Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE).

BACKGROUND: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. PATIENTS AND METHODS: In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8 mg/kg loading dose, then 6 mg/kg every 3 weeks (q3w)] and pertuzumab (840 mg loading dose, then 420 mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). RESULTS: Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54 years; 29% had received prior trastuzumab. Median treatment duration was 16 months for pertuzumab and trastuzumab and 4 months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9-22.7] months overall (19.6, 23.0 and 18.1 months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). CONCLUSIONS: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. CLINICALTRIALS.GOV: NCT01572038.

Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer.

BACKGROUND: The randomised phase III TANIA trial demonstrated that continuing bevacizumab with second-line chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC) after progression on first-line bevacizumab-containing therapy significantly improved progression-free survival (PFS) compared with chemotherapy alone [hazard ratio (HR) = 0.75, 95% confidence interval (CI) 0.61-0.93]. We report final results from the TANIA trial, including overall survival (OS) and health-related quality of life (HRQoL). PATIENTS AND METHODS: Patients with HER2-negative LR/mBC that had progressed on or after first-line bevacizumab plus chemotherapy were randomised to receive standard second-line chemotherapy either alone or with bevacizumab. At second progression, patients initially randomised to bevacizumab continued bevacizumab with their third-line chemotherapy, but those randomised to chemotherapy alone were not allowed to cross over to receive third-line bevacizumab. The primary end point was second-line PFS; secondary end points included third-line PFS, combined second- and third-line PFS, OS, HRQoL and safety. RESULTS: Of the 494 patients randomised, 483 received second-line therapy; 234 patients (47% of the randomised population) continued to third-line study treatment. The median duration of follow-up at the final analysis was 32.1 months in the chemotherapy-alone arm and 30.9 months in the bevacizumab plus chemotherapy arm. There was no statistically significant difference between treatment arms in third-line PFS (HR = 0.79, 95% CI 0.59-1.06), combined second- and third-line PFS (HR = 0.85, 95% CI 0.68-1.05) or OS (HR = 0.96, 95% CI 0.76-1.21). Third-line safety results showed increased incidences of proteinuria and hypertension with bevacizumab, consistent with safety results for the second-line treatment phase. No differences in HRQoL were detected. CONCLUSIONS: In this trial, continuing bevacizumab beyond first and second progression of LR/mBC improved second-line PFS, but no improvement in longer term efficacy was observed. The second-line PFS benefit appears to be achieved without detrimentally affecting quality of life. CLINICALTRIALSGOV: NCT01250379.

An evaluation of prenatal ultrasound screening for CTEV: accuracy data from a single NHS University Teaching Hospital.

Congenital Talipes Equinovarus (CTEV) is one of the most common congenital limb deformities. We reviewed the records of infants who had received treatment for structural CTEV between 1 January 2007 and 30 November 2012. This was cross-referenced with the prenatal scans of mothers over a corresponding period of time. We investigated the sensitivity, specificity, and positive and negative predictive values of the fetal anomaly scan for the detection of CTEV and explored whether the publication of Fetal Anomaly Screening Programme guidelines in 2010 affected the rate of detection. During the study period there were 95 532 prenatal scans and 34 373 live births at our hospital. A total of 37 fetuses with findings suggestive of CTEV were included in the study, of whom 30 were found to have structural CTEV at birth. The sensitivity of screening for CTEV was 71.4% and the positive predictive value was 81.1%. The negative predictive value and specificity were more than 99.5%. There was no significant difference between the rates of detection before and after publication of the guidelines (p = 0.5). We conclude that a prenatal fetal anomaly ultrasound screening diagnosis of CTEV has a good positive predictive value enabling prenatal counselling. The change in screening guidance has not affected the proportion of missed cases. This information will aid counselling parents about the effectiveness and accuracy of prenatal ultrasound in diagnosing CTEV.

Febrile neutropenia and related complications in breast cancer patients receiving pegfilgrastim primary prophylaxis versus current practice neutropaenia management: results from an integrated analysis.

Granulocyte colony-stimulating factors (G-CSFs) reduce febrile neutropaenia (FN) incidence but may be used inconsistently in current practice (CP). This study compared the efficacy of pegfilgrastim primary prophylaxis (PPP) with CP neutropaenia management in breast cancer. Individual patient data (N=2282) from 11 clinical trials and observational studies using chemotherapy regimens with > or =15% FN risk and PPP (6 mg, all cycles) or CP (no G-CSF or any cycle G-CSF/pegfilgrastim) were included in an integrated analysis. Most patients received docetaxel-containing regimens. A generalised linear mixed model was fitted (N=2210). Neutropaenia prophylaxis (PPP versus CP), age and disease stage influenced the incidence of FN. Overall, FN was less frequent with PPP than with CP (odds ratio [OR]: 0.124; 95% confidence interval [CI]: 0.08, 0.194; P<0.0001). Odds for cycle 1 FN, dose reductions > or =15% and FN-related hospitalisation were also significantly lower with PPP. These data support PPP in breast cancer patients receiving chemotherapy with moderately high/high FN risk.

Pegfilgrastim supports delivery of FEC-100 chemotherapy in elderly patients with high risk breast cancer: a randomized phase 2 trial.

This randomized phase 2 study explored the feasibility of delivering four to six cycles of the dose-intensified regimen FEC-100 (5-fluorouracil, epirubicin, and cyclophosphamide) to elderly patients with stage II-III breast cancer, using pegfilgrastim for neutrophil support. Sixty patients aged 65-77 years received single 6mg doses of pegfilgrastim on day 2 of FEC-100, either as primary prophylaxis (all cycles: PP), or as secondary prophylaxis (all cycles following a neutropenic event: SP). Neutropenic events (a composite endpoint that included grade 3 neutropenia+fever, grade 4 neutropenia, infectious complication requiring systemic anti-infectives and chemotherapy dose delay/reduction) occurred in 24/30 (80%) of the PP and 21/29 (72%) of the SP group in the first cycle. Most patients received all chemotherapy cycles at full dose on schedule (26/30 [87%] PP; 20/29 [69%] SP). These data indicate that delivery of FEC-100 is feasible with pegfilgrastim support in elderly breast cancer patients.

Achieving full-dose, on-schedule administration of ACE chemotherapy every 14 days for the treatment of patients with extensive small-cell lung cancer.

Extensive small-cell lung cancer (SCLC) is commonly treated with multiple cycles of chemotherapy. Reducing the time interval between cycles of chemotherapy (dose-dense chemotherapy) may improve outcomes in the treatment of extensive SCLC, as it has in other chemosensitive malignancies. To evaluate the feasibility of dose-dense chemotherapy in patients with extensive SCLC, this study evaluates a dose-dense doxorubicin/cyclophosphamide/etoposide (ACE) regimen, supported by the once-per-cycle administration of the hematopoietic growth factor pegfilgrastim. Patients received up to six 14-day cycles of ACE chemotherapy (doxorubicin 40 mg/m,(2) cyclophosphamide 1000 mg/m(2), etoposide 120 mg/m(2) on day 1 IV, plus oral etoposide 240 mg/m(2) daily on days 2-3). On day 4 of each cycle, patients received pegfilgrastim 6 mg by subcutaneous injection. Of 30 patients enrolled, 27 started chemotherapy and received pegfilgrastim. Full-dose, on-schedule chemotherapy was given to all 22 patients starting cycle 2, and in 107 (88%) of 121 cycles. Eighteen of the 27 patients (67%) received full-dose, on-schedule chemotherapy for all 6 cycles. The overall response rate was 17/27 (63%). Nine patients (33%) experienced hematologic toxicities that investigators considered severe or life-threatening. Four patients (15%) had febrile neutropenia. Full-dose, on-schedule dose-dense ACE chemotherapy is feasible with once-per-cycle pegfilgrastim support in extensive SCLC.

Traumatic brain injury in childhood: intensive care time series data and outcome.

Age-specific norms are necessary to determine potential secondary brain insult after head injury in children. We describe and quantify the secondary physiological derangement recorded in children of different ages following traumatic brain injury, and relate it to outcome at 12 months post-injury. Prospective time-series data (including intracranial pressure, arterial blood pressure, cerebral perfusion pressure, oxygen saturation, temperature and heart rate) downloaded from ICU monitors, were examined to identify abnormal (i.e. outside normal age-specific limits) recordings lasting more than 5 min. Cumulated total duration of derangement was calculated for each parameter and as a percentage of the time that the ICP monitor was in situ. Univariate and multivariate logistic regression modelling was used to evaluate predictors of outcome. Age-specificity allows realistic comparisons of physiological data among children. Duration of age-specific derangement of CPP was found to predict outcome (dead v. alive: p = 0.003 and Glasgow Outcome Score 1-3 v. 4-5, i.e. poor v. independent outcome p = 0.004).

Traumatic brain injury and subarachnoid hemorrhage: in vivo occult pathology demonstrated by magnetic resonance spectroscopy may not be "ischaemic". A primary study and review of the literature.

OBJECTIVES: To look for evidence of early ischaemic neurochemical changes in patients suffering severe traumatic brain injury (TBI) and severe subarachnoid haemorrhage (SAH). Proton metabolite concentrations were measured in normal and abnormal areas of brain on T2 MR imaging, in regions considered particularly vulnerable to ischaemic injury. METHODS: Intensive care patients underwent T2 weighted imaging in a 1.5 Tesla MR scanner and proton magnetic resonance spectroscopy (single voxel or chemical shift imaging). Metabolite values in areas that appeared 'normal' and 'abnormal' on T2 MR imaging were compared with those obtained from normal controls. RESULTS: 18 TBI and 6 SAH patients were imaged at 1 to 26 days. N-acetyl aspartate (NAA) was lower in TBI and SAH patients compared to controls in both T2 normal and T2 abnormal areas (p<0.0005). SAH, but not TBI patients also had increased choline and creatine compared to controls in the T2 normal (p<0.02, p<0.02 respectively) and T2 abnormal (p=0.0003, p=0.003) areas. No lactate was found in TBI or SAH patients. CONCLUSIONS: Significant loss of normal functioning neurones was present in TBI and SAH, but no evidence of anaerobic metabolism using lactate as a surrogate marker, questioning the role of 'ischemia' as a major mechanism of damage. Increased choline and creatine were found in SAH patients suggestive of increased cell-wall turnover. Current theories of brain injury after TBI or SAH do not explain these observed neurochemical changes and further research is required.

Which CT features help predict outcome after head injury?

BACKGROUND: Information collected at baseline can be useful in predicting patient outcome after head injury. The appearance of the CT brain scan may add useful baseline information. The aim of this study was to evaluate which features on the admission CT scan might add significantly to other baseline clinical information for predicting survival in patients with head injury. METHODS: Baseline CT scans were reviewed for patients with all grades of traumatic head injury in a head injury registry, in which baseline demographic and injury status and outcome at 1 year were recorded. Details from the CT scan on haemorrhage, brain swelling, and focal or diffuse damage were noted blind to clinical or outcome information and the scans classified according to the simple seven point grading (normal, mild, moderate, or severe focal injury, mild, moderate, or severe diffuse injury). An existing CT scoring system, the trauma coma databank (TCDB) classification, was also used. Logistic regression modelling was used to test the value of the CT appearance, in addition to the other baseline clinical characteristics, in predicting survival at 1 year. RESULTS: 425 CT scans were read from patients with all severities of injury. Significant independent outcome predictors were age, Glasgow coma score (GCS), pupil reaction, presence of subarachnoid blood, and the simple grading of the overall appearance of the scan (all p<0.001). The TCDB classification was not a significant predictor of outcome. CONCLUSION: Age, GCS, and pupil reaction were all previously shown to be significant predictors of patient survival after head injury. A further two, easy to identify, CT scan variables are independent prognostic variables, and might help to identify patients at high risk of death at the time of admission.

What is the most sensitive non-invasive imaging strategy for the diagnosis of intracranial aneurysms?

OBJECTIVES: To determine whether combining non-invasive tests for intracranial aneurysms together would significantly improve aneurysm detection over individual tests. METHODS: 114 patients undergoing intra-arterial digital subtraction angiography to confirm or exclude an intracranial aneurysm were also examined by CT angiography, MR angiography, and transcranial power Doppler ultrasound. The reviewers and ultrasonographers were blinded to the angiogram result, other imaging results and all clinical information. RESULTS: The combination of non-invasive tests did improve diagnostic performance on a per patient basis. The combination of power Doppler and CT angiography had the greatest sensitivity for aneurysm detection (0.83; 05% confidence interval (95% CI) 0.66-0.93) and the level of agreement for this strategy with the reference angiographic standard was excellent (kappa 0.84; 95% CI 0.72-0.95). The improvement in sensitivity of adding power Doppler to CT angiography was not significant (p=0.55) but the improvement in the level of agreement with the reference standard was substantial. However, even the most sensitive combination strategy performed poorly in the detection of small (3-5 mm) and very small (<3 mm) aneurysms with a sensitivity of 0.43 (95% CI 0.23-0.66) and 0.00 (95% CI 0.00-0.31) respectively. CONCLUSIONS: The addition of transcranial power Doppler ultrasound to either CT angiography or MR angiography does improve diagnostic performance on a per patient basis but aneurysms of 5 mm or smaller can still not be reliably identified by current standard clinical non-invasive imaging modalities.

Power transcranial Doppler ultrasound in the detection of intracranial aneurysms.

BACKGROUND AND PURPOSE: We sought to perform a large, prospective, multicenter, blinded study comparing power transcranial color duplex sonography (power TCDS) with intra-arterial digital subtraction angiography (IADSA) in the detection of intracranial aneurysms. METHODS: Contemporaneous TCDS and IADSA examinations were performed in 171 subjects with suspected intracranial aneurysm. Via the temporal bone window, a 2-dimensional hand-held noncontrast transcranial duplex ultrasound imaging system was used operating in power and spectral modes. Sonographers were blinded to clinical history and results of brain CT and IADSA. RESULTS: We found that 157 subjects (92%) had an adequate bone window. Sensitivity per patient was 0.78 (95% CI, 0.66 to 0.87) and 0.46 (95% CI, 0.36 to 0.56) for any anterior circulation aneurysms. Sensitivity was 0.35 (95% CI, 0.24 to 0.46) for aneurysms 5 mm. Accuracy was lower for aneurysms on the cavernous and terminal internal carotid arteries, including posterior communicating artery origin (0.71; 95% CI, 0.63 to 0.79), than for those on the anterior (0.82; 95% CI, 0.74 to 0.89) or the middle cerebral arteries (0.79; 95% CI, 0.71 to 0.86). CONCLUSIONS: Power TCDS is a promising, inexpensive, noninvasive test for anterior circulation intracranial aneurysms but is less sensitive per aneurysm than alternatives such as CT angiography or MR angiography. Sensitivity is poor for aneurysms

Intracranial aneurysms: CT angiography and MR angiography for detection prospective blinded comparison in a large patient cohort.

PURPOSE: To compare computed tomographic (CT) angiography and magnetic resonance (MR) angiography with intraarterial digital subtraction angiography (DSA) in the detection of intracranial aneurysms. MATERIALS AND METHODS: One hundred forty-two patients underwent intraarterial DSA to detect aneurysms. CT angiography, three-dimensional time-of-flight MR angiography, and intraarterial DSA were performed contemporaneously. Film hard-copy images and maximum intensity projection reconstructions of the CT angiograms and MR angiograms were reviewed at different times. RESULTS: The accuracy per patient for the best observer was 0.87 at CT angiography and 0.85 at MR angiography. The accuracy per aneurysm for the best observer was 0.73 at CT angiography and 0.67 at MR angiography. Differences between readers and modalities were not significant. Interobserver agreement was good: kappa value of 0.73 for CT angiography and of 0.74 for MR angiography. The sensitivity for detection of aneurysms smaller than 5 mm was 0.57 for CT angiography and 0.35 for MR angiography compared with 0.94 and 0.86, respectively, for detection of aneurysms 5 mm or larger. The accuracy of both CT angiography and MR angiography was lower for detection of internal carotid artery aneurysms compared with that at other sites. With low observer confidence, the likelihood of correct interpretation was significantly poorer. CONCLUSION: CT angiography and MR angiography have limited sensitivity in the detection of small aneurysms but good interobserver agreement. There is no significant difference in diagnostic performance between the noninvasive modalities.

Increased jugular bulb saturation is associated with poor outcome in traumatic brain injury.

The objective was to compare secondary insults, particularly decreases in jugular bulb oxyhaemoglobin saturation (SjO(2)), during intensive care in patients with "poor" and "good" outcomes 12 months after traumatic brain injury. A prospective observational study of patients' physiological data collected each minute from multimodality monitoring was carried out. Patients had duration of physiological insults quantified as a percentage of their validated monitoring time (once invalid data due to technical reasons were removed). Treatment protocols were designed to minimise secondary insults by maintaining intracranial pressure (ICP) less than 20 mm Hg, and cerebral perfusion pressure (CPP) greater than 70 mm Hg, with prompt correction of hypoxia and pyrexia. Twelve months after injury patients' neurological function was assessed using the Glasgow outcome scale (GOS). A poor outcome was defined as GOS 1 to 3 (group 1) and a good outcome as GOS 4 and 5 (group 2). Seventy five patients (64 male), median age of 34 years (range 15 to 70), were studied. At 12 months 33 patients had a poor outcome (group 1), and 42 a good outcome (group 2). Group 1 spent proportionately more time with SjO(2) greater than 75% compared with group 2 (p<0.05), and more time with SjO(2) below 54% (p<0.04). Group 1 patients also spent proportionately more time with CPP less than 70 mm Hg than group 2 (p<0.04). Patients in group 1 were older (p<0.04) and had a lower postresuscitation Glasgow coma score (p<0.002). There was no difference between the groups for ICP, injury severity score, peripheral pulse saturation, and pyrexia. This study confirms that secondary insults, including an increased SjO(2), occur significantly more in patients with poor outcomes. More research into strategies to reduce the impact of secondary insults, including management of increased SjO(2), is required.

Can noninvasive imaging accurately depict intracranial aneurysms? A systematic review.

PURPOSE: To perform a systematic review to determine the accuracy of computed tomographic (CT) angiography, magnetic resonance (MR) angiography, and transcranial Doppler ultrasonography (US) in depicting intracranial aneurysms. MATERIALS AND METHODS: A 1988-1998 literature search for studies with 10 or more subjects in which noninvasive imaging was compared with angiography was undertaken. Studies meeting initial criteria were evaluated by using intrinsically weighted standardized assessment to determine suitability for inclusion. Studies scoring greater than 50% were included. RESULTS: Of 103 studies that met initial criteria, 38 scored greater than 50%. CT angiography and MR angiography had accuracies per aneurysm of 89% (95% CI: 87%, 91%) and 90% (95% CI: 87%, 92%), respectively. For US, data were scanty and accuracy was lower, although the CIs overlapped those of CT angiography and MR angiography. Sensitivity was greater for detection of aneurysms larger than 3 mm than for detection of aneurysms 3 mm or smaller-for CT angiography, 96% (95% CI: 94%, 98%) versus 61% (95% CI: 51%, 70%), and for MR angiography, 94% (95% CI: 90%, 97%) versus 38% (95% CI: 25%, 53%). Diagnostic accuracy was similar for anterior and posterior circulation aneurysms. CONCLUSION: CT angiography and MR angiography depicted aneurysms with an accuracy of about 90%. Most studies were performed in populations with high aneurysm prevalence, which may have introduced bias toward noninvasive examinations.

1H spectroscopic imaging of acute head injury--evidence of diffuse axonal injury.

Using single slice two-dimensional spectroscopic imaging (SI), nine acute head injury patients and six controls have been successfully scanned. The problems presented by the need for ITU monitoring of these patients during MR scanning was overcome using MR compatible monitoring equipment. In previous studies of head injury which used proton spectroscopy, single voxel localisation procedures have meant that the spatial extent of the spectral data has been limited. With spectral data from a whole axial slice, we have been able to identify NAA abnormalities in regions remote to any T2 visible lesions. This suggests that SI (of NAA in particular) will be useful for the diagnosis of diffuse axonal injury.

Accuracy of a miniature intracranial pressure monitor, its function during magnetic resonance scanning, and assessment of image artifact generation.

OBJECTIVE: We examined the accuracy and repeatability of an intracranial pressure (ICP) monitor (Codman MicroSensor; Johnson & Johnson Professional, Inc., Raynham, MA) in a nonmagnetic environment and during magnetic resonance imaging (MRI). The resulting image artifact generation was calculated. ICP monitoring is essential in management of severe head injury, but few ICP monitoring devices are compatible with use in an MRI scanner. The use of MRI to assess head injury is increasing, and developing safe methods of continuously monitoring ICP may improve patient care. METHODS: A water manometer was used as the standard for comparison. We assessed pressure readings from the ICP monitor in a nonmagnetic environment using a standard and a long connector cable between the pressure transducer and display unit. This long cable permitted testing during MRI sequences because the display unit could be distanced from the magnet. Accuracy was determined during T2-weighted imaging, proton spectroscopy, and diffusion-weighted imaging, and artifact generation was assessed. RESULTS: We found a high degree of accuracy for repeated measurements over a clinical pressure range using both standard and long connector cables outside the MRI room. During MRI scanning, the ICP monitor was accurate during T2 and proton spectroscopy sequences. Accuracy during diffusion-weighted imaging, however, was clinically unacceptable. This ICP monitor creates a reduction in signal-to-noise ratio in the received signal during T2-weighted imaging and proton spectroscopic imaging, with the obtained images still radiologically interpretable. CONCLUSION: The Codman ICP monitor is sufficiently accurate and free of artifact generation to be used during most clinical MRI applications. This could enhance patient monitoring and safety.