Background:In patients with advanced hepatocellular carcinoma (hcc) following sorafenib failure, it is unclear which treatment is most efficacious, as treatments in the second-line setting have not been directly compared and no standard therapy exists. This systematic review and network meta-analysis (nma) aimed to compare the clinical benefits and toxicities of these treatments. Methods:A systematic review of randomized controlled trials (rcts) was conducted to identify phase iii rcts in advanced hcc following sorafenib failure. Baseline characteristics and outcomes of placebo were examined for heterogeneity. Primary outcomes of interest were extracted for results, including overall survival (os), progression-free survival (pfs), objective response rate (orr), grade 3/4 toxicities, and subgroups. An nma was conducted to compare both drugs through the intermediate placebo. Comparisons were expressed as hazard ratios (hrs) for os and pfs, and as risk difference (rd) for orr and toxicities. Subgroup analyses for os and pfs were also performed. Results:Two rcts were identified (1280 patients) and compared through an indirect network; celestial (cabozantinib vs. placebo) and resorce (regorafenib vs. placebo). Baseline characteristics of patients in both trials were similar. Both trials also had similar placebo outcomes. Cabozantinib, compared with regorafenib, showed similar os [hazard ratio (hr): 1.21; 95% confidence interval (ci): 0.90 to 1.62], pfs (hr: 1.02; 95% ci: 0.78 to 1.34) and orr (-3.0%; 95% ci: -7.6% to 1.7%). Both treatments showed similar toxicities, but there were marginally higher risks of grade 3/4 hand-foot syndrome (5%; 95% ci: 0.1% to 9.8%), diarrhea (4.8%; 95% ci: 1.1% to 8.5%), and anorexia (4.4%; 95% ci: 0.8% to 8.0%) for cabozantinib. Subgroup results for os and pfs were consistent with overall results. Conclusions:Overall, this nma determined that cabozantinib and regorafenib have similar clinical benefits and toxicities for second-line hcc.

Antibody-detecting tests for Mycobacterium avium ssp. paratuberculosis (MAP) have low sensitivity and imperfect specificity for detection of infection. Sensitivity increases as the disease progresses. Aside from infection status and stage of disease, several factors affect test performance. These factors have not yet been studied in dairy cows producing lower volumes of milk with higher solids concentration, such as those managed in low-input, pasture-based production systems. Furthermore, the effect of correcting for these associations on individual and herd test status is also unknown. The first objective of this study was to examine the relationship between MAP antibody response in milk and milk yield, somatic cell count (SCC), fat and protein contents, and stage of lactation in dairy cows enrolled in the national Johne's Disease Control Programme (JDCP) in Ireland. The second objective was to examine the effect of correcting the antibody response for these associations on the test status of individual cows and herds, given that individual tests are often used to define a herd's status. Data were extracted for herds in the JDCP from January 2014 to December 2015 inclusive, consisting of 42,657 milk recordings from 18,569 cows across 187 dairy herds. Two linear regression models were constructed to investigate the association between log-transformed MAP sample-to-positive ratio and milk recording data and in primi- and multiparous cows. Days in milk was modeled as a B-spline in each model, and cow and herd were included as random effects. Across both models, natural log-transformed MAP antibody response was negatively associated with milk yield, positively associated with protein and fat production, and had a curvilinear association with log-transformed SCC. The association between MAP antibody response and days in milk varied over the course of the lactation. However, when combined, these variables explained only 5.1% of the variation in the antibody response of the population. After correcting for these associations, 93 multiparous cows and 20 primiparous cows changed category (negative, suspect, or positive). When considered at the herd-test level, out of a total of 531 herd tests, 1 herd changed from negative to positive, and 5 herds changed from positive to negative. This study provides useful information to aid in the interpretation of antibody results for herds testing animals for the presence of MAP infection. At an overall population level, correction of the serological response for non-disease-associated factors has the potential to change the status of only a small number of cows. At the herd level, the proportion of herds changing status was minimal. However, depending on the implications of a herd-level serological diagnosis, consideration should be given to correcting for these non-disease-associated variables within the context of national JD control programs.

Historically, brain metastases from non-small cell lung cancer (NSCLC) have been associated with short prognosis, with limited benefits from whole brain radiotherapy (WBRT) or cytotoxic chemotherapy.1 The effectiveness of tyrosine kinase inhibitors (TKIs) in advanced EGFR- and ALK-driven NSCLC has translated into survival times far longer than chemotherapy in unselected patients.2,3 Among these patients, brain metastases may occur in 20-40% at first presentation, and up to 50% over the course of their illness.4,5 In spite of this, patients may live for several years following diagnosis of brain metastases and are accordingly at risk of longer-term toxicity from central nervous system (CNS)-directed treatments.4,6,7 For patients diagnosed with brain metastases from EGFR- or ALK-driven NSCLC, initial treatment options range from TKI alone, through WBRT, stereotactic radiosurgery (SRS) to craniotomy and resection. All eligible patients will ultimately receive systemic therapy with TKI, and this is likely to be the most important component in preventing or delaying further CNS metastases. The utility of local radiotherapy is therefore worthy of debate in this patient population. Multiple retrospective series have attempted to examine this effect, the largest of which is a US multi-institution study, which reported longer overall survival (OS) for patients treated with SRS and TKI over TKI alone (median OS 46 vs 25 months, p<0.001).7 Studies in Canada and China did not find a difference in survival, but all of these are largely subject to confounding and bias based on the selection of patients for local treatments, as well as potential bias in the follow-up of brain lesions.6,8 In addition, most patients included in all of these studies were treated with 1st generation TKIs targeting EGFR or ALK. Within randomized trials including patients treated with modern TKIs, relatively few develop CNS progression, at least as their first evidence of progressive disease. This is evident among patients with brain metastases enrolled in the FLAURA trial in first-line EGFR mutation positive NSCLC, where CNS progression was seen in 12% of the osimertinib group and 30% of the control group, comprising of 1st and 2nd generation TKIs (p=0.01).9 In ALK-rearranged NSCLC, results from the ALEX trial demonstrate much better CNS control with alectinib , with brain progression in 12% compared with 45% of those treated with crizotinib (p<0.001).5 Among patients with measurable CNS metastases treated with alectinib, the objective response rate (ORR) was 81%, with complete responses seen in 45%, compared with an ORR of 59% for crizotinib and complete responses in 9%. Patients in both studies with CNS disease at entry were treated with SRS for control of brain metastases at study entry, but the high response rates and relatively low rates of progression speak to the efficacy of these TKIs in suppressing micrometastatic disease that would not be controlled by focal radiotherapy. With promising results like these, why would we wish to move away from radiotherapy? The purpose of palliative treatments for patients with advanced cancer is generally to preserve quality of life and function for as long as possible, with treatments that are not overly burdensome or toxic. The data from these trials of modern TKIs would suggest that for most patients, systemic therapy will effectively control their overt or subclinical brain metastases, and they can be spared the inconvenience and potential toxicity of locoregional treatments. Recently, there has been a move from WBRT towards SRS even for the treatment of multiple brain metastases, driven primarily by data reporting the neurocognitive toxicity of WBRT.10 Although the rates of decline in neurocognition appear lower with SRS, in the setting of questionable clinical benefit and when patients are expected to live several years with CNS metastases, the risk of toxicity may not be justified. There are, however, patients where local therapy such as radiotherapy or surgery are indicated – those with major neurological symptoms, hydrocephalus, or in circumstances where molecular testing is delayed or where effective TKIs are unavailable or contraindicated. However, for most patients with oncogene-driven lung cancer who will receive TKI therapy, delaying upfront radiotherapy for brain metastases may not negatively affect patient outcomes. Data from randomized trials of targeted therapy alone or with radiotherapy will be required to definitively answer this question. 1. Chao JH, Phillips R, Nickson JJ: Roentgen-ray therapy of cerebral metastases. Cancer 7:682-9, 1954 2. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-57, 2009 3. Solomon BJ, Mok T, Kim D-W, et al: First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. New England Journal of Medicine 371:2167-2177, 2014 4. Soria J-C, Ohe Y, Vansteenkiste J, et al: Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer. New England Journal of Medicine 378:113-125, 2018 5. Peters S, Camidge DR, Shaw AT, et al: Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer. New England Journal of Medicine 377:829-838, 2017 6. Doherty MK, Korpanty GJ, Tomasini P, et al: Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancer. Radiotherapy and Oncology. 11, 2017 7. Magnuson WJ, Lester-Coll NH, Wu AJ, et al: Management of brain metastases in tyrosine kinase inhibitor-Naive epidermal growth factor receptor-mutant non-small-cell lung cancer: A retrospective multi-institutional analysis. Journal of Clinical Oncology 35:1070-1077, 2017 8. Liu S, Qiu B, Chen L, et al: Radiotherapy for asymptomatic brain metastasis in epidermal growth factor receptor mutant non-small cell lung cancer without prior tyrosine kinase inhibitors treatment: a retrospective clinical study. Radiat Oncol 10:118, 2015 9. Vansteenkiste J, Reungwetwattana T, Nakagawa K, et al: CNS response to osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFR-TKI sensitising mutation (EGFRm)-positive advanced non-small cell lung cancer (NSCLC): Data from the FLAURA study. Ann Oncol 28, 2017 10. Chang EL, Wefel JS, Hess KR, et al: Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. The Lancet Oncology 10:1037-1044, 2009 ALK, brain metastases, EGFR

BACKGROUND:Failure of passive transfer of maternal immunity via colostrum can occur in the bovine, and a number of blood tests have been developed to test calves for this failure. It is not clear which test is most suitable for this purpose. The objective was to examine the most commonly used tests for failure of passive transfer and to decide which is most suitable for routine laboratory use. 126 serum samples were taken from calves of dairy cows after birth but prior to colostrum feeding, and at 48 h of age. Five different tests were compared against radial immunodiffusion which is considered the appropriate reference method. These tests were serum gamma-glutamyltransferase levels, serum protein levels, serum globulin levels, an enzyme linked immunosorbent assay and the zinc sulphate turbidity test.RESULTS:The tests examined displayed high sensitivity but widely varying specificity. Examination of the use of different cut-off points allowed some improvement in specificity at the expense of sensitivity, but the tests which had performed best at the original cut-off points still displayed the best performance. Gamma-glutamyltransferase levels as a measure of colostrum absorption returned, in this study, the best balance between sensitivity and specificity. The ELISA used in this study and serum globulin levels displayed performance similar to the gamma-glutamyltransferase levels. Serum total protein was less successful than others examined at providing both sensitivity and specificity but may, when performed via refractometer, be useful for on-farm testing. As currently performed the poor sensitivity for which the zinc sulphate turbidity test is most often criticized is evident. Modification of the cut-off point to increase specificity is less successful at balancing these parameters than the ELISA, gamma-glutamyltransferase levels, and globulin levels.CONCLUSIONS:Gamma-glutamyltransferase levels, ELISA testing and circulating globulin levels performed best in detecting failure of passive transfer in serum samples, although all three had some practical considerations.

Bovine perinatal mortality is defined as the death of a full-term calf before, during or up to 48h after calving. Recent studies indicate that the prevalence of bovine perinatal mortality is increasing, particularly in Holstein primiparae. Factors leading to a greater incidence of dystocia are the most important modifiable variables influencing the risk of perinatal mortality. Modifiable predictors are largely (age at first calving, breeding method, sire, calving management, feto-maternal health status and gestational nutrition) or moderately (calf breed, sex, gestation length) under the control of the dairy farm manager. Unlike non-modifiable risk factors, such as primiparity and fetal plurality, these factors can be manipulated to reduce the incidence of perinatal mortality.

Mastitis continues to be a cause of significant economic loss to the dairy industry internationally. Despite significant advances in our understanding of the disease, clinical and sub-clinical mastitis remains a problem in dairy herds and prevalence rates in many countries remain similar to those published decades ago. In the complex milieu of the modern dairy farm, it is the interaction of production diseases including mastitis, their relationship with nutritional strategy, housing, environment and the fundamental influence of social and attitudinal factors that make prevention and control such a challenge. Thus, dairy cows are eight times more likely to develop mastitis if they suffered milk fever at parturition. Mastitis is the most costly disease of cattle; it impacts on animal health and welfare, on market image, on profitability and, critically, on the quality of life of dairy farmers. Mastitis is stressful for both cows and farmers. Importantly, clinical mastitis represents only the 'tip of the iceberg' and it is the significance of the sub-clinical disease that is frequently underestimated. While there will always be more to learn about mastitis at the cellular and molecular levels, a significant body of knowledge already exists, which should allow us to optimally manage and prevent the disease. The scientific knowledge base has been rapidly increasing, but there has been inadequate emphasis on the application of existing knowledge to the development of disease management systems or on increasing the capacity for knowledge uptake. One of the challenges facing the Irish dairy industry will be the development, implementation and economic assessment of practical solutions to mastitis control. Addressing this challenge will require an integrated, partnership approach involving the farmer and the veterinarian along with Teagasc and other agricultural advisors. The special supplement of the Irish Veterinary Journal, from which these abstracts are taken, is a compilation of peer-reviewed papers presented by leading international scientists at a two-day symposium, sponsored by Alltech, entitled 'Focus on Mastitis: Knowledge into Practice' and hosted by the Herd Health Group at University College Dublin. The supplement is available to download on http://www.irishveterinaryjournal.com The various topics covered include global perspectives on the dairy industry, potential applications of HACCP-like approaches to control, exploration of the contagious-environmental mastitis paradigm, therapeutic strategies and nutritional influences on the immune response. We hope that this special supplement will be regarded as an authoritative learning resource by veterinarians, farmers, advisors, researchers and undergraduate students and, given the recent launch of the Animal Health Ireland initiative by the Minister for Agriculture, Fisheries and Food, we believe that the material provides a topical, timely and authoritative review on one of the priority issues to be addressed by that important national herd health initiative. To download a copy of the peer-reviewed publication, Focus on Bovine Mastitis: Knowledge into Practice, visit the Irish Veterinary Journal website, http://www.irishveterinaryjournal.com

Parenteral nutrition (PN) may be a rewarding but expensive therapeutic option in calves when enteric alimentation is precluded for a finite period: as, for instance, in protracted chronic diarrhoea. Supportive fluid and electrolyte therapy will address some of the more immediate disturbances of homeostasis but it will not meet nutritional requirements. PN should aim to provide sufficient energy in the form of dextrose or lipid solutions, in order to spare amino acids for anabolic purposes. Concurrent oral administration of small amounts of food should stimulate the enterocytes and induce digestive enzymes in preparation for resumption of enteric feeding.Administration of PN is merely an extension of current procedures for fluid therapy; when performed with due care it should not cause serious clinical complications.The subject of the case report was a chronically diarrhoeic calf that was treated with PN, returned to enteral nutrition, and was discharged from the Veterinary Teaching Hospital with a good prognosis.

Corynebacterium pseudotuberculosis was isolated from superficial abscesses on the ventral aspect of the mandible of a two-year-old pedigree Suffolk ewe that had been recently imported into the Republic of Ireland from England. Osteomyelitis of the mandible was present, from which Corynebacterium pseudotuberculosis and other bacteria were isolated.

Parafilaria bovicola is a parasite that is not endemic to Ireland. In other countries such as Sweden it has caused widespread economic losses to the cattle industry due to carcass trimming and lowered value of hides. A Charolais bull, recently imported from France, was presented with multiple bleeding points consistent with a clinical diagnosis Of parafilariosis. On examination of smears taken from the bleeding points, eggs and microfilariae of P. bovicola were observed, confirming infection in this animal. The lesions rapidly resolved after treatment with invermectin. Musca autumnalis is the vector and intermediate host of P. bovicola in Sweden. Because of the widespread abundance of this insect in Ireland and the poor efficacy of anthelmintic treatment against early larval stages at the time of importation this parasite must be considered a potential threat to the national herd.