The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up

BACKGROUND: The role of adjuvant dose-intensive chemotherapy and its efficacy according to baseline features has not yet been established. PATIENTS AND METHODS: Three hundred and forty-four patients were randomized to receive seven courses of standard-dose chemotherapy (SD-CT) or three cycles of dose-intensive epirubicin and cyclophosphamide (epirubicin 200 mg/m(2) plus cyclophosphamide 4 mg/m(2) with filgrastim and progenitor cell support). All patients were assigned tamoxifen at the completion of chemotherapy. The primary end point was disease-free survival (DFS). This paper updates the results and explores patterns of recurrence according to predicting baseline features. RESULTS: At 8.3-years median follow-up, patients assigned DI-EC had a significantly better DFS compared with those assigned SD-CT [8-year DFS percent 47% and 37%, respectively, hazard ratio (HR) 0.76; 95% confidence interval 0.58-1.00; P = 0.05]. Only patients with estrogen receptor (ER)-positive disease benefited from the DI-EC (HR 0.61; 95% confidence interval 0.39, 0.95; P = 0.03). CONCLUSIONS: After prolonged follow-up, DI-EC significantly improved DFS, but the effect was observed only in patients with ER-positive disease, leading to the hypothesis that efficacy of DI-EC may relate to its endocrine effects. Further studies designed to confirm the importance of endocrine responsiveness in patients treated with dose-intensive chemotherapy are encouraged.

High-dose daunorubicin in older patients with acute myeloid leukemia

BACKGROUND: A complete remission is essential for prolonging survival in patients with acute myeloid leukemia (AML). Daunorubicin is a cornerstone of the induction regimen, but the optimal dose is unknown. In older patients, it is usual to give daunorubicin at a dose of 45 to 50 mg per square meter of body-surface area. METHODS: Patients in whom AML or high-risk refractory anemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square meter by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square meter (411 patients) or at an escalated dose of 90 mg per square meter (402 patients); this treatment was followed by a second cycle of cytarabine at a dose of 1000 mg per square meter every 12 hours [DOSAGE ERROR CORRECTED] for 6 days. The primary end point was event-free survival. RESULTS: The complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P=0.002); the rates of remission after the first cycle of induction treatment were 52% and 35%, respectively (P<0.001). There was no significant difference between the two groups in the incidence of hematologic toxic effects, 30-day mortality (11% and 12% in the two groups, respectively), or the incidence of moderate, severe, or life-threatening adverse events (P=0.08). Survival end points in the two groups did not differ significantly overall, but patients in the escalated-treatment group who were 60 to 65 years of age, as compared with the patients in the same age group who received the conventional dose, had higher rates of complete remission (73% vs. 51%), event-free survival (29% vs. 14%), and overall survival (38% vs. 23%). CONCLUSIONS: In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects. (Current Controlled Trials number, ISRCTN77039377; and Netherlands National Trial Register number, NTR212.)

Scleroderma Renal Crisis: A Rare but Severe Complication of Systemic Sclerosis

Scleroderma renal crisis (SRC) is a major complication in patients with systemic sclerosis (SSc). It is characterized by malignant hypertension and oligo/anuric acute renal failure. SRC occurs in 5% of patients with SSc, particularly in the first years of disease evolution and in the diffuse form. The occurrence of SRC is more common in patients treated with glucocorticoids, the risk increasing with increasing dose. Left ventricular insufficiency and hypertensive encephalopathy are typical clinical features. Thrombotic microangiopathy is detected in 43% of the cases. Anti-RNA-polymerase III antibodies are present in one third of patients who develop SRC. Renal biopsy is not necessary if SRC presents with classical features. However, it can help to define prognosis and guide treatment in atypical forms. The prognosis of SRC has dramatically improved with the introduction of angiotensin-converting enzyme inhibitors (ACEi). However, 5 years survival in SSc patients who develop the full picture of SRC remains low (65%). SRC is often triggered by nephrotoxic drugs and/or intravascular volume depletion. The treatment of SRC relies on aggressive control of blood pressure with ACEi, if needed in combination with other types of antihypertensive drugs. Dialysis is frequently indicated, but can be stopped in approximately half of patients, mainly in those for whom a perfect control of blood pressure is obtained. Patients who need dialysis for more than 2 years qualify for renal transplantation.

Use of gold markers for setup in image-guided fractionated high-dose-rate brachytherapy as a monotherapy for prostate cancer

BACKGROUND AND PURPOSE: In order to use a single implant with one treatment plan in fractionated high-dose-rate brachytherapy (HDR-B), applicator position shifts must be corrected prior to each fraction. The authors investigated the use of gold markers for X-ray-based setup and position control between the single fractions. PATIENTS AND METHODS: Caudad-cephalad movement of the applicators prior to each HDR-B fraction was determined on radiographs using two to three gold markers, which had been inserted into the prostate as intraprostatic reference, and one to two radiopaque-labeled reference applicators. 35 prostate cancer patients, treated by HDR-B as a monotherapy between 10/2003 and 06/2006 with four fractions of 9.5 Gy each, were analyzed. Toxicity was scored according to the CTCAE Score, version 3.0. Median follow-up was 3 years. RESULTS: The mean change of applicators positions compared to baseline varied substantially between HDR-B fractions, being 1.4 mm before fraction 1 (range, -4 to 2 mm), -13.1 mm before fraction 2 (range, -36 to 0 mm), -4.1 mm before fraction 3 (range, -21 to 9 mm), and -2.6 mm at fraction 4 (range, -16 to 9 mm). The original position of the applicators could be readjusted easily prior to each fraction in every patient. In 18 patients (51%), the applicators were at least once readjusted > 10 mm, however, acute or late grade > or = 2 genitourinary toxicity was not increased (p = 1.0) in these patients. CONCLUSION: Caudad position shifts up to 36 mm were observed. Gold markers represent a valuable tool to ensure setup accuracy and precise dose delivery in fractionated HDR-B monotherapy of prostate cancer.

Association of urethral toxicity with dose exposure in combined high-dose-rate brachytherapy and intensity-modulated radiation therapy in intermediate- and high-risk prostate cancer

INTRODUCTION: To report acute and late toxicities in patients with intermediate- and high-risk prostate cancer treated with combined high-dose-rate brachytherapy (HDR-B) and intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: From March 2003 to September 2005, 64 men were treated with a single implant HDR-B with 21 Gy given in three fractions, followed by 50 Gy IMRT along with organ tracking. Median age was 66.1 years, and risk of recurrence was intermediate in 47% of the patients or high in 53% of the patients. Androgen deprivation therapy was received by 69% of the patients. Toxicity was scored according to the CTCAE version 3.0. Median follow-up was 3.1 years. RESULTS: Acute grade 3 genitourinary (GU) toxicity was observed in 7.8% of the patients, and late grades 3 and 4 GU toxicity was observed in 10.9% and 1.6% of the patients. Acute grade 3 gastrointestinal (GI) toxicity was experienced by 1.6% of the patients, and late grade 3 GI toxicity was absent. The urethral V(120) (urethral volume receiving > or =120% of the prescribed HDR-B dose) was associated with acute (P=.047) and late > or = grade 2 GU toxicities (P=.049). CONCLUSIONS: Late grades 3 and 4GU toxicity occurred in 10.9% and 1.6% of the patients after HDR-B followed by IMRT in association with the irradiated urethral volume. The impact of V(120) on GU toxicity should be validated in further studies.

Toxicity and early treatment outcomes in low- and intermediate-risk prostate cancer managed by high-dose-rate brachytherapy as a monotherapy

PURPOSE: To determine the acute and late genitourinary (GU) and gastrointestinal (GI) toxicity and present short-term biochemical no evidence of disease (bNED) rates after high-dose-rate brachytherapy (HDR-B) monotherapy. METHODS AND MATERIALS: Between October 2003 and June 2006, 36 patients with low (28) and intermediate (8) risk prostate cancer (PCA) were treated by HDR-B monotherapy. All patients received one implant and four fractions of 9.5Gy within 48h for a total prescribed dose (PD) of 38Gy. Five patients received hormonal therapy (HT). Median age was 63.5 years and median followup was 3 years (range, 0.4-4 years). Toxicity was scored according to the CTCAE version 3.0. Biochemical failure was defined according to the Phoenix criteria. RESULTS: Acute and late Grade 3 GU toxicity was observed in 1 (3%) and 4 (11%) patients, respectively. Grade 3 GI toxicity was absent. The three- year bNED survival rate was 100%. The sexual preservation rate in patients without HT was 75%. Late Grade 3 GU toxicity was associated with the planning target volume (PTV) V(100) (% PTV receiving > or =100% of the PD; p=0.036), D(90) (dose delivered to 90% of the PTV; p=0.02), and the urethral V(120) (urethral volume receiving > or =120% of the PD; p=0.043). The urethral V(120) was associated with increased PTV V(100) (p<0.001) and D(90) (p=0.003). CONCLUSIONS: After HDR-B monotherapy, late Grade 3 GU toxicity is associated with the urethral V(120) and the V(100) and D(90) of the PTV. Decrease of the irradiated urethral volume may reduce the GU toxicity and potentially improve the therapeutic ratio of this treatment.

Detection of urinary stones at reduced radiation exposure: a phantom study comparing computed radiography and a low-dose digital radiography linear slit scanning system

OBJECTIVE: In this experimental study we assessed the diagnostic performance of digital linear slit scanning radiography compared with computed radiography (CR) for the detection of urinary calculi in an anthropomorphic phantom imitating patients weighing approximately 58-88 kg. CONCLUSION: Compared with CR, linear slit scanning radiography is superior for the detection of urinary stones and may be used for pretreatment localization and follow-up at a lower patient exposure.

Thoracoabdominal-aortoiliac multidetector-row CT angiography at 80 and 100 kVp: assessment of image quality and radiation dose

OBJECTIVE: To compare image quality and radiation dose of thoracoabdominal computed tomography (CT) angiography at 80 and 100 kVp and to assess the feasibility of reducing contrast medium volume from 60 to 45 mL at 80 kVp. MATERIALS AND METHODS: This retrospective study had institutional review board approval; informed consent was waived. Seventy-five patients who had undergone thoracoabdominal 64-section multidetector-row CT angiography were divided into 3 groups of 25 patients each. Patients of groups A (tube voltage, 100 kVp) and B (tube voltage, 80 kVp) received 60 mL of contrast medium at 4 mL/s. Patients of group C (tube voltage, 80 kVp) received 45 mL of contrast medium at 3 mL/s. Mean aortoiliac attenuation, image noise, and contrast-to-noise ratio were assessed. The measurement of radiation dose was based on the volume CT dose index. Three independent readers assessed the diagnostic image quality. RESULTS: Mean aortoiliac attenuation for group B (621.1 +/- 90.5 HU) was significantly greater than for groups A and C (485.2 +/- 110.5 HU and 483.1 +/- 119.8 HU; respectively) (P < 0.001). Mean image noise was significantly higher for groups B and C than for group A (P < 0.05). The contrast-to-noise ratio did not significantly differ between the groups (group A, 35.0 +/- 13.8; group B, 31.7 +/- 10.1; group C, 27.3 +/- 11.5; P = 0.08). Mean volume CT dose index in groups B and C (5.2 +/- 0.4 mGy and 4.9 +/- 0.3 mGy, respectively) were reduced by 23.5% and 27.9%, respectively, compared with group A (6.8 +/- 0.8 mGy) (P < 0.001). The average overall diagnostic image quality for the 3 groups was graded as good or better. The score for group A was significantly higher than that for group C (P < 0.01), no difference was seen between group A and B (P = 0.92). CONCLUSIONS: Reduction of tube voltage from 100 to 80 kVp for thoracoabdominal CT angiography significantly reduces radiation dose without compromising image quality. Reduction of contrast medium volume to 45 mL at 80 kVp resulted in lower but still diagnostically acceptable image quality.

Is body weight the most appropriate criterion to select patients eligible for low-dose pulmonary CT angiography? Analysis of objective and subjective image quality at 80 kVp in 100 patients

The objective of this retrospective study was to assess image quality with pulmonary CT angiography (CTA) using 80 kVp and to find anthropomorphic parameters other than body weight (BW) to serve as selection criteria for low-dose CTA. Attenuation in the pulmonary arteries, anteroposterior and lateral diameters, cross-sectional area and soft-tissue thickness of the chest were measured in 100 consecutive patients weighing less than 100 kg with 80 kVp pulmonary CTA. Body surface area (BSA) and contrast-to-noise ratios (CNR) were calculated. Three radiologists analyzed arterial enhancement, noise, and image quality. Image parameters between patients grouped by BW (group 1: 0-50 kg; groups 2-6: 51-100 kg, decadally increasing) were compared. CNR was higher in patients weighing less than 60 kg than in the BW groups 71-99 kg (P between 0.025 and <0.001). Subjective ranking of enhancement (P = 0.165-0.605), noise (P = 0.063), and image quality (P = 0.079) did not differ significantly across all patient groups. CNR correlated moderately strongly with weight (R = -0.585), BSA (R = -0.582), cross-sectional area (R = -0.544), and anteroposterior diameter of the chest (R = -0.457; P < 0.001 all parameters). We conclude that 80 kVp pulmonary CTA permits diagnostic image quality in patients weighing up to 100 kg. Body weight is a suitable criterion to select patients for low-dose pulmonary CTA.

Dual energy versus single energy MDCT: measurement of radiation dose using adult abdominal imaging protocols

RATIONALE AND OBJECTIVES: The aim of this study was to measure the radiation dose of dual-energy and single-energy multidetector computed tomographic (CT) imaging using adult liver, renal, and aortic imaging protocols. MATERIALS AND METHODS: Dual-energy CT (DECT) imaging was performed on a conventional 64-detector CT scanner using a software upgrade (Volume Dual Energy) at tube voltages of 140 and 80 kVp (with tube currents of 385 and 675 mA, respectively), with a 0.8-second gantry revolution time in axial mode. Parameters for single-energy CT (SECT) imaging were a tube voltage of 140 kVp, a tube current of 385 mA, a 0.5-second gantry revolution time, helical mode, and pitch of 1.375:1. The volume CT dose index (CTDI(vol)) value displayed on the console for each scan was recorded. Organ doses were measured using metal oxide semiconductor field-effect transistor technology. Effective dose was calculated as the sum of 20 organ doses multiplied by a weighting factor found in International Commission on Radiological Protection Publication 60. Radiation dose saving with virtual noncontrast imaging reconstruction was also determined. RESULTS: The CTDI(vol) values were 49.4 mGy for DECT imaging and 16.2 mGy for SECT imaging. Effective dose ranged from 22.5 to 36.4 mSv for DECT imaging and from 9.4 to 13.8 mSv for SECT imaging. Virtual noncontrast imaging reconstruction reduced the total effective dose of multiphase DECT imaging by 19% to 28%. CONCLUSION: Using the current Volume Dual Energy software, radiation doses with DECT imaging were higher than those with SECT imaging. Substantial radiation dose savings are possible with DECT imaging if virtual noncontrast imaging reconstruction replaces precontrast imaging.

Effect of automatic tube current modulation on radiation dose and image quality for low tube voltage multidetector row CT angiography: phantom study

RATIONALE AND OBJECTIVES: To evaluate the effect of automatic tube current modulation on radiation dose and image quality for low tube voltage computed tomography (CT) angiography. MATERIALS AND METHODS: An anthropomorphic phantom was scanned with a 64-section CT scanner using following tube voltages: 140 kVp (Protocol A), 120 kVp (Protocol B), 100 kVp (Protocol C), and 80 kVp (Protocol D). To achieve similar noise, combined z-axis and xy-axes automatic tube current modulation was applied. Effective dose (ED) for the four tube voltages was assessed. Three plastic vials filled with different concentrations of iodinated solution were placed on the phantom's abdomen to obtain attenuation measurements. The signal-to-noise ratio (SNR) was calculated and a figure of merit (FOM) for each iodinated solution was computed as SNR(2)/ED. RESULTS: The ED was kept similar for the four different tube voltages: (A) 5.4 mSv +/- 0.3, (B) 4.1 mSv +/- 0.6, (C) 3.9 mSv +/- 0.5, and (D) 4.2 mSv +/- 0.3 (P > .05). As the tube voltage decreased from 140 to 80 kVp, image noise was maintained (range, 13.8-14.9 HU) (P > .05). SNR increased as the tube voltage decreased, with an overall gain of 119% for the 80-kVp compared to the 140-kVp protocol (P < .05). The FOM results indicated that with a reduction of the tube voltage from 140 to 120, 100, and 80 kVp, at constant SNR, ED was reduced by a factor of 2.1, 3.3, and 5.1, respectively, (P < .001). CONCLUSIONS: As tube voltage decreases, automatic tube current modulation for CT angiography yields either a significant increase in image quality at constant radiation dose or a significant decrease in radiation dose at a constant image quality.

Image quality of supine chest radiographs: intra-individual comparison of computed radiography and low-dose linear-slit digital radiography

The purpose of this retrospective study was to intra-individually compare the image quality of computed radiography (CR) and low-dose linear-slit digital radiography (LSDR) for supine chest radiographs. A total of 90 patients (28 female, 62 male; mean age, 55.1 years) imaged with CR and LSDR within a mean time interval of 2.8 days +/- 3.0 were included in this study. Two independent readers evaluated the image quality of CR and LSDR based on modified European Guidelines for Quality Criteria for chest X-ray. The Wilcoxon test was used to analyse differences between the techniques. The overall image quality of LSDR was significantly better than the quality of CR (9.75 vs 8.16 of a maximum score of 10; p < 0.001). LSDR performed significantly better than CR for delineation of anatomical structures in the mediastinum and the retrocardiac lung (p < 0.001). CR was superior to LSDR for visually sharp delineation of the lung vessels and the thin linear structures in the lungs. We conclude that LSDR yields better image quality and may be more suitable for excluding significant pathological features of the chest in areas with high attenuation compared with CR.

Peri-operative adrenocortical response to low-dose (1 microg) ACTH and relation to postoperative complications in patients undergoing elective abdominal surgery

BACKGROUND: To test the hypothesis that reduced responsiveness to adrenocorticotropin (ACTH) stimulation before elective major abdominal surgery is associated with an increased incidence of postoperative complications. METHODS: A low-dose (1 microg) ACTH test was performed the day before surgery, during the operation, on the first postoperative day, and before discharge from the hospital in 77 patients undergoing major abdominal surgery (age 62 [47;69] yrs [median, quartiles]; 30 female). Thirty-one patients undergoing minor, non-abdominal surgery (mostly inguinal hernia repair) (age 57 [40;66] yrs; 14 female) served as controls with minor surgical stress. A stimulated plasma cortisol concentration >or=500 nmol/l or an increment of >or=200 nmol/l in response to 1 microg ACTH was defined as normal. Scores for surgical stress and comprehensive risk, postoperative complications, and length of hospital stay (LOS) were assessed. RESULTS: On the day before major abdominal surgery, basal and stimulated plasma cortisol were 242 (165;299) nmol/l and 497 (404;568) nmol/l, respectively. Eighteen (23%) patients had an abnormal ACTH test, and 7 of these (39%) had complications versus 25 (42%) of the 59 patients with normal ACTH tests (P = .992). Surgical stress, comprehensive risk, and intra- and postoperative basal cortisol levels were higher and the response to ACTH stimulation smaller in patients with major abdominal compared to minor surgery. The peri-operative course of ACTH responses was not associated with complications or LOS in abdominal surgery patients. CONCLUSION: In patients scheduled for abdominal surgery, pre-operatively reduced adrenal response to stimulation with 1 microg ACTH is common but not associated with postoperative complications.

Dynamic contrast-enhanced and diffusion-weighted MRI for early detection of tumoral changes in single-dose and fractionated radiotherapy: evaluation in a rat rhabdomyosarcoma model

We aimed to examine different intratumoral changes after single-dose and fractionated radiotherapy, using diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI in a rat rhabdomyosarcoma model. Four WAG/Rij rats with rhabdomyosarcomas in the flanks received single-dose radiotherapy of 8 Gy, and four others underwent fractionated radiotherapy (five times 3 Gy). In rats receiving single-dose radiotherapy, a significant perfusion decrease was found in the first 2 days post-treatment, with slow recuperation afterwards. No substantial diffusion changes could be seen; tumor growth delay was 12 days. The rats undergoing fractionated radiotherapy showed a similar perfusion decrease early after the treatment. However, a very strong increase in apparent diffusion coefficient occurred in the first 10 days; growth delay was 18 days. DW-MRI and DCE-MRI can be used to show early tumoral changes induced by radiotherapy. Single-dose and fractionated radiotherapy induce an immediate perfusion effect, while the latter induces more intratumoral necrosis.

Particles induce apical plasma membrane enlargement in epithelial lung cell line depending on particle surface area dose

Background Airborne particles entering the respiratory tract may interact with the apical plasma membrane (APM) of epithelial cells and enter them. Differences in the entering mechanisms of fine (between 0.1 μm and 2.5 μm) and ultrafine ( ≤ 0.1 μm) particles may be associated with different effects on the APM. Therefore, we studied particle-induced changes in APM surface area in relation to applied and intracellular particle size, surface and number. Methods Human pulmonary epithelial cells (A549 cell line) were incubated with various concentrations of different sized fluorescent polystyrene spheres without surface charge (∅ fine – 1.062 μm, ultrafine – 0.041 μm) by submersed exposure for 24 h. APM surface area of A549 cells was estimated by design-based stereology and transmission electron microscopy. Intracellular particles were visualized and quantified by confocal laser scanning microscopy. Results Particle exposure induced an increase in APM surface area compared to negative control (p < 0.01) at the same surface area concentration of fine and ultrafine particles a finding not observed at low particle concentrations. Ultrafine particle entering was less pronounced than fine particle entering into epithelial cells, however, at the same particle surface area dose, the number of intracellular ultrafine particles was higher than that of fine particles. The number of intracellular particles showed a stronger increase for fine than for ultrafine particles at rising particle concentrations. Conclusion This study demonstrates a particle-induced enlargement of the APM surface area of a pulmonary epithelial cell line, depending on particle surface area dose. Particle uptake by epithelial cells does not seem to be responsible for this effect. We propose that direct interactions between particle surface area and cell membrane cause the enlargement of the APM.