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PubMedDate not supplied

[Side effects and efficiency of 15 mg and 25 mg methotrexate per week in chronic polyarthritis].

To examine the rate of side effects and the dose dependence of side effects 185 consecutive patients with active rheumatoid arthritis were randomized to receive 15 mg (group A) or 25 mg (group B) methotrexate (MTX) per week and studied prospectively over 12 months. Dose adjustments were performed according to tolerability and efficacy. With 168 patients eligible for evaluation the rate of withdrawal for any reason was 26% in group A and 27% in B. Withdrawal due to side effects occurred in 16% versus 18%, dose reduction due to side effects in 10% versus 9%. The higher dose was associated with a significantly higher rate of gastrointestinal side effects (28% vs. 17%, p < 0.05) and a tendency for more frequent elevations of transaminases. Other side effects were not dose dependent. A significantly higher rate of dose reduction due to improvement (35% versus 10%, p < 0.001), a more rapid decline of morning stiffness, and a higher number of patients reporting marked improvement are evidence in favour of higher therapeutic efficacy of the higher dose. In conclusion, an initial dose of 25 mg MTX/week is not associated with a higher rate of limiting side effects as compared with 15 mg/week. The efficacy of doses up to 25 mg/week should be examined in more detail.

Adult↗
PubMed2005

Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer.

PURPOSE: ABI-007 is a novel nanoparticle, albumin-bound paclitaxel that is free of solvents. This multicenter phase II study was designed to evaluate the efficacy and safety of ABI-007 for the treatment of metastatic breast cancer (MBC). PATIENTS AND METHODS: Sixty-three women with histologically confirmed and measurable MBC received 300 mg/m2 ABI-007 by intravenous infusion over 30 minutes every 3 weeks without premedication. Forty-eight patients received prior chemotherapy; 39 patients received no prior treatment for metastatic disease. RESULTS: Overall response rates (complete or partial responses) were 48% (95% CI, 35.3% to 60.0%) for all patients. For patients who received ABI-007 as first-line and greater than first-line therapy for their metastatic disease, the respective response rates were 64% (95% CI, 49.0% to 79.2%) and 21% (95% CI, 7.1% to 42.1%). Median time to disease progression was 26.6 weeks, and median survival was 63.6 weeks. No severe hypersensitivity reactions were reported despite the lack of premedication. Toxicities observed were typical of paclitaxel and included grade 4 neutropenia (24%), grade 3 sensory neuropathy (11%), and grade 4 febrile neutropenia (5%). Patients received a median of six treatment cycles; 16 patients had 25% dose reductions because of toxicities, and two of these patients had subsequent dose reductions. CONCLUSION: ABI-007, the first biologically interactive albumin-bound form of paclitaxel in the nanoparticle state, uses the natural carrier albumin rather than synthetic solvents to deliver paclitaxel and allows for safe administration of high paclitaxel doses without premedication, resulting in significant antitumor activity in patients with MBC, including those receiving the drug as first-line therapy.

Adult↗
PubMed1994

Investigating severe and fatal asthma.

BACKGROUND: Severe asthma continues to present a major therapeutic problem despite advances in our understanding of the disease. Innovative ideas for investigating the underlying causes and treatment of severe asthma are few, and many patients still become dependent on oral steroids. We describe two separate studies: first, a prospective investigation measuring the responses of persons with severe asthma to an allergen-free environment; second, a retrospective analysis of factors associated with eight fatalities and one near fatality caused by asthma exacerbations. METHODS: In the prospective study 17 persons with severe asthma were admitted to a hospital clinical research unit containing an allergen-free room for steroid dose reduction. Peak flow measurements, treatment requirements, and evidence of infection were followed up. In the retrospective study, the cases of nine patients who had been evaluated for asthma and who subsequently died during an asthma attack were reviewed; where possible allergen levels in their house dust and specific IgE antibodies to common indoor allergens were measured. RESULTS: Analysis of the patients in the prospective study revealed two categories of responses to steroid dose reduction: (1) asthmatic persons who either maintained or improved peak flow values on steroid reduction; these patients were predominantly allergic to indoor allergens; (2) asthmatic persons whose condition deteriorated; these patients were unable to tolerate reduction in steroid dose. The second group included persons with sensitization to fungal antigens who had asthmatic exacerbations in association with culture-documented fungal colonization. The retrospective study revealed that in five of the eight fatalities caused by asthma, exposure to a relevant allergen had occurred at home before death. CONCLUSION: Some steroid-dependent persons with severe asthma are allergic to inhalant allergens and may benefit from avoiding allergens. In some cases there is no evidence that antigen exposure from diet, inhalants, fungal infections, or sinusitis is relevant to their disease. However, persons with severe asthma include individuals infected with and sensitized to fungal antigens. The results suggest that cases of severe asthma should be investigated to identify treatable causes.

Adrenal Cortex Hormones↗
PubMed1989

Cerebrospinal fluid GABA and seizure control with vigabatrin.

1. To evaluate the relationship between the clinical response and enhancement of GABAergic neurotransmission, for 6 months we administered vigabatrin (gamma-vinyl-GABA, GVG) to 75 patients with complex partial epilepsy. Total GABA (TGABA), free GABA (FGABA), homocarnosine (HC), and GVG concentrations were measured in CSF of these patients before and during GVG treatment. 2. Over 50% reduction in seizures was found in 55% of the patients. Dose-reduction resulted in a relapse, i.e. the return of seizures. 3. At baseline TGABA, FGABA, and HC did not differ in responders and nonresponders. After GVG treatment, the TGABA and HC levels were lower in nonresponders (P less than 0.001), but the GVG and FGABA levels did not differ. The GVG dose reduction resulted in a concomitant decrease in TGABA, FGABA, HC and GVG (P less than 0.001). 4. According to our results GVG is an effective anticonvulsant drug in complex partial seizures. In nonresponders the poor anticonvulsant response may be related to the lower elevation of the CSF markers of GABAergic neuronal activity in this group compared with the responders.

Adolescent↗
PubMed2000

[Reduction of the radiation exposure of patients caused by selected interventional and angiographic procedures].

PURPOSE: To reduce patient doses caused by selected interventional and angiographic procedures using the digital C-arm unit "Multiskop". MATERIALS AND METHODS: After a patient study done previously, physical measurements with test phantoms were carried out, and physical-technical parameters such as distance between focus and image intensifier, additional filtration, and radiation dose per image were optimised. Then, the dose-area product (DAP) and the fluoroscopic time were measured for 130 percutaneous transluminal angioplasties (PTA), 40 PTA with stent implantation, 61 embolisations, and 302 digital subtraction angiographies (DSA). In the case of 16 PTA, 9 embolisations, and 38 DSA the number of radiographs was determined, and the DAP was divided into two parts, fluoroscopy and radiography. The measuring values were compared with data of the patient study done previously. RESULTS: The median values of the DAP and the fluoroscopic time amounted to 25 Gy cm2 and 9.7 min for PTA, 97 Gy cm2 and 8.5 min for PTA with stent implantation, 88 Gy cm2 and 17.2 min for embolisation as well as 54 Gy cm2 and 2.8 min for DSA. For the relation between DAP caused by fluoroscopy and radiography, and the number of radiographs, median values of 0.76 and 63 for PTA, 0.81 and 123 for embolisation as well as 1.85 and 134 for DSA were determined. In comparison to the patient study done previously the median values of the DAP were reduced by 31% for PTA, 26% for PTA with stent implantation, 55% for embolisation, and 38% for DSA. CONCLUSIONS: The comparison between the patient studies done previously and recently indicates the great potential of dose reduction for interventional and angiographic procedures. Although the X-ray equipment is ten years old the patient dose can be reduced by organizational and physical-technical modifications to such an extent that preliminary national reference dose values will not be exceeded. For further significant dose reductions while maintaining adequate image quality it will be necessary to purchase a modern X-ray equipment with pulsed fluoroscopy and automatic filter selection.

Angiography↗
PubMed1994

Monitoring for anthracycline cardiotoxicity.

OBJECTIVE: To review the basis for recommendations of the Cardiology Committee of the Children's Cancer Study Group, published in Pediatrics, for serial cardiac monitoring of cancer patients during anthracycline therapy and reduction of therapy should cardiac studies show abnormalities. DESIGN: Because the effects of overall morbidity and mortality should be considered when a recommendation is made to withhold potentially lifesaving chemotherapy based on abnormal cardiac findings of patients without clinical evidence of cardiac dysfunction, supporting studies referenced in the published recommendations were reviewed. Specifically, studies were evaluated to determine whether a reduction in anthracycline dose, as a result of abnormal cardiac findings by monitoring, reduced cardiac morbidity and related mortality compared with a prospectively followed control population without dose modification. In addition, the effects of cardiac monitoring and subsequent anthracycline dose modification on oncologic morbidity and mortality were reviewed in these studies. Finally, the contributions of the cardiac and oncologic effects of dose modification were examined to determine the effect of this change in therapy on overall morbidity and mortality. RESULTS: None of the studies cited in developing these recommendations prospectively determined, with controls, the effects of cardiac monitoring and anthracycline dose modification on cardiac, oncologic, or overall morbidity and mortality. Therefore, none of the studies cited in support of cardiac monitoring and subsequent dose reduction demonstrated the efficacy of such an approach. In the absence of such data, concerns are raised as to whether such a monitoring program with subsequent dose modification might do more harm than good. In addition, none of the methods of screening for anthracycline cardiotoxicity has been shown to be adequately predictive of early or late cardiac outcomes. Finally, adoption of these recommendations would inhibit the investigation of the efficacy of the proposed plan. CONCLUSION: Given the absence of supportive data and the potential to do harm, no recommendation for dose modification based on abnormal cardiac findings in patients without clinical evidence of cardiotoxicity can be endorsed, including those of the Cardiology Committee of the Children's Cancer Study Group. When clinical evidence of cardiotoxicity is present, anthracycline dose modification is recommended. A prospective controlled study to determine the effects of dose modification based on cardiac test results is indicated.

Antibiotics, Antineoplastic↗
PubMed1998

Dose-dependent reduction of the minimum local analgesic concentration of bupivacaine by sufentanil for epidural analgesia in labor.

BACKGROUND: The minimum local analgesic concentration (MLAC) has been defined as the median effective local analgesic concentration in a 20-ml volume for epidural analgesia in the first stage of labor. The aim of this study was to determine the local anesthetic-sparing efficacy of epidural sufentanil by its effect on the MLAC of bupivacaine. METHODS: In this double-blind, randomized, prospective study, 147 parturients at < or = 7 cm cervical dilation who requested epidural analgesia were allocated to one of four study groups. After a lumbar epidural catheter was placed, study participants received 20 ml bupivacaine (n = 38), bupivacaine with sufentanil 0.5 microg/ml (n = 38), bupivacaine with sufentanil 1 microg/ml (n = 33), or bupivacaine with sufentanil 1.5 microg/ml (n = 38). The concentration of bupivacaine was determined by the response of the previous patient using up-down sequential allocation. The analgesic efficacy was assessed using 100-mm visual analog pain scores, with < or = 10 mm within 30 min defined as effective. RESULTS: The MLAC of bupivacaine alone was 0.104% wt/vol (95% CI, 0.090-0.117). The addition of sufentanil at doses of 0.5 microg/ml, 1 microg/ml, and 1.5 microg/ml resulted in significant reductions (P < 0.0001) in the MLAC of bupivacaine to 0.048% wt/vol (95% CI, 0.030- 0.065), 0.021% wt/vol (95% CI, 0-0.055), and 0.009% wt/vol (95% CI, 0-0.023), respectively. CONCLUSIONS: This study showed a significant (P < 0.0001) dose-dependent reduction in the MLAC ofbupivacaine by sufentanil.

Analgesia, Epidural↗
PubMed2000

An off-line strategy for constructing a patient-specific planning target volume in adaptive treatment process for prostate cancer.

PURPOSE: To improve the efficacy of dose delivery and dose escalation for external beam radiotherapy of prostate cancer, an off-line strategy for constructing a patient-specific planning target volume is developed in the adaptive radiotherapy process using image feedback of target location and patient setup position. MATERIALS AND METHODS: We hypothesize that a patient-specific confidence-limited planning target volume (cl-PTV), constructed using an initial sequence of daily measurements of internal target motion and patient setup error, exists and ensures that the clinical target volume (CTV) in the prostate cancer patient receives the prescribed dose within a predefined dose tolerance. A patient-specific bounding volume to correct for target location and compensate for target random motion was first constructed using the convex hull of the first k days of CT measurements. The bounding volume and the initial days of CT measurements were minimized based on a predefined dosimetric criterion. The hypothesis was tested using multiple daily CT images by mimicking the actual treatment of both conventional 4-field-box and intensity-modulated radiotherapy (IMRT) on each of 30 patients with prostate cancer. For each patient, a patient-specific setup margin was also applied to the bounding volume to form the final cl-PTV. This margin was determined using the random setup error predicted from the initial days of portal imaging measurements and the residuals after correcting for the systematic setup error. RESULTS: The bounding volume constructed using daily CT measurements in the first week of treatment are adequate for the conventional beam delivery to achieve maximum dose reduction in the CTV of 2% or less of the prescription dose, for at least 80% of patients (p = 0.08), and 4.5% or less for 95% of patients (p = 0.1). However, for IMRT delivery, 2 weeks of daily CT measurements are required to achieve a similar level of the dosimetric criterion, otherwise the maximum dose reduction of 7%, on average, in the CTV is expected. Furthermore, the patient-specific setup margin required for the IMRT treatment is at least twice larger than that for the conventional treatment, to maintain the same dosimetric criterion. As compared to the conventional PTV, the volume of cl-PTV is significantly reduced, while maintaining the same dosimetric criterion. CONCLUSION: The cl-PTV for prostate treatment can be constructed within the first week of treatment using the feedback of imaging measurements. The cl-PTV has the capability to exclude the systematic variation and compensate for the patient-specific random variation on target location and patient setup position. This implies that in the current off-line image feedback adaptive treatment process, a single plan modification can be performed within the second week of treatment to improve the efficacy of dose delivery and dose escalation for external beam therapy of prostate cancer.

Algorithms↗
PubMed2000

Timing of midazolam and propofol administration for co-induction of anaesthesia.

We aimed to determine the optimum timing of midazolam administration prior to propofol to achieve the maximal reduction in the dose of propofol required to induce anaesthesia. Female (ASA 1-2) patients, aged 18 to 45 years, weighing 40 to 75 kg and scheduled for gynaecological surgery were eligible for the study. Consenting patients were randomly assigned to six groups. Group 1 received saline and Groups 2 to 6 received midazolam 3 mg at 1, 2, 4, 6 or 10 minutes respectively prior to propofol (n = 20 to 22 per group) in a blinded manner. Propofol was administered i.v. over 10 seconds and flushed in with saline 5 ml. Two minutes later, the patient's response to pressure applied to the finger was determined as an index of loss of consciousness. The ED50 of propofol in each group was determined by the up-and-down method. Propofol ED50 was reduced to 34 to 67% (P < 0.001) in the midazolam treated groups. There was no significant (P = 0.14) difference in propofol ED50 among the five groups which received midazolam. Patients who received midazolam had less recollection of events surrounding induction (P < 0.001) and recalled the induction experience as being more pleasant (P = 0.03) than those who did not receive midazolam. These results indicate that midazolam may be given up to 10 minutes prior to propofol and still achieve a substantial dose reduction.

Adult↗
PubMed2004

[Low-dose spiral CT of the lung in the follow-up of non-malignant lung disease].

PURPOSE: To assess image quality of chest CT with an 80 to 90 percent dose reduction in follow-up studies of patients with lung disease, dose and image quality of a low-dose protocol was investigated. MATERIALS AND METHODS: A follow-up low-dose CT (ND-CT, 120 kV, 10 mAs/slice, 3 mm slice thickness) was performed on 35 patients with non-malignant lung disease and compared with the initial standard dose CT (= SD-CT, 100 mAs/slice, 3 or 5 mm slice thickness). The dose was measured by thermo-luminescence in an Alderson phantom. Image quality was assessed by four independent radiologists in six perihilar, central and peripheral lung regions using a 4-point-scale ("very good", "good", "moderate", and "poor"). RESULTS: Effective dose was 0.5 mSv for ND-CT and 4.0 - 5.0 mSv for SD-CT. The ratings "very good"/"good" were given in the perihilar regions in ND-CT 97.5 % versus SD-CT 99.3 % (n. s.), in the central regions in ND-CT 96.4 % versus SD-CT 94.6 % (n. s.), and in the peripheral regions in ND-CT 70.0 % versus SD-CT 88.2 % (p < 0.01). CONCLUSION: Follow-up CT of pulmonary structures in patients with chronic lung disease can be performed with substantial dose reduction. A decrease of image quality may result in peripheral lung regions.

Adolescent↗
PubMed2002

A method to obtain the same levels of CT image noise for patients of various sizes, to minimize radiation dose.

The aim of this study was to develop a method of obtaining the same levels of CT image noise for patients of various sizes to minimize radiation dose. Two CT systems were evaluated regarding noise characteristics using phantoms and dosimetric measurements. Both CT systems performed well at dose levels used in normal clinical imaging, but only one was found to be suitable for low radiation dose applications. The CT system with the lowest noise level was used for further detailed studies. A simple strategy for manual selection of patient-specific scan parameters, considering patient size and required image quality, was implemented and verified on 11 volunteers. Images were obtained with at least the prescribed image quality at significantly reduced radiation dose levels compared with standard scan parameters. Depending on the diameter of the tomographic section, i.e. size of the subject, the dose levels could be reduced to 1-45% of the radiation dose with standard scan parameters (120 kV, 250 mAs, 10 mm). The results indicate a general potential for dose reduction in CT for slim patients. For tissue volume determination, large dose reductions can be achieved by adjusting the scan parameters for each individual. The concept of patient-specific scan parameters could be fully automated in the CT system design, but would require the scan to be specified in terms of image quality rather than X-ray tube load.

Adult↗
PubMed1996

[Initial experiences with pulsed fluoroscopy on a multifunctional fluoroscopic unit].

PURPOSE: Comparison of radiation doses in pulsed and continuous fluoroscopy to quantify the dose reduction by pulsed fluoroscopy. Further, the applicability of pulsed fluoroscopy in clinical routine has been evaluated. MATERIALS AND METHODS: In a human pelvic phantom, the radiation dose (skin entry dose in cGycm2) was measured at two pulses per second (pps), 3 pps, 6 pps, 12 pps and continuous fluoroscopy mode, respectively, using image-intensifier entries of 38 cm, 25 cm, and 17 cm. 300 examinations were carried out, and the results of the different fluoroscopy modes were registered. RESULTS: Dose reduction depends on the image-intensifier entry. Compared to the radiation dose in continuous fluoroscopy, with 12 pps fluoroscopy the radiation dose can be reduced at a minimum of 51%, with 6 pps fluoroscopy to 40%, with 3 pps fluoroscopy to 20%, and with 2 pps fluoroscopy to a minimum of 14.5%. Clinical routine has shown that 78% of all examinations can be performed with 2 or 3 pps fluoroscopy mode. In 12.7% of the cases pulsed fluoroscopy of diverse frequencies was used, in an additional 2% combined with continuous fluoroscopy. Exclusively, continuous fluoroscopy has been employed in 2% of the cases. CONCLUSIONS: Using pulsed fluoroscopy, an 80% reduction of the radiation dose compared to continuous fluoroscopy is possible. About 96% of all examinations can be performed with pulsed fluoroscopy of different pulse rate and without using continuous fluoroscopy.

Diagnostic Tests, Routine↗
PubMed2004

Effect of growth hormone replacement therapy on pituitary hormone secretion and hormone replacement therapies in GHD adults.

OBJECTIVE: We tested the impact of commencement of GH replacement therapy in GH-deficient (GHD) adults on the circulating levels of other anterior pituitary and peripheral hormones and the need for re-evaluation of other hormone replacement therapies, especially the need for dose changes. METHODS: 22 GHD patients were investigated in a double-blind randomized study and 90 GHD patients in an open study at baseline and after 6 and 12 months of GH replacement therapy. RESULTS: In the placebo-controlled trial, the FT(3) levels increased after 6 months in the GH-treated group, and in the open study the FT(3) levels tended to increase. Other hormone concentrations did not change in either part of the study. Four patients required an increase in thyroxine dose, while 2 patients needed dose reduction. One originally euthyroid patient required thyroxine replacement. Two patients with originally conserved pituitary-adrenal function developed ACTH insufficiency. The hydrocortisone dose was increased in 1 and decreased in 1 of the 66 patients with secondary hypocortisolism. None of the females required any adjustment of sex hormone replacement therapy. Two of 37 males needed dose increase of testosterone, while 1 needed dose reduction. CONCLUSION: GH replacement therapy required dose adjustments regarding other hormone replacement therapies in 12.2% (n = 11), while initiation of new hormone replacement was performed in 3.3% (n = 3) of the 90 patients during the 1-year follow-up. Monitoring of pituitary hormone axes is advisable after commencement of GH replacement therapy, since changes of hormone replacement therapy was observed in a small but clinically significant number of patients.

Adult↗
PubMed2003

Early experience with sirolimus in lung transplant recipients with chronic allograft rejection.

BACKGROUND: Chronic lung allograft rejection, commonly manifest as obliterative bronchiolitis (OB/BOS), hinders long-term survival after lung transplantation (LT). OB/BOS is traditionally treated with augmented immunosuppression and results in short-term stabilization in pulmonary function for most patients. However, peribronchiolar fibroproliferation and airway obstruction usually recur despite initial improvements seen with increases in immunosuppression. In this observational, uncontrolled study, the effect of sirolimus, a novel immunosuppressant with anti-proliferative activity, was assessed in LT patients with OB/BOS. METHODS: Between June 1999 to November 2000, LT recipients with newly diagnosed or progressive OB/BOS received sirolimus in combination with a calcineurin inhibitor (CI) and prednisone. Pulmonary function, laboratory data and adverse effects were monitored for the first 24 weeks of therapy. RESULTS: Sirolimus was utilized in 12 LT recipients with OB/BOS. After drug initiation, 58% of patients required a reduction in CI dose to maintain appropriate CI trough concentrations. Despite CI dose reduction, serum creatinine rose in 75% of patients. Unexpected adverse effects included anemia of chronic disease (100%), edema (50%) and malignancy (17%). For the group, the rate of change in FEV(1) and FEF(25%-75%) was unchanged with sirolimus, but individual responses varied. CONCLUSIONS: For the group, the decline in pulmonary function was not affected by the addition of sirolimus. However, among individuals with rapidly declining pulmonary mechanics, sirolimus resulted in stabilization or improvement in pulmonary function. Significant adverse effects resulted from combination sirolimus plus CI therapy. Until optimal dosing strategies and a more complete adverse effect profile are established, combination therapy should be utilized cautiously in these patients.

Bronchiolitis Obliterans↗
PubMed1998

A randomized, double-blind study comparing the efficacy, safety and optimal dose of two formulations of cyclosporin, Neoral and Sandimmun, in patients with severe psoriasis. OLP302 Study Group.

This study compared the efficacy, safety and optimal dose of two formulations of cyclosporin, Sandimmun and Neoral, in patients with severe, chronic plaque-type psoriasis. Patients were randomized on a 1:1 basis to 24 weeks of treatment with Neoral (n = 152) or Sandimmun (n = 157). The starting dose of each formulation was 2.5 mg/kg per day. Dose increases to maintain efficacy were allowed after 4 weeks. In patients who achieved remission, the dose was down-titrated at 4-week intervals from week 16. The maximum permitted dose for each formulation was 5.0 mg/kg per day. Neoral produced a more rapid response than Sandimmun: remission rates were higher for Neoral during the first 8 weeks of treatment. The number of dose reductions for safety was similar in both treatment groups, but there were more dose increases to maintain efficacy in the Sandimmun group (198) than the Neoral group (146). The number of patients with dose reductions after week 16 was higher for Neoral (n = 83) than for Sandimmun (n = 73). The frequency and nature of adverse events were similar for both treatment groups. The mean dose required to control the disease was approximately 10% lower with Neoral and fewer dose changes were needed. The increased bioavailability and reduced pharmacokinetic variability of cyclosporin provided by the Neoral formulation may facilitate short-course, intermittent therapy.

Adolescent↗
PubMed2000

Biological aspects of conformal therapy.

Both conformal and intensity-modulated radiation therapy have great potential to further increase tumor control rates and decrease morbidity. A homogeneous escalation of 'biological' dose within a tumor should increase the likelihood of local cure, especially within the mid-range (e.g. 15% to 80%) of tumor control rates, and conversely, a lower control rate should follow a homogeneously reduced dose. However, when the dose to critical normal tissues is tightly constrained, the dose distributions within the treatment volume may necessarily be heterogeneous, and the effect on tumor control probability will depend upon the magnitude of over- or underdosage, and on the proportions of the tumor clonogen population receiving higher or lower than the nominal dose. Dose-volume histograms provide a measure of heterogeneity of dose within the planned treatment volume, but tumor control probability is also influenced by other variables, e.g. inherent tumor clonogen radiosensitivity and growth rates during a course of treatment, alpha/beta ratios, oxygenation and clonogen density throughout the target volume. Heterogeneity in these factors introduces heterogeneity in tumor responses and a less steep change in tumor control probability with change in dose, reducing the gains or losses that would be predicted to result from heterogeneity of dose. Similarly, modeling the effect of inhomogeneous dose distributions on estimates of probability of complications in normal tissues is hindered by uncertainty of estimates for alpha/beta ratios, especially for late-responding tissues, and lack of data on volume effects. Although the effects of dose inhomogeneity cannot be presented with sufficiently reliable quantitation to be directly applicable to dose prescriptions in radiation therapy, the relative influences of heterogeneities in dose and volume can be modeled to provide a framework for clinical decision-making. The magnitude of a dose reduction is the major determinant of decline in tumor control probability. A large dose reduction to even a small volume of tumor can profoundly decrease tumor control probability. Conversely, the most rapid improvement in tumor control probability occurs the closer to 100% the amount of tumor exposed to an increased dose. Escalation of dose is of little value unless it is distributed through most of the tumor: even very large increases in dose to small volumes are of little benefit.

Dose Fractionation, Radiation↗
PubMed2006

A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer.

PURPOSE: Patients with advanced cancer received temsirolimus (Torisel, CCI-779), a novel inhibitor of mammalian target of rapamycin, i.v. once daily for 5 days every 2 weeks to determine the maximum tolerated dose, toxicity profile, pharmacokinetics, and preliminary antitumor efficacy. EXPERIMENTAL DESIGN: Doses were escalated in successive cohorts of patients using a conventional phase I clinical trial design. Samples of whole blood and plasma were collected to determine the pharmacokinetics of temsirolimus and sirolimus, its principal metabolite. RESULTS: Sixty-three patients were treated with temsirolimus (0.75-24 mg/m(2)/d). The most common drug-related toxicities were asthenia, mucositis, nausea, and cutaneous toxicity. The maximum tolerated dose was 15 mg/m(2)/d for patients with extensive prior treatment because, in the 19 mg/m(2)/d cohort, two patients had dose-limiting toxicities (one with grade 3 vomiting, diarrhea, and asthenia and one with elevated transaminases) and three patients required dose reductions. For minimally pretreated patients, in the 24 mg/m(2)/d cohort, one patient developed a dose-limiting toxicity of grade 3 stomatitis and two patients required dose reductions, establishing 19 mg/m(2)/d as the maximum acceptable dose. Immunologic studies did not show any consistent trend toward immunosuppression. Temsirolimus exposure increased with dose in a less than proportional manner. Terminal half-life was 13 to 25 hours. Sirolimus-to-temsirolimus exposure ratios were 0.6 to 1.8. A patient with non-small cell lung cancer achieved a confirmed partial response, which lasted for 12.7 months. Three patients had unconfirmed partial responses; two patients had stable disease for >/=24 weeks. CONCLUSION: Temsirolimus was generally well tolerated on this intermittent schedule. Encouraging preliminary antitumor activity was observed.

Adult↗
PubMed1999

Ursodeoxycholic acid as adjunctive therapy for problematic type 1 autoimmune hepatitis: a randomized placebo-controlled treatment trial.

To evaluate the efficacy of ursodeoxycholic acid as adjunctive therapy in type 1 autoimmune hepatitis, 37 patients who had experienced treatment failure, repeated relapse, or incomplete response were randomized to ursodeoxycholic acid (13-15 mg/kg daily) or placebo for 6 months in addition to their usual corticosteroid schedule. Serum aspartate transaminase (70% vs. 31%, P =.04) and alkaline phosphatase (47% vs. 7%, P =.02) levels improved more commonly in the 21 patients randomized to ursodeoxycholic acid. Mean serum levels, however, were similar before and after the treatment period. The frequency of dose reduction or corticosteroid withdrawal was comparable in both groups (29% versus 31%, P >.9), and clinical improvement (48% vs. 44%, P >.9) or its absence (52% vs. 56%, P >.9) occurred as commonly in patients receiving ursodeoxycholic acid or placebo. The modified histological activity score (3.5 +/- 0.8 vs. 3. 5 +/- 0.9) and the modified fibrosis score (2.4 +/- 0.4 vs. 2.4 +/- 0.4) were similar before and after treatment with ursodeoxycholic acid and no different than after placebo therapy. We conclude that ursodeoxycholic acid can improve certain laboratory tests in problematic patients with type 1 autoimmune hepatitis when administered adjunctively for 6 months. Short-term therapy, however, does not facilitate reduction in the dose of corticosteroids or its withdrawal, affect clinical outcome, or reduce histological activity.

Adult↗