Immortal Bias Research Articles

Early Integration of High Dose Methotrexate to Frontline DLBCL Therapy Does Not Impact CNS Relapse Compared to End of Treatment Delivery: A Multicentre International Analysis of 1384 Patients

Early Integration of High Dose Methotrexate to Frontline DLBCL Therapy Does Not Impact CNS Relapse Compared to End of Treatment Delivery: A Multicentre International Analysis of 1384 Patients

High-Dose Methotrexate Is Not Associated with Reduction in CNS Relapse in Patients with Aggressive B-Cell Lymphoma: An International Retrospective Study of 2300 High-Risk Patients

High-Dose Methotrexate Is Not Associated with Reduction in CNS Relapse in Patients with Aggressive B-Cell Lymphoma: An International Retrospective Study of 2300 High-Risk Patients

Cardiovascular events among recipients of hematopoietic stem cell transplantation

Abstract Background Allogeneic and autologous hematopoietic stem cell transplantation (HSCT) are potential curative treatments for several hematological malignancies (1). Survival after HSCT has improved over the last decade, but survivors remain at risk for health issues after transplantation. Cardiovascular complications after HSCT are increasingly recognized (2). Cardiovascular diseases may be an important cause of mortality and morbidity in patients after HSCT owing to the toxicities of the cancer therapies; however, the incidence of cardiovascular events (CVEs) in this population has not been completely characterized. The objective of this systematic review is to summarize the evidence on the incidence of CVEs in HSCT recipients. Methods Medline and Embase were searched from inception to December 2020 without language restriction. Two authors independently screened the titles and abstracts. Inclusion criteria were: cohort studies and phase 3 randomized controlled trials that reported CVEs (i.e., heart failure, arrythmias, acute coronary syndrome, and stroke) or cardiovascular death among adults who underwent HSCT for a hematological malignancy. All-cause mortality, relapse-related mortality, and non-relapse-related mortality (NRM) were also collected. Studies in which the follow up period was not started immediately after HSCT were excluded due to the risk of immortal bias. Results Of 8151 nonduplicate articles, 30 studies including 14019 individuals post autologous HSCT, and 22 studies including 31049 individuals post allogeneic HSCT met the inclusion criteria. The cumulative incidence of CVEs in the first 100 days post autologous HSCT was 9% and arrhythmia (i.e., atrial fibrillation) was the most common CVE. In recipients of allogeneic HSCT, the 100-day cumulative incidence of CVEs was 3%, and heart failure (HF) was the most common reported CVE. In recipients of autologous and allogeneic HSCT, cardiovascular death was responsible for 43% and 10% of NRM within 100 days, respectively (Table 1). The incidence of CVEs was 4.96 per 1000-person years (95% CI; 4.21–5.80) in long-term survivors (beyond 100-days) of autologous HSCT, and HF was the most common CVE in this population. In long-term survivors of allogeneic HSCT, the incidence of CVEs was 1.90 per 1000-person years (95% CI: 1.59–2.24). Cardiovascular death was the most frequently reported CVE in long-term survivors of allogeneic HSCT (Table 2). Conclusion CVEs remain a major cause of non relapse morbidity and mortality in recipients of HSCT, especially recipients of autologous HSCT within the first 100 days. Future studies are needed to identify the risk factors for CVEs that are specific to HSCT recipients. Funding Acknowledgement Type of funding sources: None.

1016-P: Effectiveness of Early vs. Delayed Pharmacotherapy in Chinese Adults with Type 2 Diabetes: A Retrospective Cohort Study

Although early pharmacotherapy is recommended for type 2 diabetes (T2DM), the effectiveness of early treatment in Chinese adults is understudied. Chinese populations have a different pattern of complications to Western populations. We analysed a cohort of Chinese adults with T2DM from 2007 to 2017 in the Hong Kong public health care system. Early and delayed groups was defined as pharmacotherapy within 3 months and 3-12 months after T2DM diagnosis respectively. We fitted Cox proportional hazard models on 3122 pairs of propensity-score matched participants to assess treatment intensification with insulin, all-cause mortality, and complications (myocardial infarction, ischemic heart disease, stroke, heart failure, peripheral vascular disease, neuropathy, amputation, skin ulcer, renal failure, retinopathy, cataracts). We accounted for immortality bias by beginning follow-up at the end of the exposure window (12m post-diagnosis). Early pharmacotherapy was associated with reduced risk of treatment intensification with insulin (HR: 0.758; 95% CI: 0.584-0.984). This finding was consistent using alternative thresholds for early treatment (3m intervals from 0-9 months) and for metformin monotherapy. No statistically significant difference for other clinical outcomes were observed. Longer follow-up and larger sample size are required to evaluate other clinical outcomes. Disclosure Y. Lau: None. Y. Yuen: None. C. Ng: None. J. Quan: None. Funding Research Grants Council of Hong Kong (27112518)

Pooled analyses of immune-related adverse events (irAEs) and efficacy from the phase 3 trials IMpower130, IMpower132, and IMpower150.

9002 Background: PD-L1/PD-1 inhibitors have transformed the treatment (tx) of advanced NSCLC. Evidence suggests that the occurrence of irAEs with these agents may predict improved outcomes in cancers such as NSCLC. Atezolizumab (atezo; anti–PD-L1) has shown efficacy and tolerability in NSCLC and is currently approved in the 1L and 2L+ settings. The Ph 3 IMpower130, IMpower132 and IMpower150 trials evaluated atezo + chemo ± bevacizumab (bev) as 1L tx of NSCLC. We explore the association between irAEs and efficacy in these trials. Methods: Each trial enrolled tx-naive patients (pts) with nonsquamous stage IV NSCLC. Pts were randomized to: carboplatin (carbo) + nab-paclitaxel alone or with atezo in IMpower130; carbo or cisplatin alone or with atezo in IMpower132; atezo (A) + bev (B) + carbo + paclitaxel (CP), ACP or BCP in IMpower150. Data were pooled (data cutoffs: Mar 15 2018 [IMpower130]; May 22 2018 [IMpower132]; Sep 13 2019 [IMpower150]) and analyzed by tx (atezo-containing vs control) and irAE status. A time-dependent Cox model and landmark analyses at 1, 3, 6 and 12 mo were used to control for immortal bias. Study protocols required atezo tx interruption/discontinuation for grade (Gr) ≥3 irAEs. Results: 2503 pts were included in the analysis (atezo, n = 1577; control, n = 926). In both arms, baseline characteristics were generally balanced between pts with irAEs (atezo, n = 753; control, n = 289) and without irAEs (atezo, n = 824; control, n = 637). Any-Gr irAEs occurred in 48% (atezo) and 32% (control) of pts; Gr 3-5 irAEs occurred in 11% (atezo) and 5% (control). The most common irAEs (atezo vs control) were rash (28% vs 18%), hepatitis (lab abnormalities; 15% vs 10%) and hypothyroidism (12% vs 4%). Median time to onset of first irAE was 1.7 (atezo) vs 1.4 mo (control). OS HRs (95% CI) from the time-dependent Cox model between pts with vs without irAEs were 0.69 (0.60, 0.78) in the atezo arm and 0.82 (0.68, 0.99) in the control arm; after excluding rash (perceived as the least specific irAE), OS HRs (95% CI) were 0.75 (0.65, 0.87) and 0.90 (0.71, 1.12), respectively. OS landmark data are in the Table. Conclusions: In this exploratory pooled analysis, pts with irAEs had longer OS vs pts without irAEs in the atezo-containing and control arms per the time-dependent Cox model and landmark analyses; this trend remained for the atezo arm after excluding rash. Landmark analyses suggest that in the atezo arm, pts with Gr 1/2 irAEs had the longest OS and pts with Gr ≥3 irAEs had the shortest OS, potentially due to tx interruption/discontinuation. Clinical trial information: NCT02367781; NCT02657434; NCT02366143. [Table: see text]

POS-061 THE IMPACT OF NEGLECTING URINARY OUTPUT WHEN DEFINING AKI IN PREDICTION MODELLING: A BIG DATA ANALYSIS

KDIGO criteria have improved standardization of AKI definition, but most published automated algorithms fail to include the urinary output (UO) criterium in their ground truth definition of AKI. UO is also associated with mortality, and ignoring this parameter in the AKI definition might thus not accurately reflect the risk associated with the label AKI. We classified KDIGO AKI stage≥2 using routinely collected ICU data to identify the impact of including UO or not in an automated AKI algorithm on estimates of AKI incidence and prognostic value. All patients admitted to an intensive care unit (ICU) in a tertiary care centre between 1/1/2013 and 31/12/2017 were prospectively included. We used different interpretations for the baseline of the serum creatinine (Screa) criterion, and/or the urinary output (UO) criterion (either a moving 12h time window or in each of its 12 constituent 1h blocks) to identify patients fulfilling KDIGO AKI stage≥2 diagnosis. As outcome, we assessed incidence of AKI and association with ICU mortality using state of the art statistics to avoid immortality bias. In 13,403 ICU admissions (62.2% male, age 60.8±16.8 years, SOFA at admission 7.0±4.1), incidence of KDIGO AKI stage≥2 varied from 4.3% to 19.3% for the different baseline definitions of the Screa criterion, and 14.1 to 34.3% for the two interpretations of the UO criteria (fig dashed columns). Cause-specific hazard ratios of ICU mortality for patients with versus without AKI diagnosis also ranged from 1.76 (95% CI: 1.47–2.10) to 2.38 (95% CI: 2.09–2.71) for the Screa criteria and from 3.00 (95%CI: 2.55-3.53) to 3.21 (95%CI: 2.80-3.69) for the two interpretations of the UO criteria (Fig plain columns). Neglecting urinary output when defining AKI according to KDIGO negatively impacts the sensitivity and prognostic value of the label AKI. Despite its higher incidence, AKI based on UO had a higher ICU based mortality risk than AKI based on any of the Screa criteria of KDIGO. Algorithms to detect or predict AKI should therefore include urinary output in their ground truth definition of AKI.

Non-maintenance intravesical Bacillus Calmette\u2013Gu\xe9rin induction therapy with eight doses in patients with high- or highest-risk non-muscle invasive bladder cancer: a retrospective non-randomized comparative study

BackgroundTo explore possible solutions to overcome chronic Bacillus Calmette–Guérin (BCG) shortage affecting seriously the management of non-muscle invasive bladder cancer (NMIBC) in Europe and throughout the world, we investigated whether non-maintenance eight-dose induction BCG (iBCG) was comparable to six-dose iBCG plus maintenance BCG (mBCG).MethodsThis observational study evaluated 2669 patients with high- or highest-risk NMIBC who treated with iBCG with or without mBCG during 2000–2019. The patients were classified into five groups according to treatment pattern: 874 (33%) received non-maintenance six-dose iBCG (Group A), 405 (15%) received six-dose iBCG plus mBCG (Group B), 1189 (44%) received non-maintenance seven−/eight-dose iBCG (Group C), 60 (2.2%) received seven−/eight-dose iBCG plus mBCG, and 141 (5.3%) received only ≤5-dose iBCG. Recurrence-free survival (RFS), progression-free survival, and cancer-specific survival were estimated and compared using Kaplan–Meier analysis and the log-rank test, respectively. Propensity score-based one-to-one matching was performed using a multivariable logistic regression model based on covariates to obtain balanced groups. To eliminate possible immortal bias, 6-, 12-, 18-, and 24-month conditional landmark analyses of RFS were performed.ResultsRFS comparison confirmed that mBCG yielded significant benefit following six-dose iBCG (Group B) in recurrence risk reduction compared to iBCG alone (groups A and C) before (P < 0.001 and P = 0.0016, respectively) and after propensity score matching (P = 0.001 and P = 0.0074, respectively). Propensity score-matched sequential landmark analyses revealed no significant differences between groups B and C at 12, 18, and 24 months, whereas landmark analyses at 6 and 12 months showed a benefit of mBCG following six-dose iBCG compared to non-maintenance six-dose iBCG (P = 0.0055 and P = 0.032, respectively). There were no significant differences in the risks of progression and cancer-specific death in all comparisons of the matched cohorts.ConclusionsAlthough non-maintenance eight-dose iBCG was inferior to six-dose iBCG plus mBCG, the former might be an alternative remedy in the BCG shortage era. To overcome this challenge, further investigation is warranted to confirm the real clinical value of non-maintenance eight-dose iBCG.

Ketoanalogue supplements reduce mortality in patients with pre-dialysis advanced diabetic kidney disease: A nationwide population-based study

Metabolism dysregulation and protein energy wasting occur in patients with chronic kidney disease (CKD) and are associated with poor survival, especially in patients prior to starting dialysis. Accumulating evidence indicates that dietary supplementation with ketoanalogues (KAs, a mixture of branched-chain amino acids) exerts a variety of beneficial effects for patients with CKD. However, the role of KAs in diabetic kidney disease (DKD), one of the major causes of CKD, is still controversial. The aim of this study was to explore the impact of KA supplements on survival in patients with stage 5 DKD who have not yet started dialysis (DKD-5-ND). We analyzed a nationwide cohort retrieved from the National Health Insurance Research Database in Taiwan to study the long-term impact of KA supplements in patients with DKD-5-ND. We enrolled 15,782 incident pre-dialysis DKD patients between January 1, 2004 and December 31, 2007. Landmark analysis was used to eliminate immortal bias, and overlap weighting was used to balance differences between the KA users and nonusers in the beginning. The primary study endpoint was all-cause mortality, and the occurrence of permanent dialysis (presenting the end-stage renal disease, ESRD) and major adverse cardiovascular events (MACEs) was also evaluated. All patients were followed for five years or until death. The prevalence of KA usage in the DKD-5-ND patients was 6.3%. The 5-year all-cause mortality rate in the KA users was lower than that in the nonusers (34.7% vs 42.7%). After adjusting for known covariates, the KA users still had a lower risk of mortality (adjusted hazard ratio [aHR]: 0.73, 95% confidence interval [CI]: 0.66-0.82). In addition, the incidence of ESRD was also slightly lower among the KA users (90.9% for users vs 91.2% for nonusers, adjusted cause-specific hazard ratio [aCSHR]: 0.65, 95% CI: 0.61-0.69), and the occurrence of MACEs was lower (adjusted incidence rate ratios [aIRR]: 0.76, 95% CI: 0.67-0.86). Although the all-cause mortality was higher among patientsolder than 70 years (60.5% for KA users vs 46.5% for nonusers) the risk reduction seemed prominent among older patients (aHR: 0.65, 95% CI: 0.56-0.76 for patients aged ≥70 years; aHR: 0.82, 95% CI: 0.71-0.96 for patients aged<70 years). The reduction in risks of mortality was consistent in subgroup analysis and sensitivity tests. The use of KA supplements seemed to be beneficial for patients with DKD-5-ND; further in-depth analysis of using KA for these patients is warranted.

COVID-19 cytokine storm: targeting the appropriate cytokine.

COVID-19 cytokine storm: targeting the appropriate cytokine.

Cytoreductive Surgery for Selected Patients Whose Metastatic Gastric Cancer was Treated with Systemic Chemotherapy.

The authors hypothesized that cytoreductive surgery (CRS, comprising gastrectomy combined with metastasectomy) in addition to systemic chemotherapy (SC) is associated with a better survival than chemotherapy alone for patients with metastatic gastric adenocarcinoma (MGA). Patients with MGA who received SC between 2004 and 2016 were identified using the National Cancer Database (NCDB). Nearest-neighbor 1:1 propensity score-matching was used to create comparable groups. Overall survival (OS) was compared between subgroups using Kaplan-Meier analyses. Immortal bias analysis was performed among those who survived longer than 90days. The study identified 29,728 chemotherapy-treated patients, who were divided into the following four subgroups: no surgery (NS, n=25,690), metastasectomy alone (n=1170), gastrectomy alone (n=2248), and CRS (n=620) with median OS periods of 8.6, 10.9, 14.8, and 16.3 months, respectively (p<0.001). Compared with the patients who underwent NS, the patients who had CRS were younger (58.9±13.4 vs 62.0±13.1years), had a lower proportion of disease involving multiple sites (4.6% vs 19.1%), and were more likely to be clinically occult (cM0 stage: 59.2% vs 8.3%) (p<0.001 for all). The medianOS for the propensity-matched patients who underwent CRS (n=615) was longer than for those with NS (16.4 vs 9.3months; p<0.001), including inthose with clinical M1 stage (n=210). In the Cox regression model using the matched data, the hazard ratio for CRS versus NS was 0.56 (95% confidence interval [CI], 0.49-0.63). In the immortal-matched cohort, the corresponding median OS was 17.0 versus 9.5 months (p<0.001). In addition to SC, CRS may be associated with an OS benefit for a selected group of MGA patients meriting further prospective investigation.

Convalescent Plasma Improves Overall Survival in Patients with B-Cell Lymphoid Malignancies and COVID-19: &amp;nbsp;A Longitudinal Cohort and Propensity Score Analysis

Patients with hematological malignancies and COVID-19 display a high mortality rate. In such patients, immunosuppression due to underlying disease and previous specific treatment impairs humoral response, limiting viral clearance. Thus, COVID-19 convalescent plasma (CCP) therapy appears to be a promising approach through the transfer of neutralizing antibodies specific to SARS-CoV-2.Our study reports the effect of CCP in a cohort of patients with hematological malignancies and COVID-19 between 1 May 2020 and 1 April 2021. Overall, 112 hospitalized patients with severe COVID-19 (83 B-cell neoplasm, 19 plasma cell neoplasm, and 10 myeloid neoplasm) were included. The overall survival of the whole cohort was 65% [56–74.9] and 77.5% [68.5–87.7] for patients with B-cell neoplasm. Prior anti-CD20 monoclonal antibodies therapy was associated with better overall survival whereas age, high blood pressure, and COVID-19 severity were associated with a poor outcome after CCP transfusion. A retrospective analysis in the subgroup of COVID-19 patients with B-cell neoplasm treated with CCP (n=81) was compared to a similar group of patients (n=120) treated only with standard of care. An inverse probability of treatment weighting (IPTW) approach, performed to limit confusion and immortality bias, revealed a decreased mortality of 63% (95% CI=31%–80%) in the main analysis and 50% (95% CI=28%–66%) in the overall population of the CCP-treated group of patients with similar findings in the other sensitivity analyses.Convalescent plasma may be beneficial in COVID-19 patients with B-cell neoplasm who are unable to mount a humoral immune response. Comparing CCP to other passive immunotherapy approaches such as anti-SARS-CoV-2 monoclonal antibodies is warranted.Funding Information: This study was funded by Sorbonne University, Paris, France. Declaration of Interests: None to declare. Ethics Approval Statement: Patients gave their written informed consent for the retrospective data collection, and ethical clearance was obtained from the French Infectious Diseases Society (IRB number: 00011642)

Prognosis of acute kidney injury during acute heart failure: the role of diuretics

Abstract Background Acute kidney injury (AKI) frequently occurs after diuretic treatment initiation during acute heart failure (AHF). Treatment-induced hemoconcentration seems associated with improved prognosis. Transient AKI, with or without hemoconcentration, is of unsettled prognosis. Purpose We aimed to determine the independent prognostic values of transient AKI, persistent AKI and hemoconcentration in the context of hospitalized AHF. Methods Data were obtained from our institution's Clinical Data Warehouse. Patients that visited our unit at least once were screened. All hospitalizations in our institution were examined (&amp;gt;30 hospitals). Inclusion criteria were: ≥1 hospitalization with ≥1 recorded furosemide administration and ≥1 AHF ICD-10 code. Only the first hospitalization fulfilling these criteria was considered. AKI during 1–13 days following first furosemide administration was defined based on Kidney Disease Improving Global Outcome guidelines. Hemoconcentration was defined as an increase in serum proteins ≥5 g/l during the same period. We performed multivariate logistic regression to determine which characteristics were predictive of AKI. We used Cox regression of 100-days all-cause mortality using several confounders to determine the prognostic values of transient AKI (lasting &amp;lt;14 days), persistent AKI (lasting ≥14 days) and hemoconcentration. To account for immortality bias, AKI and hemoconcentration were treated as time-dependent covariates. Results We included 579 patients in the study. Median follow-up was 114 days. AKI following furosemide initiation occurred in 234 patients (40.4%). Patients that experienced AKI more frequently suffered from chronic kidney disease (43.6% vs. 33%, p=0.01) or presented with right ventricular dilatation (12% vs. 6.7%, p=0.04). Independent predictors of AKI were arterial hypertension (adjusted OR: 1.86 [1.08–3.22]), elevated serum creatinine at baseline (adjusted OR: 1.07 [1.01–1.14] per 10 μmol/l increase) and initial intravenous furosemide (adjusted OR: 2.42 [1.39–4.29]). Death during follow-up occurred in 35% of patients in the AKI group compared to 21% in the non-AKI group (p&amp;lt;0.001). In Cox regression, persistent AKI was independently associated with increased mortality in a period of 100 days following furosemide initiation (adjusted HR: 2.31 [1.07–4.99]). Transient AKI was not significantly associated with mortality (adjusted HR: 0.64 [0.34–1.19]). Hemoconcentration was independently associated with decreased mortality (adjusted HR: 0.46 [0.27–0.79]). Conclusion In the context of hospitalized AHF, AKI that developed 1–13 days after furosemide initiation and that lasted ≥14 days was independently associated with decreased 100 days survival. Hemoconcentration, using a clinically relevant definition, was independently associated with improved survival. These findings show that serum creatinine and proteins, routinely used and with limited cost, accurately stratify mortality risk during AHF. Kaplan-Meier curves Funding Acknowledgement Type of funding source: None

Quantifying the Treatment Effect of Kidney Transplantation Relative to Dialysis on Survival Time: New Results Based on Propensity Score Weighting and Longitudinal Observational Data from Sweden.

Using observational data to assess the treatment effects on outcomes of kidney transplantation relative to dialysis for patients on renal replacement therapy is challenging due to the non-random selection into treatment. This study applied the propensity score weighting approach in order to address the treatment selection bias of kidney transplantation on survival time compared with dialysis for patients on the waitlist. We included 2676 adult waitlisted patients who started renal replacement therapy in Sweden between 1 January 1995, and 31 December 2012. Weibull and logistic regression models were used for the outcome and treatment models, respectively. The potential outcome mean and the average treatment effect were estimated using an inverse-probability-weighted regression adjustment approach. The estimated survival times from start of renal replacement therapy were 23.1 years (95% confidence interval (CI): 21.2−25.0) and 9.3 years (95% CI: 7.8−10.8) for kidney transplantation and dialysis, respectively. The survival advantage of kidney transplantation compared with dialysis was estimated to 13.8 years (95% CI: 11.4−16.2). There was no significant difference in the survival advantage of transplantation between men and women. Controlling for possible immortality bias reduced the survival advantage to 9.1–9.9 years. Our results suggest that kidney transplantation substantially increases survival time compared with dialysis in Sweden and that this consequence of treatment is equally distributed over sex.

TO019PROGNOSTIC VALUE OF ACUTE KIDNEY INJURY AND HEMOCONCENTRATION DURING ACUTE HEART FAILURE

Abstract Background and Aims Acute kidney injury (AKI) occurring after diuretic treatment initiation for acute heart failure (AHF) is a common phenomenon, with an incidence estimated between 20 and 50% of AHF hospitalizations. Previous studies found that persistent AKI is associated with poor prognosis. Treatment-induced hemoconcentration is associated with improved prognosis, but several definitions previously used are not suited for clinical practice. Transient AKI, with or without hemoconcentration, is of unsettled prognosis. We aim to determine the independent prognostic value of transient AKI, persistent AKI and hemoconcentration in the context of AHF hospitalization, using practical definitions. Method Data were obtained from the Greater Paris University Hospitals (GPUH) Clinical Data Warehouse. Patients hospitalized for AHF in various GPUH units were included. AHF hospitalization was defined as hospitalization with at least one AHF ICD-10 code and at least one recorded furosemide administration. Bumetanide is rarely used in GPUH hospitals hence it was not considered. AKI in a period of 14 days following first furosemide administration was defined based on KDIGO guidelines. Hemoconcentration was defined as an increase in serum proteins ≥ 5 g/l during the same period. Multivariate logistic regression was performed to determine which characteristics were predictive of AKI. Cox regression of 100 days all-cause mortality using multiple confounders was performed to determine the prognostic value of transient AKI (&amp;lt; 14 days), persistent AKI (≥ 14 days) and hemoconcentration. Patients with AKI upon hospital entry were excluded from regression analyses. AKI and hemoconcentration were treated as time-dependent covariates to adjust for immortality bias. Results Five hundred seventy nine patients were included. Among them, 529 had no AKI upon hospital entry and 513 had at least one recorded serum proteins and creatinine value following furosemide initiation. Median follow-up was 114 days. AKI in a period of 14 days following furosemide initiation occurred in 234 patients (40.4%). At baseline, patients in the AKI group more frequently suffered from chronic kidney disease or presented with clinical and echocardiographic signs of right heart failure. Independent predictors of AKI were arterial hypertension upon furosemide initiation (adjusted OR 1.86 [1.08 – 3.22]), elevated serum creatinine upon furosemide initiation (adjusted OR 1.07 [1.01 – 1.14] per 10 µmol/l increase) and initial intravenous administration of furosemide (adjusted OR 2.42 [1.39 – 4.29]). Death during follow-up occurred in 35% of patients in the AKI group compared to 21% in the non-AKI group (p &amp;lt; 0.001). In multivariate analysis, persistent AKI was independently associated with increased mortality in a period of 100 days following furosemide initiation (adjusted HR 2.31 [1.07 – 4.99]). Transient AKI was not significantly associated with mortality (adjusted HR 0.64 [0.34 – 1.19]). Hemoconcentration was independently associated with decreased mortality (adjusted HR 0.46 [0.27 – 0.79]). Conclusion After furosemide initiation during hospitalization for AHF, persistent AKI (≥ 14 days) was independently associated with increased 100 days mortality. Hemoconcentration, using a definition suited for clinical practice (≥ 5 g/l increase in serum proteins), was independently associated with decreased 100 days mortality. No significant association was found between mortality and transient AKI (&amp;lt; 14 days). Those findings show that laboratory tests at a limited cost – serum proteins and creatinine – are helpful to evaluate treatment response and mortality risk during AHF. Prospective randomized controlled trials are needed to establish diuretic strategies based on both AKI and hemoconcentration.

Cytoreductive surgery in selected patients with metastatic gastric cancer treated with systemic chemotherapy.

409 Background: Cytoreductive surgery (CRS – gastrectomy combined with metastasectomy) for non-palliative indications is controversial for patients with metastatic gastric adenocarcinoma (MGA). We hypothesized that CRS in addition to systemic chemotherapy is associated with an improved survival when compared to patients with MGA receiving chemotherapy alone. Methods: Patients with MGA who received systemic chemotherapy between 2004-2016 were identified using the National Cancer Database (NCDB). Nearest neighbor 1:1 propensity score matching of demographic, tumor-related and treatment-related factors was used to create comparable groups. Overall survival (OS) was compared between subgroups using Kaplan-Meier analyses. Immortal bias analysis was performed among those that survived at least 90 days. Results: We identified 29,728 chemotherapy-treated patients who were divided into 4 subgroups: No surgery (NS, n = 25,690), metastasectomy alone (n = 1170), gastrectomy alone (n = 2248) and CRS (n = 620) with a median OS of 8.6, 10.9, 14.8 and 16.3 months, respectively (p &lt; 0.001). Compared to patients who underwent no surgery, patients who underwent CRS were younger (58.9±13.4 vs. 62.0±13.1 years), had lower proportion of disease involving multiple sites (5.0% vs. 26.2%), and were more likely to have clinically occult disease (cM0 58.9% vs. 7.3%) - all p &lt; 0.001. OS for propensity matched patients who underwent CRS (n = 490) was longer than NS (16.3 vs. 8.8 months, p &lt; 0.001), including those with clinical M1 stage (n = 203) in both unmatched and propensity matched (median OS 19.7 vs. 8.6 months, p &lt; 0.001) cohorts. On Cox regression model using the matched data, the hazard ratio for CRS vs. NS was 0.80 (95%CI 0.76-0.84). In the immortal matched cohort, the corresponding median OS was 16.7 vs. 9.7 months, p &lt; 0.001. Conclusions: CRS in addition to systemic chemotherapy may be associated with an OS benefit in a selected group of patients with metastatic gastric adenocarcinoma. Suboptimal matching for tumor burden is our major limitation. In contrast to studies that focus on gastrectomy alone in the setting of MGA, this study highlights the role of CRS among patients receiving systemic chemotherapy.

Major Deviations in the Delivery of Induction Chemotherapy Are Associated with an Increased Risk of Relapse in Acute Lymphoblastic Leukaemia: Results from UKALL2003

Introduction As survival rates for acute lymphoblastic leukaemia (ALL) in children and young people improve, the need to understand and mitigate toxicity becomes increasingly important. The contribution of toxicity to mortality or significant morbidity is well described. However, the impact of dose reductions, drug omissions or delays in treatment which result from toxicity is poorly understood, other than the established association between effective count suppression during maintenance chemotherapy and a reduction in relapse rate. We report the significance of treatment delays and dose reductions in induction chemotherapy in the UKALL2003 trial. Methods UKALL2003 was a prospective multicenter phase 3 study recruiting patients aged 1-24 years with newly diagnosed Philadelphia chromosome negative ALL in the UK. Data regarding 4 different protocol deviations were prospectively collected at the end of each block of therapy; a) not given allocated regimen, b) &lt;90% of one or more of the protocol drugs administered, c) change of Asparaginase product and d) delay of &gt; 1 week in commencing the next treatment block. Univariable (UVA) and Multivariable (MVA) Cox regression was used to assess the association of each deviation with risk of relapse. To control for immortality bias, this was assessed at the end of each therapy block with only patients alive and relapse free at the end of the block included in the analysis. Patients with Down Syndrome were excluded from all analyses. Results Of 2991 patients without Down Syndrome completing induction chemotherapy, 9 patients did not receive the allocated regimen, 1558 patients received &lt;90% of one or more drugs, 9 patients were switched to an alternative Asparaginase product and 72 had a greater than 1 week delay in commencing consolidation. On UVA, reduction of &gt;90% of one or more drugs and delay of greater than 1 week was significantly associated with an increased risk of relapse with hazard ratios of 1.70 (95% CI 1.11 - 2.60, p=0.014) and 1.99 (95% CI 1.14 - 3.48, p=0.013) respectively. On MVA (complete cases, n=2464), including other factors of established prognostic significance, both deviations remained significantly associated with an increased risk of relapse (Table 1). The impact of a major deviation (defined here as dose reduction of &gt;90% of one or more drugs or treatment delay of &gt;1week) was seen in both the paediatric (&lt;16 years) and older (16-24 years) groups with a slightly larger effect in the older group (HRs 1.73 and 2.40 respectively), though the interaction between age and deviation was not significant (p=0.49)( Figure 1). Patients with dose omissions &gt;90% of one or more drugs in induction were also more likely to have major deviations in subsequent blocks of therapy (p&lt;0.001) and remained at significantly higher risk of relapse when starting the maintenance phase of treatment (n=2343, HR: 1.81 (1.06 - 3.09, p = 0.03). Conclusion Major deviations in the delivery of induction chemotherapy on UKALL2003 were significantly associated with a greater risk of further deviations in subsequent blocks of therapy and a higher risk of relapse. Further improvement in efficacy of ALL therapy in children and young people will require a greater understanding of which toxicities lead to major deviations in therapy and strategies developed to mitigate these risks. Disclosures Rowntree: Novartis: Consultancy.

Cancer Risk among Population near Nuclear Power Plants in Korea

To the Editor: I read with great interest the recent article (1) and subsequent debate (2, 3) regarding the cohort study on cancer risks among those residing near nuclear power plants. Since the issue of health effects among populations living near nuclear facilities is an important topic within public health discourse, further scientific communication would contribute to a more complete understanding of radiation exposure and health. In this light, I would like to add a few comments on this issue. First, the study objective of the original investigation is indeed a fundamental issue which cannot be dismissed as a 'silly question'. If the study purpose is to identify the cancer risk due to radiation exposure from nuclear power plants, then it is difficult to justify why the original study did not include radiation-sensitive subpopulations such as fetuses or children from the beginning of the study. Also, considering that accurate exposure assessment is a vital component of environmental epidemiology, the simple application of a crude exposure index (i.e., distance from nuclear power plant) in this study raises questions related to the study purpose. I would judge that the main purpose of the original study was to build a prospective cohort of adults for cancer and other diseases rather than one focused on radiation exposure and cancer. Therefore, we need to acknowledge that while this is in fact a well-designed general cohort study, the cohort includes certain limitations for drawing causality with radiation exposure and cancer. Therefore, the results must be analyzed with caution. In my opinion, the results of this study should not be misleadingly interpreted as solid null findings rather than as inconclusive. Second, I am convinced that conducting a re-analysis of the existing dataset would be a worthwhile undertaking in order to investigate the association in greater depth. This is not a case of right versus wrong, but a natural process of investigating the truth. Existing and future findings together will contribute to a better understanding of the full scope of the radiation effect. A re-analysis study may provide us with valuable distinct approaches and considerations. Continued monitoring of health outcomes, refinement of exposure assessment, and corresponding updates of analysis are fundamental elements and advantages of cohort studies. Since the government and a number of researchers have dedicated considerable time, effort and funds to this cohort, I believe the existing data, as a national asset, need to be actively applied in support of the public interest. However, we must at the same time acknowledge the limitations of the original cohort which may continue to hinder the investigation of the association between radiation exposure and cancer risk even after applying more sophisticated statistical analyses. Therefore, additional efforts to compensate for the limitations of this study, in particular improving exposure assessment, minimizing exposure misclassification, and conducting new epidemiologic studies focusing on children, are warranted in order to better shed light on the association between radiation exposure from nuclear power plants and the development of cancer. Third, I would like to point out that there remain certain uncertainties in estimating cancer risk associated with exposure to ionizing radiation. Even the Life Span Study of Japanese atomic bomb survivors, which serves as a quantitative basis for radiation risk estimation worldwide, featured drawbacks including selection bias, immortal bias, and missing information (4). It is difficult to state that a low level of measured radiation can on its own completely guarantee no increased cancer risk for those living near nuclear power plant sites. The discrepancy between measured radiation doses and cancer risk remains mainly unexplained, and a possible hypothesis has been suggested (5). Although the majority of previous studies on cancer risks in populations near nuclear facilities have reported null findings except in the case of childhood leukemia (6), it is the role of epidemiology to clarify this issue of whether or not the observed cancer risk is related with radiation. Therefore, I would like to emphasize the importance of epidemiologic study in combination with surveillance data on radiation doses in populations near nuclear power plants. I believe that constructive discussions focusing on research itself can further advance radiation epidemiology in Korea and I hope this journal can serve as a means to accomplish this in its basic role as a scientific journal.