in extreme hypofractionation with mean reduction in rectal and bladder dose of 43.3% (p-value: < 0.01) and 41.8% (p-value: 0.02), respectively. This study suggests that the ability to utilise patient-specific tumour biology information will provide greater incentive to employ hypofractionation in the treatment of localised prostate cancer with radiotherapy. However, to exploit the radiobiological advantages given by hypofractionation, greater attention to geometric accuracy is required due to increased sensitivity to treatment uncertainties.

Voxel-level biological optimisation of prostate IMRT using patient-specific tumour location and clonogen density derived from mpMRI.

AIMS: This study aimed to develop a framework for optimising prostate intensity-modulated radiotherapy (IMRT) based on patient-specific tumour biology, derived from multiparametric MRI (mpMRI). The framework included a probabilistic treatment planning technique in the effort to yield dose distributions with an improved expected treatment outcome compared with uniform-dose planning approaches. METHODS: IMRT plans were generated for five prostate cancer patients using two inverse planning methods: uniform-dose to the planning target volume and probabilistic biological optimisation for clinical target volume tumour control probability (TCP) maximisation. Patient-specific tumour location and clonogen density information were derived from mpMRI and geometric uncertainties were incorporated in the TCP calculation. Potential reduction in dose to sensitive structures was assessed by comparing dose metrics of uniform-dose plans with biologically-optimised plans of an equivalent level of expected tumour control. RESULTS: The planning study demonstrated biological optimisation has the potential to reduce expected normal tissue toxicity without sacrificing local control by shaping the dose distribution to the spatial distribution of tumour characteristics. On average, biologically-optimised plans achieved 38.6% (p-value: < 0.01) and 51.2% (p-value: < 0.01) reduction in expected rectum and bladder equivalent uniform dose, respectively, when compared with uniform-dose planning. CONCLUSIONS: It was concluded that varying the dose distribution within the prostate to take account for each patient's clonogen distribution was feasible. Lower doses to normal structures compared to uniform-dose plans was possible whilst providing robust plans against geometric uncertainties. Further validation in a larger cohort is warranted along with considerations for adaptive therapy and limiting urethral dose.

Radiobiological parameters in a tumour control probability model for prostate cancer LDR brachytherapy.

To provide recommendations for the selection of radiobiological parameters for prostate cancer treatment planning. Recommendations were based on validation of the previously published values, parameter estimation and a consideration of their sensitivity within a tumour control probability (TCP) model using clinical outcomes data from low-dose-rate (LDR) brachytherapy. The proposed TCP model incorporated radiosensitivity (α) heterogeneity and a non-uniform distribution of clonogens. The clinical outcomes data included 849 prostate cancer patients treated with LDR brachytherapy at four Australian centres between 1995 and 2012. Phoenix definition of biochemical failure was used. Validation of the published values from four selected literature and parameter estimation was performed with a maximum likelihood estimation method. Each parameter was varied to evaluate the change in calculated TCP to quantify the sensitivity of the model to its radiobiological parameters. Using a previously published parameter set and a total clonogen number of 196 000 provided TCP estimates that best described the patient cohort. Fitting of all parameters with a maximum likelihood estimation was not possible. Variations in prostate TCP ranged from 0.004% to 0.67% per 1% change in each parameter. The largest variation was caused by the log-normal distribution parameters for α (mean, [Formula: see text], and standard deviation, σ α ). Based on the results using the clinical cohort data, we recommend a previously published dataset is used for future application of the TCP model with inclusion of a patient-specific, non-uniform clonogen density distribution which could be derived from multiparametric imaging. The reduction in uncertainties in these parameters will improve the confidence in using biological models for clinical radiotherapy planning.

Development of a registration framework to validate MRI with histology for prostate focal therapy.

PURPOSE: Focal therapy has been proposed as an alternative method to whole-gland treatment for prostate cancer when aiming to reduce treatment side effects. The authors recently validated a radiobiological model which takes into account tumor location and tumor characteristics including tumor cell density, Gleason score, and hypoxia in order to plan optimal dose distributions for focal therapy. The authors propose that this model can be informed using multiparametric MRI (mpMRI) and in this study present a registration framework developed to map prostate mpMRI and histology data, where histology will provide the "ground truth" data regarding tumor location and biology. The authors aim to apply this framework to a growing database to develop a prostate biological atlas which will enable MRI based planning for prostate focal therapy treatment. METHODS: Six patients scheduled for routine radical prostatectomy were used in this proof-of-concept study. Each patient underwent mpMRI scanning prior to surgery, after which the excised prostate specimen was formalin fixed and mounted in agarose gel in a custom designed sectioning box. T2-weighted MRI of the specimen in the sectioning box was acquired, after which 5 mm sections of the prostate were cut and histology sections were microtomed. A number of image processing and registration steps were used to register histology images with ex vivo MRI and deformable image registration (DIR) was applied to 3D T2w images to align the in vivo and ex vivo MRI data. Dice coefficient metrics and corresponding feature points from two independent annotators were selected in order to assess the DIR accuracy. RESULTS: Images from all six patients were registered, providing histology and in vivo MRI in the ex vivo MRI frame of reference for each patient. Results demonstrated that their DIR methodology to register in vivo and ex vivo 3D T2w MRI improved accuracy in comparison with an initial manual alignment for prostates containing features which were readily visible on MRI. The average estimated uncertainty between in vivo MRI and histology was 3.3 mm, which included an average error of 3.1 mm between in vivo and ex vivo MRI after applying DIR. The mean dice coefficient for the prostate contour between in vivo and ex vivo MRI increased from 0.83 before DIR to 0.93 after DIR. CONCLUSIONS: The authors have developed a registration framework for mapping in vivo MRI data of the prostate with histology by implementing a number of processing steps and ex vivo MRI of the prostate specimen. Validation of DIR was challenging, particularly in prostates with few or mostly linear rather than spherical shaped features. Refinement of their MR imaging protocols to improve the data quality is currently underway which may improve registration accuracy. Additional mpMRI sequences will be registered within this framework to quantify prostate tumor location and biology.

Zebrafish: an emerging technology for in vivo pharmacological assessment to identify potential safety liabilities in early drug discovery.

The zebrafish is a well-established model organism used in developmental biology. In the last decade, this technology has been extended to the generation of high-value knowledge on safety risks of novel drugs. Indeed, the larval zebrafish appear to combine advantages of whole organism phenotypic assays and those (rapid production of results with minimal resource engagement) of in vitro high-throughput screening techniques. Thus, if appropriately evaluated, it can offer undeniable advantages in drug discovery for identification of target and off-target effects. Here, we review some applications of zebrafish to identify potential safety liabilities, particularly before lead/candidate selection. For instance, zebrafish cardiovascular system can be used to reveal decreases in heart rate and atrial-ventricular dissociation, which may signal human ether-a-go-go-related gene (hERG) channel blockade. Another main area of interest is the CNS, where zebrafish behavioural assays have been and are further being developed into screening platforms for assessment of locomotor activity, convulsant and proconvulsant liability, cognitive impairment, drug dependence potential and impaired visual and auditory functions. Zebrafish also offer interesting possibilities for evaluating effects on bone density and gastrointestinal function. Furthermore, available knowledge of the renal system in larval zebrafish can allow identification of potential safety issues of drug candidates on this often neglected area in early development platforms. Although additional validation is certainly needed, the zebrafish is emerging as a versatile in vivo animal model to identify off-target effects that need investigation and further clarification early in the drug discovery process to reduce the current, high degree of attrition in development.

Relationship between femoral head size and distance to lesser trochanter.

Hemiarthroplasty of the hip is a common treatment for displaced fractures of the femoral neck. However, accurate restoration of leg length may be difficult to achieve because intraoperative measurements of leg length and preoperative templating are limited by the fracture. Our primary question was whether femoral head diameter can be used to predict femoral head height. We analyzed 34 cadaveric femora to determine diameter of the femoral head, distance from the lesser trochanteric sulcus to the external center of the femoral head (head height), lateral distance from the proximal tip of the greater trochanter to the center of the femoral head (offset), and the femoral neck/shaft angle. The femoral head diameter had a linear correlation with head height expressed by the following equation: head height = 1.035 x femoral head diameter. Our results indicate the diameter of the femoral head is similar in size to the distance from the top of the lesser trochanter to the center of the femoral head in an average population of cadavers. This may be a helpful clinical measurement to assess leg length during surgical treatment of hip fractures.

Perioperative care for patients with sickle cell who are undergoing total hip replacement as treatment for osteonecrosis.

Sickle cell disease, which is characterized by chronic hemolytic anemia, is prevalent in the United States. In addition to the profound multisystem effects of vasoocclusion associated with sickle cell disease, osteonecrosis of the femoral head classically develops at an early age. Because of advanced medical technology and new treatment modalities, patients with sickle cell disease are living longer. More adults with this genetic disease are becoming candidates for total hip arthroplasty. This article describes the pathophysiology of sickle cell anemia, explains the process of osteonecrosis, and discusses total hip arthroplasty in this unique patient population.

Viscosupplementation: a new treatment option for osteoarthritis.

Osteoarthritis (OA), a degenerative joint disease affecting articular cartilage and synovial joint fluid, is the most common of the rheumatic diseases. OA is a huge public health issue that diminishes the quality of life of millions in the United States. Current treatments for OA include physical therapy, antiinflammatories, narcotics, steroids, and surgery. Unfortunately there is currently no cure for OA and many of the effective treatment modalities have many harsh side effects. Quite recently patients suffering from OA had little alternative to total joint replacement surgery once they exhausted their allotment of steroid injections and started to experience the GI complications associated with traditional NSAIDs. The introduction of viscosupplements, injectable compounds that mimic healthy synovial fluid and often relieve the suffering caused OA, has given patients with OA a longer-term, nonsurgical treatment alternative.

Quantifying passive resistance to motion in the straight-leg-raising test on asymptomatic subjects.

The clinician needs an objective way to measure limb motion in the straight-leg-raising test. A biomechanical algorithm was used to quantify resistance to motion in 15 asymptomatic subjects. Measurements from a pendulum electrogoniometer and hand-held load cell were used to calculate a moment representing passive resistance to motion. After three measurement trials, significant increases in range of motion (4.7%) and moment (8.4%) occurred. Then, an isometric contraction-relaxation of the hip extensors produced a highly significant increase in motion (8.8%) but decrease in moment (< 14.3%). A third order polynomial fit of moment per angle stratified the sample into two groups according to their change in moment. Motion in group 1 increased 8.0%, and in group 2, 9.5%. However, group 1 had no change in moment whereas group 2 had a highly significant decrease in moment (22.9%). The measured change in resistance demonstrated that a simple biomechanical algorithm quantified properties in a clinical test that were not observed in range of motion alone.

Inhibition of the immune response to experimental fresh osteoarticular allografts.

The immune response to osteoarticular allografts is capable of destroying the cartilage--a tissue that has antigens on its cells identical to those on the bone and marrow cells. Osteoarticular allografts of the distal femur were performed in rats using various methods to attempt to temporarily inhibit the antibody response. The temporary systemic immunosuppressant regimens investigated were cyclophosphamide, azathioprine and prednisolone, cyclosporine A, and total lymphoid irradiation. The most successful appeared to be cyclosporine A, but significant side effects were observed. To specifically inhibit the immune response in the allograft antigens without systemically inhibiting the entire immune system, passive enhancement and preadministration of donor blood were tried. Neither was as effective as coating the donor bone with biodegradable cements, a method previously found to be successful. Cyclosporine A was investigated in dogs in a preliminary study of medial compartmental knee allografts and was found to be successful in inhibiting the antibody response and in producing a more successful graft; however, some significant side effects were similarly observed.

Works in progress #2. Threaded acetabular components. Design rationale and preliminary clinical experience.

Two design rationales for threaded acetabular components, the S-ROM Anderson cup and S-ROM SuperCup, are discussed. Components have been followed for at least six months, with a range of six to 24 months. The average follow up is nine months. One hundred components in 96 patients had sufficient follow up and full clinical and roentgenographic evaluations to be included in this study. The 100 hips were divided into four groups based on S-ROM Anderson cup versus S-ROM SuperCup and on primary versus revision. Each hip was evaluated on a clinical and radiologic basis. Based on clinical and roentgenographic evaluations of both the primary and revision situations of the S-ROM SuperCup, consistently good to excellent results were observed. To date, no case has undergone revision for clinical or roentgenographic failure. Dramatic pain relief was exhibited by 96% of patients. Although early results are very encouraging, longer follow ups are necessary.

Effects of enteral and parenteral nutrition on tumor response to chemotherapy in experimental animals.

The effects of oral and intravenous nutrition on host and tumor responses to graded doses of methotrexate (MTX) were evaluated in 150 adult Sprague-Dawley rats. All animals were inoculated with Walker-256 carcinosarcoma and were fed a regular diet for ten days before assigning them to three dietary groups. Group I (n = 64) received a constant intravenous infusion of 30% dextrose-5% amino acids (IVH), group II (n = 64) received an identical solution orally ad libitum, and group III (n = 22) received a regular diet ad libitum. Animals in groups I and II were then divided into three subgroups each that received either 20 mg/kg, 40 mg/kg, or 60 mg/kg of MTX intramuscularly. Ten days later, all surviving animals were killed. Animals fed the 30% dextrose-5% amino acid diet orally and given 20 mg/kg and 40 mg/kg of MTX lost slightly less body weight when compared with their IVH counterparts. In the 60 mg/kg treatment group, orally fed animals lost 52 gm of body weight compared with 23 gm in IVH animals. IVH rats given 20 mg/kg and 40 mg/kg of MTX demonstrated significant inhibition of tumor growth and decreased tumor weight/body weight ratios when compared with orally fed rats. No improvement in tumor response to 60 mg/kg of MTX was observed, however, when IVH animals were compared with orally fed rats. In a second study, nutrient intake was maintained at a constant level by intravenous infusion in one group and intrajejunal infusion in another group of tumor-bearing rats. Host and tumor responses to 20 mg/kg of MTX were similar in both groups of animals.

Effects of nutritional repletion on host and tumor response to chemotherapy.

Host and tumor response to methotrexate (MTX) was studied in 122 tumor-bearing, malnourished rats during nutritional repletion. Sprague-Dawley rats with transplanted Walker-256 carcinosarcoma were fed a regular diet (RD) for five days followed by a protein-free diet (PFD) for ten days. On day 15, one group was orally repleted with a regular diet, while the other group continued on PFD. Methotrexate (20 mg/kg) therapy was begun in RD groups either on day 17 or day 21. Similarly, MTX (20 mg/kg) was begun in PFD groups either on day 17 or day 21. Untreated (no MTX) rats served as control animals and gained more body weight than MTX-treated rats. Tumor weight (TW) to carcass weight (CW) ratios were significantly less in both PFD and RD groups when MTX was given two days after dietary manipulation compared with results when MTX was given six days after dietary manipulation. Maximum tumor inhibition by MTX (least change in tumor diameter compared with control rats) was significantly greater when MTX was given to nutritionally repleted animals compared with results when MTX was given to animals continued on the protein-free diet. Dietary protein depletion inhibited tumor growth and tumor response to methotrexate. Nutritional repletion stimulated host and tumor growth. A short period of nutritional repletion (two days) prior to MTX chemotherapy resulted in improved host nutritional status and maximum tumor inhibition.

Tumor growth in experimental animals: nutritional manipulation and chemotherapeutic response in the rat.

The effects of nutritional manipulation on host body weight dynamics, tumor growth patterns and host-tumor responses to chemotherapy were studied in Sprague-Dawley rats with Walker-256 carcinosarcomas. Group I maintained throughout on a regular diet (RD) gained carcass weight steadily. Group II lost carcass weight while fed a protein-free diet (PFD) but rapidly gained weight after switching to RD on day 15. Mean tumor volume increased 105% in Group I from day 15 to 21, 218% in Group II and 77% in Group III (continued on PFD p less than 0.05). From day 21 to day 33 tumor growth patterns were similar in Groups I and II, while mean tumor volume eventually plateaued in Group III. In Study B, Group II animals were given Methotrexate (MTX-20 mg/kg) two days and six days after switching from PFD to RD. The mean change in tumor volume in the MTX-treated rats was 1.31 +/- 0.1 cm3 compared with 8.14 +/- 0.1 cm3 (p less than 0.001) in the saline-treated control rats. MTX did not significantly affect tumor growth patterns in Group III (PFD) rats. In Study A, protein-calorie malnutrition resulted in host carcass weight loss and tumor growth retardation while nutritional repletion restored host carcass weight and stimulated tumor growth. In Study B, MTX was maximally effective in tumor-bearing rats that were switched from PFD to RD demonstrating that nutritional manipulation can improve host nutritional status and increase tumor response to chemotherapy.