A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma.

BACKGROUND: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC. PATIENTS AND METHODS: Patients with mRCC and 2-3 prior lines of therapy were randomized 1 : 1 to CRLX101 + bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. RESULTS: In total, 111 patients were randomized and received ≥1 dose of drug (CRLX101 + bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101 + bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0-4.3) and 3.9 months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P = 0.831). The objective response rate by IRR was 5% with CRLX101 + bevacizumab versus 14% with SOC (Mantel-Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101 + bevacizumab combination was generally well tolerated, and no new safety signal was identified. CONCLUSIONS: Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101 + bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned. CLINICAL TRIAL IDENTIFICATION: NCT02187302 (NIH).

The aversion of broiler chickens to concurrent vibrational and thermal stressors.

The requirement for assessing the effects of multiple concurrent stressors in improving the welfare of broiler chickens during transport has not been widely recognised. A discrete-choice technique was used to investigate the aversion of broiler chickens to concurrent vibrational and thermal transport stressors. In experiment 1, 12 female broiler chickens, aged 42+/-3 days were studied individually using two choice-chambers. Each chamber had four compartments connected via a central zone and offered four treatments; thermal (T: air temperature; 40 degrees C, 21% RH), vibrational (V: frequency; 2Hz, acceleration; 1ms(-2)), concurrent vibrational and thermal (VT) and no applied stressors (N). Coloured compartment wall panels, allocated at random, assisted chickens' identification of compartments. Birds were fasted overnight and were required to make five consecutive choices on each of four consecutive days. A choice was defined as entering a compartment and feeding (5g pellets), whereupon confinement for 60min was initiated. Choices were totalled over all birds and analysed using a log-linear generalised linear model. The vibration was significantly avoided (V and VT versus N and T; P<0.05) but the thermal stressor was not (T and VT versus N and V; P>0.05) and there was no interaction. In experiment 2, the procedure was repeated with 12 more birds and modifications to increase method sensitivity and maximise bird learning. Choices were more disparate than before with vibration avoided to a greater extent (V and VT versus T and N; P<0.01) but there was still no main effect of the thermal treatment or a significant interaction. Substantial differences between individuals were observed in both experiments. The overall response to vibration supported previous findings for short-term exposure, however, non-avoidance of the thermal treatment was unexpected. Possibly, the birds were unable to associate the delayed heat stress with the compartment. Alternatively, the thermal conditions were not perceived as aversive either initially or throughout the 60min confinement. The preference method provides a useful starting point for assessing combinations of stressors which affect broiler welfare, allowing relative ranking of treatments from an animal-centred perspective.

Effect of whole-body vibration in the vertical axis on cortisol and adrenocorticotropic hormone levels in piglets.

Vibration, being a consequence of motion during transport, may impair the welfare of pigs. Therefore, the primary objectives of this study were 1) to evaluate during transport simulation the use of ACTH and cortisol plasma levels, which are part of a basic adaptation mechanism of pigs and 2) to define comfort conditions for pigs related to the frequency and acceleration of vibration. Pigs with a body weight between 20 and 25 kg were vibrated in the vertical direction for 2 h at 2, 4, 8, and 18 Hz, in combination with root mean square acceleration magnitudes of 1 or 3 m/s2. Blood was sampled at regular intervals before, during, and after vibration as the pig's behaviors were recorded. Data on ACTH, cortisol, and behavior could be collected from 104 vibrated pigs and 21 controls. In addition, eight animals (3 controls, 5 vibrated) were treated with 0.1 mg of dexamethasone/kg BW, eight animals (3 controls, 8 vibrated) with 0.1 mg naloxone/kg BW, and six (2 controls, 4 vibrated) with a physiological salt solution. Blood samples were taken and products were administrated via an intravenous catheter. The pigs spent less time lying during both hours of vibration treatment than during control conditions. Compared with 2 and 4 Hz, time spent lying was 10 times shorter at 8 Hz and 18 times shorter at 18 Hz. At 1030, ACTH levels were significantly higher than basal levels in animals vibrated at 2 (P < 0.0001), 4 (P < 0.002), and 18 Hz (P < 0.0006). After 1 h, levels returned to basal values. Cortisol levels increased very rapidly after the beginning of vibration (P < 0.0001) and remained higher until 1 h after cessation of vibration (P < 0.003). An inferrence of the lines of equal responses for ACTH and cortisol indicated that, in the beginning of vibration exposure, pigs were extremely susceptible to vibrations at lower frequencies (2 and 4 Hz), whereas at the end of vibration exposure the responses were higher at 18 Hz. The application of dexamethasone and naloxone underpinned the emotional component of the response strategy of pigs to vibration. Hence, vibration during transport should be minimized in order to enhance the adaptive capacities of pigs.

Influence of vertical vibration on heart rate of pigs.

Pigs with a body weight between 15 and 20 kg were vibrated in the vertical direction for 1 h at 2, 8, and 18 Hz, in combination with root mean square (RMS) acceleration magnitudes of 1 or 3 m/s2. Welfare and stress were quantified by comparing heart rate characteristics during a control period (2200 to 0600) before vibration exposure and during vibration (1000 to 1100). The level of maximum heart rate and number of ventricular ectopic beats during vibration at 2 and 8 Hz in combination with a RMS acceleration of 3 m/s2 indicated a larger fear response than at 1 m/s2. Isocomfort contours based on mean heart rate during vibration showed the greatest specific sensitivity of the pigs to vibration at a frequency of 8 and 18 Hz, especially in combination with a RMS acceleration of 3 m/s2. During transport, RMS acceleration should be less than 3 m/s2 to protect pigs' welfare. Pigs were more sensitive to acceleration than to frequencies within the range of treatments in this investigation. Although the response of the pigs in this experiment fit within the model concept for adult humans and for domestic fowl, changes in heart rate are dependent on body weight.

Claw lesions in dairy cattle: methods for assessment of sole and white line lesions.

Claw lesions are a major cause of lameness in dairy cattle. Analysis of the development of lesions is aided by numerical representation of their significance. Using data from observations on 31 heifers at 9 weeks post-calving, 5 lesion scoring method were compared. These were: (1) number of lesions; (2) severity; (3) adjusted severity; (4) size (measured by a novel technique involving image analysis of distal view photographs) and (5) size multiplied by adjusted severity (combined score). Relationships between scores for sole and white line lesions and between different claws within a cow were investigated. The small size but high clinical significance of severe lesions means that severity must be weighted if combined with size in a score. Sole and white line lesions showed a moderate but significant correlation in terms of severity but none in terms of size. The highest correlation between scores for a single claw (the right hind outer) and the remaining claws was found for adjusted severity of sole lesions.

Resonant frequencies of standing humans.

Many forms of industrial illness are thought to result from the effects of vibration on the human body. Prolonged exposure causes undue stress and discomfort. At the human whole-body resonant frequency there is maximum displacement between the organs and the skeletal structure and thus this is one frequency of vibration that should be minimized in the workplace and elsewhere. The vertical whole-body resonant frequencies of 113 fully-clothed standing humans were measured using a vibrating beam method, which imposed a very low acceleration magnitude at the subjects' feet. The overall range of resonant frequencies was found to be from 9 to 16 Hz and independent of mass, height and mass to height ratio. The mean values (+/-1 s.e.) were 12.2 +/- 0.1 Hz for males and 12.8 +/- 0.2 Hz for females with an overall mean population value of 12.3 +/- 0.1 Hz.

Claw lesions in dairy cattle: development of sole and white line haemorrhages during the first lactation.

The development of claw haemorrhages was monitored in first-calving dairy heifers from 4 weeks before calving to 32 weeks after calving. Before calving, lesions were few but the number, extent and severity of claw haemorrhages increased following simultaneous calving and housing. Lesions were most severe in the white line at 9 weeks, and in the sole at 14 weeks, but recovery began while the animals were still housed. That the increase in white line lesions after calving, and the subsequent recovery preceded that of the sole, suggests that the pathogenesis of the lesions may differ in these two anatomical regions. It is proposed that an initial insult to the corium primarily affects the laminar region and that corium damage increases with the resulting alteration in the physical forces on the sole.

Thalamic infarction in childhood due to extracranial vertebral artery abnormalities.

We report two children who developed thalamic infarctions which were demonstrated by CT. Both children had apparently normal angiograms although the extra cranial portions of the vertebral arteries were not demonstrated on the initial examination. Subsequent angiograms demonstrated abnormalities of the cervical portion of the vertebral arteries, dissection and pseudoaneurysm in one case and a large fusiform aneurysm in the other. Both children made full neurological recoveries. The thalamus is supplied by branches from the vertebro-basilar circulation and it is important to study the entire length of the extra cranial vertebral arteries as well as the intracranial vasculature.

Vibration on poultry transporters.

1. This research established the magnitudes and frequencies of vibration acceleration on two typical broiler bird transporters, one with leaf and the other with air suspension. 2. Vibration measurements were made using triaxial accelerometers mounted on the chassis and in the bird containers, with vehicles both loaded and unloaded. 3. In the vertical axis the fundamental vehicle frequency is between 1 and 2 Hz with a secondary peak at 10 Hz. 4. In the lateral axis with air suspension, the maximum level of vibration on the chassis occurred at 12 to 18 Hz; this was less evident with leaf suspension. 5. The magnitudes of vibration acceleration occurring in the bird containers would be fairly uncomfortable for the seated human. Frequency weightings and response to different axes and magnitudes of vibration must be established before the response of birds can be predicted.

Diffuse pneumocephalus due to Clostridium septicum cerebritis in haemolytic uraemic syndrome: CT demonstration.

The computed tomography finding of diffuse pneumocephalus due to infection by gas-forming organisms is very unusual. We report such a case due to secondary infection by Clostridium septicum in a child with diarrhoea-associated haemolytic uraemic syndrome.

Cervical mucus score and in vitro sperm mucus interaction in spontaneous and clomiphene citrate cycles.

OBJECTIVE: Assessment of the effects of clomiphene citrate (CC) on cervical mucus score and in vitro sperm mucus interaction. DESIGN: Prospective study of cervical mucus score and in vitro sperm mucus interaction in a spontaneous cycle followed by a CC cycle to compare paired data. SETTING: Tertiary institutional infertility clinic. PATIENTS, PARTICIPANTS: Twenty-two couples with primary unexplained infertility were studied in both cycles. INTERVENTIONS: Clomiphene citrate (150 mg) on days 5 to 9 in CC cycles. MAIN OUTCOME MEASURES: Cervical mucus score and sperm-mucus penetration test score. RESULTS: Mean cervical mucus score in spontaneous cycles was 9.3 (95% confidence interval [CI] 8.4 to 10.2) and in CC cycles 5.6 (95% CI 4.6 to 6.6), P less than 0.0001. Sperm-mucus penetration test score in spontaneous cycles was 11.4 (95% CI 7.6 to 15.2) and in CC cycles 3.9 (95% CI 1.17 to 6.63), P less than 0.01. CONCLUSIONS: Clomiphene citrate has an adverse effect on both cervical mucus score and sperm-mucus penetration.

Transvaginal sonographic assessment of follicular and endometrial growth in spontaneous and clomiphene citrate cycles.

OBJECTIVE: Assessment of follicular development and endometrial growth using transvaginal sonography in spontaneous and clomiphene citrate (CC) cycles with a spontaneous luteinizing hormone surge. DESIGN: Prospective study of a spontaneous cycle followed by a CC cycle to compare paired data. SETTING: Institutional tertiary referral infertility clinic. PATIENTS: Eighteen couples with primary unexplained infertility voluntarily recruited from the infertility clinic. INTERVENTION: Daily transvaginal sonography and endocrine monitoring. Clomiphene citrate (150 mg) was administered on days 5 to 9 of CC cycle. MAIN OUTCOME MEASURES: Leading follicular diameter and endometrial thickness. RESULTS: The growth rate of the leading follicle was similar in both study cycles, although in CC cycles the leading follicle diameter was significantly larger. Endometrial thickness was reduced in CC cycles. CONCLUSION: Follicular development and endometrial thickness are altered in CC cycles.

The effects of clomiphene citrate upon ovulation and endocrinology when administered to patients with unexplained infertility.

Twenty-four couples with unexplained infertility were studied in a spontaneous cycle followed by a clomiphene citrate (CC) cycle (150 mg, days 5-9). All spontaneous cycles were ovulatory, as defined by follicular collapse determined by transvaginal sonography. In CC cycles, 6/24 (25%) cycles demonstrated luteinized unruptured follicles (LUF). In 2/6 LUF cycles there was no apparent luteinizing hormone (LH) surge. LUF cycles had significantly elevated LH levels in the follicular phase compared to ovulatory CC cycles. There was no apparent difference in serum oestradiol. In CC cycles multifollicular development occurred in 87.5% of cycles, with significantly elevated serum oestradiol. Luteinizing hormone and follicle-stimulating hormone were elevated in the follicular phase compared to spontaneous cycles. This study suggests a high incidence of LUF when CC is administered to ovulatory patients, and its use in patients with ovulatory infertility is questioned.

Transvaginal ultrasonic assessment of endometrial growth in spontaneous and hyperstimulated menstrual cycles.

Endometrial thickness and reflectivity were assessed by transvaginal ultrasound in both spontaneous and hyperstimulated menstrual cycles. Two groups of women with ovulatory cycles were examined; women in group 1 had unexplained infertility and women in group 2 were having artificial insemination by donor because of reduced spermatogenesis; a third group (group 3) comprised women with tubal infertility undergoing hyperstimulation for in-vitro fertilization. There was no difference in endometrial thickness or reflectivity between the three groups. A basic pattern of endometrial appearance common to all cycles was found, consisting of hypoechoic, isoechoic and hyperechoic images, occurring in the early follicular, late follicular and luteal phases, respectively. In all three groups a positive correlation was found between proliferative phase plasma oestradiol concentration and endometrial thickness. Group 1 r = 0.403, P less than 0.01; group 2 r = 0.439, P less than 0.01; and group 3 r = 0.617, P less than 0.01. There was a progressive increase in endometrial growth throughout the normal cycle until a plateau was reached 5 days after the LH surge. This pattern was also seen without acceleration of the process in hyperstimulated cycles, despite supranormal levels of oestrogen. Assessment of endometrial thickness is not a useful variable in monitoring hyperstimulated cycles. No aberrations of endometrial growth or pattern were observed in the women with unexplained infertility.