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AbstractObjectiveVitamin D status plays an important role in immunoregulation, and a deficiency is believed to be related to Graft Versus Host Disease (GVHD) in patients after hematopoietic stem cell transplantation (HSCT). We aim to study the association between vitamin D deficiency and GVHD after HSCT.MethodsA literature search was conducted utilizing MEDLINE, EMBASE, and The Cochrane Library Database from inception to July 2019. Eligible studies were required to1 be clinical trials or observational studies (cohort, case‐control, or cross‐sectional studies);2 provide data to calculate the odds ratios (OR) of GVHD in HSCT patients with vitamin D deficiency. Two reviewers independently extracted the data and assessed the risk of bias. Pooled odds ratios (OR) with 95% confidence interval (CI) were estimated using random‐effects meta‐analysis through the Comprehensive Meta‐Analysis 3.3 software.ResultsIn total, 8 observational studies consisting of 1335 HSCT patients were enrolled in this systematic review. Overall, there was no significant association between vitamin D deficiency and acute GVHD (OR = 1.06, 95% CI 0.74‐1.53, P > 0.05). There was no significant association between vitamin D deficiency and chronic GVHD (OR = 1.75, 95% CI 0.72‐4.26, P > 0.05). Funnel plots and Egger regression asymmetry test were performed and showed no publication bias.ConclusionThere is not a statistically significant association between vitamin D deficiency and neither acute nor chronic GVHD.

Background: Calcium-phosphate product is associated with mortality among patients with end-stage kidney disease on dialysis. However, clinical evidence among hospitalized patients is limited. The objective of this study was to investigate the relationship between admission calcium-phosphate product and 1-year mortality in hospitalized patients. Materials and Methods: All adult patients admitted to a tertiary referral hospital in 2009–2013 were studied. Patients who had both available serum calcium and phosphate measurement within 24 h of hospital admission were included. Admission calcium-phosphate product (calcium × phosphate) was stratified based on its distribution into six groups: <21, 21–<27, 27–<33, 33–<39, 39–<45, and ≥45 mg 2 /dL 2 . Multivariate cox proportional hazard analysis was performed to evaluate the association between admission calcium-phosphate product and 1-year mortality, using the calcium-phosphate product of 33–<39 mg 2 /dL 2 as the reference group. Results: A total of 14,772 patients were included in this study. The mean admission calcium-phosphate product was 34.4 ± 11.3 mg 2 /dL 2 . Of these patients, 3194 (22%) died within 1 year of hospital admission. In adjusted analysis, admission calcium-phosphate product of ≥45 mg 2 /dL 2 was significantly associated with increased 1-year mortality with hazard ratio of 1.41 (95% 95% confidence interval 1.25–1.67), whereas lower admission calcium-phosphate product was not significantly associated with 1-year mortality. Conclusion: Elevated calcium-phosphate product was significantly associated with increased 1-year mortality in hospitalized patients.

Abstract Proteasome inhibitors are used in the treatment of myeloma and are under evaluation for the treatment of other malignancies including acute myeloid leukemia (AML). Via high throughput screening for inhibitors of cyclin D2 transactivation, we identified the off-patent antimicrobial, Clioquinol (CQ) that we subsequently determined acted by inhibiting the proteasome. CQ is a copper-binding halogenated 8-hydroxyquinoline that was used in the 1950’s-1970’s as an oral anti-parasitic agent. We determined that CQ decreased expression of cyclin D2, arrested cells in the G1 phase, and increased expression of p21, p27 and the abundance of ubiquitinated proteins. This constellation of changes can be associated with inhibition of the proteasome, so we evaluated the effects of CQ on proteasomal function. AML and myeloma cell lines as well as primary AML and normal hematopoietic cells were incubated with increasing concentrations of CQ. After a 24 hour incubation, cell lysates were prepared and the chymotrypsin-like activity of the proteasome was measured by monitoring the rate of cleavage of the fluorescent substrate Suc-LLVY-AMC. In cell lines and primary AML samples, CQ inhibited chymotrypsin-like activity at low micromolar concentrations and at concentrations associated with reductions in cyclin D2, G1 arrest, and increased p21 and p27 expression. Conversely, CQ did not inhibit the proteasome in normal hematopoietic cells up to 100 μM. As CQ is a copper-binding molecule, we tested the requirement of copper for its effects on the proteasome. Supplementing CQ with copper increased CQ’s potency as a proteasome inhibitor, but also negated its preferential inhibition of the proteasome in malignant cells over normal hematopoietic cells. Of note, copper alone had no effect on proteasomal function when added to intact cells. Since inhibiting the proteasome induces cell death, we tested the effects of CQ on the viability of AML (n=6), myeloma (n=14), and solid tumor (n=5) cell lines as well as primary AML samples (n=6) and primary normal hematopoietic cells (n=3). Forty-eight hours after incubation, CQ induced cell death in 6/6 AML, 12/14 myeloma, 0/5 solid tumor, 6/7 primary AML patient samples and 0/3 normal hematopoietic cells with an IC50 &lt;20 μM. Of note, after oral administration of CQ, trough serum concentrations of 20 μM can be achieved in patients. CQ-mediated reductions in cell viability were associated with its ability to inhibit the proteosome, as no proteasomal inhibition was detected in CQ-resistant cell lines. CQ-induced cell death was copper-dependent as supplementing copper in the medium enhanced the toxicity of CQ, while adding the strong copper chelator, tetrathiomoylbdate, abrogated CQ-induced cell death. Given the effects of CQ on AML cell lines and primary patient samples, we evaluated CQ in a mouse model of leukemia. Twice daily oral gavage with CQ prevented the growth of MDAY-D2 leukemia cells in DBA2 mice without evidence of toxicity. Thus, we have identified the off-patent anti-microbial agent CQ that inhibits the proteasome and induces apoptosis preferentially in malignant cells at clinically achievable concentrations. It acts through a copper-dependent mechanism and leverages the higher copper levels present in malignant cell. As such, CQ could be rapidly advanced into clinical trial as an oral proteasome inhibitor for the treatment of AML and myeloma.

Abstract Cyclin Ds are key regulators of the cell cycle that are frequently over-expressed in multiple myeloma and leukemia and act to promote the phosphorylation of Rb, thereby facilitating the transition from G1 to S phase. Over-expression of cyclin Ds increases cell proliferation and chemoresistance. In contrast, reducing cyclin Ds levels directly or indirectly through G1 arrest can decrease cellular proliferation and induce apoptosis. To identify novel pharmaceutical inhibitors of cyclin D transactivation, we screened the LOPAC and Prestwick libraries of drugs and natural compounds (n = 2400) using NIH 3T3 cells stably expressing the Cyclin D2 promoter-driving a luciferase reporter gene. From this library screen and subsequent validation experiments we identified Cyproheptadine as a novel inhibitor of Cyclin D2 transactivation. Cyproheptadine has been used previously for the treatment of atopic dermatitis and anorexia, but its ability to inhibit cyclin D expression has not previously been reported. By immunoblotting, Cyproheptadine decreased expression of cyclin D1, D2 and D3 proteins in human myeloma and leukemia cell lines at low micromolar concentrations. Consistent with effects on the cyclin Ds, Cyproheptadine arrested cells in the G1 phase at concentrations associated with reduction in cyclin D expression. Decreased cyclin D expression and G1 arrest can induce apoptosis, so we tested the effects of Cyproheptadine on cell viability. Myeloma and leukemia cell lines were treated with increasing concentrations of Cyproheptadine and viability was measured by the MTS assay. Cyproheptadine reduced the viability of 7/10 myeloma and 7/8 AML cells lines with an IC50 ranging from 10–25μM. In contrast, it was less toxic to HeLa or NIH3T3 cells with IC20 &gt; 50 μM. Cyproheptadine also reduced the viability of primary myeloma (8/8) and AML patient samples (7/9) with an IC50 &lt;25 μM, but was less toxic to normal hematopoietic cells (IC20 &gt; 50 μM). In a MDAY-D2 mouse model of leukemia, treatment with Cyproheptadine (50mg/kg/d) abolished formation of malignant leukemic ascites without untoward toxicity. Cyproheptadine-induced cell death was associated with reductions in mitochondrial membrane potential. Furthermore, reductions of pro-caspases -3 and -9 were observed prior to the reduction in pro-caspase-8, indicating that Cyproheptadine activates the mitochondrial pathway of caspase activation. Cyproheptadine is a known H1 histamine and serotonin receptor inhibitor, but pre-incubation with histamine, serotonin, or a combination of histamine and serotonin did not abrogate Cyproheptadine-induced cell death. Moreover, the structurally related H1 receptor inhibitor loratadine did not decrease cyclin D expression or reduce cell viability. Therefore, the pro-apoptotic activity of Cyproheptadine is not due to a competitive inhibition of the H1 and/or serotonin receptors, suggesting that Cyproheptadine has additional targets. In summary, Cyproheptadine arrests cells in G1, reduces cyclin D expression, and induces apoptosis via the mitochondrial pathway of caspase activation. Given the prior safety and toxicity record of Cyproheptadine, this drug could be rapidly advanced into clinical trial for the treatment of hematologic malignancies.

Background: Steatotic grafts are increasingly being used for liver transplant (LT); however, the impact of graft steatosis on renal function has not been well described. Methods: A total of 511 allografts from Mayo Clinic Arizona and Minnesota were assessed. We evaluated post-LT acute kidney injury (AKI) patterns, perioperative variables and one-year outcomes for patients receiving moderately steatotic allografts (>30% macrovesicular steatosis, n = 40) and compared them to non-steatotic graft recipients. Results: Post-LT AKI occurred in 52.5% of steatotic graft recipients versus 16.7% in non-steatotic recipients (p < 0.001). Ten percent of steatotic graft recipients required new dialysis post-LT (p = 0.003). At five years, there were no differences for AKI vs. no AKI patient survival (HR 0.95, 95% CI 0.08–10.6, p = 0.95) or allograft survival (HR 1.73, 95% CI 0.23–13.23, p = 0.59) for those using steatotic grafts. Lipopeliosis on biopsy was common in those who developed AKI (61.0% vs. 31.6%, p = 0.04), particularly when the Model for End-Stage Liver Disease (MELD) was ≥20 (88.9%; p = 0.04). Lipopeliosis was a predictor of post-LT AKI (OR 6.0, 95% CI 1.1–34.6, p = 0.04). Conclusion: One-year outcomes for moderately steatotic grafts are satisfactory; however, a higher percentage of post-LT AKI and initiation of dialysis can be expected. Presence of lipopeliosis on biopsy appears to be predictive of post-LT AKI.

Background and objectives This study aimed to investigate the association between in-hospital trajectories of serum sodium and risk of in-hospital and 1-year mortality in patients in hospital. Design, setting, participants, & measurements This is a single-center cohort study. All adult patients who were hospitalized from years 2011 through 2013 who had available admission serum sodium and at least three serum sodium measurements during hospitalization were included. The trend of serum sodium during hospitalization was analyzed using group-based trajectory modeling; the five main trajectories were grouped as follows: ( 1 ) stable normonatremia, ( 2 ) uncorrected hyponatremia, ( 3 ) borderline high serum sodium, ( 4 ) corrected hyponatremia, and ( 5 ) fluctuating serum sodium. The outcome of interest was in-hospital mortality and 1-year mortality. Stable normonatremia was used as the reference group for outcome comparison. Results A total of 43,539 patients were analyzed. Of these, 47% had stable normonatremia, 15% had uncorrected hyponatremia, 31% had borderline high serum sodium, 3% had corrected hyponatremia, and 5% had fluctuating serum sodium trajectory. In adjusted analysis, there was a higher in-hospital mortality among those with uncorrected hyponatremia (odds ratio [OR], 1.33; 95% CI, 1.06 to 1.67), borderline high serum sodium (OR, 1.66; 95% CI, 1.38 to 2.00), corrected hyponatremia (OR, 1.50; 95% CI, 1.02 to 2.20), and fluctuating serum sodium (OR, 4.61; 95% CI, 3.61 to 5.88), compared with those with the normonatremia trajectory. One-year mortality was higher among those with uncorrected hyponatremia (hazard ratio [HR], 1.28; 95% CI, 1.19 to 1.38), borderline high serum sodium (HR, 1.18; 95% CI, 1.11 to 1.26), corrected hyponatremia (HR, 1.24; 95% CI, 1.08 to 1.42), and fluctuating serum sodium (HR, 2.10; 95% CI, 1.89 to 2.33) compared with those with the normonatremia trajectory. Conclusions More than half of patients who had been hospitalized had an abnormal serum sodium trajectory during hospitalization. This study demonstrated that not only the absolute serum sodium levels but also their in-hospital trajectories were significantly associated with in-hospital and 1-year mortality. The highest in-hospital and 1-year mortality risk was associated with the fluctuating serum sodium trajectory. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_03_25_CJN.12281019.mp3

Objectives The objective of this study was to evaluate the risk of acute respiratory failure in all hospitalised patients based on admission serum ionised calcium. Design A retrospective cohort study. Setting A tertiary referral hospital in Rochester, Minnesota, USA. Participants All hospitalised patients who had serum ionised calcium measurement within 24 hours of hospital admission from January 2009 to December 2013. Patients who were mechanically ventilated at admission were excluded. Predictors Admission serum ionised calcium levels was stratified into six groups: ≤4.39, 4.40–4.59, 4.60–4.79, 4.80–4.99, 5.00–5.19 and ≥5.20 mg/dL. Primary outcome measure The primary outcome was the development of acute respiratory failure requiring mechanical ventilation during hospitalisation. Logistic regression analysis was fit to assess the independent risk of acute respiratory failure based on various admission serum ionised calcium, using serum ionised calcium of 5.00–5.19 mg/dL as the reference group. Results Of 25 709 eligible patients, with the mean serum ionised calcium of 4.8±0.4 mg/dL, acute respiratory failure requiring mechanical ventilation occurred in 2563 patients (10%). The incidence of acute respiratory failure was lowest when admission serum ionised calcium was 5.00–5.19 mg/dL, with the progressively increased risk of acute respiratory failure with decreased serum ionised calcium. In multivariate analysis with adjustment for potential confounders, the increased risk of acute respiratory failure requiring mechanical ventilation was significantly associated with admission serum ionised calcium of ≤4.39 (OR 2.52; 95% CI 2.12 to 3.00), 4.40–4.59 (OR 1.76; 95% CI 1.49 to 2.07) and 4.60–4.79 mg/dL (OR 1.48; 95% CI 1.27 to 1.72), compared with serum ionised calcium of 5.00–5.19 mg/dL. The risk of acute respiratory failure was not significantly increased when serum ionised calcium was at least 4.80 mg/dL. Conclusion The increased risk of acute respiratory failure requiring mechanical ventilation was observed when admission serum ionised calcium was lower than 4.80 mg/dL in hospitalised patients.

7536 Background: While most patients (pts) with follicular lymphoma (FL) achieve an initial response to treatment, the majority relapse. Recently, Goldman et al. reported that surveillance imaging (SI) in FL is not associated with improved post-relapse outcomes and is frequently associated with false positive scans (ASH 2017). The goal of this study was to validate these findings. Methods: Pts were enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER), a prospective cohort of newly diagnosed lymphoma pts. All pts were followed for events including relapse, re-treatment, and death, with events verified by medical records. Pts eligible for this study had biopsy proven FL grade 1, 2, or 3a who had achieved a response after induction therapy and later relapsed. Initial and post-treatment management was per treating physician. Medical records were re-reviewed in pts with events for clinical details at relapse in relationship to planned follow-up visits and SI. Relapse detection was categorized either by clinical suspicion (CS) via history, exam, and/or labs; or by SI in an asymptomatic pt. Univariate survival analysis was conducted for each variable. The hazard ratio with 95% confidence interval based on Cox Proportional Hazard models was presented along with the log rank test p-value. Kaplan-Meier plots were produced to evaluate the difference in overall survival (OS) between groups. Results: 1121 FL pts were enrolled in MER from 2002-2015, of which 117 were eligible. Median age at diagnosis was 60 years (range 35-83), and 61% were men. Median time to relapse of the 117 pts was 26 months (range 9-125). At a median follow-up from relapse of 69 months (range 0.23-179), 26 pts died. Pts completed a median of 3 imaging studies (range 0-15) during post-induction surveillance. 63 relapses (56%) were detected based on CS; 50 (44%) were detected by SI; and 4 were unknown. There was no difference in OS from relapse for those with relapse detected via CS vs. SI (HR = 0.98 [0.45,2.12], p = 0.96). Conclusions: Routine SI does not appear to improve survival outcomes in FL after achieving first remission, and its common practice should be questioned. Further investigation of prognostic markers to identify high-risk FL pts who may benefit from SI is needed.

Context.— As pharmacogenetic testing is incorporated into routine care, it is essential for laboratories to provide accurate and consistent results. Certified laboratories must successfully complete proficiency testing. Objectives.— To understand and examine trends in participation and performance of laboratories participating in the College of American Pathologists pharmacogenetic proficiency testing surveys. Design.— Results from College of American Pathologists pharmacogenetic proficiency testing challenges from 2012 through 2017 were reviewed for concordance with expected genotype and phenotype for each sample (intended responses). Results.— Laboratories correctly reported results for 96.7% to 100% of samples with no variants. Excluding CYP2D6, laboratories correctly detected and reported variant alleles for each gene (93.7%–99.2% correct). CYP2D6 showed lower concordance, with 83.1% of laboratories reporting the intended genotype across all samples; however, in many cases, the laboratories that did not report a variant allele did not test for that allele. Among laboratories reporting the intended genotype, most successfully reported the intended phenotype (85.9%–99.0%). Conclusions.— Although laboratories are generally performing well, there is room for additional improvement, particularly for challenging genes, such as CYP2D6. Efforts in the field of pharmacogenomics to recommend alleles that should be included in clinical tests, identify reference materials, and standardize translation from genotype to phenotype may address some of the remaining variability in results.