The translational inhibitor and amnestic agent emetine also suppresses ongoing hippocampal neural activity similarly to other blockers of protein synthesis.

The consolidation of memory is thought to ultimately depend on the synthesis of new proteins, since translational inhibitors such as anisomycin and cycloheximide adversely affect the permanence of long-term memory. However, when applied directly in brain, these agents also profoundly suppress neural activity to an extent that is directly correlated to the degree of protein synthesis inhibition caused. Given that neural activity itself is likely to help mediate consolidation, this finding is a serious criticism of the strict de novo protein hypothesis of memory. Here, we test the neurophysiological effects of another translational inhibitor, emetine. Unilateral intra-hippocampal infusion of emetine suppressed ongoing local field and multiunit activity at ipsilateral sites as compared to the contralateral hippocampus in a fashion that was positively correlated to the degree of protein synthesis inhibition as confirmed by autoradiography. This suppression of activity was also specific to the circumscribed brain region in which protein synthesis inhibition took place. These experiments provide further evidence that ongoing protein synthesis is necessary and fundamental for neural function and suggest that the disruption of memory observed in behavioral experiments using translational inhibitors may be due, in large part, to neural suppression.

Omentum as non-strangled inguino scrotal hernia content in stallion: case report / [Omento como conteúdo de hérnia inguino-escrotal não estrangulada em garanhão: relato de caso]

Non-strangulated acquired hernias in stallions are rare, especially when the herniated content is not intestinal loops. Thus, the aim of the current study is to describe a case of acquired non-strangulated inguinoscrotal hernia in a stallion, whose herniated content was the omentum. The patient was a Criollo stallion with history of rhabdomyolysis, laminitis and bilateral scrotal volume increase observed in the left scrotal region. The animal presented pain in both thoracic limbs, abnormal blood test, especially hypoproteinemia, and mild pain during palpation in the left inguinal ring region. Hydrocele secondary to hypoproteinemia was suspected. After admission, the animal showed signs of acute abdomen, which were clinically reversed. With this, the animal was subjected to ultrasound examination of the scrotal region, whose findings suggested non-strangulated inguinal hernia, although the content could not be identified. Surgical treatment was chosen in order to identify the herniated content and remove the left testicle. Access to the affected scrotum was performed, in which the presence of fluid and a portion of the omentum was observed surrounding the testis and adhering to it. The animal was discharged after he recovered from the surgery and from laminitis. During the breeding season, the stallion remained with a herd of mares for natural mating. After 15 months of surgery, the animal was reassessed and showed no active signs of inflammatory and degenerative processes in the remaining testis. On this occasion, a pregnancy diagnosis was also performed, and all the mares were pregnant. It is concluded that the presence of omentum as a herniated content does not represent a surgical emergency but can make the reproductive prognosis reserved. In addition, removal of the affected testicle can benefit the spermatogenesis of the remaining testicle.(AU)

As hérnias adquiridas não estranguladas em garanhões são raras, principalmente quando o conteúdo herniado não é de alças intestinais. Assim, o objetivo deste trabalho foi descrever um caso de hérnia inguino escrotal adquirida e não estrangulada em garanhão, cujo conteúdo herniado era composto pelo omento. Foi atendido um garanhão da raça Crioula com histórico de rabdomiólise, laminite e aumento de volume escrotal bilateral, evidenciado na região escrotal esquerda. O animal apresentava dor nos membros torácicos, alterações na avaliação sanguínea, destacando-se a hipoproteinemia, e demonstrava dor leve à palpação na região do anel inguinal esquerdo. Suspeitou-se de hidrocele secundária a hipoproteinemia. Após a internação, o animal apresentou sinais de abdômen agudo, revertidos clinicamente. Com isso, realizou-se ultrassonografia da região escrotal, cujos achados sugeriram hérnia inguinal não estrangulada, sem que o conteúdo pudesse ser identificado. Optou-se pelo tratamento cirúrgico, com o intuito de identificação do conteúdo herniado e remoção do testículo esquerdo. Foi realizado acesso à bolsa escrotal afetada, na qual se observou presença de líquido e de uma porção do omento envolvendo o testículo e aderido a ele. O animal recebeu alta após restabelecimento da cirurgia e da laminite. Na propriedade, durante temporada reprodutiva, o garanhão permaneceu com uma manada de éguas para realização de monta natural. Passados 15 meses da cirurgia, o animal foi reavaliado e não demonstrou sinais ativos de processo inflamatório e degenerativos no testículo remanescente. Nessa ocasião, também foi realizado diagnóstico de gestação e todas as éguas encontravam-se prenhes. Conclui-se que a presença de omento como conteúdo herniado não representa uma emergência cirúrgica, mas pode tornar o prognóstico reprodutivo reservado. Ainda, a remoção do testículo afetado pode trazer benefícios à espermatogênese do remanescente.(AU)

Analyzing the effect of physician assignment in the survival of patients with advanced non-small-cell lung cancer.

Background: Non-small-cell lung cancer (nsclc) is the most common cause of cancer deaths worldwide, with a 5-year survival of 17%. The low survival rate observed in patients with nsclc is primarily attributable to advanced stage of disease at diagnosis, with more than 50% of cases being stage iv at presentation. For patients with advanced disease, palliative systemic therapy can improve overall survival (os); however, a recent review at our institution of more than 500 consecutive cases of advanced nsclc demonstrated that only 55% of the patients received palliative systemic therapy. What is unknown to date is whether that observed low rate of systemic therapy in our previous study is uniform across oncologists. Methods: With ethics approval, we performed a retrospective analysis of newly diagnosed patients with stage iv nsclc seen as outpatients at our institution between 2009 and 2012 by 4 different oncologists. Demographics, treatment, and survival data were collected and compared for the 4 oncologists. Results: The 4 oncologists saw 528 patients overall, with D seeing 115; L, 158; R, 137; and M, 118. Significant variation was observed in the proportion receiving 1 line or more of chemotherapy: D, 60%; L, 65%; R, 43%; and M, 52%. Physician assignment was not associated with a difference in median os, with D's cohort having a median os of 6.8 months; L, 8.4 months; R, 7.0 months; and M, 7.0 months. Conclusions: Practice size and proportion of patients treated varied between oncologists, but those differences did not translate into significantly different survival outcomes for patients.

A Canadian cancer trials group phase IB study of durvalumab (anti-PD-L1) plus tremelimumab (anti-CTLA-4) given concurrently or sequentially in patients with advanced, incurable solid malignancies.

Background The IND.226 study was a phase Ib study to determine the recommended phase II dose of durvalumab + tremelimumab in combination with standard platinum-doublet chemotherapy. Sequential administration of multiple agents increases total chair time adding costs overall and inconvenience for patients. This cohort of the IND.226 study evaluated the safety and tolerability of durvalumab + tremelimumab given either sequentially (SEQ) or concurrently (CON). Methods Patients with advanced solid tumours were enrolled and randomised to either SEQ tremelimumab 75 mg IV over 1 h followed by durvalumab 1500 mg IV over 1 h q4wks on the same day, or CON administration over 1 h. The serum pharmacokinetic profile of SEQ versus CON of durvalumab and tremelimumab administration was also evaluated. Results 14 patients either received SEQ (n = 7pts) or CON (n = 7 pts). There were no infusion related reactions. Drug related adverse events (AEs) were mainly low grade and manageable, and comparable in frequency between SEQ/CON- fatigue (43%/57%), rash (43%/43%), pruritus (43%/29%) and nausea (14%/29%). One patient in each cohort discontinued treatment due to toxicity. The PK profiles of durvalumab and tremelimumab were similar between CON and SEQ, and to historical reference data. Conclusions Concurrent administration of durvalumab and tremelimumab over 1 h is safe with a comparable PK profile to sequential administration.

The osmotic effect of hyper-saline hydraulic fracturing fluid on rainbow trout, Oncorhynchus mykiss.

Flowback and produced water (FPW) is a complex, often brackish, solution formed during the process of hydraulic fracturing. Despite recent findings on the short-term toxicity of FPW on aquatic biota, longer-term impacts of FPW on fish have not yet been investigated and the mechanisms of chronic effects remain unknown. The aim of the present study was to observe the effect of a diluted FPW on ionoregulatory endpoints in the rainbow trout Oncorhynchus mykiss, following a 28-d sub-chronic exposure. A salinity-matched control solution (SW), recreating the salt content of the FPW, was used to differentiate the specific effect of the salts from the effects of the other FPW components (i.e. organics and metals). Overall, fish ionoregulation was not impacted by the chronic exposure. An accumulation of strontium (Sr) and bromide (Br) occurred in the plasma of the FPW-exposed fish only, however no change of plasma ions (Na, K, Cl, Ca, Mg) was observed in SW- or FPW-exposed fish. Similarly, exposures did not alter branchial activity of the osmoregulatory enzymes sodium/potassium ATPase and proton ATPase. Finally, FPW exposure resulted in modifications of gill morphology over time, with fish exposed to the fluid displaying shorter lamellae and increased interlamellar-cell mass. However, these effects were not distinct from morphological changes that also occurred in the gills of control groups.

Shedding light on the effects of hydraulic fracturing flowback and produced water on phototactic behavior in Daphnia magna.

The effluent produced during hydraulic fracturing (i.e. flowback and produced water; FPW), is a complex hyper-saline solution that is known to negatively impact the survival and the fitness of the water flea Daphnia magna, but to date effects on behavior are unstudied. In the current study, the effects of FPW on phototactic behavior of D. magna were examined. Exposure of naïve animals to FPW resulted in a dose-dependent increase in the speed of appearance of daphnids in the illuminated zone of the test apparatus (i.e. a faster positive phototaxis response). A similar dose-dependent response was observed in a test solution where the salt content of FPW was recreated in the absence of other components, suggesting that the effect was largely driven by salinity. The effect of FPW was significant when the raw FPW sample was diluted to 20% of its initial strength, while the effect of salt-matched solution was significant at a 10% dilution. A distinct effect was observed following FPW pre-exposure. After a 24 h pre-exposure to 1.5% FPW, Daphnia displayed a significantly inhibited positive phototaxis response when examined in control water, relative to control animals that were not pre-exposed to FPW. This effect was not observed in salinity pre-exposed animals, however these daphnids displayed a significantly reduced phototactic response when tested in saline waters, indicating a loss of the positive phototaxis seen in naïve organisms. These data indicate that FPW can induce perturbations in the behavior of aquatic invertebrates, an effect that may influence processes such as feeding and predation rates.

Survey of dental diseases in Crioulo breed horses reared in an extensive farming system / Levantamento de afecções dentárias em equinos da raça Crioula mantidos em sistema de criação extensivo

The present study aimed to identify and quantify dental diseases in Crioulo horses reared exclusively under extensive farming conditions. In total, 254 Crioulo horses were evaluated, that were reared exclusively in native pastures with predominantly Eragrostis plana (Annoni grass). The animals were divided into three groups according to age: three to five years (G1), six to 12 years (G2), and 13 to 26 years (G3). In total, 46.1% of the animals in G1, 63.8% in G2, and 82.3% in G3 had two or more incisor disorders; 37.5% in G1, 52.5% in G2 and 45.5% in G3 had two or more disease findings in the canines; and 28.9% in G1, 35.4% in G2, and 64.7% in G3 had four or more disease findings in the second, third, and fourth premolars and molars. However, dental calculus was observed in 90.5% of G2 animals, whereas in G3, the occurrence rate of excessive enamel points and calculus was 82.4%. Although all of the horses studied were reared in an extensive farming system, dental changes were very common in the Crioulo breed reared under these management conditions.(AU)

O presente estudo teve por objetivo identificar e quantificar as afecções odontológicas de equinos da raça Crioula criados exclusivamente em regime extensivo. No total, foram avaliados 254 cavalos Crioulos, criados em pastagens nativas com predominância de Eragrostis plana (capim-annoni). Os animais foram divididos em três grupos, de acordo com a idade: de três a cinco anos (G1), seis a 12 anos (G2 ) e 13 a 26 anos (G3). No total, 46,1% dos animais do G1, 63,8% do G2 e 82,3% do G3 apresentaram dois ou mais transtornos incisivos; 37,5% do G1, 52,5% do G2 e 45,5% do G3 tiveram duas ou mais alterações nos caninos; 28,9% do G1, 35,4% do G2 e 64,7% do G3 mostraram quatro ou mais distúrbios no segundo, terceiro e quarto pré-molares e molares. Contudo, cálculo dentário foi observado em 90,5% dos animais do G2, enquanto no G3, a taxa de ocorrência de pontas excessivas de esmalte dentário e cálculo foi de 82,4%. Concluiu-se que, apesar de todos os equinos estudados serem mantidos em sistema extensivo, as afecções dentárias mostraram-se muito comuns na raça Crioula sob estas condições de manejo.(AU)

Canadian Cancer Trials Group (CCTG) IND215: A phase Ib study of Selumetinib in patients with untreated advanced or metastatic NSCLC who are receiving standard chemotherapy regimens.

Introduction Selumetinib (AZD6244, ARRY-142886) is a potent inhibitor of MEK1/2, thereby inhibiting phosphorylation of ERK2. We investigated the toxicity and the recommended phase II dose of the combination of selumetinib with two platinum based first line chemotherapy combinations in non-small cell lung cancer. Methods This was a phase I trial of escalating doses of selumetinib with carboplatin (AUC 6), paclitaxel (200 mg/m2) (cohort 1) or pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) (cohort 2) in patients with chemotherapy naïve, advanced or metastatic NSCLC. Patients enrolled on cohort 2 had non-squamous histology. Dose escalation of selumetinib proceeded using a 3 + 3 design: 50 mg b.i.d. days 2-19 (dose level 1); 75 mg b.i.d. days 2-19 (dose level 2); and 75 mg b.i.d. continuously. Adverse events were evaluated using CTC AE v4 and response by RECIST 1.1. Results Thirty-nine patients were enrolled (cohort 1 n = 16; cohort 2, n = 23). There were no dose limiting toxicities in either cohort and the recommended phase II dose for both regimens was standard doses of carboplatin, paclitaxel or pemetrexed and cisplatin with continuous selumetinib at a dose of 75 mg b.i.d. Most adverse events were grade 1 or 2 and were predominantly diarrhea, nausea, stomatitis, peripheral edema, neutropenia, and skin rash. Response rate was 37.5% for cohort 1 and 30.4% for cohort 2. Conclusion Selumetinib at a dose of 75 mg b.i.d continuously can be safely combined with paclitaxel and carboplatin or pemetrexed and cisplatin in patients with advanced or metastatic NSCLC. This trial provided the dose for the regimens used in a randomized phase II trial in NSCLC (CCTG IND.219).

Are clinical trial eligibility criteria an accurate reflection of a real-world population of advanced non-small-cell lung cancer patients?

Background: Advanced non-small-cell lung cancer (nsclc) represents a major health issue globally. Systemic treatment decisions are informed by clinical trials, which, over years, have improved the survival of patients with advanced nsclc. The applicability of clinical trial results to the broad lung cancer population is unclear because strict eligibility criteria in trials generally select for optimal patients. Methods: We performed a retrospective chart review of all consecutive patients with advanced nsclc seen in outpatient consultation at our academic institution between September 2009 and September 2012, collecting data about patient demographics and cancer characteristics, treatment, and survival from hospital and pharmacy records. Two sets of arbitrary trial eligibility criteria were applied to the cohort. Scenario A stipulated Eastern Cooperative Oncology Group performance status (ecog ps) 0-1, no brain metastasis, creatinine less than 120 µmol/L, and no second malignancy. Less-strict scenario B stipulated ecog ps 0-2 and creatinine less than 120 µmol/L. We then used the two scenarios to analyze treatment and survival of patients by trial eligibility status. Results: The 528 included patients had a median age of 67 years, with 55% being men and 58% having adenocarcinoma. Of those 528 patients, 291 received at least 1 line of palliative systemic therapy. Using the scenario A eligibility criteria, 73% were trial-ineligible. However, 46% of "ineligible" patients actually received therapy and experienced survival similar to that of the "eligible" treated patients (10.2 months vs. 11.6 months, p = 0.10). Using the scenario B criteria, only 35% were ineligible, but again, the survival of treated patients was similar in the ineligible and eligible groups (10.1 months vs. 10.9 months, p = 0.57). Conclusions: Current trial eligibility criteria are often strict and limit the enrolment of patients in clinical trials. Our results suggest that, depending on the chosen drug, its toxicities and tolerability, eligibility criteria could be carefully reviewed and relaxed.

Environmental and Human Health Impacts of Spreading Oil and Gas Wastewater on Roads.

Thirteen states in the United States allow the spreading of O&G wastewaters on roads for deicing or dust suppression. In this study, the potential environmental and human health impacts of this practice are evaluated. Analyses of O&G wastewaters spread on roads in the northeastern, U.S. show that these wastewaters have salt, radioactivity, and organic contaminant concentrations often many times above drinking water standards. Bioassays also indicated that these wastewaters contain organic micropollutants that affected signaling pathways consistent with xenobiotic metabolism and caused toxicity to aquatic organisms like Daphnia magna. The potential toxicity of these wastewaters is a concern as lab experiments demonstrated that nearly all of the metals from these wastewaters leach from roads after rain events, likely reaching ground and surface water. Release of a known carcinogen (e.g., radium) from roads treated with O&G wastewaters has been largely ignored. In Pennsylvania from 2008 to 2014, spreading O&G wastewater on roads released over 4 times more radium to the environment (320 millicuries) than O&G wastewater treatment facilities and 200 times more radium than spill events. Currently, state-by-state regulations do not require radium analyses prior to treating roads with O&G wastewaters. Methods for reducing the potential impacts of spreading O&G wastewaters on roads are discussed.

CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials.

Background: Central nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC). Osimertinib has shown systemic efficacy in patients with CNS metastases, and early clinical evidence shows efficacy in the CNS. To evaluate osimertinib activity further, we present a pre-specified subgroup analysis of CNS response using pooled data from two phase II studies: AURA extension (NCT01802632) and AURA2 (NCT02094261). Patients and methods: Patients with T790M-positive advanced NSCLC, who had progressed following prior epidermal growth factor receptor-tyrosine kinase inhibitor treatment, received osimertinib 80 mg od (n = 411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment; prior CNS treatment was allowed. Patients with ≥1 measurable CNS lesion (per RECIST 1.1) on baseline brain scan by blinded independent central neuroradiology review (BICR) were included in the evaluable for CNS response set (cEFR). The primary outcome for this CNS analysis was CNS objective response rate (ORR) by BICR; secondary outcomes included CNS duration of response, disease control rate (DCR) and progression-free survival (PFS). Results: Of 128 patients with CNS metastases on baseline brain scans, 50 were included in the cEFR. Confirmed CNS ORR and DCR were 54% [27/50; 95% confidence interval (CI) 39-68] and 92% (46/50; 95% CI 81-98), respectively. CNS response was observed regardless of prior radiotherapy to the brain. Median CNS duration of response (22% maturity) was not reached (range, 1-15 months); at 9 months, 75% (95% CI 53-88) of patients were estimated to remain in response. Median follow-up for CNS PFS was 11 months; median CNS PFS was not reached (95% CI, 7, not calculable). The safety profile observed in the cEFR was consistent with the overall patient population. Conclusions: Osimertinib demonstrated clinically meaningful efficacy against CNS metastases, with a high DCR, encouraging ORR, and safety profile consistent with that reported previously. ClinicalTrials.gov number: NCT01802632; NCT02094261.

Chemotherapy in recurrent advanced non-small-cell lung cancer after adjuvant chemotherapy.

INTRODUCTION: Despite adjuvant systemic therapy in patients with completely resected non-small-cell lung cancer (nsclc), many will subsequently relapse. We investigated treatment choices at relapse and assessed the effect of palliative platinum doublet systemic therapy in this population. METHODS: With research ethics board approval, we performed a retrospective chart review of all patients with resected nsclc who received adjuvant systemic therapy from January 2002 until December 2008 at our institution. The primary outcome was the response rate to first-line palliative systemic therapy among patients who relapsed. RESULTS: We identified 176 patients who received adjuvant platinum doublet systemic therapy (82% received cisplatin-vinorelbine). In the 85 patients who relapsed (48%), median time to relapse was 18.5 months (95% confidence interval: 15 months to 21.3 months). Palliative systemic therapy was given in 43 patients. Of those 43 patients, 25 (58%) were re-challenged with platinum doublet systemic therapy, with a response rate of 29% compared with 18% in 18 patients who received other systemic therapy (p = 0.48). We observed a trend toward an increased clinical benefit rate (complete response + partial response + stable disease) in patients who were treated with a platinum doublet (67% vs. 41%, p = 0.12). Median overall survival (os) from relapse was 15.3 months in patients receiving palliative systemic therapy and 7.8 months in those receiving best supportive care alone. Compared with patients treated with non-platinum regimens, the platinum-treated group experienced longer survival after relapse (18.4 months vs. 9.7 months, p = 0.041). CONCLUSIONS: In patients previously treated with adjuvant systemic therapy, re-treatment with platinum doublet chemotherapy upon relapse is feasible. Moreover, compared with patients receiving other first-line systemic therapy, patients receiving platinum doublets experienced higher response rates and significantly longer survival.

A retrospective review of cancer treatments and outcomes among Inuit referred from Nunavut, Canada.

BACKGROUND: Cancer is a health concern in Inuit populations. Unique cultural, dietary, and genetic factors and geographic isolation influence cancer epidemiology in this group. Inuit-specific data about oncology treatments and survival outcomes in Canadian Inuit referred to urban treatment centres are lacking. METHODS: A retrospective chart review of Inuit patients referred to The Ottawa Hospital Cancer Centre (tohcc) from the Baffin region of Nunavut between 2000 and 2010 was conducted. Nunavut cancer registry data were used to establish the percentage of cancer cases referred and their survival outcomes. RESULTS: Of 307 cancer patients registered among Baffin-region Inuit, 216 [70% (63 men, 153 women)] were referred to tohcc for chemotherapy (ct) and radiation therapy (rt). Mean age in the referred group was 59.3 years (range: 25-89 years), and current smokers constituted half the group (52%). The cancers most commonly leading to referral in men were lung (55%), colorectal (19%), and nasopharyngeal (11%) cancers; in women, they were lung (46%), colorectal (24%), breast (10%), nasopharyngeal (6%), and cervical (5%) cancers. Of the 216 referred patients, 82 (38%) had already undergone surgery, and 18 (8%) received chemoradiation or rt only, all given with curative intent. Among the surgical patients referred, 33 (40%) and 23 (28%) went on to receive adjuvant ct and adjuvant rt respectively. Among 116 patients referred for palliative care, 64 (55%) received ct, 76 (66%) received rt, 43 (37%) received both ct and rt, and 19 (16%) received neither treatment. Median all-stage overall survival was 10 months for patients with lung cancer [95% confidence interval: 6.1 to 13.9 months] and 37 months for patients with colorectal cancer [95% confidence interval: 14.8 to 59.2 months]. CONCLUSIONS: High uptake of palliative and adjuvant ct and rt was observed in the Inuit patients referred to tohcc. Lung cancer was the most common cancer in referred Inuit men and women. The survival rates for Inuit lung cancer patients referred to tohcc were comparable to those in the rest of Canada. Further research is required to understand reasons for non-referral of Canadian Inuit to tohcc.

A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1).

BACKGROUND: This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced non-small cell lung cancer (NSCLC) and to identify patient populations most likely to benefit from the combination. PATIENTS AND METHODS: Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75 mg/m(2) on day 1) was administered alone or with ganetespib (150 mg/m(2) on days 1 and 15) every 3 weeks. The primary end points were progression-free survival (PFS) in two subgroups of the adenocarcinoma population: patients with elevated lactate dehydrogenase (eLDH) and mutated KRAS (mKRAS). RESULTS: Of 385 patients enrolled, 381 were treated. Early in the trial, increased hemoptysis and lack of efficacy were observed in nonadenocarcinoma patients (n = 71); therefore, only patients with adenocarcinoma histology were subsequently enrolled. Neutropenia was the most common grade ≥3 adverse event: 41% in the combination arm versus 42% in docetaxel alone. There was no improvement in PFS for the combination arm in the eLDH (N = 114, adjusted hazard ratio (HR) = 0.77, P = 0.1134) or mKRAS (N = 89, adjusted HR = 1.11, P = 0.3384) subgroups. In the intent-to-treat adenocarcinoma population, there was a trend in favor of the combination, with PFS (N = 253, adjusted HR = 0.82, P = 0.0784) and overall survival (OS) (adjusted HR = 0.84, P = 0.1139). Exploratory analyses showed significant benefit of the ganetespib combination in the prespecified subgroup of adenocarcinoma patients diagnosed with advanced disease >6 months before study entry (N = 177): PFS (adjusted HR = 0.74, P = 0.0417); OS (adjusted HR = 0.69, P = 0.0191). CONCLUSION: Advanced lung adenocarcinoma patients treated with ganetespib in combination with docetaxel had an acceptable safety profile. While the study's primary end points were not met, significant prolongation of PFS and OS was observed in patients >6 months from diagnosis of advanced disease, a subgroup chosen as the target population for the phase III study.

A phase I pharmacokinetic and safety analysis of epothilone folate (BMS-753493), a folate receptor targeted chemotherapeutic agent in humans with advanced solid tumors.

Background The folate receptor alpha is selectively over-expressed in a number of human cancers. BMS-753493 is a folate conjugate of the epothilone analog BMS-748285 that was designed to selectively target folate receptor expressing cancer cells. Methods BMS-753493 was investigated in two parallel multi-institutional first-in-human phase I/IIa studies in patients with advanced solid tumors. In Study 1, patients were treated on a schedule of once daily dosing of BMS-753493 administered on Days 1, 4, 8 and 11 every 21 days with a starting dose of 5 mg daily and in Study 2, patients were treated once daily on Days 1-4 every 21 days, with a starting dose of 2.5 mg daily. Results A total of 65 patients were treated across the two studies. The maximum tolerated dose (MTD) was 26 mg in Study 1 and 15 mg in Study 2. Fatigue, transaminitis, gastrointestinal toxicity, and mucositis were dose-limiting toxicities. One patient in Study 2 developed Stevens-Johnson syndrome attributed to BMS-753493. Plasma exposures of both the conjugated and free epothilone increased in a dose related fashion in both studies and the half-life of the conjugated epothilone was 0.2-0.6 h across dose levels. No objective tumor responses were seen in either study. Conclusions BMS-753493 was generally tolerable and toxicities known to be associated with epothilone class of anticancer agents were common, although peripheral neuropathy and neutropenia appear to have been less frequent and less severe as compared to epothilones. Antitumor activity was not demonstrated and further development of BMS-753493 has been discontinued.

Effects of polymer-coated metal oxide nanoparticles on goldfish (Carassius auratus L.) neutrophil viability and function.

Exposure effects from polyacrylic acid (PAA) metal-oxide nanoparticles (TiO2, CeO2, Fe2O3, ZnO) on fish neutrophil viability and effector functions (degranulation, respiratory burst, inflammatory gene expression) were investigated using primary kidney goldfish (Carassius auratus L.) neutrophils as a model. Several studies have reported cytotoxic effects of NPs but there are limited reports on their potential to perturb the innate immune system of aquatic organisms. PAA-TiO2 significantly decreased neutrophil viability in a time and dose-dependent manner at all measured time points (0-48 h) and concentrations (0-200 µg/mL). Maximum viability decreased by (mean ± SEM): 67.1 ± 3.3%, 78.4 ± 4.2% and 74.9 ± 5.0% when exposed to 50, 100 and 200 µg/mL for 48 h, respectively. PAA-ZnO also significantly decreased neutrophil viability but only at 48 h exposures at higher concentrations. Neutrophil degranulation increased by approximately 3% after 30 min and by 8% after 4 h when exposed to sublethal doses (10 µg/mL) of PAA-CeO2 or PAA-Fe2O3. All PAA-NPs induced an increase in neutrophil respiratory burst when exposed to 10 µg/mL for 30 and 60 min, however, PAA-Fe2O3 was the only NP where the response was significant. Lastly, NPs altered the expression of a number of pro-inflammatory and immune genes, where PAA-TiO2 most significantly increased the mRNA levels of pro-inflammatory genes (il-1b, ifng) in neutrophils by 3 and 2.5 times, respectively. Together, these data demonstrate that goldfish neutrophils can be negatively affected from exposures to PAA-coated NPs and are functionally responsive to specific core-material properties at sublethal doses. These changes could perturb the innate response and affect the ability of fish to respond to pathogens.

Randomised, double-blind trial of carboplatin and paclitaxel with daily oral cediranib or placebo in patients with advanced non-small cell lung cancer: NCIC Clinical Trials Group study BR29.

INTRODUCTION: This randomised double-blind placebo-controlled study evaluated the addition of cediranib, an inhibitor of vascular endothelial growth factor receptors 1-3, to standard carboplatin/paclitaxel chemotherapy in advanced non-small cell lung cancer. METHODS: Eligible patients received paclitaxel (200mg/m(2)) and carboplatin (area under the concentration time curve 6) intravenously every 3 weeks. Daily oral cediranib/placebo 20mg was commenced day 1 of cycle 1 and continued as monotherapy after completion of 4-6 cycles of chemotherapy. The primary end-point of the study was overall survival (OS). The trial would continue to full accrual if an interim analysis (IA) for progression-free survival (PFS), performed after 170 events of progression or death in the first 260 randomised patients, revealed a hazard ratio (HR) for PFS of ⩽ 0.70. RESULTS: The trial was halted for futility at the IA (HR for PFS 0.89, 95% confidence interval [CI] 0.66-1.20, p = 0.45). A final analysis was performed on all 306 enrolled patients. The addition of cediranib increased response rate ([RR] 52% versus 34%, p = 0.001) but did not significantly improve PFS (HR 0.91, 95% CI 0.71-1.18, p = 0.49) or OS (HR 0.94, 95% CI 0.69-1.30, p=0.72). Cediranib patients had more grade 3 hypertension, diarrhoea and anorexia. CONCLUSIONS: The addition of cediranib 20mg daily to carboplatin/paclitaxel chemotherapy increased RR and toxicity, but not survival.

The effects of necrotic enteritis, aflatoxin B1, and virginiamycin on growth performance, necrotic enteritis lesion scores, and mortality in young broilers.

The effects of increasing aflatoxin B1 concentration (0, 0.75, 1.5 mg/kg) on broilers with or without necrotic enteritis or virginiamycin were determined. In the 23-d study, 22 male Cobb 500 chicks per pen were allotted to 12 treatments (3 × 2 × 2 factorial arrangement) with 8 replications. Intestines of 5 birds per pen were examined for lesions on d 21. Birds were allowed to consume feed and water ad libitum. Aflatoxin was included in the diets from d 0. All birds received a 10× dose of coccidiosis vaccine on d 10. Pens of birds where necrotic enteritis was being induced were on Clostridium perfringens pathogen (CPP) contaminated litter from d 0. Aflatoxin decreased gain and feed intake and resulted in poorer feed:gain, increased mortality, and higher lesion scores. Inducing necrotic enteritis increased lesion scores and decreased feed intake and gain. Adding virginiamycin to the diets improved gain, feed intake, feed conversion, and decreased mortality. There was a 3-way interaction (aflatoxin × virginiamycin × CPP) on gain; increasing aflatoxin decreased gain and the effects of CPP and virginiamycin were dependent on aflatoxin concentration. In the absence of aflatoxin virginiamycin increased gain but was unable to prevent the growth suppression caused by CPP. At 0.75 mg/kg of aflatoxin virginiamycin no longer increased growth in non-CPP challenged birds but was able to increase growth in CPP-challenged birds. At the 1.5 mg/kg of aflatoxin concentration, virginiamycin increased gain in non-CPP-challenged birds but challenging birds with CPP had no effect on gain. Virginiamycin improved overall feed conversion with the greatest improvement at 1.5 mg/kg (aflatoxin × virginiamycin, P < 0.05). Aflatoxin increased lesion scores in unchallenged birds but not in challenged birds (aflatoxin × CPP, P < 0.001). Aflatoxin and necrotic enteritis decrease broiler performance and interact to decrease weight gain, virginiamycin helps improve gain in challenged birds at 0.75 mg/kg of aflatoxin, but not at 1.5 mg/kg of aflatoxin.

Patterns of chemotherapy treatment for women with invasive epithelial ovarian cancer--a population-based study.

OBJECTIVE: Ovarian cancer five-year survival is poor at <40%. In the absence of effective screening or new treatments, ensuring all women receive optimal treatment is one avenue to improve survival. There is little population-based information regarding the primary chemotherapy treatment that women with epithelial ovarian cancer receive. This information is essential to identify potential gaps in care. METHODS: Cancer registries identified all women diagnosed with invasive epithelial ovarian cancer in Australia in 2005 (n=1192). Histopathology, chemotherapy and comorbidity information was abstracted from medical records. Multivariable logistic regression was used to identify factors associated with chemotherapy commencement, regimen, and completion. RESULTS: Women >70 years (p<0.0001), those with high-grade, stage IA/IB cancers (vs. stages IC-IV, p=0.003) and those with mucinous cancers (p=0.0002) were less likely to start chemotherapy. Most treated women received platinum-based drugs (97%), but only 68% received combination carboplatin-paclitaxel and only half completed six cycles without treatment modification/delay. Approximately 19% received single-agent carboplatin: mostly those aged >70 (p<0.0001) and/or with co-morbidities (p<0.0001). Age was the strongest predictor of completing six cycles of combination therapy. CONCLUSIONS: For specific patient groups, particularly older women, there is notable variation from standard treatment. Understanding how treatment variations affect survival and determining optimal regimens for these groups are research priorities.

A multicenter, randomized trial of flat dosing versus intrapatient dose escalation of single-agent carboplatin as first-line chemotherapy for advanced ovarian cancer: an SGCTG (SCOTROC 4) and ANZGOG study on behalf of GCIG.

BACKGROUND: The aim of the study is to demonstrate that intrapatient dose escalation of carboplatin would improve the outcome in ovarian cancer compared with flat dosing. PATIENTS AND METHODS: Patients with untreated stage IC-IV ovarian cancer received six cycles of carboplatin area under the curve 6 (AUC 6) 3 weekly either with no dose modification except for toxicity (Arm A) or with dose escalations in cycles 2-6 based on nadir neutrophil and platelet counts (Arm B). The primary end-point was progression-free survival (PFS). RESULTS: Nine hundred and sixty-four patients were recruited from 71 centers. Dose escalation was achieved in 77% of patients who had ≥1 cycle. The median AUCs (cycle 2-6) received were 6.0 (Arm A) and 7.2 (Arm B) (P < 0.001). Grade 3/4 non-hematological toxicity was higher in Arm B (31% versus 22% P = 0.001). The median PFS was 12.1 months in Arm A and B [hazard ratio (HR) 0.99; 95% confidence interval (CI) 0.85-1.15; P = 0.93]. The median overall survival (OS) was 34.1 and 30.7 months in Arms A and B, respectively (HR 0.98; 95% CI 0.81-1.18, P = 0.82). In multivariate analysis, baseline neutrophil (P < 0.001), baseline platelet counts (P < 0.001) and the difference between white blood cell (WBC) and neutrophil count (P = 0.009) had a significant adverse prognostic value. CONCLUSIONS: Intrapatient dose escalation of carboplatin based on nadir blood counts is feasible and safe. However, it provided no improvement in PFS or OS compared with flat dosing. Baseline neutrophils over-ride nadir counts in prognostic significance. These data may have wider implications particularly in respect of the management of chemotherapy-induced neutropenia.