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PurposeIrinotecan (IR) displays significant PK/PD variability. This study evaluated functional hepatic imaging (HNI) and extensive pharmacogenomics (PGs) to explore associations with IR PK and PD (toxicity and response).MethodsEligible patients (pts) suitable for Irinotecan-based therapy. At baseline: (i) PGs: blood analyzed by the Affymetrix-DMET™-Plus-Array (1936 variants: 1931 single nucleotide polymorphisms [SNPs] and 5 copy number variants in 225 genes, including 47 phase I, 80 phase II enzymes, and membrane transporters) and Sanger sequencing (variants in HNF1A, Topo-1, XRCC1, PARP1, TDP, CDC45L, NKFB1, and MTHFR), (ii) HNI: pts given IV 250 MBq-99mTc-IDA, data derived for hepatic extraction/excretion parameters (CLHNI, T1/2-HNI, 1hRET, HEF, Td1/2). In cycle 1, blood was taken for IR analysis and PK parameters were derived by non-compartmental methods. Associations were evaluated between HNI and PGs, with IR PK, toxicity, objective response rate (ORR) and progression-free survival (PFS).ResultsN = 31 pts. The two most significant associations between PK and PD with gene variants or HNI parameters (P < 0.05) included: (1) PK: SN38-Metabolic Ratio with CLHNI, 1hRET, (2) Grade 3+ diarrhea with SLC22A2 (rs 316019), GSTM5 (rs 1296954), (3) Grade 3+ neutropenia with CLHNI, 1hRET, SLC22A2 (rs 316019), CYP4F2 (rs2074900) (4) ORR with ALDH2 (rs 886205), MTHFR (rs 1801133). (5) PFS with T1/2-HNI, XDH (rs 207440), and ABCB11 (rs 4148777).ConclusionsExploratory associations were observed between Irinotecan PK/PD with hepatic functional imaging and extensive pharmacogenomics. Further work is required to confirm and validate these findings in a larger cohort of patients.Australian New Zealand Clinical Trials Registry (ANZCTR) NumberACTRN12610000897066, Date registered: 21/10/2010.

BackgroundBody surface area (BSA)–based dosing of irinotecan (IR) does not account for its pharmacokinetic (PK) and pharmacodynamic (PD) variabilities. Functional hepatic nuclear imaging (HNI) and excretory/metabolic/PD pharmacogenomics have shown correlations with IR disposition and toxicity/efficacy. This study reports the development of a nonlinear mixed-effect population model to identify pharmacogenomic and HNI-related covariates that impact on IR disposition to support dosage optimization.MethodsPatients had advanced colorectal cancer treated with IR combination therapy. Baseline blood was analysed by Affymetrix DMET™ Plus Array and, for PD, single nucleotide polymorphisms (SNPs) by Sanger sequencing. For HNI, patients underwent 99mTc-IDA hepatic imaging, and data was analysed for hepatic extraction/excretion parameters. Blood was taken for IR and metabolite (SN38, SN38G) analysis on day 1 cycle 1. Population modelling utilised NONMEM version 7.2.0, with structural PK models developed for each moiety. Covariates include patient demographics, HNI parameters and pharmacogenomic variants.ResultsAnalysis included (i) PK data: 32 patients; (ii) pharmacogenomic data: 31 patients: 750 DMET and 22 PD variants; and (iii) HNI data: 32 patients. On initial analysis, overall five SNPs were identified as significant covariates for CLSN38. Only UGT1A3_c.31 T > C and ABCB1_c.3435C > T were included in the final model, whereby CLSN38 reduced from 76.8 to 55.1%.ConclusionThe identified UGT1A3_c.31 T > C and ABCB1_c.3435C > T variants, from wild type to homozygous, were included in the final model for SN38 clearance.

Traumatic brain injury (TBI) has a high incidence of long-term neurologic and neuropsychiatric morbidity. Metabolic and structural changes in rat brains were assessed after TBI using serial (18)F-FDG PET and 3-dimensional MRI in vivo. Rats underwent lateral fluid percussion injury (FPI; n = 16) or a sham procedure (n = 11). PET and MR images were acquired at 1 wk and at 1, 3, and 6 mo after injury. Morphologic changes were assessed using MRI-based regions of interest, and hippocampal shape changes were assessed with large-deformation high-dimensional mapping. Metabolic changes were assessed using region-of-interest analysis and statistical parametric mapping with the flexible factorial analysis. Anxiety-like behavior and learning were assessed at 1, 3, and 6 mo after injury. PET analyses showed widespread hypometabolism in injured rats, in particular involving the ipsilateral cortex, hippocampus, and amygdalae, present at 1 wk after FPI, most prominent at 1 mo, and then decreasing. Compared with the sham group, rats in the FPI group had decreased structural volume which progressively increased over 3-6 mo, occurring in the ipsilateral cortex, hippocampus, and ventricles after FPI (P < 0.05). Large-deformation high-dimensional mapping showed evolving hippocampal shape changes across the 6 mo after FPI. Injured rats displayed increased anxiety-like behavior (P < 0.05), but there were no direct correlations between the severity of the behavior abnormalities and functional or structural imaging changes. In selected brain structures, FPI induces early hypometabolism and delayed progressive atrophic changes that are dynamic and continue to evolve for months. These findings have implications for the understanding of the pathophysiology and evolution of long-term neurologic morbidity following TBI, and indicate an extended window for targeted neuroprotective interventions.

BackgroundImmunoPET is a multicentre, single arm, phase 0–1 study that aims to establish if 89Zr-durvalumab PET/CT can be used to interrogate the expression of PD-L1 in larger, multicentre clinical trials.MethodsThe phase 0 study recruited 5 PD-L1+ patients with metastatic non-small cell lung cancer (NSCLC). Patients received 60MBq/70 kg 89Zr-durva up to a maximum of 74 MBq, with scan acquisition at days 0, 1, 3 or 5±1 day. Data on (1) Percentage of injected 89Zr-durva dose found in organs of interest (2) Absorbed organ doses (µSv/MBq of administered 89Zr-durva) and (3) whole-body dose expressed as mSv/100MBq of administered dose was collected to characterise biodistribution.The phase 1 study will recruit 20 patients undergoing concurrent chemoradiotherapy for stage III NSCLC. Patients will have 89Zr-durva and FDG-PET/CT before, during and after chemoradiation. In order to establish the feasibility of 89Zr-durva PET/CT for larger multicentre trials, we will collect both imaging and toxicity data. Feasibility will be deemed to have been met if more than 80% of patients are able complete all trial requirements with no significant toxicity.Ethics and disseminationThis phase 0 study has ethics approval (HREC/65450/PMCC 20/100) and is registered on the Australian Clinical Trials Network (ACTRN12621000171819). The protocol, technical and clinical data will be disseminated by conference presentations and publications. Any modifications to the protocol will be formally documented by administrative letters and must be submitted to the approving HREC for review and approval.Trial registration numberAustralian Clinical Trials Network ACTRN12621000171819.

ImmunoPET is a multicentre, single arm, phase 0-1 study that aims to establish if Zr-durvalumab PET/CT can be used to interrogate the expression of PD-L1 in larger, multicentre clinical trials. The phase 0 study recruited 5 PD-L1+ patients with metastatic non-small cell lung cancer (NSCLC). Patients received 60MBq/70 kg Zr-durva up to a maximum of 74 MBq, with scan acquisition at days 0, 1, 3 or 5±1 day. Data on (1) Percentage of injected Zr-durva dose found in organs of interest (2) Absorbed organ doses (µSv/MBq of administered Zr-durva) and (3) whole-body dose expressed as mSv/100MBq of administered dose was collected to characterise biodistribution.The phase 1 study will recruit 20 patients undergoing concurrent chemoradiotherapy for stage III NSCLC. Patients will have Zr-durva and FDG-PET/CT before, during and after chemoradiation. In order to establish the feasibility of Zr-durva PET/CT for larger multicentre trials, we will collect both imaging and toxicity data. Feasibility will be deemed to have been met if more than 80% of patients are able complete all trial requirements with no significant toxicity. This phase 0 study has ethics approval (HREC/65450/PMCC 20/100) and is registered on the Australian Clinical Trials Network (ACTRN12621000171819). The protocol, technical and clinical data will be disseminated by conference presentations and publications. Any modifications to the protocol will be formally documented by administrative letters and must be submitted to the approving HREC for review and approval. Australian Clinical Trials Network ACTRN12621000171819.

Ionizing radiation (IR) and germline mutations in the retinoblastoma tumor suppressor gene (RB1) are the strongest risk factors for developing osteosarcoma. Recapitulating the human predisposition, we found that Rb1+/- mice exhibited accelerated development of IR-induced osteosarcoma, with a latency of 39 weeks. Initial exposure of osteoblasts to carcinogenic doses of IR in vitro and in vivo induced RB1-dependent senescence and the expression of a panel of proteins known as senescence-associated secretory phenotype (SASP), dominated by IL-6. RB1 expression closely correlated with that of the SASP cassette in human osteosarcomas, and low expression of both RB1 and the SASP genes was associated with poor prognosis. In vivo, IL-6 was required for IR-induced senescence, which elicited NKT cell infiltration and a host inflammatory response. Mice lacking IL-6 or NKT cells had accelerated development of IR-induced osteosarcomas. These data elucidate an important link between senescence, which is a cell-autonomous tumor suppressor response, and the activation of host-dependent cancer immunosurveillance. Our findings indicate that overcoming the immune response to senescence is a rate-limiting step in the formation of IR-induced osteosarcoma.

The education and training model envisioned for advanced practice registered nurses (APRNs) is a postbaccalaureate doctorate of nursing practice (DNP) without the master’s degree that is held by the vast majority of nurse practitioners (NPs) currently in practice. Assuming that the student had already completed enough of the DNP program to satisfy what would have been required for a master’s degree, should the student be able to “step-out” of the DNP program and be awarded a master’s degree? -Donald Gardenier Tina Escobedo Tina Escobedo, DNP, FNP-BC, is assistant clinical professor at the Sue & Bill Gross School of Nursing at the University of California, Irvine, where she directs the master's entry program and coordinates clinical education for NP programs. Comments or suggestions for future columns should be sent to Department Editor Donald Gardenier at jnppcpeditor@gmail.com Rod Hicks Rodney (Rod) Hicks, PhD, RN, FAANP, FAAN, is a professor at the College of Graduate Nursing at Western University of Health Sciences in Pomona, CA, where he teaches in the DNP program.

[...]clinical placements build relationships between preceptors and academic programs. [...]faculty can fulfill their evaluative role responsibilities of teaching and accreditation through clinical site visits. Yes Front-loaded didactic content followed by clinical immersion should emerge as best practice in today’s health care environment. Comments or suggestions for future columns should be sent to Department Editor Donald Gardenier at jnppcpeditor@gmail.com Cathleen Crowley-Koschnitzki Cathleen Crowley-Koschnitzki, DNP, FNP-C, CNM, WHNP-BC, CNE, is an associate professor in the FNP program at Chamberlain College of Nursing in Downers Grove, IL, where she serves as a strategic leader for clinical courses. Preceptors can also seek clinical experiences based on course objectives and reinforce content through the discussion of patient presentation and management as students gain knowledge of disease, assessment, and medication management. Students develop early role identification, preceptors experience satisfaction as students master skills, and faculty are assured of competence through course work and preceptor clinical evaluation.

Lewis later worked for a Rupert Murdoch-owned company that was reeling from the fallout of a British phone-hacking scandal involving journalists from one of his newspapers who had sorted through illegally obtained voicemails of celebrities, politicians and others looking for potential stories. All money ain't good money While reporting on the temporary suspension of an attorney for overcharging clients, the Chicago Sun-Times discovered he was trying to use an advertising contract with the newspaper to prevent it from running negative stories about him. The SPJ Code of Ethics advises journalists to \"deny favored treatment to advertisers, donors or any other special interests, and resist internal and external pressure to influence coverage\" It's hard for newspapers to turn down advertising dollars, which have been dwindling for at least two decades and, coupled with declining subscription revenue, have been a driving force behind newspapers shutting down at a rate of nearly 2% per week, ing to the Medill Local News Initiative at Northwestern University. When sources are overly helpful As a way to reach Black voters ahead of last year's presidential race, Joe Biden's re-election campaign set up interviews for the then-incumbent president to speak to Black radio hosts in two swing states.