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Clinical outcomes for men with positive surgical margins after radical prostatectomy—results from the South Australian Prostate Cancer Clinical outcomes Collaborative community-based registry

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Asian Journal of Urology 2023年第4期10卷 502-511页

作者： Kerri R.Beckmann Michael E.o'callaghan Andrew D.Vincent Kim L.Moretti Nicholas R.Brook Cancer Epidemiology and Population Health Research University of South AustraliaAdelaideAustralia Translational oncology and Urology Research Division of Pharmaceutical and Cancer StudiesKings College LondonLondonUK South Australian Prostate Cancer Clinical outcomes Collaborative Flinders Medical CentreAdelaideAustralia The Freemason's Foundation Centre for Men's Health Adelaide Medical SchoolUniversity of AdelaideAdelaideAustralia Discipline of Surgery University of AdelaideAdelaideAustralia Department of Urology Royal Adelaide HospitalAdelaideAustralia

objective Positive surgical margins(PSMs)after radical prostatectomy(RP)indicate failure of surgery to completely clear cancer.PSMs confer an increased risk of biochemical recurrence(BCR),but how more robust outcomes are affected is unclear.This study investigated factors associated with PSMs following RP and determined their impact on clinical outcomes(BCR,second treatment[radiotherapy and/or androgen deprivation therapy],and prostate cancer-specific mortality[PCSM]).Methods The study cohort included men diagnosed with prostate cancer(pT2-3b/N0/M0)between January 1998 and June 2016 who underwent RP from the South Australian Prostate Cancer Clinical outcomes Collaborative database.Factors associated with risk of PSMs were identified using Poisson regression.The impact of PSMs on clinical outcomes(BCR,second treatment,and PCSM)was assessed using competing risk regression.Results of the 2827 eligible participants,28%had PSMs—10%apical,6%bladder neck,17%posterolateral,and 5%at multiple locations.Median follow-up was 9.6 years with 81 deaths from prostate cancer recorded.Likelihood of PSM increased with higher pathological grade and pathological tumor stage,and greater tumour volume,but decreased with increasing surgeon volume(odds ratio[oR]:0.93;95%confidence interval[CI]:0.88-0.98,per 100 previous prostatectomies).PSMs were associated with increased risk of BCR(adjusted sub-distribution hazard ratio[sHR]2.5;95%CI 2.1-3.1)and second treatment(sHR 2.9;95%CI 2.4-3.5).Risk of BCR was increased similarly for each PSM location,but was higher for multiple margin sites.We found no association between PSMs and PCSM.Conclusion our findings support previous research suggesting that PSMs are not independently associated with PCSM despite strong association with BCR.Reducing PSM rates remains an important objective,given the higher likelihood of secondary treatment with associated comorbidities.

关键词： Prostate cancer Positive surgical margin Biochemical recurrence Radical

Human brucellosis: recent advances and future challenges

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Infectious Diseases of Poverty 2020年第4期9卷 1-2页

作者： David o'callaghan Bacterial Virulence and Infectious Disease University of MontpellierINSERMNimesFrance Brucellosis National Reference Centre(CNR) Microbiology LaboratoryCaremeau University HospitalNimesFrance

Bacteria of the genus Brucella cause brucellosis,one of the world's neglected zoonotic diseases.It is a disease of poverty;infections of livestock have a huge socioeconomic cost while human brucellosis starts as a debilitating acute infection that can be come chronic with many complications.The figure of 500000 new human cases each year is regularly cited in reviews and research papers,however this is a vast under estimation;many of the most affected countries do not have the infrastructure for diagnosis and the broad spectrum of symptoms are shared with other febrile infections.

关键词： diagnosis acute neglected

Brucellosis in China:history,progress and challenge

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Infectious Diseases of Poverty 2020年第3期9卷 101-104页

作者： Hai Jiang David o’callaghan Jia-Bo Ding State Key Laboratory for Infectious Disease Prevention and Control Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesNational Institute for Communicable Disease Control and PreventionChinese Center for Disease Control and PreventionBeijingChina VBMI Universite de MontpellierINSERMUFR Medecine186Chemin du Carreau de Lanes30908 Nimes Cedex 2France Centre National de Reference Brucella CHU de NimesNimesFrance Department of Diagnostic Technology China Institute of Veterinary Drug ControlBeijingChina

Brucellosis is a neglected zoonosis.It causes acute febrile illness and a potentially debilitating chronic infection in humans,and livestock infection has substantial socioeconomic impact.over the past two decades,improvements have been made to better understand the various aspects of human and animal brucellosis.Meanwhile,especially in the developing world,immense challenges that remain in controlling and eradicating brucellosis are novel diagnostics tools and efficacious vaccines.Here,we will focus on the remarkable issues on epidemiological survey,as well as the priority and challenge of brucellosis in China.Brucellosis will be controlled with meaningful collaboration between local and public partnerships effectively applying a one Health framework.

关键词： Brucellosis Neglected zoonosis one health

BRAF inhibitor treatment of melanoma causing colonic polyps:An alternative hypothesis

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World Journal of Gastroenterology 2017年第17期23卷 3022-3029页

作者： Fergal C Kelleher Grainne callaghan Catriona Gallagher Hazel o'Sullivan Department of Medical oncology Specialty Certification Medical Oncology Royal College of Physicians United KingdomEuropean Certification in Medical OncologyThe Adelaide and Meath Hospital The Adelaide and Meath Hospital Whangarei Base Hospital

Colonic polyps may arise from BRAF inhibitor treatment of melanoma, possibly due paradoxical activation of the mitogen-activated protein(MAP)-kinase pathway. In an alternative evidence based scenario, tubular colonic adenomas with APC gene mutations have also been identified in the context of BRAF inhibitor treatment, in the absence of mutations of MAPK genes. A minority of colorectal cancers develop by an alternative "serrated polyp pathway". This article postulates a novel hypothesis, that the established phenotypic and molecular characteristics of serrated colonic polyps/CRC offer an intriguing insight into the pathobiology of BRAF inhibitor induced colonic polyps. Serrated polyps are characterized by a Cp G island methylation phenotype, MLH1 silencing and cellular senescence. They also have BRAF mutations. The contention is that BRAF inhibitor induced polyps mimic the afore-described histology and molecular features of serrated polyps with the exception that instead of the presence of BRAF mutations they induce C-RAF homodimers and B-RAF: C-RAF heterodimers.

关键词： BRAF 禁止者恶意的黑瘤 Serrated 息肉结肠的息肉

Multi-Institutional US Experience of the occlutech AFR Device in Congenital and Acquired Heart Disease

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Congenital Heart Disease 2022年第1期17卷 107-116页

作者： Barry o’callaghan Jenny Zablah Joseph Vettukattil Daniel Levi Morris Salem Allison Cabalka Jason Anderson Makram Ebeid Ryan Alexy Gareth J.Morgan The Heart Institute Children’s Hospital ColoradoAuroraUSA Pediatric Cardiology Helen DeVos Children’s HospitalGrand RapidsUSA Pediatric Cardiology UCLA HealthMattel Children’s HospitalLos AngelesUSA Pediatric Cardiology UCLA Medical CentreLos AngelesUSA Pediatric Cardiology Mayo ClinicRochesterUSA Pediatric Cardiology University of Mississippi Medical CenterJacksonUSA Pediatric Cardiology Riley Hospital for Children at Indiana University HealthIndianapolisUSA

objectives:To detail the US multi-institutional experience with the occlutech©(occlutech International AB,Helsingborg,Sweden)atrial flow regulator(AFR)in children and adults with acquired or congenital heart disease.Background:The creation of a long-term atrial communication is desirable in several cardiovascular disease phenotypes,most notably pulmonary arterial hypertension,disorders of increased left ventricular filling and increased cavopulmonary pressures in patients with a Fontan type circulation.Methods:Patients were identified for inclusion from the AFR device manufacturer database.Data was collected using a RedCap database following IRB approval.8 weeks of follow up data was sought for each patient based on available data.Data was analyzed and summarized using SPSS.Results:We report the experience of 6 US centers in the implantation of AFR devices in 15 patients,across a wide age range,with different disease phenotypes and a variety of indications.Implantation was technically successful in all patients and improvement was noted in both clinical and hemodynamic parameters.There were no immediate or intermediate term complications reported.3 patients died remote from implantation.Their deaths were not felt to be related to the AFR device or related procedural complications.Conclusion:Compassionate use of the AFR device in children and adults with congenital&acquired heart disease is technically feasible and produces beneficial short term hemodynamic and symptomatic improvement.Widespread uptake of this technique and treatment at specialist centers has the potential to provide significant benefits to a variety of complex patients with currently limited treatment options and indeterminate prognosis.

关键词： Congenital heart disease pulmonary hypertension left atrial hypertension single ventricle palliation diastolic heart failure

SPECT imaging of distribution and retention of a brain-penetrating bispecific amyloid-β antibody in a mouse model of Alzheimer's disease

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Translational Neurodegeneration 2020年第3期9卷 473-483页

作者： Tobias Gustavsson Stina Syvänen Paul o'callaghan Dag Sehlin Department of Public Health and Caring Sciences Uppsala UniversityUppsalaSweden Department of Medical Cell Biology Uppsala UniversityUppsalaSweden

Background:Alzheimer's disease(AD)immunotherapy with antibodies targeting amyloid-B(AB)has been extensively explored in clinical trials.The aim of this study was to study the long-term brain distribution of two radiolabeled monoclonal Aβ antibody variants-RmAb158,the recombinant murine version of BAN2401,which has recently demonstrated amyloid removal and reduced cognitive decline in AD patients,and the bispecific RmAb158-scFv8D3,which has been engineered for enhanced brain uptake via transferrin receptor-mediated transcytosis.Methods:A single intravenous injection of iodine-125(251)-labeled RmAb158-scFv8D3 or RmAb158 was administered to AD transgenic mice(tg-ArcSwe).In vivo single photon emission computed tomography was used to investigate brain retention and intrabrain distribution of the antibodies over a period of 4 weeks.Activity in blood and brain tissue was measured ex vivo and autoradiography was performed in combination with Aβand CD31 immunostaining to investigate the intrabrain distribution of the antibodies and their interactions with AB.Results:Despite faster blood clearance,[125]RmAb158-scFv8D3 displayed higher brain exposure than[25]RmAb158 throughout the study.The brain distribution of[l25]RmAb158-scFv8D3 was more uniform and coincided with parenchymal Aβ pathology,while[2 I]RmAb158 displayed a more scattered distribution pattern and accumulated in central parts of the brain at later times.Ex vivo autoradiography indicated greater vascular escape and parenchymal Aβ interactions for[25]RmAb158-scFv8D3,whereas[25]RmAb158 displayed retention and Aβ interactions in lateral ventricles.Conclusions:The high brain uptake and uniform intrabrain distribution of RmAb158-scFv8D3 highlight the benefits of receptor-mediated transcytosis for antibody-based brain imaging.Moreover,it suggests that the alternative transport route of the bispecific antibody contributes to improved efficacy of brain-directed immunotherapy.

关键词： Alzheimer's disease Amyloid beta SPECT Immunotherapy Bispecific antibody Transferrin receptor

Assessment of Neurotoxicity: Use of Glial Fibrillary Acidic Protein as a Biomarker

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Biomedical and Environmental Sciences 1991年第1期4卷 197-206页

作者： JAMES P.o callaghan Neurotoxicology Division Health Effects Research Laboratory U. S Environmental Protection Agency Research Triangle Park

Diverse neurotoxic insults result in proliferation and hypertrophy of astrocytes. The hallmark of this response is enhanced expression of the major intermediate filament protein of astrocytes, glial fibrillary acidic protein (GFAP). These observations suggest that GFAP may be a useful biomarker of neurotoxicity. To investigate this possibility, we administered prototype neurotoxicants to experimental animals and assessed the effects of these agents on the tissue content of GFAP, as determined by radioimmunoassay. A review of the background, design, and results of these experiments are presented in this paper. our findings indicate that GFAP is a sensitive and specific biomarker of neurotoxicity.

关键词： GFAP Use of Glial Fibrillary Acidic Protein as a Biomarker Assessment of Neurotoxicity

Extent and predictors of grade upgrading and downgrading in an Australian cohort according to the new prostate cancer grade groupings

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Asian Journal of Urology 2019年第4期6卷 321-329页

作者： Kerri Beckmann Michael o’callaghan Andrew Vincent Penelope Cohen Martin Borg David Roder Sue Evans Jeremy Millar Kim Moretti Cancer Research Institute School of Health SciencesUniversity of South AustraliaAdelaideAustralia School of Cancer and Pharmaceutical Sciences King’s College LondonLondonUK Flinders Medical Centre Urology UnitAdelaideAustralia School of Medicine University of AdelaideAdelaideAustralia SA Pathology Health SAAdelaideSouth AustraliaAustralia Genesis Care University of AdelaideAdelaideAustralia Department of Epidemiology and Preventive Medicine Monash UniversityMelbourneAustralia

object:To determine the extent and impact of upgrading and downgrading among men who underwent radical prostatectomy(RP)according to new grade groupings and to identify predictors of upgrading from biopsy grade Group Ⅰ and Ⅱ,and downgrading to grade Group I,in a community setting.Methods:Study participants included 2279 men with non-metastatic prostate cancer diagnosed 2006-2015 who underwent prostatectomy,from the multi-institutional South Australia Prostate Cancer Clinical outcomes Collaborative registry.Extent of up-or down-grading was assessed by comparing biopsy and prostatectomy grade groupings.Risk of biochemical recurrence(BCR)with upgrading was assessed using multivariable competing risk regression.Binomial logistic regression was used to identify pre-treatment predictors of upgrading from grade Groups Ⅰ and Ⅱ,and risk group reclassification among men with low risk disease.Results:Upgrading occurred in 35%of cases,while downgrading occurred in 13%of cases.Sixty percent with grade Group I disease were upgraded following prostatectomy.Upgrading from grade Group I was associated with greater risk of BCR compared with concordant grading(Hazard ratio:3.1,95%confidence interval:1.7-6.0).older age,higher prostate-specific antigen levels(PSA),fewer biopsy cores,higher number of positive cores and more recent diagnosis predicted upgrading from grade Group Ⅰ,while higher PSA and clinical stage predicted upgrading from grade Group Ⅱ.No clinical risk factors for reclassification were identified.Conclusion:Biopsy sampling errors may play an important role in upgrading from grade Group I.Improved clinical assessment of grade is needed to encourage greater uptake of active surveillance.

关键词： Prostate cancer Grade misclassification Biopsy Radical prostatectomy Pathology

Evaluation of the acute and sub acute toxicity of Annona senegalensis root bark extracts

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Asian Pacific Journal of Tropical Medicine 2012年第4期5卷 277-282页

作者： Theophine C okoye Peter A Akah Adaobi C Ezike maureen o okoye Collins A onyeto Frankline Ndukwu Ejike ohaegbulam Lovelyn Ikele Department of Pharmacology and Toxicology.Faculty of Pharmaceutical Sciences University of NigeriaNsukka 410001Enugu StateNigeria Department of Clinical Pharmacy and Pharmacy Management Faculty of Pharmaceutical SciencesUniversity of NigeriaNsukka 410001Enugu StateNigeria Department of Pharmacology and Toxicology.Faculty of Pharmaceutical Sciences University of Nigeria.Nsukka 410001Enugu StateNigeria

objective:To investigate the safety profile of Annona senegalensis（A.senegalensis）.Methods: Dried powdered root-bark of A.senegalensis was prepared by Sohxlet extraction using methanolmethylene chloride（1:1） solution and concentrated to obtain the methanol-methylene chloride extract（MME）.MME was fractionated to obtain the n-hexane（HF）,ethylacetate（EF） and methanol（MF） fractions.Acute toxicity(LD50) test was performed with MME,HF,EF and MF in mice by oral route.The sub acute toxicity studies were performed in rats after 14 days of MME administration while haemalological and biochemical parameters were monitored.Results: Medium lethal（LD-（50）） values of 1 296.3 808.1 265 and 2 154 mg/kg were obtained for the MME.MF, HF and EF,respectively.The sub-acute toxicity studies indicated a significant（Pody weight of both the treated rats and the control.The haematological tests indicated no change in the packed cell volume values but a significant（Potal WBC count at 100 and 400 mg/kg doses.The differential analysis showed a decrease in the nutrophils and a non-significant increase in the lymphocyte counts.The liver transaminase enzymes, alanin transaminase and aspartate transaminase showed no significant increase compared to the control.Histopathological examination of the liver sections also indicted no obvious signs of hepatotoxicity except with the 400 mg/kg dose that showed degeneration and necrosis of the hepatocytes.Conclusions:These results indicated that the root bark extracts of A.Senegalensis are safe at the lower doses tested,and calls for caution in use at higher doses in treatment.

关键词： Annona senegalensis Subacute toxicity Rats Hematology Histopathology