Changes in aldehyde dehydrogenase-1 expression during neoadjuvant chemotherapy predict outcome in locally advanced breast cancer.

INTRODUCTION: Although neoadjuvant chemotherapy (NAC) for locally advanced breast cancer can improve operability and local disease control, there is a lack of reliable biomarkers that predict response to chemotherapy or long-term survival. Since expression of aldehyde dehydrogenase-1 (ALDH1) is associated with the stem-like properties of self-renewal and innate chemoresistance in breast cancer, we asked whether expression in serial tumor samples treated with NAC could identify women more likely to benefit from this therapy. METHODS: Women with locally advanced breast cancer were randomly assigned to receive four cycles of anthracycline-based chemotherapy, followed by four cycles of taxane therapy (Arm A), or the same regimen in reverse order (Arm B). Tumor specimens were collected at baseline, after four cycles, and then at surgical resection. ALDH1 expression was determined by immunohistochemistry and correlated with tumor response using Fisher's exact test while Kaplan-Meier method was used to calculate survival. RESULTS: A hundred and nineteen women were enrolled into the study. Fifty seven (48%) were randomized to Arm A and 62 (52%) to Arm B. Most of the women (90%) had ductal carcinoma and 10% had lobular carcinoma. Of these, 26 (22%) achieved a pathological complete response (pCR) after NAC. There was no correlation between baseline ALDH1 expression and tumor grade, stage, hormone receptor, human epidermal growth factor receptor 2 (HER2) status and Ki67 index. ALDH1 negativity at baseline was significantly associated with pCR (P = 0.004). The presence of ALDH1(+) cells in the residual tumor cells in non-responding women was strongly predictive of worse overall survival (P = 0.024). Moreover, serial analysis of specimens from non-responders showed a marked increase in tumor-specific ALDH1 expression (P = 0.028). Overall, there was no survival difference according to the chemotherapy sequence. However, poorly responding tumours from women receiving docetaxel chemotherapy showed an unexpected significant increase in ALDH1 expression. CONCLUSIONS: ALDH1 expression is a useful predictor of chemoresistance. The up-regulation of ALDH1 after NAC predicts poor survival in locally advanced breast cancer. Although the chemotherapy sequence had no effect on overall prognosis, our results suggest that anthracycline-based chemotherapy may be more effective at targeting ALDH1(+) breast cancer cells. TRIAL REGISTRATION: ACTRN12605000588695.

Dose-volume response in acute dysphagia toxicity: Validating QUANTEC recommendations into clinical practice for head and neck radiotherapy.

PURPOSE: To determine the validity of QUANTEC recommendations in predicting acute dysphagia using intensity-modulated head and neck radiotherapy. MATERIAL AND METHODS: Seventy-six consecutive patients with locally advanced squamous cell carcinoma (SCC) of the head and neck +/- systemic therapy were analyzed. Multiple dose parameters for the larynx (V50Gy, Dmean and Dmax) were recorded. Acute dysphagia toxicity was prospectively scored in all treatment weeks (week 1-6 or 1-7) using CTCAEv3 by three blinded investigators. QUANTEC larynx recommendations (V50Gy < 27%, Dmean < 44 Gy, Dmean < 40 Gy, Dmax < 66 Gy) were used to group the cohort (i.e. V50Gy < 27% vs. V50Gy > 27%). The proportion of patients with Grade 3 dysphagia was compared within each group. RESULTS: There was a significant reduction in the incidence of grade 3 toxicity in the V50Gy < or > 27% group at week 5 (14.3% vs. 45.2%, p = 0.01) and 6 (25.9% vs. 65.9%, p < 0.01). A significant reduction at week 5 (14.7% vs. 50.0, p = 0.02) and 6 (32.4% vs. 67.6%, p = 0.01) was seen in Dmean < 44 Gy when compared to Dmean > 44 Gy. Dmean < 40 Gy also delivered a significant reduction at week 5 (5.6% vs. 42.3%, p < 0.01) and week 6 (23.5% vs. 59.3%, p = 0.01). A significant toxicity reduction at treatment week 6 (28.0% vs. 63.0%, p = 0 < 01) was seen from Dmax < 66 Gy to Dmax > 66 Gy. V50Gy > 27% (p < 0.01), Dmean > 40 Gy (p = 0.01) and Dmax > 66 Gy (p < 0.01) were also predictors of Grade 3 dysphagia when analyzed with multiple clinical risk factors. CONCLUSIONS: QUANTEC late toxicity recommendations for dose to larynx during IMRT are a useful predictor for acute dysphagia toxicity in this patient cohort. Furthermore, this included chemoradiotherapy regimes and post-operative radiotherapy patients, allowing for prophylactic implementation of supportive care measures.

The prognostic significance of aldehyde dehydrogenase 1A1 (ALDH1A1) and CD133 expression in early stage non-small cell lung cancer.

BACKGROUND: Expression of aldehyde dehydrogenase 1A1 (ALDH1A1) and CD133 has been functionally associated with a stem cell phenotype in normal and malignant cells. The prevalence of such cells in solid tumours should therefore correlate with recurrence and/or metastasis following definitive surgical resection. The aim of this study was to evaluate the prognostic significance of ALDH1A1 and CD133 in surgically resected, early stage non-small cell lung cancer (NSCLC). METHODS: A retrospective analysis of ALDH1A1 and CD133 expression in 205 patients with pathologic stage I NSCLC was performed using immunohistochemistry. The association between the expression of both markers and survival was determined. RESULTS: We identified 62 relapses and 58 cancer-related deaths in 144 stage 1A and 61 stage 1B patients, analysed at a median of 5-years follow-up. Overexpression of ALDH1A1 and CD133, detected in 68.7% and 50.7% of primary tumours, respectively, was an independent prognostic indicator for overall survival by multivariable Cox proportional hazard model (p=0.017 and 0.039, respectively). Overexpression of ALDH1A1, but not of CD133, predicted poor recurrence-free survival (p=0.025). When categorised into three groups according to expression of ALDH1A1/CD133, patients with overexpression of both ALDH1A1 and CD133 belonged to the group with the shortest recurrence-free and overall survival (p=0.015 and 0.017, respectively). CONCLUSIONS: Expression of ALDH1A1 and CD133, and coexpression of ALDH1A1 and CD133, is strongly associated with poor survival in early-stage NSCLC following surgical resection. These data are consistent with the hypothesis that expression of stem cell markers correlates with recurrence as an indirect measure of self-renewal capacity.

Routine sonographic measurement of the near-field lateral ventricle during second-trimester morphologic scans.

OBJECTIVES: The purpose of this study was to determine whether measurement of the near-field lateral ventricular diameter can be reliably obtained within a practical time frame during second-trimester obstetric scans by angling the fetal head approximately 30° away from the horizontal image axis such that the posterior aspect of the fetal head lies closer to the transducer. METHODS: Fifty consecutive singleton pregnancies presenting for a routine-second trimester scan were recruited for this study. The far-field lateral ventricular diameter was measured, followed by the near-field lateral ventricular diameter using the proposed technique. The measurements were repeated by a second operator who was blinded to the first measurement. Both operators recorded the measurements taken and scored the level of visibility of the near-field lateral ventricle. The difference between the two operators' measurements was compared by a κ analysis. RESULTS: The near-field lateral ventricle was visualized in 49 of 50 cases (98%). There was no statistically significant difference in the measurement of the near-field lateral ventricular diameter by the two operators (P = .34). There was, however, a statistically significant difference in the time it took each operator to obtain the near-field measurement after the far-field measurement (P = .01). CONCLUSIONS: Manipulating the transducer to position the falx of the fetal head approximately 30° away from the horizontal image axis allows the near-field lateral ventricle to be routinely visualized and measured with a high degree of interoperator agreement and within a practical time frame once the operator is experienced in performing the technique.

Effectiveness of mastoid process percussion for identification of the vertebral artery ostium on Doppler studies.

OBJECTIVES: The pretransverse or first segment of the vertebral artery may be confused with adjacent branches of the proximal subclavian artery during Doppler assessment. This study investigated the effectiveness of mastoid process percussion, the "mastoid tap" maneuver, for identification of the vertebral artery ostium. METHODS: Fifty patients presenting consecutively for carotid sonography were recruited. Doppler waveforms were collected at the vertebral artery ostia, thyrocervical trunks, and proximal subclavian arteries while the mastoid tap maneuver was performed. The outcome indicator was serrate distortion of the Doppler waveform. Two raters graded the waveforms according to a 3-grade system: grade 0, no distortion; grade 1, mild distortion; and grade 3, marked distortion. The difference between the proportions of the vertebral artery ostia and thyrocervical trunks showing waveform distortion was evaluated with the χ(2) test. The differences in the extents of waveform distortion in the ipsilateral vertebral artery ostia, thyrocervical trunks, and subclavian arteries were evaluated with Friedman and Wilcoxon signed rank tests. RESULTS: Ninety-five vertebral artery ostia in 50 patients were successfully assessed. There was a significant difference between the proportions of vertebral artery ostia (95 of 95 [100%]) and thyrocervical trunks (9 of 95 [9.5%]) that showed waveform distortion (P < .001). There were significant differences in the extents of distortion between the ipsilateral vertebral artery ostia and thyrocervical trunks and between the ipsilateral vertebral artery ostia and subclavian arteries, with the vertebral artery ostia showing a higher degree of distortion in both cases (P < .001). CONCLUSIONS: The mastoid tap maneuver is useful for distinguishing between the vertebral arteries and thyrocervical trunks on Doppler studies.

Hippocampal calcification prevalence at CT: a retrospective review.

PURPOSE: To determine the prevalence of intrahippocampal calcification at brain computed tomography (CT), evaluate any association with calcification involving the intracranial arteries or lentiform nuclei, and assess the clinical importance of intrahippocampal calcification. MATERIALS AND METHODS: Study approval was obtained by the Southern Health Human Research Ethics Committee, which waived the requirement for informed consent because of the retrospective nature of the study. The presence of intrahippocampal calcification was assessed by four readers through retrospective review of 300 randomly selected nonenhanced brain CT scans. In addition, the presence of calcification involving the intracranial arteries and lentiform nuclei was assessed, and the clinical histories were reviewed in those patients with intrahippocampal calcifications and a matched control cohort without intrahippocampal calcification. Differences in proportion of patients with intrahippocampal calcifications across different age groups were assessed by using χ2 analysis. Interrater agreement and intrarater agreement were assessed by using κ analysis. RESULTS: Intrahippocampal calcification was demonstrated in 47 (15.7%) of 300 patients, and 47 (21.7%) of 217 patients older than 50 years of age. Its prevalence increased with age (P=.008). All patients with intrahippocampal calcification and the control cohort demonstrated calcification involving the intracranial arteries. Eleven (23.4%) of 47 patients with intrahippocampal calcification had calcification within the lentiform nuclei compared with 14 (29.8%) of 47 in the control cohort (P=.67). The anatomic distribution of intrahippocampal calcification was similar to that described in vascular fibrosis and calcification. CONCLUSION: The prevalence of intrahippocampal calcification appears to increase with age and is a relatively common finding in patients older than 50 years. It has a similar anatomic distribution to microscopic vascular fibrosis and calcification and likely reflects its latter stages.

Intrauterine growth restriction coupled with hyperglycemia: effects on cardiac structure in adult rats.

BACKGROUND: Intrauterine growth restriction (IUGR) has been linked to heart disease in adulthood. Hence the IUGR heart is likely to be vulnerable to diabetic heart disease. The aim of this study was to examine the effect of induction of type 1 diabetes on myocardial collagen deposition and cardiac function in adult rats with a history of IUGR, after controlling blood glucose levels. METHODS: IUGR was induced by protein restriction in the pregnant female rat. When the offspring were 24 wk of age, diabetes was induced in male IUGR and non-IUGR rats by means of streptozotocin; insulin injections were used to maintain blood glucose levels at a mild (7-10 mmol/l; n = 8 per group) or moderate level (10-15 mmol/l; n = 8 per group). Echocardiography and cardiac morphology analyses were carried out when the rats were 32 wk of age. RESULTS: IUGR offspring exhibited cardiac hypertrophy at 32 wk, including a thicker posterior wall and increased interstitial fibrosis in the left ventricle. Hyperglycemia led to an increase in heart size and myocardial fibrosis. The response to hyperglycemia was not different between IUGR and non-IUGR rats; however, cardiac fibrosis was greatest when diabetes was present along with a history of IUGR. In general, maintaining blood glucose levels at a mildly hyperglycemic level attenuated the adverse effects of hyperglycemia but did not reverse the fibrosis. CONCLUSION: Exacerbated fibrosis in hyperglycemic hearts of IUGR offspring may lead to long-term cardiac dysfunction.

Induction of hyperglycemia in adult intrauterine growth-restricted rats: effects on renal function.

Intrauterine growth restriction (IUGR) leads to a reduction in nephron endowment at birth and is linked to renal dysfunction in adulthood. The aim of the present study was to determine whether kidneys of IUGR rat offspring are more vulnerable to a secondary insult of hyperglycemia. IUGR was induced in Wistar-Kyoto rats by maternal protein restriction. At 24 wk of age, diabetes was induced in male IUGR and non-IUGR offspring by streptozotocin injection; insulin was injected daily to maintain blood glucose levels at either a mild (7-10 mmol/l; n=8/group) or a moderate (10-15 mmol/l; n=8/group) level. At 32 wk of age, renal function was assessed using ultrasound and [(3)H]inulin and [(14)C]para-aminohippurate clearance techniques. Conscious mean arterial blood pressure and heart rate were unchanged in IUGR offspring. Relative kidney length was increased significantly in IUGR offspring, and renal function was altered significantly; of importance, there was a significant increase in filtration fraction, indicative of glomerular hyperfiltration. Induction of hyperglycemia led to marked impairment of renal function. However, the response to hyperglycemia was not different between IUGR and non-IUGR offspring. Maintaining blood glucose levels at a mild hyperglycemic level led to marked improvement in all measures of renal function in IUGR and non-IUGR offspring. In conclusion, while the IUGR offspring showed evidence of hyperfiltration, the response to hyperglycemia was similar in IUGR and non-IUGR kidneys in adulthood. Importantly, maintaining blood glucose levels at a mild hyperglycemic level markedly attenuated the renal dysfunction associated with diabetes, even in IUGR offspring.

Coronary image quality of 320-MDCT in patients with heart rates above 65 beats per minute: preliminary experience.

OBJECTIVE: High heart rate may negatively influence the image quality of cardiac CT. The technical advances of 320-MDCT may overcome issues with poor image quality associated with high heart rate. This study aimed to evaluate the coronary image quality of 320-MDCT in patients with heart rates above 65 beats/min. MATERIALS AND METHODS: Patients who presented for cardiac CT were divided into two groups according to heart rate, either greater than 65 beats/min or less than or equal to 65 beats/min. Two radiologists were blinded to the patient groups and evaluated images of 15 coronary artery segments per patient using 320-MDCT with consensus agreement. The image quality was scored subjectively as 1 or 2 (diagnostic quality) or 3 (poor quality and nondiagnostic). RESULTS: There were no statistically significant differences between the two groups in terms of age, sex, and body mass index (p > 0.05). The median heart rate was 70 beats/min (range, 67-110 beats/min) for the group with heart rate greater than 65 beats/min and 60 beats/min (range, 48-65 beats/min) for the group with heart rate less than or equal to 65 beats/min (p < 0.001). In patients with heart rates greater than 65 beats/min, diagnostic quality images (scores of 1 or 2) were obtained in 95.6% of the analyzed segments, compared with 96.9% in the group with heart rate less than or equal to 65 beats/min (p = 0.7). CONCLUSION: Our initial evaluation suggests that coronary artery images of diagnostic quality can be obtained using 320-MDCT in most patients with heart rates greater than 65 beats/min, in percentages similar to those for patients with heart rates less than or equal to 65 beats/min. This finding may be the result of the inherent image acquisition and reconstruction technique of 320-MDCT.

The role of chemotherapeutic drugs in the evaluation of breast tumour response to chemotherapy using serial FDG-PET.

INTRODUCTION: The aims of this study were to investigate whether drug sequence (docetaxel followed by anthracyclines or the drugs in reverse order) affects changes in the maximal standard uptake volume (SUVmax) on [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) during neoadjuvant chemotherapy in women with locally advanced breast cancer. METHODS: Women were randomly assigned to receive either drug sequence, and FDG-PET scans were taken at baseline, after four cycles and after eight cycles of chemotherapy. Tumour response to chemotherapy was evaluated based on histology from a surgical specimen collected upon completion of chemotherapy. RESULTS: Sixty women were enrolled into the study. Thirty-one received docetaxel followed by anthracyclines (Arm A) and 29 received drugs in the reverse order (Arm B). Most women (83%) had ductal carcinoma and 10 women (17%) had lobular or lobular/ductal carcinoma. All but one tumour were downstaged during therapy. Overall, there was no significant difference in response between the two drug regimens. However, women in Arm B who achieved complete pathological response had mean FDG-PET SUVmax reduction of 87.7% after four cycles, in contrast to those who had no or minor pathological response. These women recorded mean SUVmax reductions of only 27% (P < 0.01). Women in Arm A showed no significant difference in SUVmax response according to pathological response. Sensitivity, specificity, accuracy and positive and negative predictive values were highest in women in Arm B. CONCLUSIONS: Our results show that SUVmax uptake by breast tumours during chemotherapy can be dependent on the drugs used. Care must be taken when interpreting FDG-PET in settings where patients receive varied drug protocols.

Clinical predictors of time to return to competition and of recurrence following hamstring strain in elite Australian footballers.

OBJECTIVE: To investigate early clinical predictors of time to return to competition and of recurrence following hamstring strain. DESIGN: Prospective observational study. SETTING: Elite level of Australian football competition. PARTICIPANT: 59 players who suffered a hamstring strain in 2002 season. PREDICTORS: Clinical assessment by a physiotherapist and questionnaire. MAIN OUTCOME MEASURES: Time taken to return to play and recurrence of hamstring injury within 3 weeks. RESULTS: Players taking more than 1 day to walk pain-free were significantly more likely (p=0.018) to take longer than 3 weeks to return to competition (adjusted odds ratio 4.0; 95% CI 1.3 to 12.6). Nine players (15.2%) experienced an injury recurrence, all involving the biceps femoris. Recurrence was more likely in players who reported a hamstring injury in the past 12 months (adjusted odds ratio 19.6; 95% CI 1.5 to 261.0; p=0.025). CONCLUSION: Time to walk pain-free and previous hamstring injury are predictors of time to return to competition and recurrence, respectively, and should be included in a clinical assessment to aid in prognosis.

Development of cardiovascular disease due to renal insufficiency in male sheep following fetal unilateral nephrectomy.

BACKGROUND: Renal insufficiency is associated with the development of cardiovascular disease. OBJECTIVES: This study investigated whether reduced fetal renal mass resulted in renal insufficiency, hypertension, cardiac dysfunction and whether these changes progressed with age. METHODS AND RESULTS: Fetal uninephrectomy was performed at 100-day gestation (term, 150 days) and studies performed in male sheep from 6 weeks to 24 months of age. Renal function declined with age in sham animals as demonstrated by increasing plasma creatinine levels and urinary excretion of albumin. The age-related decline in renal function was exacerbated in animals that had undergone fetal uninephrectomy. Evidence of renal insufficiency was indicated from as early as 6 weeks of age with elevations in plasma creatinine (Ptreatment < 0.001), urea (Ptreatment < 0.001) and sodium (Ptreatment < 0.05) levels in uninephrectomized lambs as compared with sham animals. At 6 months, urinary albumin excretion (P < 0.001) was increased and urinary sodium excretion (P < 0.001) decreased in the uninephrectomized animals. By 24 months, renal function had deteriorated further with significant progression of albuminuria (P(treatment x age) < 0.001). Elevation of mean arterial pressure (approximately 15 mmHg) was associated with significantly increased cardiac output, stroke volume and plasma volume at 6 months; arterial pressure (approximately 27 mmHg) had increased further in uninephrectomized animals at 24 months and was driven by increased total peripheral resistance. Cardiac functional reserve (dobutamine challenge) was reduced in uninephrectomized animals at 6 and 24 months of age (Ptreatment < 0.001), and this was associated with left ventricular enlargement (P < 0.001) and reduced fractional shortening (P < 0.01). CONCLUSION: Fetal uninephrectomy causing a reduction in nephron endowment results in an accelerated age-related decline in renal function. This is associated with an early onset of elevated blood pressure and impairments in cardiac structure and function.

Image quality of coronary 320-MDCT in patients with atrial fibrillation: initial experience.

OBJECTIVE: Noninvasive coronary angiography has generally been contraindicated in patients with atrial fibrillation because of the difficulty in synchronizing an irregular heartbeat with table gantry movement. The objective of this study was to evaluate and compare the quality of 320-MDCT images obtained in patients with atrial fibrillation and in a control group of patients in sinus rhythm. MATERIALS AND METHODS: Two reviewers were blinded to the patient groups and evaluated images of 15 coronary artery segments for each patient using 320-MDCT. The images were printed on glossy paper and scored subjectively as 1 or 2, meaning of diagnostic quality, or 3, meaning poor quality. RESULTS: No statistical difference between the groups was noted in patient age: The mean age of the patients with atrial fibrillation was 67 years (age range, 52-82 years) and that of the patients in sinus rhythm was 59 years (36-86 years) (p = 0.3). Scores of 1 and 2 (diagnostic quality) were assigned to 100% in sinus rhythm and 96% in atrial fibrillation (p < 0.05). Scores of 3 were seen only in the atrial fibrillation group (7/175, 4%). Segment 15, the distal circumflex artery, was the segment that was most frequently assigned a score of 3 (2/7, 28.6%). A discrepancy in the two reviewers' scores was seen in 25 segments (7%), requiring joint consensus. The segments that most frequently required consensus reading were segments 12 and 15. The overall mean image quality score for all three coronary arteries in atrial fibrillation was 1.25 +/- 0.47 (SD) and 1.08 +/- 0.26 in sinus rhythm (p < 0.001). The median effective dose was 19.28 and 13.55 mSv in the atrial fibrillation and sinus rhythm groups, respectively. CONCLUSION: The analysis of our initial experience shows that imaging in patients with atrial fibrillation is possible using 320-MDCT, with images of most segments obtained being of diagnostic quality. Segment 15 was the most difficult to see on 320-MDCT because of the small caliber of the vessel; poor visualization of that segment mostly occurred in the setting of a dominant right coronary arterial system.

A comparison between clinical assessment and magnetic resonance imaging of acute hamstring injuries.

BACKGROUND: Physicians evaluating hamstring strains in professional football players are increasingly turning to magnetic resonance imaging to support the clinical diagnosis and management of the injury. However, little information is available to assess how magnetic resonance imaging compares with the clinical evaluation in establishing the duration of rehabilitation required. HYPOTHESIS: Magnetic resonance imaging of hamstring strains can be useful in determining duration of rehabilitation. STUDY DESIGN: Cohort study (Diagnosis); Level of evidence, 1. METHODS: Fifty-eight professional football players with a diagnosis of hamstring injury made by the team physician were enrolled in the study. All players underwent magnetic resonance imaging and a clinical evaluation by an independent physical therapist within 3 days of the injury. Presence, type, and location of injury were recorded in each examination. The physical therapist estimated the time required until return to competition, and the radiologist used the length of the injury (coronal view) to establish rehabilitation duration. Both clinicians were blinded to the other modality. RESULTS: Clinical and magnetic resonance imaging assessments were in agreement in 38 of 58 cases (65.5%). In 18 cases (31.0%), a clinically positive diagnosis was made, but no abnormalities were evident on magnetic resonance imaging. In 2 cases (3.4%), magnetic resonance imaging detected an injury, whereas the clinical examination had negative or equivocal findings. Both clinical examination and magnetic resonance imaging findings were strongly correlated with the actual time required to return to competition (r = .69, P < .001 and r = .58, P < .001, respectively). The correlation coefficient between clinical predictions and magnetic resonance imaging findings was moderate (r = .36, P = .006). CONCLUSION: This study shows that magnetic resonance imaging is not required for estimating the duration of rehabilitation of an acute minor or moderate hamstring injury in professional football players.

Evaluation of selection criteria for graduate students in radiation therapy.

Selection of suitable students into graduate medical and specialist health professional courses can be difficult. Historically, selection of students was primarily based on prior academic performance. Recently, however, more emphasis has been placed on considering broader academic backgrounds and personal characteristics and attitudes of students, but no reliable measurement tool is available to predict student success and satisfaction with their choice of profession. The aim of this study was to survey practising radiation therapists in Australia to seek their opinions regarding suitable selection criteria for graduate entry radiation therapy (RT) students in order to optimize selection procedures for future applicants. Four hundred questionnaires were sent to nine RT centres in three states within Australia. All nine clinics participated in the survey and 189 questionnaires were returned. Results show that the majority of radiation therapists place a high level of importance upon a sound knowledge of physics and mathematics, as well as life experience, and agree that a visit to an RT clinic plus an interview comprise important components of the selection process. Humanities, psychology and a psychometric test were not viewed as essential entry requirements. Experienced radiation therapists placed less value on academic performance in the primary degree and were more likely to include an interview as a selection criterion than junior practitioners. Empathy for patients was identified as the most important personal attribute. It is thus recommended that not only cognitive but also personal skills be evaluated during the selection of prospective radiation therapists.

Validation of a 4D-PET maximum intensity projection for delineation of an internal target volume.

PURPOSE: The delineation of internal target volumes (ITVs) in radiation therapy of lung tumors is currently performed by use of either free-breathing (FB) (18)F-fluorodeoxyglucose-positron emission tomography-computed tomography (FDG-PET/CT) or 4-dimensional (4D)-CT maximum intensity projection (MIP). In this report we validate the use of 4D-PET-MIP for the delineation of target volumes in both a phantom and in patients. METHODS AND MATERIALS: A phantom with 3 hollow spheres was prepared surrounded by air then water. The spheres and water background were filled with a mixture of (18)F and radiographic contrast medium. A 4D-PET/CT scan was performed of the phantom while moving in 4 different breathing patterns using a programmable motion device. Nine patients with an FDG-avid lung tumor who underwent FB and 4D-PET/CT and >5 mm of tumor motion were included for analysis. The 3 spheres and patient lesions were contoured by 2 contouring methods (40% of maximum and PET edge) on the FB-PET, FB-CT, 4D-PET, 4D-PET-MIP, and 4D-CT-MIP. The concordance between the different contoured volumes was calculated using a Dice coefficient (DC). The difference in lung tumor volumes between FB-PET and 4D-PET volumes was also measured. RESULTS: The average DC in the phantom using 40% and PET edge, respectively, was lowest for FB-PET/CT (DCAir = 0.72/0.67, DCBackground 0.63/0.62) and highest for 4D-PET/CT-MIP (DCAir = 0.84/0.83, DCBackground = 0.78/0.73). The average DC in the 9 patients using 40% and PET edge, respectively, was also lowest for FB-PET/CT (DC = 0.45/0.44) and highest for 4D-PET/CT-MIP (DC = 0.72/0.73). In the 9 lesions, the target volumes of the FB-PET using 40% and PET edge, respectively, were on average 40% and 45% smaller than the 4D-PET-MIP. CONCLUSION: A 4D-PET-MIP produces volumes with the highest concordance with 4D-CT-MIP across multiple breathing patterns and lesion sizes in both a phantom and among patients. Freebreathing PET/CT consistently underestimates ITV when compared with 4D PET/CT for a lesion affected by respiration.

White matter fiber tractography: why we need to move beyond DTI.

OBJECT: Diffusion-based MRI tractography is an imaging tool increasingly used in neurosurgical procedures to generate 3D maps of white matter pathways as an aid to identifying safe margins of resection. The majority of white matter fiber tractography software packages currently available to clinicians rely on a fundamentally flawed framework to generate fiber orientations from diffusion-weighted data, namely diffusion tensor imaging (DTI). This work provides the first extensive and systematic exploration of the practical limitations of DTI-based tractography and investigates whether the higher-order tractography model constrained spherical deconvolution provides a reasonable solution to these problems within a clinically feasible timeframe. METHODS: Comparison of tractography methodologies in visualizing the corticospinal tracts was made using the diffusion-weighted data sets from 45 healthy controls and 10 patients undergoing presurgical imaging assessment. Tensor-based and constrained spherical deconvolution-based tractography methodologies were applied to both patients and controls. RESULTS: Diffusion tensor imaging-based tractography methods (using both deterministic and probabilistic tractography algorithms) substantially underestimated the extent of tracks connecting to the sensorimotor cortex in all participants in the control group. In contrast, the constrained spherical deconvolution tractography method consistently produced the biologically expected fan-shaped configuration of tracks. In the clinical cases, in which tractography was performed to visualize the corticospinal pathways in patients with concomitant risk of neurological deficit following neurosurgical resection, the constrained spherical deconvolution-based and tensor-based tractography methodologies indicated very different apparent safe margins of resection; the constrained spherical deconvolution-based method identified corticospinal tracts extending to the entire sensorimotor cortex, while the tensor-based method only identified a narrow subset of tracts extending medially to the vertex. CONCLUSIONS: This comprehensive study shows that the most widely used clinical tractography method (diffusion tensor imaging-based tractography) results in systematically unreliable and clinically misleading information. The higher-order tractography model, using the same diffusion-weighted data, clearly demonstrates fiber tracts more accurately, providing improved estimates of safety margins that may be useful in neurosurgical procedures. We therefore need to move beyond the diffusion tensor framework if we are to begin to provide neurosurgeons with biologically reliable tractography information.

The impact of time between staging PET/CT and definitive chemo-radiation on target volumes and survival in patients with non-small cell lung cancer.

BACKGROUND AND PURPOSE: To investigate the impact of treatment delays on radiation therapy (RT) target volumes and overall survival (OS) in patients with non-small cell lung cancer (NSCLC) who underwent two baseline FDG PET/CT scans. MATERIAL AND METHODS: Patients underwent a staging (PET1) and RT planning (PET2) FDG PET/CT scan. At PET1 all patients were eligible for radical chemo-RT. OS and progression-free survival (PFS) were compared for patients remaining eligible for radical RT and those treated palliatively because PET2 showed progression. RT target volumes were contoured using PET1 and PET2. Normal tissue doses were compared for patients remaining eligible for radical RT. RESULTS: Eighty-two patients underwent PET2 scans between October 2004 and February 2007. Of these, 21 had a prior PET1 scan, median 23 days apart (range 8-176 days). Six patients (29%) were unsuitable for radical RT after PET2; five received palliative treatment and one received no treatment. Patients treated palliatively had significantly worse OS and PFS than patients treated radically p<0.001. Mean RT tumour volume increased from 105cc to 198cc (p<0.005) between scans. CONCLUSIONS: Disease progression while awaiting initiation of curative RT in NSCLC is associated with larger treatment volumes and worse survival.

Quantitative guidelines for the prediction of ultrasound contrast agent destruction during injection.

Experiments and theory were undertaken on the destruction of ultrasound contrast agent microbubbles on needle injection, with the aim of predicting agent loss during in vivo studies. Agents were expelled through a variety of syringe and needle combinations, subjecting the microbubbles to a range of pressure drops. Imaging of the bubbles identified cases where bubbles were destroyed and the extent of destruction. Fluid-dynamic calculations determined the pressure drop for each syringe and needle combination. It was found that agent destruction occurred at a critical pressure drop that depended only on the type of microbubble. Protein-shelled microbubbles (sonicated bovine serum albumin) were virtually all destroyed above their critical pressure drop of 109 ± 7 kPa Two types of lipid-shelled microbubbles were found to have a pressure drop threshold above which more than 50% of the microbubbles were destroyed. The commercial lipid-shelled agent Definity was found to have a critical pressure drop for destruction of 230 ± 10 kPa; for a previously published lipid-shelled agent, this value was 150 ± 40 kPa. It is recommended that attention to the predictions of a simple formula could preclude unnecessary destruction of microbubble contrast agent during in vivo injections. This approach may also preclude undesirable release of drug or gene payloads in targeted microbubble therapies. Example values of appropriate injection rates for various agents and conditions are given.

Ultrasound study of liver disease caused by Schistosoma mansoni in rural Zambian schoolchildren.

OBJECTIVE: To evaluate the prevalence of Schistosoma mansoni-related liver disease in school-age children who live beside the Zambezi River in the Chitokoloki district, North Western Province, Zambia. METHODS: Liver ultrasounds of school students from the Chitokoloki day school, grades 1-12, were performed. Liver patterns, periportal branch wall thickening and portal hypertension were assessed to evaluate the presence of liver fibrosis due to S. mansoni infection. To obtain incidence rates of acute disease, stool specimens were examined from a subgroup for the presence of S. mansoni eggs using the formol detergent sedimentation technique. RESULTS: Of 976 enrolled students, 764 (78.2%) were examined by ultrasound. Of those, 284 (37.2%) had findings indicative of periportal fibrosis on ultrasound. Stool specimen were collected from 414 (54%) students of which six (1.5%) were positive for S. mansoni eggs. CONCLUSION: School students living along the Zambezi River, Zambia have a relatively high prevalence of S. mansoni-related liver disease. These findings suggest that all schoolchildren in this area should receive treatment against S. mansoni.