Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma.

BACKGROUND: Neoadjuvant therapy has been investigated for localized and locally advanced pancreatic ductal adenocarcinoma (PDAC) but no standard of care exists. Combination cetuximab/gemcitabine/radiotherapy demonstrates encouraging preclinical activity in PDAC. We investigated cetuximab with twice-weekly gemcitabine and intensity-modulated radiotherapy (IMRT) as neoadjuvant therapy in patients with localized or locally advanced PDAC. EXPERIMENTAL DESIGN: Treatment consisted of cetuximab load at 400 mg/m(2) followed by cetuximab 250 mg/m(2) weekly and gemcitabine 50 mg/m(2) twice-weekly given concurrently with IMRT to 54 Gy. Following therapy, patients were considered for resection. RESULTS: Thirty-seven patients were enrolled with 33 assessable for response. Ten patients (30%) manifested partial response and 20 (61%) manifested stable disease by RECIST. Twenty-five patients (76%) underwent resection, including 18/23 previously borderline and 3/6 previously unresectable tumors. Twenty-three (92%) of these had negative surgical margins. Pathology revealed that 24% of resected tumors had grade III/IV tumor kill, including two pathological complete responses (8%). Median survival was 24.3 months in resected patients. Outcome did not vary by epidermal growth factor receptor status. CONCLUSIONS: Neoadjuvant therapy with cetuximab/gemcitabine/IMRT is tolerable and active in PDAC. Margin-negative resection rates are high and some locally advanced tumors can be downstaged to allow for complete resection with encouraging survival. Pathological complete responses can occur. This combination warrants further investigation.

Association between Neospora caninum seropositivity and perinatal mortality in dairy heifers at first calving.

Associations between Neospora caninum infection and the reproductive performance of dairy heifers in their first and second pregnancy on 18 UK farms were examined. Six-month-old heifer calves were tested for N caninum-specific antibodies with a commercial ELISA, and were then monitored until their second calving. Random-effects regression analyses were performed on the data, using serological status as the explanatory variable. Of 460 heifers tested, 7.2 per cent were seropositive. Seropositive heifers were more likely to suffer gestational loss (late embryonic/early fetal loss and abortion) than seronegative heifers during their first (odds ratio [OR] 5.3, P<0.01) and second (OR 6.0, P<0.001) pregnancy. Seropositive heifers were also four times more likely to experience perinatal mortality (calf born dead or dying within 24 hours of parturition) at first (OR 3.9, P<0.01) and second (OR 4.5, P<0.1) calving. No significant association between seropositivity and the fertility parameters (age at first breeding and calving, days from calving to first service and conception, services per conception and calving interval) or conception failure was found. The results suggest that N caninum infection before pregnancy is a significant contributing factor to gestational loss and perinatal death, and thus serological screening of potential replacement heifers is recommended.

Effect of growth and development during the rearing period on the subsequent fertility of nulliparous Holstein-Friesian heifers.

This study investigated the effect of growth parameters and metabolic indices during the rearing period on the fertility of nulliparous Holstein-Friesian heifers managed on 17 UK dairy farms. Growth parameters (body weight [BW], heart girth, height, and crown-rump length) and metabolic indices (insulin-like growth factor-I [IGF-I], insulin, glucose, and urea) were measured at approximately 30, 180, and 450 d of age. Fertility data collected included age at first breeding (AFB), number of services per conception, pregnancy rate to first artificial insemination (AI), and age at first calving (AFC). Of the heifers initially bred (n=428), 4% failed to conceive. The mean pregnancy rate to first AI for heifers that conceived and calved without suffering reproductive loss (n=392) was 67%, and 6% required >2 inseminations. The mean AFB and AFC was 473+/-5 d (range, 357 to 936 d) and 791+/-6 d (range, 636 to 1529 d), respectively. Increased BW, girth, and IGF-I concentration (at 30, 180, and 450 d) and increased skeletal growth (at 180 and 450 d) was associated with a reduced AFB and AFC (P<0.05 to 0.001). Heifers calving at <775 d had a mean BW gain of 0.82+/-0.01kg from 30 to 180 d. Increased glucose concentration at 180 d was associated with a reduced AFB (P<0.01), but no associations were found between insulin and urea concentrations and any of the fertility traits recorded (P>0.1). Suboptimal growth associated with an increased AFC could be alleviated by improved monitoring of replacement heifers during the rearing period.

Mortality in Holstein-Friesian calves and replacement heifers, in relation to body weight and IGF-I concentration, on 19 farms in England.

The incidence of mortality and culling in Holstein-Friesian heifers from birth through first calving was determined on 19 dairy farms selected from across southern England. The outcome of 1097 calvings was determined. Size (BW, heart girth, crown-rump length and height at withers) and insulin-like growth factor-I concentration of live heifer calves were measured at a mean age of 26 ± 0.7 days (n = 506). Associations between the heifer-level variables and mortality were determined using clustered binary logistic regression. Perinatal mortality (stillbirths and mortality within the first 24 h of birth) of male and female calves was 7.9%. This figure was significantly higher in cases where calving assistance was required (19.1% v. 5.6%, P < 0.001) and in twin births (18.5% v. 7.0%, P < 0.05), and was lower in pluriparous v. primiparous dams (5.6% v. 12.1%, P < 0.01). On average, 6.8% of heifers died or were culled between 1 day and 6 months of age. Low BW at 1 month was associated with reduced subsequent survival up to 6 months. Between 6 months and first calving, a further 7.7% of heifers either died (42%) or were culled (58%); accidents and infectious disease accounted for the majority of calf deaths between 6 and 15 months, whereas infertility (16/450 animals served, 3.5%) was the main reason for culling following the start of the first breeding period. In total, 11 heifers (2.2%) were culled as freemartins; eight at birth and three around service. Overall, 14.5% of liveborn potential replacement heifers died or were culled before first calving.

Effect of management factors and blood metabolites during the rearing period on growth in dairy heifers on UK farms.

Growth rates during rearing affect the age and body weight (BW) of replacement heifers at first calving. Diet and disease can affect growth via altered metabolic hormone concentrations, but are difficult to monitor accurately on commercial farms. This study investigated the effect of management and metabolic indices (IGF-I, insulin, glucose and urea) on the growth rate of 509 Holstein-Friesian heifers on 19 UK dairy farms. Size (BW, heart girth, height and crown-rump length) was measured at approximately 1, 6 and 15 months. The mean daily weight gain up to 6 months for all calves was 0.77kg/day, with extreme variability both between cohorts of calves (range 0.49-1.02kg/day) and between individual calves within farms (range 0.45-1.13kg/day). Growth was enhanced by supplemental colostrum, by milk replacer as opposed to whole milk and by ad libitum milk feeding and was reduced by gradual weaning and dehorning after weaning. Larger group size slowed growth before weaning (>6 calves) but increased it post-weaning (>20 calves). These management differences were reflected in altered plasma IGF-I concentrations, which were positively associated with growth throughout the rearing period. Larger calves at 1 month had a greater weight gain up to 6 months. Sub-optimum growth of some heifers within each cohort was established at an early age and resulted in animals reaching the start of breeding at an inadequate size (BW range 209-498kg at 15 months). This could be alleviated by altered management strategies and improved monitoring of growing heifers.