Analysis of related factors in complications of stereotactic radiosurgery in intracranial tumors.

OBJECT: To investigate the related factors in complications of stereotactic radiosurgery for intracranial tumors. METHODS: A retrospective review of 146 patients with intracranial tumors treated with stereotactic radiosurgery was conducted. Sixty-five patients received single-dose treatment and the rest received fractionated stereotactic radiosurgery. Ninety-five patients received conventional radiotherapy in the meantime. RESULTS: Follow-up period was 18-54 months. Follow-up rate was 92.5% and 39 patients (26.7%) had different complications. The Cox statistics showed that target volume, target peripheral dose, target maximal dose, and ratio of maximal dose to peripheral dose are related to the complications. Conversely, neither type of tumor disease, gender, radiation schedule with or without conventional radiotherapy, target minimal dose, nor ratio of target peripheral isodose volume to target volume were found to be related to complications. CONCLUSION: Target volume and dose are the major factors causing complications, and the optimization of the therapeutic planning can play a significant role in reducing them.     

External stereotactic irradiation by linear accelerator

Stereotactic radiotherapy has two advantages: (a) the possibility of giving high radiation doses to small but spatially well-defined target volumes and (b) the presence of a stepped dose gradient between the target volume and the surrounding healthy tissues. To utilize these advantages, the authors built a new stereotactic head frame by which the intracranial target is fixed to the rotational isocenter of a 4-MV linear accelerator. The collimator openings are selected according to the volume and the three-dimensional configuration of the target, and the radiation dose is based on the radiosensitivity of the lesion. After the patient is fixed to the frame, the radiation source and the patient are rotated so that the target is irradiated through infinite portals distributed over the convexity of the skull. It is thereby possible to obtain very high radiation doses centered into the target with a stepped dose gradient. The preliminary radiodosimetric tests and the operative technique are described. The advantages of this technique compared to interstitial radiotherapy and Leksell's radiosurgery are emphasized. This noninvasive procedure has been used to treat a series of intracranial tumors.     

Initial and subsequent dosing of rectal acetaminophen in children: a 24-hour pharmacokinetic study of new dose recommendations

BACKGROUND: Recent studies have determined that an initial rectal acetaminophen dose of approximately 40 mg/kg is needed in children to achieve target antipyretic serum concentrations. The timing and amount of subsequent doses after a 40-mg/kg dose has not been clarified for this route of administration. Based on the authors' previous pharmacokinetic data, they examined whether a 40-mg/kg loading dose followed by 20-mg/kg doses at 6-h intervals maintain serum concentrations within the target range of 10-20 microg/ml, without evidence of accumulation. METHODS: Children (n = 16) received rectal acetaminophen (40 mg/kg) and up to three additional doses of 20 mg/kg at 6-h intervals. Venous blood samples were taken every 30 min for 4 h, then every 60 min for 4 h, and every 4 h for 16 h. The authors assessed whether their published pharmacokinetic parameters predicted the acetaminophen concentrations in the present study. They also assessed their dosing regimen by determining the fraction of time each individual maintained the target concentration. RESULTS: All patients received the initial loading dose; 10 of 16 patients received three subsequent doses. Serum concentrations with the initial dose were in the target range 38 +/- 25% of the time. With subsequent dosing, the target range was maintained 60 +/- 29% of the time. The highest serum concentration with initial or subsequent dosing was 38.6 microg/ml. Pharmacokinetic parameters from the earlier study predicted the serum concentrations observed for both initial and subsequent doses. CONCLUSIONS: A rectal acetaminophen loading dose of 40 mg/kg followed by 20-mg/kg doses every 6 h results in serum concentrations centered at the target range of 10-20 microg/ml. There was large interindividual variability in pharmacokinetic characteristics. There was no evidence of accumulation during the 24-h sampling period.     

Initial and Subsequent Dosing of Rectal Acetaminophen in Children: A 24-Hour Pharmacokinetic Study of New Dose Recommendations

Background: Recent studies have determined that an initial rectal acetaminophen dose of approximately 40 mg/kg is needed in children to achieve target antipyretic serum concentrations. The timing and amount of subsequent doses after a 40-mg/kg dose has not been clarified for this route of administration. Based on the authors' previous pharmacokinetic data, they examined whether a 40-mg/kg loading dose followed by 20-mg/kg doses at 6-h intervals maintain serum concentrations within the target range of 10-20 [mu]g/ml, without evidence of accumulation.

Methods: Children (n = 16) received rectal acetaminophen (40 mg/kg) and up to three additional doses of 20 mg/kg at 6-h intervals. Venous blood samples were taken every 30 min for 4 h, then every 60 min for 4 h, and every 4 h for 16 h. The authors assessed whether their published pharmacokinetic parameters predicted the acetaminophen concentrations in the present study. They also assessed their dosing regimen by determining the fraction of time each individual maintained the target concentration.

Results: All patients received the initial loading dose; 10 of 16 patients received three subsequent doses. Serum concentrations with the initial dose were in the target range 38 +/- 25% of the time. With subsequent dosing, the target range was maintained 60 +/- 29% of the time. The highest serum concentration with initial or subsequent dosing was 38.6 [mu]g/ml. Pharmacokinetic parameters from the earlier study predicted the serum concentrations observed for both initial and subsequent doses.     

Clinical benefits of neoral C2 monitoring in the long-term management of renal transplant recipients

BACKGROUND: Cyclosporine monitoring using the 2-hr postdose sample, C2, has been shown to have advantages in monitoring de novo renal transplant recipients. The purpose of this study was to assess cyclosporine exposure, using C2, in stable renal transplant patients previously monitored by C0 to determine the effect of dose reduction on patients with C2 more than 10% above target and the course of those with C2 at and more than 10% below target, whose dose was not modified. METHODS: One hundred and seventy-five patients, three or more months after transplantation, had C2 assessed. The relationship of C2 to C0 and of both to renal function was analyzed by linear regression. Blood pressure, serum creatinine level, and lipids were followed for a mean of 15+/-2.6 months. RESULTS: Eighty-five patients had values more than 10% above target, 42 were within 10% of target, and 48 were more than 10% below target. Cyclosporine dose was reduced in all patients above target. In this group, serum creatinine level was stable overall, but fell significantly in 46 (54%) of 85 from 153+/-55 to 132+/-49 microM. Blood pressure also fell in that group from 135/82 to 131/77. Serum creatinine level was stable in the remaining two groups of patients. CONCLUSIONS: These data suggest that dose reduction in many overexposed patients leads to improvements in renal function and blood pressure. Further study is required to confirm the long-term benefits of this strategy.     

How much heparin do we really need to go on pump? A rethink of current practices.

OBJECTIVES: Patients undergoing myocardial revascularisation using extracorporeal circulation require heparin anticoagulation. We aimed to evaluate the effect of reducing heparin dosage on target activated clotting time (ACT) and postoperative blood loss. METHODS: In a prospective randomised trial, 195 patients undergoing isolated primary CABG were randomised into four groups A, B, C, and D receiving an initial heparin dosage of 100, 200, 250 and 300 iu/kg, respectively. Extra incremental heparin (50 iu/kg) was added if required to achieve a target ACT of 480 s before initiating cardiopulmonary bypass. Postoperative blood loss was measured from the time of heparin reversal to drain removal 24h later. RESULTS: Target ACT was achieved in 0, 63, 68.3 and 82.4% of patients in groups A, B, C and D, respectively, after the initial dose of heparin. In group B, of those not achieving target act a single increment of heparin was sufficient to achieve target ACT in further 18.6%. The mean ACT after the initial dose in groups B, C and D was 482.9, 519 and 588 s, respectively (P<0.05). Postoperative blood loss in millilitre per kilogram was directly proportional to preoperative heparin dose. CONCLUSIONS: Patients receiving lower dose of heparin has lower postoperative blood loss. Of those achieving the target ACT, group B was significantly the closest to the target ACT. A starting dose of 200 iu/kg of heparin and if necessary one 50 iu/kg increment achieved target ACT in 81.5% of patients. The added benefit of significant drop in postoperative blood loss is evident.     

肾茶胶囊对大鼠脏器长期毒性的实验研究

目的考察肾茶胶囊对大鼠脏器的长期毒性反应及毒性程度,研究毒性靶器官及其损伤的可逆性。方法大鼠灌胃给予肾茶胶囊1．62、4．86、14．58g／kg（约相当于人拟临床等效剂量的10、30、90倍）,设空白对照组,1次／d,连续灌胃给药24周后各剂量组随机处死,系统尸解,检查脏器系数。结果12周及24周高剂量组、中剂量组、低剂量组试验大鼠脏器系数指标与对照组相比,组间未见显著差异和异常改变,也未见毒理学意义变化和延迟性毒性反应。结论肾茶胶囊对脏器的长期毒性较低,未发现毒性靶器官,可安全地应用于临床。     

Dosimetric comparison of CyberKnife with other radiosurgical modalities for an ellipsoidal target

OBJECTIVE: To compare treatment plans obtained with the CyberKnife (CK) (Accuray, Inc., Sunnyvale, CA) with those of other commonly used radiosurgical modalities, such as the gamma knife (GK), linear accelerator multiple arcs, conformally shaped static fields, and intensity-modulated radiotherapy (IMRT). METHODS: An ellipsoidal simulated target was chosen centrally located in a three-dimensional model of a patient's head acquired with magnetic resonance or computed tomographic imaging. It was 25 mm in diameter and 35 mm long. The aims of treatment plans were 100% target volume coverage with an appropriate isodose line, minimum radiation dose to normal tissue, and clinically acceptable delivery. These plans were evaluated by use of a dose-volume histogram and other commonly used radiosurgical parameters such as target coverage, homogeneity index, and conformity index. RESULTS: All selected treatment modalities were equivalent in providing full target coverage. For dose homogeneity, all modalities except for multiple isocenter plans for GK (homogeneity index, 2.0) were similar (homogeneity index, congruent with 1.25). Dose conformity was essentially equivalent for all treatment plans except for IMRT, which had a slightly higher value (conformity index, congruent with 1.27). There was a substantial variation in the radiation dose to normal tissue between the studied modalities, particularly at the lower dose levels. CONCLUSION: CK plans seemed to be more flexible for a given target size and shape. For a target of limited volume and essentially of any shape, one could obtain similarly good conformal dosimetry with CK and GK. For a regular-shaped but other than spherical target, homogeneous dose distribution could be obtained with all selected modalities except for multiple isocenters, linear accelerator multiple arcs, or GK. Both IMRT and conformally shaped static fields offered good alternative treatment modalities to CK, GK, or linear accelerator multiple arc radiosurgery, with slightly inferior dosimetry in conformity (IMRT).     

减小非小细胞肺癌三维适形放射治疗靶体积可行性剂量学研究

目的从剂量学探讨减小非小细胞肺癌三维适形放射治疗照射体积的可行性。方法32例非小细胞肺癌患者均做2个放射治疗计划：常规照射野三维适形放射治疗计划和小野三维适形放射治疗计划,用剂量体积直方图评估肿瘤靶区剂量和正常组织受照剂量。结果小野三维适形放射治疗仍能满足肿瘤靶区剂量的要求,亚临床灶的最小剂量、最大剂量和平均剂量分别为50．93Gy、54．60Gy和（52．37±1．02）Gy。与常规适形野相比,小野适形放疗减少了患侧肺、脊髓和食管的平均剂量（P〈0．05）。结论缩小非小细胞肺癌三维适形放射治疗照射野能满足肿瘤靶区剂量的需要,同时降低了正常组织的受照剂量,可在临床开展相关研究。     

The dual serotonin and noradrenaline reuptake inhibitor duloxetine for the treatment of interstitial cystitis: results of an observational study

PURPOSE: We report an observational study to evaluate the efficacy and tolerability of duloxetine for interstitial cystitis. MATERIALS AND METHODS: A total of 48 women were prospectively treated for 2 months following an uptitration protocol to the target dose of 2 x 40 mg duloxetine per day. Patients received the target dose for 5 weeks. The efficacy of duloxetine treatment was assessed at week 8. The primary end point was a change in the overall well-being evaluated by a patient reported global response assessment. Secondary end points were changes in pain and urgency (visual analog scales), frequency and functional bladder capacity (48-hour voiding log), and changes in overall symptom severity (O'Leary-Sant index). RESULTS: There were 5 patients (10.4%) who were identified as responders and 17 patients (35.4%) who dropped out of the study exclusively due to side effects, with nausea present in all dropouts. No severe adverse events were reported. All 5 responders reported onset of symptom improvement but not until they had reached the target dose. Regarding secondary outcome parameters, duloxetine treatment did not result in statistically significant improvement of symptoms. Maximum urinary flow rate and residual volume were influenced more prominently in patients at the target dose, however, the changes did not appear to be clinically meaningful. CONCLUSIONS: Treatment of interstitial cystitis with duloxetine did not result in significant improvement of symptoms. The drug administration was safe but the tolerability of the drug was poor mainly due to nausea occurring with the starting dose of 20 mg per day. Based on the preliminary data of this observational trial we currently cannot recommend duloxetine as a therapeutic approach for interstitial cystitis.     

Stereotactic radiosurgery of intracranial tumors in childhood

The Authors have developed an original stereotactic technique by which the radiation dose erogated by a 4 MV linear accelerator is focused into the target volume with a steep dose gradient at its borders. The technique has been employed in a series of 30 patients affected by deep seated brain tumors and AVMs. The paper deals with the preliminary results obtained in a series of 10 patients in pediatric age.     

Physics for radiosurgery with linear accelerators.

Radiosurgery had a long development period and, for more than three decades, was used only in a few specialized centers around the world. The development of LINAC-based radiosurgical techniques combined with the concurrent advances in imaging modalities during the 1980s, however, caused so much interest in this treatment modality that most major radiotherapy centers now offer this service or at least plan to offer it in the near future. When considering a LINAC for radiosurgical use, one should remember that technical and clinical requirements for accurate radiosurgery are far more stringent than those applied to standard radiotherapy. This is because in radiosurgery, the targeted volumes are much smaller and the dose is usually delivered in a single irradiation session, whereas in radiotherapy, the dose is delivered to a relatively large target volume on a fractionated basis. Linear accelerator-based radiosurgery broadens the scope of radiotherapy departments. The impetus to introduce this service at a medical center usually comes from neurosurgeons, however. Even after the service becomes routine at an institution, it is the neurosurgeon who refers the patient and who plays the most important role in determining the target volume and its location within the brain. The decision on the choice of isodose surface and the prescribed dose, however, belongs to the radiotherapist. It is becoming clear that radiosurgery is a complex treatment modality for which a successful outcome requires a collaborative team effort by several hospital-based professionals, including neurosurgeons, radiation oncologists, neuroradiologists, and medical physicists. As in standard radiotherapy, physics plays an important role in radiosurgery, not only in the development of target localization, treatment-planning, and dose delivery techniques, but also in the actual patient contact, from the diagnostic target localization procedures, through treatment planning, to patient preparation on the device and dose delivery.     

Extracranial Stereotactic Radiosurgery of Localized Targets

A method for extracranial stereotactic radiosurgery (ESRS) is described. For this treatment method a stereotactic body frame was developed and is described here. The ESRS method uses a hypofractionation schedule with 2–3 fractions with 10–20 Gy/fraction to the periphery of the target volume, at the 65% isodose. The heterogeneous target dose is used as a means to increase the probability of killing the hypoxic tumor cells. It is argued from in vitro cell survival data that the dose increase used will give a reasonable probability to eradicate at least moderate concentrations of hypoxic cells. A high reproducibility of the target position with the ESRS method is based on the definition of the patient reference system to the stereotactic system and not to the bony anatomical reference points as used in conventional radiotherapy. Important to the ESRS method is that the target position is verified by computed tomography (CT) examinations. The positional accuracy of the target in the stereotactic system is 3.1 mm (mean deviation) in the transversal plane and 5.5 mm (mean deviation) in the longitudinal direction. The setup accuracy, i.e., the correct alignment of the stereotactic system to the isocenter of the treatment unit, is within 1 mm. Other aspects of the ESRS method that are discussed are the treatment technique including collimation methods and dose distributions used, as well as target margins. ESRS has been in clinical use for several years at Radiumhemmet, Karolinska Hospital.     

Dosimetric comparison of absolute and relative dose distributions between tissue maximum ratio and convolution algorithms for acoustic neurinoma plans in Gamma Knife radiosurgery

Background

The treatment planning for Gamma Knife (GK) stereotactic radiosurgery (SRS) that performs dose calculations based on tissue maximum ratio (TMR) algorithm has disadvantages in predicting dose in tissue heterogeneity. The latest version of the planning software is equipped with a convolution dose algorithm as an optional extra and the new algorithm is able to compensate for head inhomogeneity. However, the effect of this improved calculation method requires detailed validation in clinical cases. In this study, we compared absolute and relative dose distributions of treatment plans for acoustic neurinoma between TMR and the convolution calculation.

Methods

Twenty-nine clinically used plans created by TMR algorithm were recalculated by convolution method. Differences between TMR and convolution were evaluated in terms of absolute dose (beam-on time), dosimetric parameters including target coverage, selectivity, conformity index, gradient index, radical homogeneity index and the dose-volume relationship.

Results

The discrepancy in estimated absolute dose to the target ranged from 1 to 7 % between TMR and convolution. In addition, dosimetric parameters of the two methods achieved statistical significance. However, it was difficult to see the change of relative dose distribution by visual assessment on a monitor.

Conclusions

Convolution, heterogeneity correction calculation, and the algorithm are necessary to reduce the dosimetric uncertainty of each case in GK SRS.     

Apparent low absorbers of cyclosporine microemulsion have higher requirements for tacrolimus in renal transplantation

Bioavailability and exposure of cyclosporine microemulsion and tacrolimus in renal transplantation are governed by many complex factors. Failure to achieve therapeutic two-h post-dose (C(2)) levels despite adequate doses of cyclosporine ("low absorbers") may merit conversion to tacrolimus. We compared tacrolimus dose requirements in "low absorbers" (n = 15) with a random control group of de novo tacrolimus patients (n = 14). Low absorbers failed to reach target C(2) despite increasing dose from 10.1 to 16.2 mg/kg/d. At conversion the mean C(2) was 969 ng/mL (95% CI: 684-1255; target 1700 ng/mL). Low absorbers tended to be younger, heavier, and diabetic. Despite a similar initial tacrolimus dose (0.17-0.18 mg/kg/d), low absorbers required a much higher daily dose to achieve target; 0.25 vs. 0.16 mg/kg/d (p = 0.016). Furthermore, daily maintenance tacrolimus remained much higher in low absorbers at three wk (0.22 vs. 0.13 mg/kg/d, p = 0.012). Although not statistically significant, this group experienced an acute rejection rate of 33%, compared with 21% in the control group. Patients treated with cyclosporine as initial immunosuppression who fail to reach target C(2) levels in a timely fashion are at risk for impaired bioavailability of tacrolimus. Based on our data, a starting dose of 0.25 mg/kg/d in divided doses may be warranted for low absorbers converting to tacrolimus; however, we encourage larger studies with formal pharmacokinetic analysis in this population.     

缓激肽体外选择性开放血肿瘤屏障的机制

目的原代培养大鼠脑微血管内皮细胞及星形胶质细胞，在体外探讨不同剂量缓激肽的作用靶细胞。方法细胞原代培养成功后，运用免疫荧光测定脑血管内皮细胞、星形胶质细胞及C6胶质瘤细胞在不同剂量缓激肽作用前后的细胞内钙离子变化，根据给药前后的荧光改变来确定大、小剂量缓激肽的作用靶点细胞。结果小剂量缓激肽可以引起肿瘤细胞内的钙离子水平升高。而只有大剂量缓激肽才能触发星形胶质细胞内的钙离子水平变化，脑微血管内皮细胞对大、小剂量缓激肽均无任何反应。结论缓激肽的直接作用靶点是胶质细胞及肿瘤细胞，缓激肽调节脑血管内皮细胞通透性的作用可能需要某些细胞间信使的参与。     

Optimal dose and target trough level in cyclosporine and tacrolimus conversion in renal transplantation as evaluated by lymphocyte drug sensitivity and pharmacokinetic parameters

We evaluated the relative clinical potency of cyclosporine (CyA) and tacrolimus (Tac) using pharmacodynamic and pharmacokinetic parameters of the drug to obtain the most suitable converting dose and target trough level. The relative pharmacodynamic potency was examined by the mean ratio of drug concentrations giving 50% inhibition of blastogenesis of lymphocytes (IC50) in 66 chronic renal failure patients. The relative potency estimated from clinical pharmacokinetic parameters was examined by the mean ratio of each pharmacokinetic parameter value of CyA versus Tac. The pharmacokinetic parameters were estimated by 12-hour monitoring of drug blood concentrations in seven CyA patients and seven Tac patients. The mean IC50 ratio of CyA and Tac (CyA/Tac of IC50) was 25.1. The mean area under the concentration-time curve (AUC) ratio (CyA/Tac of AUC) was 25.5, the mean trough level (C(min)) ratio (CyA/Tac of C(min)) was 13.2, and the mean dose per body weight ratio was 25.2. The relative potency estimated from AUC that is the most reliable pharmacokinetic parameter for the estimation of clinical efficacy of calcineurin inhibitors appeared to agree with the relative pharmacodynamic potency estimated from IC50. The data suggest that TAC 25-fold more potent than CyA, which represents a suitable converting dose ratio, and that target trough level of CyA is about 13-fold greater than Tac based on CyA/Tac of C(min). We conclude that these relative values may be useful to estimate the suitable dose and target trough levels to convert between CyA and Tac.     

Comparison of intensity modulated radiotherapy and dynamic three-dimensional conformal radiotherapy with regard to dose distribution and sparing of organs at risk

Dose escalation to the target while sparing the organs at risk near the lesion has been difficult over the last decade. However, recent radiotherapy techniques can deliver more sophisticated doses to the target. This study evaluated whether intensity modulated radiotherapy can deliver more homogeneous and conformal doses to the target than dynamic three-dimensional conformal radiotherapy while sparing organs at risk near the lesion in 13 patients with central nervous system tumors and other tumors around the central nervous system. Dynamic three-dimensional conformal radiotherapy and intensity modulated radiotherapy plans were calculated and dose distributions were compared for all patients with regard to the planning target volume and organs at risk. The plan of intensity modulated radiotherapy was significantly superior to that of dynamic three-dimensional conformal radiotherapy in target dose conformity (p = 0.0006) and organs at risk sparing (p = 0.0257). Intensity modulated radiotherapy could deliver more homogeneous and conformal doses to the target than dynamic three-dimensional conformal radiotherapy with sparing organs at risk near the lesion and may improve local control of radioresistant tumors via dose escalation.