Citations

Liver biopsy remains the gold standard for the histological assessment of the liver. With clear disadvantages and the rise in the incidences of liver disease, the role of neoadjuvant chemotherapy in colorectal liver metastasis (CRLM) and an explosion of surgical management options available, non-invasive serological and imaging markers of liver histopathology have never been more pertinent in order to assess liver health and stratify patients considered for surgical intervention. Liver MRI is a leading modality in the assessment of hepatic malignancy. Recent technological advancements in multiparametric MRI software such as the LiverMultiScanTM offers an attractive non-invasive assay of anatomy and histopathology in the pre-operative setting, especially in the context of CRLM. This narrative review examines the evidence for the LiverMultiScanTM in the assessment of hepatic fibrosis, steatosis/steatohepatitis, and potential applications for chemotherapy-associated hepatic changes. We postulate its future role and the hurdles it must surpass in order to be implemented in the pre-operative management of patients undergoing hepatic resection for colorectal liver metastasis. Such a role likely extends to other hepatic malignancies planned for resection.

Abstract Introduction People with heart failure (HF) have frequent hospitalizations, and emergency department (ED) visits. We examined the effects of insomnia and rest-activity rhythms (RARs) on time to hospitalizations and ED visits after controlling for other known risk factors among participants in a randomized controlled trial of cognitive behavioral therapy for insomnia compared to heart failure self-management education (attention control). Methods The analysis included 168 HF patients who had available medical records for dates of hospitalization, ED visit, transplant, and death from a randomized clinical trial for insomnia of people with HF and insomnia. The known risk factors included age, sex, New York Heart Association (NYHA) Class, ejection fraction, and comorbid conditions. We used the insomnia severity index (ISI) and evaluated the strength of RAR using the ratio of the amplitude to the MESOR estimated with cosinor analysis with activity counts from a wrist-actigraph worn for at least five consecutive days. Cox proportional hazard models were used to examine ­insomnia and the RAR metrics with the known risk factors on time to first hospitalization, ED visit, transplant, and death. Results Eighty-five (50.1%) had at least one hospitalization, and ninety-one (54.2%) participants had an ED visit. Approximately 42% of the participants were admitted to the hospital due to cardiac events. Older age, male sex, higher NYHA, and greater comorbidity were associated with earlier hospitalization or ED visits. After controlling for those risk factors, stronger RAR was associated with later time to hospitalization, and ED visit with hazard ratios (HRs) of 0.26 (95% CI=[0.07, 0.91]) and 0.25 (95% CI=[0.07, 0.89]); higher insomnia severity (ISI ≥22) was associated with shorter time to ED visits, with an HR of 2.28 (95% CI=[1.19, 4.38]). Conclusion In addition to known demographic and clinical risk factors, insomnia severity and RAR predict hospitalizations and ED visits in people with HF. Further research is necessary to assess the biological mechanism of the associations and examine whether the effects of the risk factors could be modified by improving insomnia severity and RAR in people with HF. Support (if any) This study was financially supported by grants R01NR016191 and P20NR014126 from NIH/NINR.

Abstract Introduction Cognitive behavioral therapy for insomnia (CBT-I) improves individual symptoms of fatigue and daytime sleepiness; however, little is known how CBT-I improves multiple co-occurring daytime symptoms. The purposes of this study are to (1) identify daytime symptom trajectories in adults with insomnia and stable chronic heart failure (HF) over one year, and (2) determine how symptom trajectories vary based on participation in CBT-I or HF self-management education (attention control condition). Methods We conducted a retrospective analysis of data from a randomized controlled trial that looked the sustained effects of CBT-I compared to HF self-management over one year (NCT02660385). We measured daytime symptoms (fatigue, depression, anxiety, dyspnea, pain, and daytime sleepiness) at baseline (pre-treatment) and 3, 6 and 12 months. Symptom cluster trajectory were identified using group-based trajectory modeling, and the association with CBT-I was examined using logistic regressions. Results We randomized 175 participants (M age=63.0 (12.9) years, 57% men). We found four daytime symptom cluster trajectories, (A) low improving symptoms (N = 67, 38.3%); (B) low psychological symptoms and high improving physical symptoms (N = 40, 22.8%); (C), high improving symptoms (N = 42, 24.0%); and (D) high not improving symptoms (N = 26, 14.9%). There was no statistically significant difference between CBT-I and HF self-management across 4 symptom trajectories (p = .2509). However, people who received CBT-I vs. HF self-management education had higher odds of belonging to trajectory A compared to B/C/D after controlling for baseline fatigue (OR = 3.27 95% Confidence Intervals [1.39, 7.68]). Conclusion Most participants experienced improved daytime symptom profiles over 12 months after both interventions. Participants in the CBT-I group experienced symptom improvement even when they started with low symptoms. Support (if any) National Institute of Nursing Research [R01NR016191 and P20NR014126].

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

Abstract Objective: Aberrantly methylated DNA may be used to detect minimal residual disease or early recurrence in breast cancer. As a 1st step, we aimed to develop an MDM panel to delineate between healthy women, stage I-III breast cancer in remission with no evidence of disease (NED), and metastatic breast cancer (MBC). Methods: We prospectively enrolled patients into 3 groups: healthy controls (adult females with a normal mammogram in past 12 months with no history of breast cancer), NED [stage I-III breast cancer with no clinical evidence of recurrence 6 months - 3 years post-treatment (adjuvant endocrine therapy allowed)], and MBC (collected either at initial diagnosis of untreated metastatic disease or radiographic progression). DNA was extracted from 6 mL of plasma derived from blood collected in LBgard tubes (Exact Sciences Corp., San Diego CA), and was bisulfite-treated and assayed by target enrichment long-probe quantitative amplified signal (TELQASTM) method for a panel of 15 previously identified MDMs [Table], normalized by the control gene, B3GALT6. Areas under the receiver operating characteristic curve (AUC) were calculated for each MDM to assess discrimination of MBC from other groups. With 60 patients per group, we had greater than 80% power to detect a difference of 0.20 from the null AUC of 0.7. Results: We tested samples from 60 MBC (10 untreated, 50 recurrent), 60 NED, and 60 healthy women. The median age was 63 (IQR, 55-72) and was not different between groups. The NED group was all hormone-receptor (HR) positive, with 47 (78%) being human epidermal growth factor receptor 2 negative (HER2-) and 13 (22%) HER2+; 48 (80%) were stage I and 9 (15%) were N+. The MBC group had 35 (58%) patients with HR+/HER2- tumors, 11 (18%) HR+/HER2+, and 6 (10%) HR-/HER2-, 4 (7%) HR-/HER2+, with 4 (7%) unknown. Of the 41 MBC whose original stage and nodal status were known 9 (22%) were stage I and 22 (54%) were N+. The markers were able to discriminate between MBC and NED patient samples with AUCs from 0.97 to 0.72. AUCs for 10/15 MDMs (ITPRIPL1, EMX1, C17orf64, OSR2, TRIM67, CHST2, IFFO1, TRH, FAM59B, and MPZ) were >0.90. No difference in MDMs was observed between the healthy and NED groups. Conclusions: MDMs, assayed from plasma, appear highly discriminant for metastatic breast cancer cases in comparison to control patients with NED or healthy controls. Further clinical validation of this MDM panel in a larger cohort is warranted. Table 1. Plasma MDM discrimination of metastatic breast cancer (MBC) from healthy controls and previously treated breast cancer patients with no evidence of disease (NED) Citation Format: Karthik V. Giridhar, Fergus J. Couch, Jason P. Sinnwell, Seth W. Slettedahl, William R. Taylor, Douglas W. Mahoney, Patrick H. Foote, Maria C. O’Connell, Mariah J. Robran, Mary E. Devens, Anna M. Gonser, Nicole Larson, Karen A. Doering, Kelli N. Burger, Michael Kaiser, Hatim Allawi, Kathryn Ruddy, Janet Olson, John B. Kisiel. Plasma assay of methylated DNA markers (MDM) detects patients with metastatic breast cancer (MBC) compared to healthy controls and treated breast cancer patients with no evidence of disease [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-06.