Citations

PURPOSE To evaluate the effects of daratumumab, lenalidomide, and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) on patient-reported outcomes (PROs) in the phase III MAIA study. PATIENTS AND METHODS PROs were assessed on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item and the EuroQol 5-dimensional descriptive system at baseline and every 3 months during treatment. By mixed-effects model, changes from baseline are presented as least squares means with 95% CIs. RESULTS A total of 737 transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma were randomly assigned to D-Rd (n = 368) or Rd (n = 369). Compliance with PRO assessments was high at baseline (> 90%) through month 12 (> 78%) for both groups. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item global health status scores improved from baseline in both groups and were consistently greater with D-Rd at all time points. A global health status benefit was achieved with D-Rd, regardless of age (< 75 and ≥ 75 years), baseline Eastern Cooperative Oncology Group (ECOG) performance status score, or depth of response. D-Rd treatment resulted in significantly greater reduction in pain scores as early as cycle 3 ( P = .0007 v Rd); the magnitude of change was sustained through cycle 12. Reductions in pain with D-Rd were clinically meaningful in patients regardless of age, ECOG status, or depth of response. Similarly, PRO improvements were observed with D-Rd and Rd on the EuroQol 5-dimensional descriptive system visual analog scale score. CONCLUSION D-Rd compared with Rd was associated with faster and sustained clinically meaningful improvements in PROs, including pain, in transplant-ineligible patients with newly diagnosed multiple myeloma regardless of age, baseline ECOG status, or depth of treatment response.

AbstractAlthough it is well established that human cytochrome P450 1 family enzymes are induced by cigarette smoking through activation of the Ah receptor, it is not known whether this leads to increased metabolic activation or detoxification of carcinogenic polycyclic aromatic hydrocarbons (PAH), which are present in cigarette smoke and the general environment. We gave oral doses of deuterated phenanthrene ([D10]Phe), a non-carcinogenic surrogate of carcinogenic PAH such as benzo[a]pyrene, to smokers (N = 170, 1 or 10 μg doses) and non-smokers (N = 57, 1 μg dose). Bioactivation products (dihydrodiol and tetraol) and detoxification products (phenols) of [D10]Phe were determined in 6-h urine to obtain a comprehensive metabolic profile. Cigarette smoking increased the bioactivation of [D10]Phe and decreased its detoxification resulting in significantly different metabolic patterns between smokers and non-smokers (P &lt; 0.01), consistent with increased cancer risk in smokers. The Phe bioactivation ratios ([D10]PheT/total [D9]OHPhe) were significantly higher (2.3 (P &lt; 0.01) to 4.8 (P &lt; 0.001) fold) in smokers than non-smokers. With solid human in vivo evidence, our results for the first time demonstrate that cigarette smoking enhances the metabolic activation of Phe, structurally representative of carcinogenic PAH, in humans, strongly supporting their causal role in cancers caused by smoking. The results suggest potential new methods for identifying smokers who could be at particularly high risk for cancer.

Disrupted nucleocytoplasmic transport (NCT) has been implicated in neurodegenerative disease pathogenesis; however, the mechanisms by which disrupted NCT causes neurodegeneration remain unclear. In a Drosophila screen, we identified ref(2)P/p62 , a key regulator of autophagy, as a potent suppressor of neurodegeneration caused by the GGGGCC hexanucleotide repeat expansion (G4C2 HRE) in C9orf72 that causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that p62 is increased and forms ubiquitinated aggregates due to decreased autophagic cargo degradation. Immunofluorescence and electron microscopy of Drosophila tissues demonstrate an accumulation of lysosome-like organelles that precedes neurodegeneration. These phenotypes are partially caused by cytoplasmic mislocalization of Mitf/TFEB, a key transcriptional regulator of autophagolysosomal function. Additionally, TFEB is mislocalized and downregulated in human cells expressing GGGGCC repeats and in C9-ALS patient motor cortex. Our data suggest that the C9orf72 -HRE impairs Mitf/TFEB nuclear import, thereby disrupting autophagy and exacerbating proteostasis defects in C9-ALS/FTD.

Introduction: During the COVID-19 pandemic, hospitals across the globe have been challenged with following the chain of survival with Get With The Guidelines (GWTG) metrics of time to epinephrine, CPR and early defibrillation while ensuring resuscitation teams are protected with recommended PPE. Healthcare organizations are seeking innovative processes to implement PPE during resuscitation events (codes) while maintaining a timely response. Hypothesis: Utilization of for PPE for Airborne Precautions for all resuscitation events can be achieved without compromising patient outcomes or GWTG metrics. Methods: In collaboration with Infection Prevention and Control (IPAC), the Resuscitation Subcommittee at an academic medical center developed a modified airborne PPE workflow for both inpatient and outpatient resuscitation events. For staff safety, all patients are considered as COVID-19 positive during a code response. Identifying timely donning and doffing techniques of PPE as paramount for maintaining GWTG metrics, a Safety Officer was implemented as an additional member of the code team. The role of the Safety Officer is to assist with the PPE process and to monitor code team compliance. Other measures implemented included attaching PPE supply bags to all code carts for easy access, adding viral filters on the bag valve masks, conducting educational mock code events, and providing online resources for staff. To measure process outcomes, pre COVID-19 pandemic GWTG metrics, mortality, and survival to discharge rates were compared with COVID-19 metrics utilizing the modified airborne PPE workflow. Conclusions: Despite additional use of PPE, the hospital has maintained patient outcomes and adhered to the GWTG resuscitation measures of time to epinephrine, CPR and defibrillation while ensuring the utmost safety of the code team during the COVID-19 pandemic. Table 1: GWTG-Award Measures *Preliminary Results

Background. Acral melanoma (AM) is a rare subtype of melanoma, which is one of the least common in Caucasian patients but is a common subtype of melanoma in Chinese patients. It is unclear if prognosis differs between Chinese and Caucasian patients diagnosed with AM. The aim of our study is to investigate patient characteristics and survival differences between Chinese and Caucasian AM patients. Methods. Two large institutional melanoma databases from Fudan University Shanghai Cancer Center (FUSCC) and Mayo Clinic enterprise were retrospectively reviewed from 2009 to 2015. Clinicopathologic and survival data were collected and analyzed between the two groups. The primary outcome was disease-specific survival (DSS) and was calculated using the Kaplan Meier (KM) method. Results. The Chinese group presented with more advanced disease compared with Caucasians: thicker Breslow depth (median 3.0 mm vs. 1.2 mm, p = 0.003 ), more ulcerated disease (66.1% vs. 29%; p < 0.001 ), and advanced stages (stage II/III 84.3% vs. 37.1%; p < 0.001 ). No significant difference was identified in terms of age at diagnosis, location, histologic subtypes, or node positive rate. The 5-year DSS rate was 68.4% and 73% ( p = 0.56 ) in Chinese and Caucasians AM patients, respectively. Male gender, Breslow thickness, ulceration, and positive sentinel lymph nodes were independent poor prognostic factors on multivariate analysis. Conclusions. There appears to be no difference in stage-stratified survival between Chinese and Caucasians, supporting the implementation of clinical trials for AM that could include both Chinese and Caucasian patients.

Abstract Background: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome. Methods: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case–Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data. Results: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98–1.02; arachidonic acid OR = 1.00, 95% CI = 0.99–1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87–1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex. Conclusions: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk. Impact: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.

BackgroundRenal fibrosis is a common pathway in tubulointerstitial injury and a major determinant of renal insufficiency. Collagen deposition, a key feature of renal fibrosis, may serve as an imaging biomarker to differentiate scarred from healthy kidneys.PurposeTo test the feasibility of using quantitative magnetization transfer (qMT), which assesses tissue macromolecule content, to measure renal fibrosis.Study TypeProspective.Animal ModelFifteen 129S1 mice were studied 4 weeks after either sham (n = 7) or unilateral renal artery stenosis (RAS, n = 8) surgeries.Field Strength/SequenceMagnetization transfer (MT)‐weighted images were acquired at 16.4T using an MT‐prepared fast‐low‐angle‐shot sequence. Renal B0, B1, and T1 maps were also acquired, using a dual‐echo gradient echo, an actual flip angle, and inversion recovery method, respectively.AssessmentA two‐pool model was used to estimate the bound water fraction (f) and other tissue imaging biomarkers. Masson's trichrome staining was subsequently performed ex vivo to evaluate renal fibrosis.Statistical TestsComparisons of renal parameters between sham and RAS were performed using independent samples t‐tests. Pearson's correlation was conducted to investigate the relationship between renal fibrosis by histology and the qMT‐derived bound pool fraction f.ResultsThe two‐pool model provided accurate fittings of measured MT signal. The qMT‐derived f of RAS kidneys was significantly increased compared to sham in all kidney zones (renal cortex [CO], 7.6 ± 2.4% vs. 4.6 ± 0.6%; outer medulla [OM], 8.2 ± 4.2% vs. 4.2 ± 0.9%; inner medulla [IM] + P, 5.8 ± 1.6% vs. 2.9 ± 0.6%, all P < 0.05). Measured f correlated well with histological fibrosis in all kidney zones (CO, Pearson's correlation coefficient r = 0.95; OM, r = 0.93; IM + P, r = 0.94, all P < 0.05).Data ConclusionThe bound pool fraction f can be quantified using qMT at 16.4T in murine kidneys, increases significantly in fibrotic RAS kidneys, and correlates well with fibrosis by histology. Therefore, qMT may constitute a valuable tool for measuring renal fibrosis in RAS.Level of Evidence1Technical Efficacy Stage3

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of most lethal malignancies with few known risk factors and biomarkers. Identification of disease biomarkers is critical for understanding the pathogenesis of this cancer and identifying high risk individuals for close surveillance. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of biomarkers usually in small samples. To identify novel circulating protein biomarkers of PDAC, we studied 8,280 cases and 6,728 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium, by using genetic instruments. Protein quantitative trait loci (pQTLs) for 1,226 plasma proteins identified in a large INTERVAL study of 3,301 healthy European descendants were used as instruments to evaluate associations between genetically predicted protein levels and PDAC. For proteins showing a significant association, we further conducted conditional analysis with adjustments for previously identified risk variants to assess whether the observed associations between genetically predicted protein concentrations and PDAC risk were independent of the risk variants identified in genome-wide association studies (GWAS). Furthermore, for the proteins that were associated with PDAC risk, we performed an enrichment analysis of the genes encoding these proteins to examine whether they are enriched in specific pathways, functions or networks. We observed associations between predicted concentrations of 38 proteins and PDAC risk at a false discovery rate of &lt; 0.05, including those of 23 proteins that showed a significant association even after Bonferroni correction (4.08 × 10−5). These include Histo-blood group ABO system transferase encoded by ABO, which has been previously implicated as a potential target gene of PDAC risk variant identified in GWAS. Eight of the identified proteins (Beta-crystallin B2, Dedicator of cytokinesis protein 9, VIP36-like protein, Erythrocyte band 7 integral membrane protein, Tensin-2, Transmembrane protease serine 11D, Alcohol dehydrogenase 1B, and C-X-C motif chemokine 10) were associated with PDAC risk after conditioning on previously reported pancreatic cancer risk variants (odds ratios ranged from 0.79 to 1.52, P-values from 1.28 × 10−3 to 6.47 × 10−4). Pathway enrichment analysis showed that the encoding genes for the implicated proteins were significantly enriched in cancer-related pathways, such as STAT3 and IL-15 production. In conclusion, we identified 38 protein biomarker candidates for PDAC risk, which if validated by additional studies, may contribute to the etiological understanding of PDAC tumor development. Citation Format: Jingjing Zhu, Xiang Shu, Xingyi Guo, Duo Liu, Jiandong bao, Roger Milne, Graham G Giles, Chong Wu, Mengmeng Du, Emily White, Harvey A Risch, Nuria Malats, Eric J. Duell, Phyllis J. Goodman, Donghui Li, Paige Bracci, Verena Katzke, Rachel E Neale, Steven Gallinger, Stephen Van Den Eeden, Alan Arslan, Federico Canzian, Charles Kooperberg, Brian Wolpin, Laura Beane-Freeman, Ghislaine Scelo, Kala Visvanatha, Christopher A. Haiman, Loïc Le Marchand, Herbert Yu, Gloria M Petersen, Rachael Stolzenberg-Solomon, Alison P Klein, Laufey T Amundadottir, Qiuyin Cai, Jirong Long, Xiao-Ou Shu, Wei Zheng, Lang Wu. Associations between genetically predicted blood protein biomarkers and pancreatic ductal adenocarcinoma risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1200.