Auswahl der wissenschaftlichen Literatur zum Thema „914.445 95“

ObjectiveTo quantitate the 2016 global and national burden of chronic kidney disease (CKD) attributable to ambient fine particulate matter air pollution ≤ 2.5 μm in aerodynamic diameter (PM2.5).DesignWe used the Global Burden of Disease (GBD) study data and methodologies to estimate the 2016 burden of CKD attributable to PM2.5in 194 countries and territories. Population-weighted PM2.5levels and incident rates of CKD for each country were curated from the GBD study publicly available data sources.SettingGBD global and national data on PM2.5and CKD.Participants194 countries and territories.Main outcome measuresWe estimated the attributable burden of disease (ABD), years living with disability (YLD), years of life lost (YLL) and disability-adjusted life-years (DALYs).ResultsThe 2016 global burden of incident CKD attributable to PM2.5was 6 950 514 (95% uncertainty interval: 5 061 533–8 914 745). Global YLD, YLL and DALYs of CKD attributable to PM2.5were 2 849 311 (1 875 219–3 983 941), 8 587 735 (6 355 784–10 772 239) and 11 445 397 (8 380 246–14 554 091), respectively. Age-standardised ABD, YLL, YLD and DALY rates varied substantially among geographies. Populations in Mesoamerica, Northern Africa, several countries in the Eastern Mediterranean region, Afghanistan, Pakistan, India and several countries in Southeast Asia were among those with highest age-standardised DALY rates. For example, age-standardised DALYs per 100 000 were 543.35 (391.16–707.96) in El Salvador, 455.29 (332.51–577.97) in Mexico, 408.41 (283.82–551.84) in Guatemala, 238.25 (173.90–303.98) in India and 178.26 (125.31–238.47) in Sri Lanka, compared with 5.52 (0.82–11.48) in Sweden, 6.46 (0.00–14.49) in Australia and 12.13 (4.95–21.82) in Canada. Frontier analyses showed that Mesoamerican countries had significantly higher CKD DALY rates relative to other countries with comparable sociodemographic development.ConclusionsOur results demonstrate that the global toll of CKD attributable to ambient air pollution is significant and identify several endemic geographies where air pollution may be a significant driver of CKD burden. Air pollution may need to be considered in the discussion of the global epidemiology of CKD.

Background: During last decade, several therapeutic options have emerged for newly diagnosed (ND) or relapsed / refractory (RR) patients with chronic lymphocytic leukemia (CLL). Lenalidomide (Lena) has immunomodulatory, anti-angiogenic and antitumor activity. Lena is showing antitumor activity against CLL with durable responses.The main aim of our analysis is to study the published literature on the efficacy and safety of Lena based regimens in patients with ND and RR CLL. Methods: We performed the literature search (10/5/2019) using following databases (PubMed, Embase, Cochrane Library, Web of Science, and Clinical trials.gov) identified a total of 4835 articles. Following PRISMA guidelines, we selected twenty articles (Phase I/II/III) with a total of 1309 patients (pts) in which eleven articles (n= 914) were about ND CLL pts and nine articles (n=396) had pts with RR CLL. CMA software v.3 was used for meta-analysis. Results: Lenalidomide based regimens in previously untreated CLL Based on the pooled analysis,(table 1)(an overall response rate (ORR) of 59.9% (95% CI: 55.4-64.2) with complete response (CR) of 17.6% (95% CI: 8.9-31.8) is observed in previously untreated CLL and ORR of 57.6% (95% CI: 50.4-64.4) with a CR of 12.9% (95% CI: 7.7-20.8) in RR CLL were calculated. Most common grade (G) ≥3 adverse events (AE's) based on regimen were calculated using pooled analysis in CLL pts and results are given intable2. Lena in single drug regimen: Three studies (n=445) evaluated the efficacy of Lena as single agent (5mg-25mg). Subgroup pooled analysis showed an ORR of 56.4% (95% CI: 51.6-61) with CR of 7.3% (95% CI: 4.4-11.3). Pooled analysis for safety profile on most common G ≥3 AE's were neutropenia 72.2% (95% CI: 45.1-89.2), thrombocytopenia (tcp) 29.7% (95% CI: 9.1-64), anemia 0.8% (95% CI: 0.1-11.1), fatigue 3% (95% CI: 1.5-5.8) and infections 5% (95% CI: 1.22-18.7). Lena in two drug regimen: One study (n=69) evaluated the efficacy of Lenaas double regimen with ofatumumab. Sub-group pooled analysis showed an ORR of 88% (95% CI: 78-93.8) with CR of 16% (95% CI: 9.1-26.6). Best response was seen when Lena was used with Ofatumumab, with reported ORR of 71%. Pooled analysis for safety profile on most common G ≥3 AE's were neutropenia 58% (95% CI: 46.1-69), anemia 10% (95% CI: 4.8-19.6), tcp 3% (95% CI: 0.8-11) and fatigue 6% (95% CI: 2.3-14.7). Lena in three drug regimen: For six studies (n=375), a pooled analysis on Lena as three drug regimen calculated an ORR of 59.2% (95% CI: 45.2-86) with CR of 24.1% (95% CI: 18.5-30.7). Pooled analysis for safety profile on most common G ≥3 AE's were neutropenia 55% (95% CI: 28.4-79.1), tcp 17.6% (95% CI: 6.1-41.3), anemia 13.9% (95% CI: 4.2-37.5), fatigue 29.1% (95% CI: 0.8-95.6) and infection 10.4% (95% CI: 5.6-18.5). Lena in four drug combination regimen: One study (n=25) evaluated Lena in quadruple regimen (Lena, rituximab, cyclophosphamide and fludarbine) with ORR of 98.1% (95% CI: 75.6-99.9) with CR 75% (95% CI: 54.8-88.1). Pooled analysis for common AE's were neutropenia of 51.6% (95% CI: 37.7-70), tcp of 1.6% (95% CI: 0.1-27), anemia of 1.6% (95% CI: 0-27) and infections of 3% (95% CI: 0.3-23.5) Lena based regimens in Relapsed or Refractory (RR) CLL Nine studies ( n=396)(table 1) evaluated the efficacy of Lena in RR CLL and have given promising results in these pts. Three studies (n=209) evaluated the efficacy of Lena as single agent, pooled analysis (95% CI) on Lena as mono measured an ORR of 32.7% (95% CI: 15.1-57)(fig. 1) with CR of 8.8% (95% CI: 3.1-22.8). Similarly subgroup pooled analysis for double regimen which includes four studies (n=139) measured ORR of 63.2% (95% CI: 54.4- 71.3) with CR of 14% (95% CI: 5.7-30.4). Two studies (n=56) evaluated Lena as triple regimen, an ORR of 52.5% (95% CI: 39.5-65.2) with CR of 21% (95% CI: 10.4-37.8) was calculated. Pooled analysis (95% CI) common G ≥3 AE's are neutropenia 69.9% (62.8-76.2), tcp 26.5% (18.4-36.5), anemia 9.4% (6.4-13.5), infections 29.4% (10.7-59) and fatigue 14.6% (6.2-30.6)(table 2) Conclusion: Lenalidomide is highly efficacious when used for treatment of previously untreated or RR CLL. Regimen efficacy is greater in untreated CLL compared to RR CLL. Four drug Lena based combination regimen showed the best result with an ORR of 98.1% (95%CI: 75.6-99.9). Large prospective studies are required to evaluate efficacy and safety of Lena in newer combination regimens. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

With the use of a modified acid version of a current lipid-extraction technique [Bligh & Dyer (1959) Can. J. Biochem. Physiol. 37, 911-917], 92% of phosphatidylinositol 4,5-bisphosphate obtained by means of three sequential extractions from intact human erythrocytes was obtained during the first one. Some 95% of the haem co-extracted with the lipids could then be removed, with a maximal loss of polyphosphoinositides of less than 3%. About 58 nmol of phosphatidylinositol 4,5-bisphosphate was found per ml of erythrocytes.

Abstract Newly diagnosed multiple myeloma (NDMM) patients treated with immunomodulatory drugs are at high risk of venous thromboembolism (VTE), but data are lacking from large prospective cohorts. We present thrombosis outcome data from Myeloma IX (n = 1936) and Myeloma XI (n = 4358) phase 3 randomized controlled trials for NDMM that treated transplant-eligible and transplant-ineligible patients before and after publication of thrombosis prevention guidelines. In Myeloma IX, transplant-eligible patients randomly assigned to cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) induction had higher risk of VTE compared with patients treated with cyclophosphamide, thalidomide, and dexamethasone (CTD) (22.5% [n = 121 of 538] vs 16.1% [n = 89 of 554]; adjusted hazard ratio [aHR],1.46; 95% confidence interval [95% CI], 1.11-1.93). For transplant-ineligible patients, those randomly assigned to attenuated CTD (CTDa) induction had a higher risk of VTE compared with those treated with melphalan and prednisolone (MP) (16.0% [n = 68 of 425] vs 4.1% [n = 17 of 419]; aHR, 4.25; 95% CI, 2.50-7.20). In Myeloma XI, there was no difference in risk of VTE (12.2% [n = 124 of 1014] vs 13.2% [n = 133 of 1008]; aHR, 0.92; 95% CI, 0.72-1.18) or arterial thrombosis (1.2% [n = 12 of 1014] vs 1.5% [n = 15 of 1008]; aHR, 0.80; 95% CI, 0.37-1.70) between transplant-eligible pathways for patients treated with cyclophosphamide, lenalidomide, and dexamethasone (CRD) or CTD. For transplant-ineligible patients, there was no difference in VTEs between attenuated CRD (CRDa) and CTDa (10.4% [n = 95 of 916] vs 10.7% [n = 97 of 910]; aHR, 0.97; 95% CI, 0.73-1.29). However, arterial risk was higher with CRDa than with CTDa (3.1% [n = 28 of 916] vs 1.6% [n = 15 of 910]; aHR, 1.91; 95% CI, 1.02-3.57). Thrombotic events occurred almost entirely within 6 months of treatment initiation. Thrombosis was not associated with inferior progression-free survival (PFS) or overall survival (OS), apart from inferior OS for patients with arterial events (aHR, 1.53; 95% CI, 1.12-2.08) in Myeloma XI. The Myeloma XI trial protocol incorporated International Myeloma Working Group (IMWG) thrombosis prevention recommendations and compared with Myeloma IX, more patients received thromboprophylaxis (80.5% vs 22.3%) with lower rates of VTE for identical regimens (CTD, 13.2% vs 16.1%; CTDa, 10.7% vs 16.0%). However, thrombosis remained frequent in spite of IMWG-guided thromboprophylaxis, suggesting that new approaches are needed.

Equine twin pregnancies are almost exclusively dizygotic, without the application of advanced reproductive technologies, requiring 2ovulations in 1 estrous cycle. Breeding records were used to determine the effects of sunlight hours, prostaglandin F2α, human chorionicgonadotropin, deslorelin (a gonadotropin releasing hormone agonist), and progesterone and estradiol on double ovulation rates,and singleton and twin pregnancy rates. Breeding records of mares (n = 267) and their estrous cycles (n = 914) were analysed. Doubleovulations occurred in 10.5% (96/914) of estrous cycles. Twin pregnancies were observed in 42.7% (38/89) of mares that had doubleovulations. Overall, per estrous cycle pregnancy rate was 47.2% (405/858) and twin pregnancies was 4.4% (38/858). Double ovulationshad higher (p < 0.001) per cycle singleton pregnancy rate (69.7%; 62/89) than 1-ovulation cycles (44.6%; 343/769). Deslorelinincreased (p < 0.05; OR =1.24 95% CI) double ovulations and human chorionic gonadotropin tended (p = 0.089; OR =1.68; 95%CI) to increase double ovulations. Deslorelin use resulted in an odds ratio of 2.47 for a positive pregnancy (either singleton or twin)diagnosis compared to cycles without deslorelin use. None of the factors examined had a substantial impact on twin pregnancy rates.

425 Background: A randomized phase III trial (JAVELIN Bladder 100; NCT02603432) to investigate avelumab (anti–PD-L1) as 1L maintenance therapy in patients with advanced UC met its primary objective, demonstrating significantly prolonged overall survival (OS) with Ave + BSC vs BSC alone in all randomized patients and in patients with PD-L1+ tumors. We report efficacy and safety in Japanese patients enrolled in this study. Methods: Eligible patients with unresectable locally advanced or metastatic UC that had not progressed with 4-6 cycles of gemcitabine with either cisplatin or carboplatin were randomized 1:1 to receive maintenance Ave (10 mg/kg IV every 2 weeks) + BSC or BSC alone, stratified by best response to 1L chemotherapy (complete/partial response vs stable disease) and by visceral vs nonvisceral disease when initiating 1L chemotherapy. The primary endpoint was OS, assessed from randomization in all randomized patients and in patients with PD-L1+ tumors (Ventana SP263 assay). Secondary endpoints included progression-free survival (PFS) per blinded independent central review and safety. Results: Japanese patients (n=73) were randomized to receive Ave + BSC (n=36) or BSC alone (n=37); 52.8% vs 62.2% had PD-L1+ tumors, respectively. Median OS (95% CI) was 24.7 months (18.2-not estimable [NE]) with Ave + BSC vs 18.7 months (12.8-33.0) with BSC alone (HR, 0.81 [95% CI; 0.409-1.585]) in all randomized patients and 18.6 months (9.4-NE) with Ave + BSC vs 19.4 months (11.7-33.0) with BSC alone (HR, 1.00 [95% CI, 0.413-2.412]) in patients with PD-L1+ tumors. Median PFS (95% CI) was 5.6 months (1.9-9.4) with Ave + BSC vs 1.9 months (1.9-3.8) with BSC alone (HR, 0.63 [95% CI, 0.358-1.113]) in all randomized patients and 5.6 months (1.8-11.2) with Ave + BSC vs 1.9 months (1.9-3.8) with BSC alone (HR, 0.62 [95% CI, 0.298-1.301]) in patients with PD-L1+ tumors. The most common treatment-emergent adverse events (all grade; grade ≥3) in the Ave + BSC arm were pyrexia (10 [27.8%]; 0), nasopharyngitis (7 [19.4%]; 0), and anemia (7 [19.4%]; 4 [11.1%]). Conclusions: Ave 1L maintenance + BSC was efficacious and tolerable in Japanese patients with advanced UC, and results were generally consistent with those in the overall population. Clinical trial information: NCT02603432.

Background: It is unknown if improvements in ischemic stroke (IS) outcomes reported after cerebral reperfusion therapies (CRT) in developed countries are also applicable to the “real world” scenario of low and middle-income countries. We aimed to measure the long-term outcomes of severe IS treated or not with CRT in Brazil. Methods: Patients from a stroke center of a state-run hospital were included. We compared the survival probability and functional status at 3 and 12 months in patients with severe IS treated or not with CRT. From 2010 to 2011, we performed intravenous reperfusion when patients arrived within 4.5 h time-window (IVT group) and after 2011, mechanical thrombectomy (MT) combined or not with intravenous alteplase (IAT group). Those who arrived >4.5 h in 2010-2011 and >6 h in 2012-2017 did not undergo CRT (NCRT group). Results: From 2010 to 2017, we registered 917 patients: 74% (677/917) in the NCRT group, 19% (178/917) in the IVT group and 7% (62/917) in the IAT group. Compared to the NCRT group, IVT patients had a 28% higher (HR: 0.72; 95% CI 0.53-0.96) 3-month adjusted probability of survival and risk of functional dependence was 19% lower (adjusted RR: 0.81; 95% CI 0.73-0.91). For those who underwent MT, the adjusted probability of survival was 59 % higher (HR: 0.41; 95% CI 0.21-0.77) and the risk of functional dependence was 21% lower (adjusted RR: 0.79; 95% CI 0.66-094). These outcomes remained significantly better throughout the first year. Conclusion: CRT led to better outcomes in patients with severe IS in Brazil.

435 Background: Surgical resection is the cornerstone of curative therapy for extrahepatic biliary tumors (EHBTs) Postoperative complications (POCs) can negatively impact survival after oncologic resection. We evaluated the impact of POCs on survival after resection of EHBTs. Methods: We analyzed 914 patients from ten institutions of the U.S. Extrahepatic Biliary Malignancy Consortium who underwent curative resection for gallbladder adenocarcinoma (n=389), hilar (n=295) and distal (n=294) cholangiocarcinoma between 1998 and 2015. POCs were graded using the modified Clavien-Dindo system. Overall survival (OS) probabilities were estimated using the method of Kaplan and Meier and analyzed using multivariate Cox regression. Results: Median follow-up was 20 months. The median age was 66 years, and the overall complication rate was 54%. Complication rates were significantly higher in patients with distal or hilar cholangiocarcinoma (62%) when compared with gallbladder cancer (41%, p<0.001). For all cancer types, patients who experienced POCs had lower 5-year OS when compared with those who did not (18% vs 28%, p<0.001). On multivariate Cox regression, POC remained an independent predictor for decreased OS (HR 1.5, 95% CI 1.3-1.9, p<0.001; Table). Among patients who experienced POCs, survival did not differ by greatest Clavien grade of complication experienced (p=0.89), however patients who had 2 or more POCs did have decreased long term survival when compared with patients with only a single POC (HR 1.5, 95% CI 1.2-1.8, p=0.001). Conclusions: POCs adversely affect long-term outcomes after curative resection for extra-hepatic biliary tumors. While any complication grade did not have a significant impact on long-term survival, increasing number of POCs did significantly worsen the prognosis for OS. [Table: see text]

e12073 Background: Incidence of febrile neutropenia (FN) is reported as 5% in breast cancer patients receiving TC (Jones et al., JCO 2006), which would not justify the usage of prophylactic granulocyte colony stimulating factors (G-CSF). We previously showed that the incidence of FN may be as high as 23% in a small study. (N = 130, Soni et al., ASCO 2011). In the current study, we determined the incidence of FN in a larger cohort (N = 415), and evaluated the usage of G-CSF and its relation to FN, age, stage, and hormonal status. Methods: We retrospectively reviewed the electronic medical records from patients diagnosed with breast cancer who received at least one standard dose cycle of adjuvant TC between 2010-2016 at a university-based breast oncology practice. Chi-square or Fisher’s exact tests were used to assess differences between groups. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using multiple logistic regression models. Results: We identified in total 415 patients who received adjuvant TC. Median age at diagnosis was 58 (range: 25-86), the majority had stage I or II (N = 382; 92.1%) disease, and 315 (75.9%) were ER+, 277 (66.8%) PR+, 42 (10.1%) HER2+, 22 (5.3%) triple-positive, and 81 (19.5%) triple-negative. Prophylactic G-CSF was utilized in 247 patients (59.5%), and unknown for 43 (10.4%). Overall 39 (9.4%) patients experienced febrile neutropenia. Incidence of FN among those receiving G-CSF was 4.5% versus 17.6% among those who did not (p < 0.001). Use of G-CSF significantly lowered risk of FN, OR (95%CI): 0.20 (0.10-0.43) adjusted for age at diagnosis and stage. Use of G-CSF on incidence of FN did not differ significantly by age, stage, or hormonal status. Conclusions: Our data confirms a high rate of FN in patients receiving TC without G-CSF prophylaxis. Our institutional high rate of G-CSF use ( > 50%) reduced the incidence of FN to 4.5% and the observed significant difference in FN incidence between the non G-CSF group and G-CSF group suggests that prophylaxis may be considered when administering TC. Age, stage, and hormonal status do not seem to affect the usage of G-CSF or incidence of FN in our population.

448 Background: Metastatic colorectal cancer patients with KRAS codon 12 or 13 mutated tumors are presently excluded from treatment with cetuximab (Cmab). On the other hand, a few patients who have mutated KRAS status occasionally respond to Cmab. The tumors of those patients predominantly had codon 13 mutation, and all codon 13 responder have mutation of p.G13D. We now compared the efficacy of Cmab among patients with p.G13D- mutant, other KRAS mutant and KRAS wild-type colorectal cancer. Methods: The patients from 9 Japanese institutions were retrospectively collected and analyzed. All patients were refractory to fluoropyrimidine, oxaliplatin and irinotecan, and were treated with Cmab and irinotecan combination regimen. Response rate (RR), progression-free survival (PFS) and overall survival (OS) were calculated respectively according to KRAS status. Results: Ninety four patients were treated with combination therapy. Among 94 cases, 7 cases were p.G13D-mutant KRAS, 23 cases were other mutant KRAS and 63 cases were wild-type KRAS. Baseline characteristics by each subset were well-balanced. While one partial response (PR) and 4 stable diseases (SD) cases were found in 7 p.G13D-mutated cases, no PR was found in other KRAS mutated cases. Median PFS of the patients with p.G13D-mutant, other KRAS mutant and KRAS wild-type were 4.5 months (95%CI 1.7-), 2.3 months (95%CI 1.9-4.3), 4.6 months (95%CI 3.5-6.5) respectively. And median OS of the patients with p.G13D- mutant, other KRAS mutant and KRAS wild-type were 9.3months (95%CI 8.5- 11.8), 7.4 months (95%CI 4.5-9.4), 12.2 months (95%CI 8.7-19.8) respectively. Although statistical significance was not found between the two mutated groups, there are trends that the patients with p.G13D-mutant may have received better clinical benefits from Cmab than the patients with other KRAS mutant. Conclusions: Cmab may have therapeutic benefit in the patients with KRAS p.G13D-mutant colorectal cancer although further evaluation is warranted. No significant financial relationships to disclose.