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.

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.

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).

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.

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.

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.

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 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.

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 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.

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.

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.

A phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors.

BACKGROUND: This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors. PATIENTS AND METHODS: Ninety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD. RESULTS: Across part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180-800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly ≤1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ≥600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts. CONCLUSION: In patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses ≤800 mg orally q.d., the recommended phase II study dose.

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.

Na+/H+ exchange activity during phagocytosis in human neutrophils: role of Fcgamma receptors and tyrosine kinases.

In neutrophils, binding and phagocytosis facilitate subsequent intracellular killing of microorganisms. Activity of Na+/H+ exchangers (NHEs) participates in these events, especially in regulation of intracellular pH (pHi) by compensating for the H+ load generated by the respiratory burst. Despite the importance of these functions, comparatively little is known regarding the nature and regulation of NHE(s) in neutrophils. The purpose of this study was to identify which NHE(s) are expressed in neutrophils and to elucidate the mechanisms regulating their activity during phagocytosis. Exposure of cells to the phagocytic stimulus opsonized zymosan (OpZ) induced a transient cytosolic acidification followed by a prolonged alkalinization. The latter was inhibited in Na+-free medium and by amiloride analogues and therefore was due to activation of Na+/H+ exchange. Reverse transcriptase PCR and cDNA sequencing demonstrated that mRNA for the NHE-1 but not for NHE-2, 3, or 4 isoforms of the exchanger was expressed. Immunoblotting of purified plasma membranes with isoform-specific antibodies confirmed the presence of NHE-1 protein in neutrophils. Since phagocytosis involves Fcgamma (FcgammaR) and complement receptors such as CR3 (a beta2 integrin) which are linked to pathways involving alterations in intracellular [Ca2+]i and tyrosine phosphorylation, we studied these pathways in relation to activation of NHE-1. Cross-linking of surface bound antibodies (mAb) directed against FcgammaRs (FcgammaRII > FcgammaRIII) but not beta2 integrins induced an amiloride-sensitive cytosolic alkalinization. However, anti-beta2 integrin mAb diminished OpZ-induced alkalinization suggesting that NHE-1 activation involved cooperation between integrins and FcgammaRs. The tyrosine kinase inhibitors genistein and herbimycin blocked cytosolic alkalinization after OpZ or FcgammaR cross-linking suggesting that tyrosine phosphorylation was involved in NHE-I activation. An increase in [Ca2+]i was not required for NHE-1 activation because neither removal of extracellular Ca2+ nor buffering of changes in [Ca2+]i inhibited alkalinization after OpZ or Fc-gammaR cross-linking. In summary, Fc-gammaRs and beta2 integrins cooperate in activation of NHE-1 in neutrophils during phagocytosis by a signaling pathway involving tyrosine phosphorylation.

The role of the epidermal growth factor receptor tyrosine kinase inhibitors as therapy for advanced, metastatic, and recurrent non-small-cell lung cancer: a Canadian national consensus statement.

PURPOSE: To provide consensus recommendations on the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIS) in patients with advanced or meta-static non-small-cell lung cancer (NSCLC). METHODS: Using a systematic literature search, phase II trials, randomized phase III trials, and meta-analyses were identified for inclusion. RESULTS: A total of forty-six trials were included. Clear evidence is available that EGFR-TKIS should not be administered concurrently with platinum-based chemotherapy as first-line therapy in advanced or metastatic nsclc. Evidence is currently insufficient to recommend single-agent EGFR-TKIS as first-line therapy either in unselected populations or in populations selected on the basis of molecular or clinical characteristics. Following failure of platinum-based chemotherapy, the evidence suggests that second-line EGFR-TKIS or second-line chemotherapy result in similar survival. Quality of life and symptom improvement for patients treated with an EGFR-TKI appear better than they do for patients treated with second-line docetaxel. Sequence of therapy may not appear to be important, but if survival is the outcome of interest, the goal should be to optimize the number of patients receiving three lines of therapy. Based on available data, molecular markers and clinical characteristics do not appear to be predictive of a differential survival benefit from an EGFR-TKI and therefore those factors should not be used to select patients for EGFR-TKI therapy. CONCLUSIONS: The EGFR-TKIS represent an additional therapy in the treatment of advanced or metastatic NSCLC. The results of ongoing clinical trials may define the optimal role for these agents and the effectiveness of combinations of these agents with other targeted agents.

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.

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.

The effect of low-molecular-weight heparin on cancer survival. A systematic review and meta-analysis of randomized trials.

BACKGROUND: Low-molecular-weight heparins (LMWH) have an antitumor effect in vitro and in experimental animal models of malignancy. Retrospective data suggest that it might improve survival in cancer patients. OBJECTIVES: To evaluate the effect of LMWH compared to placebo or no anticoagulant intervention on the survival of cancer patients. METHODS: We conducted a systematic review of randomized trials specifically evaluating the impact of LMWH on the survival of cancer patients. DATA SOURCES WERE: MEDLINE, EMBASE, HealthSTAR, Cochrane library, gray literature and cross-referencing from reference lists. Data extraction was performed by one reviewer, and accuracy was independently verified by a second reviewer. Meta-analysis was conducted using: (i) odds ratio (OR) and relative risk (RR); (ii) survival rates using censored endpoints; and (iii) hazard ratios (HR). RESULTS: The pooled HR in all patients was 0.83 (95% CI 0.70-0.99; P = 0.03), and in patients with advanced disease it was 0.86 (95% CI 0.74-0.99; P = 0.04), both in favor of the LMWH group. The results of the OR, RR and survival meta-analysis consistently favored the LMWH group. Sensitivity analyses according to tumor type were not conducted, because of a lack of information. CONCLUSIONS: LMWH improves overall survival in cancer patients, even in those with advanced disease. Additional trials are required to define the tumor types, disease stages and dosing schedules most likely to provide the greatest survival benefit.