Relationship between protein biomarkers of chemotherapy response and microsatellite status, tumor mutational burden and PD-L1 expression in cancer patients.

Chemotherapy and checkpoint inhibitor immunotherapies are increasingly used in combinations. We determined associations between the presence of anti-PD-1/PD-L1 therapeutic biomarkers and protein markers of potential chemotherapy response. Data were extracted from a clinical-grade testing database (Caris Life Sciences; February 2015 through November 2017): immunotherapy response markers (microsatellite instability-high [MSI-H], tumor mutational burden-high [TMB-H], and PD-L1 protein expression) and protein chemotherapy response markers (excision repair complementation group 1 [ERCC1], topoisomerase 1 [TOPO1], topoisomerase 2 [TOP2A], thymidylate synthase [TS], tubulin beta 3 [TUBB3], ribonucleotide reductase regulatory subunit M1 [RRM1] and O-6-methyl guanine DNA methyltransferase [MGMT]). Relationships were determined by the Mantel-Haenszel chi-squared test or Fischer's exact tests. Overall, 28,034 patients representing a total of 40 tumor types were assessed. MSI-H was found in 3.3% of patients (73% were also TMB-H), TMB-H, 8.4% (28.3% were also MSI-H) and PD-L1 expression in 11.0% of patients (5.1% were also MSI-H; 16.4% were also TMB-H). Based on concurrent biomarker expression, combinations of immunotherapy with platinum (ERCC1 negativity) or with doxorubicin, epirubicin or etoposide (TOP2A positivity) have a higher probability of response, whereas combinations with irinotecan or topotecan (TOPO1 positivity), with gemcitabine (RRM1 negativity), and fluorouracil, pemetrexed or capecitabine (TS negativity) may be of less benefit. The potential for immunotherapy and taxane (TUBB3 negativity) combinations is present for MSI-H but not TMB-H or PD-L1-expressing tumors; for temozolomide and dacarbazine (MGMT negative), PD-L1 is frequently coexpressed, but MSI-H and TMB-H are not associated. Protein markers of potential chemotherapy response along with next-generation sequencing for immunotherapy response markers can help support rational combinations as part of an individualized, precision oncology approach

Efficacy and safety of anticancer drug combinations: a meta-analysis of randomized trials with a focus on immunotherapeutics and gene-targeted compounds.

Hundreds of trials are being conducted to evaluate combination of newer targeted drugs as well as immunotherapy. Our aim was to compare efficacy and safety of combination versus single non-cytotoxic anticancer agents. We searched PubMed (01/01/2001 to 03/06/2018) (and, for immunotherapy, ASCO and ESMO abstracts (2016 through March 2018)) for randomized clinical trials that compared a single non-cytotoxic agent (targeted, hormonal, or immunotherapy) versus a combination with another non-cytotoxic partner. Efficacy and safety endpoints were evaluated in a meta-analysis using a linear mixed-effects model (guidelines per PRISMA Report).We included 95 randomized comparisons (single vs. combination non-cytotoxic therapies) (59.4%, phase II; 41.6%, phase III trials) (29,175 patients (solid tumors)). Combinations most frequently included a hormonal agent and a targeted small molecule (23%). Compared to single non-cytotoxic agents, adding another non-cytotoxic drug increased response rate (odds ratio [OR]=1.61, 95%CI 1.40-1.84)and prolonged progression-free survival (hazard ratio [HR]=0.75, 95%CI 0.69-0.81)and overall survival (HR=0.87, 95%CI 0.81-0.94) (all p<0.001), which was most pronounced for the association between immunotherapy combinations and longer survival. Combinations also significantlyincreased the risk of high-grade toxicities (OR=2.42, 95%CI 1.98-2.97) (most notably for immunotherapy and small molecule inhibitors) and mortality at least possibly therapy related (OR: 1.33, 95%CI 1.15-1.53) (both p<0.001) (absolute mortality = 0.90% (single agent) versus 1.31% (combinations)) compared to single agents. In conclusion, combinations of non-cytotoxic drugs versus monotherapy in randomized cancer clinical trials attenuated safety, but increased efficacy, with the balance tilting in favor of combination therapy, based on the prolongation in survival

Alibi įrodinėjimo baudžiamajame procese kriminalistiniai ir procesiniai aspektai.

Straipsnyje yra analizuojami klausimai susiję su alibi įrodinėjimu baudžiamajame procese. Alibi patikrinimas -vienas iŠ svarbiausių nusikaltimo tyrimo uždavinių. Alibi patikrinimo rezultatai dažniausiai turi lemiamos reikšmės įrodinėjant konkrečių asmenų kaltę. Remiantis specialia užsienio šalių literatūra pirmojoje straipsnio dalyje yra apžvelgiami bendrieji teoriniai alibi sampratos klausimai, loginė struktūra ir rūšys. Šioje dalyje autorius taip pat analizuoja alibi ir nusikaltimų tyrimo versijų panašumus ir skirtumus, pateikia jų atribojimo požymius. Straipsnio antrojoje dalyje yra analizuojami praktiniai, taikomieji alibi patikrinimo klausimai - kriminalistinės-taktinės rekomendacijos taikytinos tikrinant bei išaiškinant klaidinančias alibi

Nusikaltimo tyrimo versijų teorijos realizavimo galimybės.

Nusikaltimų tyrimo kokybei visų pirma įtaką daro tyrėjo meistriškumas, patirtis, sugebėjimas sumaniai pritaikyti kriminalistikos taktinius ir mokslinius techninius metodus tiriant konkrečios kategorijos bylas. Sėkmingas nusikaltimo atskleidimas ir ištyrimas priklauso nuo tinkamo tyrimo organizavimo ir planavimo, ypač pradiniame tyrimo etape. Šiuo atveju vienas iš svarbiausių tyrimo proceso elementų yra tinkamas, laiku atliktas nusikaltimo tyrimo versijų formulavimas ir patikrinimas. Versijos (arba nusikaltimo tyrimo versijos) yra vienos iš pagrindinių ir sudėtingiausių kriminalistikos teorijos sąvokų. Tai lemia jų „strateginis“ vaidmuo, jų pažintinė reikšmė, pasireiškianti specifinėje visuomenės srityje – tiriant nusikaltimus. Versija, kaip tyrimo objektas, yra daugelio mokslų – logikos, filosofijos, psichologijos, modeliavimo, baudžiamosios teisės, baudžiamojo proceso, kriminalistikos ir kitų – akiratyje

Evaluating Home Health Care Nursing Outcomes With OASIS and NOC

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73163/1/j.1547-5069.2007.00209.x.pd

Teismo ekonominė ekspertizė Lietuvoje 2004 metais.

Law system reform in Lithuania touched upon the area of forensic examination. Experts from Forensic Science Centre of Lithuania began compete with private forensic experts by their knowledge and experience in such way: experts’ economists with auditors and inspectors. Turning of various specialists into forensic experts -economists promotes new problems related with variety of methodological research, private experts’ independence, experts’ collaboration. System of economical examination in Lithuania must be formed with responsibility including auditors and property appraisers, ensuring uniform methodology, exchanging experts’ experience and strengthening their independence. Auditor, which intents to become forensic expert, must get forensic expert’s qualification. The goal of this article is to review getting on practice of economic forensic examination within last period. Auditors’ and inspectors’ tasks, its relation with economic forensic examination are discussed in details, methodological, process and practical differences of expert economist’s or auditor’s activity are indicated, authors propose to improve practice of forensic expert’s preparation. Great attention is directed to economic examinations done in Forensic Science Centre of Lithuania, its kinds and tasks, structure of examinations are presented. Value of statement of examination is properly adapted method of expert research. Examinations are done by means of examinational methods of document verification, comparison and contrary verification, control comparison, research of overall quantitative account, economic analysis, computer aided account. Examinations meeting with the loss of information basis are done employing indirect methods of research that usually have been employed in analysis of transaction prices, determining tax basis, quantity of black money. In examinational practice more frequently indirect research methods are employed and principal of it is method of economic model. Problems of indirect application of methodology are discussed, that illustrated by generalized samples of examinational practice. Application of methods of economic modeling needs new scientific knowledge, preparedness and extensive historical and analogue information, quantitative viewpoint. In examinations done indirect method it is necessary to evaluate competitive environment, to take account for circumstances of the activity of enterprises, changes of market conjuncture and inflation. Doing the calculation of black money and prognosis it is necessary to do presumption about equal distribution of earnings in time and among economy subjects but it not always corresponds to reality and it enables to employ the method of arithmetical mean. In earnings prognosis by method of linear extrapolation it is necessary to calculate limits of confiding interval of the prognosis. Expert’s opinion on (he basis of indirect methods is problematic. Instilling quality management system in Forensic Science Centre of Lithuania will provide an excellent provision to do inventory, revision, classification of existing methods, to outline landmarks for seeking improvement expert’s work reserve. After becoming of Lithuania the member of European Union the best European practice must be adopted and employed in the area of forensic examination.Lietuvoje vykusi teisinės sistemos reforma palietė teismo ekspertizės sritį. Lietuvos teismo ekspertizės centro ekspertai savo žiniomis ir patirtimi pradėjo konkuruoti su privačiais- teismo ekspertais: ekspertai ekonomistai su auditoriais ir revizoriais. Įvairiems specialistams tapus- teismo ekspertais ekonomistais, iškilo naujų problemų, susijusių su metodologine tyrimo įvairove, privačių ekspertų nepriklausomumu, ekspertų bendradarbiavimu. Straipsnio tikslas - apžvelgti besiklostančią pastarojo laikotarpio teismo ekonominės ekspertizės praktiką. Detaliai gvildenami auditorių ir revizorių uždaviniai, jų santykis su ekonomine teismo ekspertize, nurodomi metodologiniai, procesiniai bei praktiniai eksperto ekonomisto ir auditoriaus veiklos skirtumai, pateikiami siūlymai dėl teismo ekspertų rengimo praktikos. Daug dėmesio skiriama Lietuvos teismo ekspertizės centre atsekamoms ekonominėms ekspertizėms, apžvelgiamos jų rūšys, uždaviniai Ir struktūra. Ekspertizės atliekamos dokumentinio patikrinimo, palyginimo ir priešpriešinio patikrinimo, kontrolinio sulyginimo, kiekinės-suminės apskaitos tyrimo, ekonominės analizės, kompiuterizuotos apskaitos ir nesant dokumentų tyrimo metodais. Vis dažniau ekspertinėje praktikoje pradedami taikyti netiesioginio tyrimo metodai, iš jų svarbiausias - ekonominio modelio metodas. Aptariamos ir ekspertinės praktikos apibendrintais pavyzdžiais iliustruojamos netiesioginės metodologijos taikymo problemos