Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors.

Pasireotide long-acting repeatable (LAR) is a novel somatostatin analog (SSA) with avid binding affinity to somatostatin receptor subtypes 1, 2, 3 (SSTR1,2,3) and 5 (SSTR5). Results from preclinical studies indicate that pasireotide can inhibit neuroendocrine tumor (NET) growth more robustly than octreotide in vitro. This open-label, phase II study assessed the clinical activity of pasireotide in treatment-naïve patients with metastatic grade 1 or 2 NETs. Patients with metastatic pancreatic and extra-pancreatic NETs were treated with pasireotide LAR (60 mg every 4 weeks). Previous systemic therapy, including octreotide and lanreotide, was not permitted. Tumor assessments were performed every 3 months using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), overall radiographic response rate (ORR), and safety. Twenty-nine patients were treated with pasireotide LAR (60 mg every 4 weeks) and 28 were evaluable for response. The median PFS was 11 months. The most favorable effect was observed in patients with low hepatic tumor burden, normal baseline chromogranin A, and high tumoral SSTR5 expression. Median OS has not been reached; the 30-month OS rate was 70%. The best radiographic response was partial response in one patient (4%), stable disease in 17 patients (60%), and progressive disease in ten patients (36%). Although grade 3/4 toxicities were rare, pasireotide LAR treatment was associated with a 79% rate of hyperglycemia including 14% grade 3 hyperglycemia. Although pasireotide appears to be an effective antiproliferative agent in the treatment of advanced NETs, the high incidence of hyperglycemia raises concerns regarding its suitability as a first-line systemic agent in unselected patients. SSTR5 expression is a potentially predictive biomarker for response.

Production and reproduction of Fleckvieh, Brown Swiss, and 2 strains of Holstein-Friesian cows in a pasture-based, seasonal-calving dairy system.

The first objective of this study was to compare the productive and reproductive performance of Holstein-Friesian (CH HF), Fleckvieh (CH FV), and Brown Swiss (CH BS) cows of Swiss origin with New Zealand Holstein-Friesian (NZ HF) cows in pasture-based compact-calving systems; NZ HF cows were chosen as the reference population for such grazing systems. The second objective was to analyze the relationships within and between breeds regarding reproductive performance, milk yield, and body condition score (BCS) dynamics. On 15 commercial Swiss farms, NZ HF cows were paired with Swiss cows over 3 yr. Overall, the study involved 259 complete lactations from 134 cows: 131 from 58 NZ HF, 40 from 24 CH HF, 43 from 27 CH FV, and 45 from 25 CH BS cows. All production parameters were affected by cow breed. Milk and energy-corrected milk yield over 270 d of lactation differed by 1,000 kg between the 2 extreme groups; CH HF having the highest yield and CH BS the lowest. The NZ HF cows had the greatest milk fat and protein concentrations over the lactation and exhibited the highest lactation persistency. Body weight differed by 90 kg between extreme groups; NZ HF and CH BS being the lightest and CH HF and CH FV the heaviest. As a result, the 2 HF strains achieved the highest milk production efficiency (270-d energy-corrected milk/body weight(0.75)). Although less efficient at milk production, CH FV had a high 21-d submission rate (86%) and a high conception rate within 2 inseminations (89%), achieving high pregnancy rates within the first 3 and 6 wk of the breeding period (65 and 81%, respectively). Conversely, poorer reproductive performance was recorded for CH HF cows, with NZ HF and CH BS being intermediate. Both BCS at nadir and at 100 d postpartum had a positive effect on the 6-wk pregnancy rate, even when breed was included in the model. The BCS at 100 d of lactation also positively affected first service conception rate. In conclusion, despite their high milk production efficiency, even in low-input systems, CH HF were not suited to pasture-based seasonal-calving production systems due to poor reproductive performance. On the contrary, CH FV fulfilled the compact-calving reproduction objectives and deserve further consideration in seasonal calving systems, despite their lower milk production potential.

Molecular analysis and prenatal diagnosis of human fumarase deficiency.

Fumarase deficiency is a rare autosomal recessive disorder of the citric acid cycle causing severe neurological impairment. The cDNA for both the rat and human enzymes has been cloned previously and shown to encode a coding region of 1.46 kb. To scan for mutations in fumarase-deficient patients we amplified the coding region of fumarase from fibroblast/lymphoblast cDNA employing the oligonucleotide primers designed from the published human and rat cDNA sequence. We then directly sequenced the polymerase chain reaction product. In seven unrelated patients, we detected four missense mutations (A265T, D383V, F269C, K187R), a nonsense mutation (W458X), a 3-bp AAA insertion that introduces an additional lysine residue at codon 435, and a spontaneous new mutation resulting in a 74-bp deletion (66del74). Seven at-risk pregnancies were monitored with one prenatal diagnosis of fumarase deficiency by molecular analysis and favorable outcome of the other pregnancies as predicted by enzyme assay of cultured fetal cells or molecular analysis.

Interactions between body condition at calving and cooling of dairy cows during lactation in summer.

This study examined the interactions between dietary manipulation for increased body condition during the last trimester of pregnancy (spring) and postpartum cooling (summer lactation). Effects of diet on milk production of Holstein cows were examined to determine whether body stores could compensate for reduced DMI during heat stress. Cows calving between May and July with high (3.8 on a six-point scale) or low (2.7) body condition scores were assigned postpartum to be cooled by sprinkling and ventilation or to serve as uncooled controls. Cooled cows ate 1.6 kg more DM/d and consumed 9 L less of water/d than uncooled cows. Cooled cows maintained body temperatures below 38.9 degrees C during day hours; peak body temperature for uncooled cows was 39.7 degrees C. For 8 wk postpartum, glucose and insulin concentrations in plasma were unaltered by cooling or body condition. The NEFA were lower, and urea was slightly higher, for cows with low body condition. Milk production increased 1.9 kg/d with cooling, fat production increased with both body condition and cooling, and protein production increased with cooling but not with body condition. Performance was lowest for the uncooled subgroup with low body condition. Among cooled cows, no advantage was attributable to high body condition. An additive effect of high body condition and cooling on milk production in summer was not evident.

Reduced and compensatory growth: endocrine and metabolic changes during food restriction and refeeding in steers.

Effects of food restriction, followed by refeeding, on energy and nitrogen metabolism, growth rates and blood levels of hormones and metabolites were studied in steers. During the restriction period, which lasted for almost 5 mo, allowance for energy and nitrogen were close to maintenance requirements. Heat production and growth rates were markedly lowered. In response to reduced food intake concentrations of thyroxine (T4), 3,5,3'-triiodothyronine (T3), insulin (IRI), glucose and alpha-amino-acid nitrogen (AAN) were reduced, those of growth hormone (GH) and nonesterified fatty acids (NEFA) were elevated, whereas 3,3',5'-triiodothyronine (rT3) and albumin were not different from levels measured in nonrestricted animals. During refeeding heat production and energy balances increased, nitrogen balances were transiently elevated and the animals exhibited compensatory growth. In response to refeeding, concentrations of T4, T3 and IRI increased within days. In contrast, GH decreased whereas rT3 did not change. Within 2 d of refeeding there was a rapid fall of NEFA, and an increase of glucose, and beta-hydroxybutyrate within 2 and 12 d, respectively. The data demonstrate the ability of growing ruminants to adapt rapidly to variations in food intake by closely linked metabolic and endocrine changes, which are associated with shifts in energy and nitrogen metabolism and, finally, by reduced or compensatory growth.