Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?
In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.
AbstractThe ability to accurately differentiate treatment-related changes (ie, pseudoprogression and radiation necrosis) from recurrent glioma remains a critical diagnostic problem in neuro-oncology. Because these entities are treated differently and have vastly different outcomes, accurate diagnosis is necessary to provide optimal patient care. In current practice, this diagnostic quandary commonly requires either serial imaging or histopathologic tissue confirmation. In this article, experts in the field debate the utility of 2-deoxy-2[18F]fluoro-d-glucose positron emission tomography (FDG PET) as an imaging tool to distinguish tumor recurrence from treatment-related changes in a patient with glioblastoma and progressive contrast enhancement on magnetic resonance (MR) following chemoradiotherapy.
Garetosmab Reduces Flare-ups in Patients With Fibrodysplasia Ossificans Progressiva
Abstract Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, autosomal dominant disorder driven by mutations in ACVR1 that render it responsive to Activin A. FOP is characterized by progressive heterotopic ossification (HO) and distressing inflammatory events called “flare-ups.” Flare-ups can precede new HO; however, limited prospective data exists on this phenomenon. Garetosmab (GAR), an investigational human monoclonal antibody against Activin A, blocks formation of new HO in FOP. Methods: This is a post-hoc analysis of LUMINA-1 (NCT03188666) a phase 2, randomized, double-blind, placebo-controlled study, which evaluated the safety and efficacy of GAR (10 mg/kg/week IV) versus placebo (PBO) in adult patients with FOP over 28 weeks. Patient-reported flare-ups were collected via a patient diary and severity level was reported as mild, moderate or severe. Clinician-reported flare-ups were collected as adverse events in the trial. HO lesions were imaged by 18F-NaF positron emission tomography (PET) and whole-body low-dose X-ray computed tomography (CT). Results: There was a two-fold higher proportion of patients who reported one or more flare-ups on PBO 17/24 (71%) compared with GAR 7/20 (35%). Clinicians reported a four-fold higher proportion of patients experiencing one or more flare-ups on PBO 10/24 (42%) compared with GAR 2/20 (10%). Overall rates of flare-up events were two-fold higher on PBO vs. GAR (1.4 vs. 0.65 events/patient/28 weeks) for patient-reported events and eight-fold higher on PBO vs. GAR by clinician report (0.83 vs. 0.10 events/patient/28 weeks). Most flare-ups occurred on the extremities and back; pain was the most commonly reported symptom. Patient-reported flare-ups on PBO were more frequently reported as severe (29.4%) compared with GAR (7.7%). Among subjects with at least 12 weeks of follow-up from start of patient-reported flare-up, development of new HO near the site was 5/27 (18.5%) on PBO and (0%) on GAR. Of all new HO lesions, 41% on PBO and 0% on GAR occurred with spatial and temporal relation to flare-up. Conclusions: Approximately two-thirds of patients on PBO reported flare-ups over 28 weeks. GAR was associated with reductions in frequency and severity of flare-ups. Fewer than 20% of patient-reported flare-ups were associated with new HO, indicating frequent discordance of these phenomena, and compatible with previous reports. GAR’s ability to reduce patient- and clinician-reported flare-ups, as well as new HO lesions may provide an important therapeutic option.
Soluble CD163 Identifies Those at Risk for Increased Hepatic Inflammation & Fibrosis
Abstract Background Liver disease remains a significant cause of morbidity and mortality in HIV-infected persons. Soluble CD163 is a marker of Kupffer cell activation that is highly associated with development of hepatic fibrosis. The relative contributions of HIV-associated systemic immune activation vs other etiologies of injury are poorly characterized. Methods We utilized subjects in the Miami Adult Studies on HIV (MASH) cohort to evaluate 464 participants including 361 people with HIV (PWH) and 103 hepatitis C virus (HCV)/HIV-uninfected controls. Subjects underwent testing for hepatic fibrosis using both magnetic resonance elastography and the Enhanced Liver Fibrosis Index. Steatosis was evaluated by magnetic resonance imaging–derived proton density fat fraction. Immune activation markers and cytokines were quantitated using Luminex methodologies. Results Participants with HIV with or without HCV coinfection had higher levels of sCD163 than uninfected controls (P < .05). Soluble sCD163 was highly associated with elevated alanine aminotransferase, a key marker of inflammation/injury and with hepatic fibrosis. Hepatic steatosis was also associated with a cytokine pattern suggestive of Kupffer cell activation but was not associated with an increase in sCD14 or sCD27. Conclusions Injury and resultant hepatic fibrosis occur by distinct though overlapping mechanistic pathways. In PWH, sCD163 is highly associated with both injury and fibrosis, suggesting that persistent systemic immune activation is a major contributor to long-term outcomes, adding to damage caused by alcohol, steatosis, and other hepatotoxic drug effects.
Health-Related Quality of Life and Pain with Selinexor in Patients with Advanced Dedifferentiated Liposarcoma
Metabolic reprogramming, which is characteristic of cancer cells that rapidly adapt to the hypoxic microenvironment and is crucial for tumor growth and metastasis, is recognized as one of the major mechanisms underlying therapeutic resistance. Mitochondria, which are directly involved in metabolic reprogramming, are used to design novel mitochondria-targeted anticancer agents. Despite being targeted by melatonin, the functional role of mitochondria in melatonin’s oncostatic activity remains unclear. In this study, we aim to investigate the role of melatonin in mitochondrial metabolism and its functional consequences in head and neck cancer. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 100, 500, and 1500 µM of melatonin for 1, 3, and 5 days, and found a connection between a change of metabolism following melatonin treatment and its effects on mitochondria. Our results demonstrate that melatonin induces a shift to an aerobic mitochondrial metabolism that is associated with changes in mitochondrial morphology, function, fusion, and fission in HNSCC. We found that melatonin increases oxidative phosphorylation (OXPHOS) and inhibits glycolysis in HNSCC, resulting in increased ROS production, apoptosis, and mitophagy, and decreased cell proliferation. Our findings highlight new molecular pathways involved in melatonin’s oncostatic activity, suggesting that it could act as an adjuvant agent in a potential therapy for cancer patients. We also found that high doses of melatonin, such as those used in this study for its cytotoxic impact on HNSCC cells, might lead to additional effects through melatonin receptors.
Amphiregulin Improves Stratification of the Refined Minnesota Acute Graft-Versus-Host Disease Risk Score: Results from BMT CTN 0302/0802
Abstract Introduction: Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand that can restore integrity to damaged intestinal mucosa in murine models of acute graft-versus-host disease (aGVHD). We previously described AREG as a circulating biomarker of late-onset aGVHD, but its relevance combined with clinical risk factors has not yet been tested in a large cohort of patients with aGVHD occurring prior to day 100 post-transplant. We therefore tested samples from two aGVHD first-line treatment trials, Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0302 and 0802, and identified a clinically relevant threshold level of circulating AREG at aGVHD onset. We then investigated whether incorporating AREG into the refined Minnesota Risk Score could further risk-stratify patients. Patients and Methods: Blood samples were obtained at the onset of systemic aGVHD treatment within BMT CTN 0302 (serum) and BMT CTN 0802 (plasma). All patients with response data and samples for analysis from both trials were included (N=251). We determined the association of AREG with clinical outcomes, including risk stratification by the refined Minnesota criteria, day 28 complete/partial response (CR/PR) to first-line therapy, 2-year overall survival (OS) and 6-month and 2-year non-relapse mortality (NRM). We investigated the effect of AREG on clinical endpoints per a doubling in the value of AREG, defined a clinically relevant threshold level in the AREG values using two-fold cross-validation, and confirmed the clinical relevance of this cut-point in independent samples (N=92) from pooled from drawn from the Chronic GVHD Consortium and the Mount Sinai Acute GVHD International Consortium (MAGIC). Results: In patients enrolled in BMT CTN 0302/0802, AREG levels were 1.7-fold higher in patients with Minnesota high-risk (HR) compared to standard-risk (SR) aGVHD (HR median 53.4 vs SR 31 pg/ml, p<0.01). Every 2-fold increase in AREG was associated with a 33% decrease in the likelihood of day 28 CR/PR (odds ratio [OR] 0.67, p<0.01, table). Clinical factors alone, as determined by the refined Minnesota Risk Score, were associated with day 28 CR/PR (p=0.02, table). Adding AREG to the Minnesota Risk Score could further risk-stratify patients. Minnesota SR patients with elevated AREG ≥ 33 pg/mL showed a 59% lower odds of day 28 CR/PR than SR patients with low AREG (OR 0.41, p=0.02). Patients with Minnesota HR aGVHD with AREG ≥ 33 pg/mL had the worst outcomes, with an 82% lower odds of day 28 CR/PR in comparison to HR with low AREG (OR 0.18, p<0.01). High AREG was associated with worse OS and NRM in both Minnesota SR (hazard ratios 2-year OS 2.3, p<0.01 and 6 month NRM 2.95, p=0.01, respectively) and HR patients (hazard ratios 2-year OS 3.35, p<0.01 and 6-month NRM 9.38, p<0.01 respectively, figure). Finally, in independent samples from the Chronic GVHD Consortium/MAGIC we confirmed that high AREG was associated with worse day 28 CR/PR (55.2% vs. 79.4%, p=0.02) and significantly worse 6-month survival after the onset of aGVHD (57.1% vs. 82.5%, p=0.01). Conclusion: AREG is elevated in patients with poor aGVHD outcomes and adds to the accuracy of risk stratification when combined with the refined Minnesota Risk Score. AREG ≥33 pg/mL at aGVHD onset is associated with lower day 28 CR/PR and higher mortality in samples from 4 multicenter cohorts. The mechanism of elevated circulating AREG in severe aGVHD is not yet known, although we hypothesize the degree of AREG elevation reflects the intensity of immune-mediated tissue injury resulting in AREG release. With accumulating evidence of altered EGFR ligands in aGVHD, further investigation into epithelial repair pathways involving AREG may lead to new adjunctive therapies to overcome poor steroid response in high-risk aGVHD. Disclosures Holtan: Incyte: Other: One-time advisory board member. Khera: Novartis: Consultancy. Lee: Mallinckrodt: Honoraria; Amgen: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Kadmon: Other: One-time advisory board member. Chen: Immudex: Research Funding. Arora: Takeda Oncology: Consultancy. Flowers: Pharmacyclics: Consultancy. Cutler: Pfizer: Consultancy; Kite: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Consultancy; Astellas: Consultancy. Jagasia: Janssen: Consultancy, Research Funding; Therakos: Consultancy, Research Funding; Mallinckrodt: Consultancy. Hexner: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Levine: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. MacMillan: Magenta Therapeutics: Research Funding.
Improving the quality of care for patients requiring continuous renal replacement therapy
AbstractContinuous renal replacement therapy (CRRT) is the preferred extracorporeal kidney support therapy employed to support critically ill patients with acute or chronic kidney dysfunction in intensive care units. Significant heterogeneity in CRRT practice exists in part due to variable logistics, resources, and scarcity of evidence‐based CRRT practices. Importantly, homogenization of practice patterns by developing substantial evidence and effective dissemination among providers is essential for optimizing CRRT practices. The emphasis on quality of CRRT delivery has prompted identification of potential quality indicators, development of multifaceted quality improvement initiatives, effective computer science utilization, and a surge of multidisciplinary quality assurance teams that advocate for “best” CRRT practices. This manuscript provides an overview of quality improvement methodologies and reviews candidate quality indicators of CRRT and the impact of quality improvement on enhancing CRRT delivery practices.
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)
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