Cumulative pemetrexed dose increases the risk of nephrotoxicity.

INTRODUCTION: Pemetrexed is a pharmacotherapeutic cornerstone in the treatment of non-small cell lung cancer. As it is primarily eliminated by renal excretion, adequate renal function is essential to prevent toxic exposure. There is growing evidence for the nephrotoxic potential of pemetrexed, which even becomes a greater issue now combined immuno-chemotherapy prolongs survival. Therefore, the aim of this study was to describe the incidence of nephrotoxicity and related treatment consequences during pemetrexed-based treatment. METHODS: A retrospective cohort study was conducted in the Jeroen Bosch Hospital, Den Bosch, the Netherlands. All patients that received at least 1 cycle of pemetrexed based therapy were included in the dataset. The primary outcome was defined as a ≥25 % reduction in eGFR. Additionally, the treatment consequences of decreased renal function were assessed. Logistic regression was used to identify risk factors for nephrotoxicity during treatment with pemetrexed. RESULTS: Of the 359 patients included in this analysis, 21 % patients had a clinically relevant decline in renal function after treatment and 8.1 % of patients discontinued treatment due to nephrotoxicity. Cumulative dose (≥10 cycles of pemetrexed based therapy) was identified as a risk factor for the primary outcome measure (adjusted OR 5.66 (CI 1.73-18.54)). CONCLUSION: This study shows that patients on pemetrexed-based treatment are at risk of developing renal impairment. Risk significantly increases with prolonged treatment. Renal impairment is expected to become an even greater issue now that pemetrexed-based immuno-chemotherapy results in longer survival and thus longer treatment duration.

Thyroid hormone in the regulation of hepatocellular carcinoma and its microenvironment.

Hepatocellular carcinoma (HCC) commonly arises from a liver damaged by extensive inflammation and fibrosis. Various factors including cytokines, morphogens, and growth factors are involved in the crosstalk between HCC cells and the stromal microenvironment. Increasing our understanding of how stromal components interact with HCC and the signaling pathways involved could help identify new therapeutic and/or chemopreventive targets. It has become increasingly clear that the cross-talk between tumor cells and host stroma plays a key role in modulating tumor growth. Emerging reports suggest a relationship between HCC and thyroid hormone signaling (dysfunction), raising the possibility that perturbed thyroid hormone (TH) regulation influences the cancer microenvironment and cancer phenotype. This review provides an overview of the role of thyroid hormone and its related pathways in HCC and, specifically, its role in regulating the tumor microenvironment.

Peripartum acute-phase protein serum amyloid-A concentration in plasma of cows and fetuses.

Concentration of the acute-phase protein serum amyloid-A (SAA) was measured by means of an indirect ELISA method, in plasma of 3 pregnant cows and in plasma taken by cannula from another 4 pregnant cows and, by separate cannula, from their fetuses. Blood samples were taken daily from approximately 72 hours before until 72 hours after parturition. After parturition, SAA concentration increased significantly (P < 0.05) in maternal plasma. In fetal plasma, only a nonsignificant increase was found at time of delivery. The concentration of maternal SAA started to increase within the first 24 hours after delivery, reaching a peak value between 24 and 48 hours after delivery. In the aforementioned plasma samples from the 4 pregnant cows and their fetuses, the concentration of maternally derived cortisol increased nonsignificantly after parturition. The concentration of fetally derived cortisol was significantly (P < 0.05) increased at parturition (t = 0), compared with the initial fetal cortisol concentration at 120 hours before delivery. Peripartum concentration of maternal SAA increased and maternal cortisol remained low, whereas fetal SAA concentration remained low and fetal cortisol concentration increased. These findings indicate possible suppressive action of fetal cortisol on fetal SAA production. However, it might be argued that the main cause of the difference in SAA concentration is the difference in tissue damage between cows and fetuses at parturition.

The role of endotoxin in the pathogenesis of acute bovine laminitis.

To study the possible role of endotoxin in the pathogenesis of bovine laminitis, local and systemic injections of endotoxin (E. coli 0111 B4) with different doses were given to three groups of four cows each. Clinical and haematologic parameters indicated an acute-phase response, including positive plasma ethanol gelation (soluble fibrin), the occurrence of fibrin degradation products and decreased thrombocyte counts. Local Shwartzman reactions were not evoked. Clinical examination of the claws and the gait of the animals revealed no signs of laminitis. However, on histopathological examination of the claw corium signs of laminitis such as vacuolisation of the Stratum basale, lymphocyte and leucocyte infiltration and thrombosis were found. These results indicate that endotoxin indeed may be involved in the pathogenesis of laminitis. For the development of a clinical acute laminitis model in cattle either another dosage, other toxins or factors in addition to the endotoxin used in this experiment are needed.

Bovine laminitis: clinical aspects, pathology and pathogenesis with reference to acute equine laminitis.

This review deals with the features of clinical and subclinical laminitis in cattle. Prominent clinical signs of acute laminitis are a tender gait and arched back. The sole horn reveals red and yellowish discolourations within five days. In subacute and chronic cases clinical signs are less severe. In chronic laminitis the shape of the claws is altered. Laminitis is frequently followed by sole ulceration and white zone lesions. Blood tests showed no significant changes for laminitic animals. Arteriographic studies of claws affected by laminitis indicated that blood vessels had narrowed lumens. Gross pathology revealed congestion of the corium and rotation of the distal phalanx. Histopathologic studies indicate that laminitis is associated with changes of the vasculature. Peripartum management and nutrition are important factors in its aetiology. It is hypothesised that laminitis is evoked by disturbed digital circulation. In the pathogenesis of acute laminitis three factors are considered important: the occurrence of thrombosis, haemodynamic aspects of the corium, and endotoxins which trigger these pathologic events.

The influence of calving and puerperium on clinical and histopathologic changes associated with laminitis and sole ulceration in a group of first-calving cows.

The left hind and front claws of 43 heifers having recently calved were studied for signs of laminitis and sole ulceration. The left hind and front claws of 8 non-pregnant heifers served as controls. Thirty claws were selected for histologic examination. No influence of parturition and puerperium was found on signs of laminitis in both clinical and histologic investigations. A remarkable histologic finding was the occurrence of numerous vascular buds in the solar corium. It is suggested that the vascular buds may give rise to the glomus-like vascular clusters, which are commonly found in older cattle.

Sympathico-adrenal effects of endotoxaemia in cattle.

Intradermal injection of 46 micrograms E coli endotoxin had no effect on the plasma cortisol and noradrenaline concentrations of four dairy cows. Mean values were similar to normal values reported in the literature. Intravenous injection of 75 micrograms of endotoxin on the following day caused a massive increase in plasma cortisol concentrations which lasted for seven hours. Plasma noradrenaline concentrations increased rapidly after the intravenous administration of endotoxin and remained high for at least one hour. A possible relationship between endotoxaemia and the pathogenesis of acute laminitis is discussed.

Serum amyloid A concentrations in cows given endotoxin as an acute-phase stimulant.

The concentrations of serum amyloid A (SAA) in 4 cows given Escherichia coli endotoxin as an acute-phase stimulant were quantitatively evaluated by use of an indirect micro-ELISA method and compared with other clinical hematologic values. Serum amyloid A concentration changed minimally after intradermal infection of endotoxin. The concentration of SAA was increased 5 hours after IV injection of endotoxin, with maximal concentration after 17 to 20 hours. The increase in SAA concentration coincided with decreasing serum Zn and Fe concentrations; however, with decreasing serum Zn and Fe concentrations; however, Zn and Fe concentrations appeared to be restored when SAA concentration was still maximal. It was concluded that the SAA response of cattle is comparable with that of other species and can be used for monitoring the activity of clinical inflammation and tissue injury.

Histopathology of the bovine pododerma in relation to age and chronic laminitis.

The histopathology of chronic bovine laminitis was investigated in 20 rear lateral claws (from cows aged 2, 3, 4 and 5 years) with clinical signs of chronic laminitis and compared with a control group without signs of chronic laminitis. Five histological parameters were evaluated using a semiquantitative score. In all tissue samples examined the parameters were invariably indicative of chronic degenerative changes. However, statistical analysis demonstrated that the claws affected with chronic laminitis were not more severely affected with chronic degenerative changes than the control group. The number of arterio-venous shunts increased significantly with age. The typical ulceration place scored significantly higher than the other locations for four out of five parameters. From these findings it was suggested that chronic bovine laminitis may be solely induced by altered haemodynamics (ischaemia) in the digit.

Arteriographical and pathological changes in chronic laminitis in dairy cattle.

The arteriographic appearance of 76 bovine hind digits, obtained from a slaughterhouse, was related to the macroscopic signs of chronic laminitis in the digits. There were statistically significant correlations between the macroscopic and the arteriographic appearance of the claws. Subsequent histological examination of the radiographically abnormal arteries revealed features indicative of arteriosclerosis. The results of this study indicate that chronic laminitis develops following a subclinical attack of laminitis due to a continous hypoperfusion of the digit.

[Pathogenesis and drug therapy of acute laminitis in horses: a literature review]. / Pathogenese en medicamenteuze behandeling van acute hoefbevangenheid: een literatuuroverzicht.

Impairment of the microcirculation in the distal part of the foot is an important factor in the aetiology of equine laminitis. To prevent the development of chronic laminitis and the resulting complications, two new therapeutical principles were tested in the treatment of acute laminitis. Thrombosis which frequently occurs in the corium of the foot, could be controlled by administration of anticoagulants such as heparin. Alpha-receptor blocking agents such as phenoxybenzamine were used, to improve the peripheral blood flow. The use of these drugs and that of anti-inflammatory agents during the onset of acute laminitis is discussed in this review paper.

[Detrimental sequelae of a sodium hydroxide standing foot bath for cattle for the control of Italian interdigital dermatitis]. / De nare gevolgen van een natronloog-stabad voor koeien ter bestrijding van Italiaanse stinkpoot infecties.

Eighteen cases of severe damage to digits of cattle are reported. These animals had been standing in a footbath containing sodium hydroxide and sodium hypochlorite for the treatment of digital dermatitis. The lesions on the digit and their healing are discussed in this paper.