Pulse-Administered Toceranib Phosphate Plus Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs.

BackgroundNonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy.Hypothesis/objectivesThe primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse-administered toceranib phosphate (TOC) combined with lomustine.AnimalsForty-seven client-owned dogs with measurable MCT.MethodsToceranib phosphate was given PO on days 1, 3 and 5 of a 21-day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m(2) . All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone.ResultsThe MTD of lomustine was established at 50 mg/m(2) when combined with pulse-administered TOC; the dose-limiting toxicity was neutropenia. Forty-one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression-free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy.Conclusions and clinical importanceCombined treatment with pulse-administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT

Obesity and prostate cancer-specific mortality after radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database.

BackgroundAt the population level, obesity is associated with prostate cancer (PC) mortality. However, few studies analyzed the associations between obesity and long-term PC-specific outcomes after initial treatment.MethodsWe conducted a retrospective analysis of 4268 radical prostatectomy patients within the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Cox models accounting for known risk factors were used to examine the associations between body mass index (BMI) and PC-specific mortality (PCSM; primary outcome). Secondary outcomes included biochemical recurrence (BCR) and castration-resistant PC (CRPC). BMI was used as a continuous and categorical variable (normal <25 kg/m2, overweight 25-29.9 kg/m2 and obese ⩾30 kg/m2). Median follow-up among all men who were alive at last follow-up was 6.8 years (interquartile range=3.5-11.0). During this time, 1384 men developed BCR, 117 developed CRPC and 84 died from PC. Hazard ratios were analyzed using competing-risks regression analysis accounting for non-PC death as a competing risk.ResultsOn crude analysis, higher BMI was not associated with risk of PCSM (P=0.112), BCR (0.259) and CRPC (P=0.277). However, when BMI was categorized, overweight (hazard ratio (HR) 1.99, P=0.034) and obesity (HR 1.97, P=0.048) were significantly associated with PCSM. Obesity and overweight were not associated with BCR or CRPC (all P⩾0.189). On multivariable analysis adjusting for both clinical and pathological features, results were little changed in that obesity (HR=2.05, P=0.039) and overweight (HR=1.88, P=0.061) were associated with higher risk of PCSM, but not with BCR or CRPC (all P⩾0.114) with the exception that the association for overweight was no longer statistical significant.ConclusionsOverweight and obesity were associated with increased risk of PCSM after radical prostatectomy. If validated in larger studies with longer follow-up, obesity may be established as a potentially modifiable risk factor for PCSM

Use of Desulfovibrio and Escherichia coli Pd-nanocatalysts in reduction of Cr(VI) and hydrogenolytic dehalogenation of polychlorinated biphenyls and used transformer oil

BACKGROUND Desulfovibrio spp. biofabricate metallic nanoparticles (e.g. ‘Bio-Pd’) which catalyse the reduction of Cr(VI) to Cr(III) and dehalogenate polychlorinated biphenyls (PCBs). Desulfovibrio spp. are anaerobic and produce H2S, a potent catalyst poison, whereas Escherichia coli can be pre-grown aerobically to high density, has well defined molecular tools, and also makes catalytically-active ‘Bio-Pd’. The first aim was to compare ‘Bio-Pd’ catalysts made by Desulfovibrio spp. and E. coli using suspended and immobilised catalysts. The second aim was to evaluate the potential for Bio-Pd-mediated dehalogenation of PCBs in used transformer oils, which preclude recovery and re-use.\ud RESULTS Catalysis via Bio-PdD. desulfuricans and Bio-PdE. coli was compared at a mass loading of Pd:biomass of 1:3 via reduction of Cr(VI) in aqueous solution (immobilised catalyst) and hydrogenolytic release of Cl- from PCBs and used transformer oil (catalyst suspensions). In both cases Bio-PdD. desulfuricans outperformed Bio-Pd E. coli by ~3.5-fold, attributable to a ~3.5-fold difference in their Pd-nanoparticle surface areas determined by magnetic measurements (Bio-PdD. desulfuricans) and by chemisorption analysis (Bio-PdE. coli). Small Pd particles were confirmed on D. desulfuricans and fewer, larger ones on E. coli via electron microscopy. Bio-PdD. desulfuricans-mediated chloride release from used transformer oil (5.6 $\pm$ 0.8 $\mu$g mL-1 ) was comparable to that observed using several PCB reference materials. \ud CONCLUSIONS At a loading of 1:3 Pd: biomass Bio-PdD. desulfuricans is 3.5-fold more active than Bio-PdE. coli, attributable to the relative catalyst surface areas reflected in the smaller nanoparticle sizes of the former. This study also shows the potential of Bio-PdD. desulfuricans to remediate used transformer oil

Surgery of chest wall deformities

OBJECTIVE: To evaluate the medium-term results of 77 surgical corrections in patients with chest wall deformities, 53 (68.8%) with pectus excavatum and 24 with pectus carinatum, operated upon from 1985 to 1994. METHODS: The mean age of the patients was 14.7 years (4-39 years) and 77% were younger than 15 years of age. There were 59 male (76.7%) and 18 female patients. Only four had a family history of the malformation. Seven patients (9.1%) presented with asthma-like symptoms, and 13 (16.9%) referred dyspnea and tiredness for small efforts. The remainder (74.2%) were asymptomatic, but most were psychologically disturbed by the deformity and postural abnormality. Two patients had other skeletal abnormalities. The modified surgical technique used in all cases consisted of subperichondrial resection of the abnormal costal cartilages, transverse and longitudinal osteotomies of the sternum and internal stabilization with a steel rod which was generally removed between 6 and 12 months postoperatively. RESULTS: There was neither early nor late mortality. One patient had a pneumothorax which required chest tube drainage. The mean admission time was 10.5 days (8-14 days). Follow-up was complete, and 90% of the patients had increased effort tolerance. Five of the seven patients (72%) with 'asthmatic' symptoms showed a decrease in the frequency of the crises. Two patients had recurrence of the depression by 3 and 8 months, respectively. The remaining 75 patients (97.3%) were satisfied with the cosmetic result of the surgery. CONCLUSIONS: Surgical treatment of chest wall deformities using this technique leads to good cosmetic, orthopedic and psychological results. We believe that the operations should be performed at any age in patients who have at least a moderate deformity

Synthesis of new chiral organosulfur donors with hydrogen bonding functionality and their first charge transfer salts

The syntheses of a range of enantiopure organosulfur donors with hydrogen bonding groups are described including TTF related materials with two, four, six and eight hydroxyl groups and multiple stereogenic centres and a pair of chiral N-substituted BEDT-TTF acetamides. Three charge transfer salts of enantiopure poly-hydroxy-substituted donors are reported, including a 4:1 salt with the meso stereoisomer of the dinuclear [Fe2(oxalate)5 ]4- anion in which both cation and anion have chiral components linked together by hydrogen bonding, and a semiconducting salt with triiodide

Spatial methods for infectious disease outbreak investigations: systematic literature review

Investigations of infectious disease outbreaks are conventionally framed in terms of person, time and place. Although geographic information systems have increased the range of tools available, spatial analyses are used relatively infrequently. We conducted a systematic review of published reports of outbreak investigations worldwide to estimate the prevalence of spatial methods, describe the techniques applied and explore their utility. We identified 80 reports using spatial methods published between 1979 and 2013, ca 0.4% of the total number of published outbreaks. Environmental or waterborne infections were the most commonly investigated, and most reports were from the United Kingdom. A range of techniques were used, including simple dot maps, cluster analyses and modelling approaches. Spatial tools were usefully applied throughout investigations, from initial confirmation of the outbreak to describing and analysing cases and communicating findings. They provided valuable insights that led to public health actions, but there is scope for much wider implementation and development of new methods.</jats:p

Practical Fertilization Procedure and Embryonic Development of the New Zealand Geoduck Clam (Panopea Zelandica)

Copyright © Marine Biological Association of the United Kingdom 2016Cultivation of the geoduck Panopea zelandica (Quoy & Gaimard, 1835) requires knowledge on embryonic development to produce spat in hatcheries. This study investigated the development of P. zelandica embryos at 15°C and 35 ppt and the optimal sperm:egg ratios for fertilization under hatchery conditions. Panopea zelandica broodstock were induced to spawn by serotonin injection. Sperm and eggs were collected and fertilization was conducted at sperm:egg ratios of: 50:1, 100:1, 500:1, 1000:1 and 10,000:1 over 40 min. The optimal sperm:egg ratio was <500:1 and the normal embryo yield at 3 and 18 h post-fertilization (hpf) ranged from 83–96%. Panopea zelandica eggs (~80 μm diameter) developed the first and second polar bodies within 15–20 and 50–55 min post-fertilization, respectively. The blastula appeared at ~8 hpf, including the XR and XL cells and the presumptive shell field depression. Gastrulation occurred at 12–18 hpf with organic material apparent at the shell field depression. The mid-stage trochophore, which appeared at around 35 hpf had an apical plate with an apical tuft. The shell field spread to form the periostracum, which expanded and folded into right and left segments covering the late trochophore. The early D-stage veliger appeared at 45 hpf with the soft body being enclosed by two valves and the appearance of the velum. These observations will serve as the basis for future analyses of P. zelandica embryogenesis and for optimization of commercial production of D-veliger larvae

Working with cancer: Health and employment among cancer survivors

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Purpose: Cancer affects a growing proportion of US workers. Factors contributing to whether they continue or return to work after cancer diagnosis include: age, physical and mental health, health insurance, education, and cancer site. The purpose of this study was to assess the complex relationships between health indicators and employment status for adult cancer survivors. Methods: We analyzed pooled data from the 1997-2012 US National Health Interview Survey (NHIS). Our sample included adults with a self-reported physician diagnosis of cancer (n = 24,810) and adults with no cancer history (n = 382,837). Using structural equation modeling (SEM), we evaluated the relationship between sociodemographic factors, cancer site, and physical and mental health indicators on the overall health and employment status among adults with a cancer history. Results: The overall model for cancer survivors fit the data well (χ2 (374) = 3654.7, P < .001; comparative fit index = 0.98; root mean square error of approximation = 0.04). Although black cancer survivors were less likely to report good-to-excellent health, along with Hispanic survivors, they were more likely to continue to work after diagnosis compared with their white counterparts. Health insurance status and educational level were strongly and positively associated with health status and current employment. Age and time since diagnosis were not significantly associated with health status or employment, but there were significant differences by cancer site. Conclusions: A proportion of cancer survivors may continue to work because of employment-based health insurance despite reporting poor health and significant physical and mental health limitations. Acute and long-term health and social support are essential for the continued productive employment and quality of life of all cancer survivors.The work was supported in part by a National Cancer Institute (NCI) fellowship at the National Institutes of Health (1F31CA153937); the National Institute for Occupational Safety and Health (NIOSH R01 OH03915); and the European Regional Development Fund Programme and European Social Fund Convergence Programme for Cornwall and the Isles of Scilly (the University of Exeter Medical School)

Working with cancer: health and employment among cancer survivors.

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Available online 4 August 2015PURPOSE: Cancer affects a growing proportion of US workers. Factors contributing to whether they continue or return to work after cancer diagnosis include: age, physical and mental health, health insurance, education, and cancer site. The purpose of this study was to assess the complex relationships between health indicators and employment status for adult cancer survivors. METHODS: We analyzed pooled data from the 1997-2012 US National Health Interview Survey (NHIS). Our sample included adults with a self-reported physician diagnosis of cancer (n = 24,810) and adults with no cancer history (n = 382,837). Using structural equation modeling (SEM), we evaluated the relationship between sociodemographic factors, cancer site, and physical and mental health indicators on the overall health and employment status among adults with a cancer history. RESULTS: The overall model for cancer survivors fit the data well (χ(2) (374) = 3654.7, P < .001; comparative fit index = 0.98; root mean square error of approximation = 0.04). Although black cancer survivors were less likely to report good-to-excellent health, along with Hispanic survivors, they were more likely to continue to work after diagnosis compared with their white counterparts. Health insurance status and educational level were strongly and positively associated with health status and current employment. Age and time since diagnosis were not significantly associated with health status or employment, but there were significant differences by cancer site. CONCLUSIONS: A proportion of cancer survivors may continue to work because of employment-based health insurance despite reporting poor health and significant physical and mental health limitations. Acute and long-term health and social support are essential for the continued productive employment and quality of life of all cancer survivors.The work was supported in part by a National Cancer Institute (NCI) fellowship at the National Institutes of Health (1F31CA153937); the National Institute for Occupational Safety and Health (NIOSH R01 OH03915); and the European Regional Development Fund Programme and European Social Fund Convergence Programme for Cornwall and the Isles of Scilly (the University of Exeter Medical School)

Pharmacokinetic studies in children: recommendations for practice and research.

Optimising the dosing of medicines for neonates and children remains a challenge. The importance of pharmacokinetic (PK) and pharmacodynamic (PD) research is recognised both in medicines regulation and paediatric clinical pharmacology, yet there remain barriers to undertaking high-quality PK and PD studies. While these studies are essential in understanding the dose-concentration-effect relationship and should underpin dosing recommendations, this review examines how challenges affecting the design and conduct of paediatric pharmacological studies can be overcome using targeted pharmacometric strategies. Model-based approaches confer benefits at all stages of the drug life-cycle, from identifying the first dose to be used in children, to clinical trial design, and optimising the dosing regimens of older, off-patent medications. To benefit patients, strategies to ensure that new PK, PD and trial data are incorporated into evidence-based dosing recommendations are needed. This review summarises practical strategies to address current challenges, particularly the use of model-based (pharmacometric) approaches in study design and analysis. Recommendations for practice and directions for future paediatric pharmacological research are given, based on current literature and our joint international experience. Success of PK research in children requires a robust infrastructure, with sustainable funding mechanisms at its core, supported by political and regulatory initiatives, and international collaborations. There is a unique opportunity to advance paediatric medicines research at an unprecedented pace, bringing the age of evidence-based paediatric pharmacotherapy into sight