Citations

Abstract Aims To evaluate sex-specific disparities in acute kidney injury (AKI) complicating acute myocardial infarction-related cardiogenic shock (AMI-CS) in the United States. Methods and results This was a retrospective cohort study from 2000 to 2014 from the National Inpatient Sample (20% sample of all hospitals in the United States). Patients >18 years admitted with a primary diagnosis of AMI and concomitant CS that developed AKI were included. The endpoints of interest were the prevalence, trends, and outcomes of men and women with AKI in AMI-CS. Multivariable hierarchical logistic regression was used to control for confounding, and a two-sided P < 0.05 was considered statistically significant. During this 15 year period, 440 257 admissions with AMI-CS met the inclusion criteria, with AKI noted in 155 610 (35.3%). Women constituted 36.3% of the cohort and were older, of non-White race, and with higher co-morbidity compared with men. Women with AKI less often received coronary angiography (59% vs. 66%), percutaneous coronary intervention (39% vs. 43%), mechanical circulatory support (39% vs. 48%), mechanical ventilation (49% vs. 54%), and haemodialysis (9% vs. 10%) compared with men (all P < 0.001). Adjusted in-hospital mortality was higher in women—odds ratio 1.16 (95% confidence interval 1.14–1.19); P < 0.001—compared with men. Women had shorter lengths of stay (12 ± 14 vs. 13 ± 14 days), lower hospital costs ($150 071 ± 180 796 vs. $181 260 ± 209 674), and were less often discharged to home (19% vs. 31%) (all P < 0.001). Conclusions Women with AKI in AMI-CS received fewer cardiac and non-cardiac interventions, had higher in-hospital mortality, and were less often discharged to home compared with men.

Colorectal cancer (CRC) is the third most frequent neoplastic disorder and is a main cause of tumor-related mortality, as many patients progress to stage IV metastatic CRC. Standard care consists of combination chemotherapy (FOLFIRI or FOLFOX). Patients with WT KRAS typing are eligible to receive anti-EGFR therapy combined with chemotherapy. Unfortunately, predicting efficacy of CRC anti-EGFR therapy has remained challenging. Here we uncovered that the EGFR pathway component RasGRP1 acts as a CRC tumor suppressor in the context of aberrant Wnt signaling. We found that RasGRP1 suppresses EGF-driven proliferation of colonic epithelial organoids. Having established that RasGRP1 dosage levels impact biology, we next focused on CRC patients. Mining 5 different data platforms, we establish that RasGRP1 expression levels decrease with CRC progression and predict poor clinical outcome of patients. Last, deletion of 1 or 2 Rasgrp1 alleles made CRC spheroids more susceptible to EGFR inhibition. Retrospective analysis of the CALGB 80203 clinical trial showed that addition of anti-EGFR therapy to chemotherapy significantly improved outcome for CRC patients when tumors expressed low levels of RasGRP1 suppressor. In sum, our data support RasGRP1 as a biomarker in the EGFR pathway that has potential relevance to anti-EGFR therapy for CRC patients.

Abstract Purpose: Young age has been shown to be an independent predictor of poor outcome in breast cancer. In HER2-positive breast cancer, the effects of aging remain largely unknown. Experimental Design: A total of 4,547 patients were included [3,132 from North Central Cancer Treatment Group (NCCTG) N9831 and 1,415 from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31]. Pathologic stromal tumor-infiltrating lymphocyte (sTIL) and molecular tumor infiltrating lymphocyte (mTIL) signatures were evaluated. Results: In NCCTG N9831, comparable benefit of trastuzumab was observed in all patients [age ≤ 40; HR, 0.43; 95% confidence interval (CI), 0.28–0.66; P < 0.001; and age > 40; HR, 0.56; 95% CI, 0.45–0.69; P < 0.001]. Similar results were observed in NSABP B-31 (age ≤ 40; HR, 0.45; 95% CI, 0.29–0.68; P < 0.001; and age > 40; HR, 0.42; 95% CI, 0.33–0.54; P < 0.001). Among patients who received chemotherapy alone, younger age was associated with poor outcome in the hormone receptor–positive subset, but not the hormone receptor–negative subset, in both trials. Although there was no association between sTILs and age, a small, but significant increase in mTIL CD45 and some immune subset signatures were observed. Among patients who received chemotherapy alone, patients over 40 years of age with lymphocyte-predominant breast cancer had excellent outcome, with 95% remaining recurrence free at 15 years. Conclusions: Among patients treated with trastuzumab, there was no significant difference in outcome related to age. Our study suggests that trastuzumab can negate the poor prognosis associated with young age.

Abstract Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

Sepsis continues to be a leading cause of mortality and morbidity in the intensive care unit. Cardiovascular dysfunction in sepsis is associated with worse short- and long-term outcomes. Sepsis-related myocardial dysfunction is noted in 20%–65% of these patients and manifests as isolated or combined left or right ventricular systolic or diastolic dysfunction Echocardiography is the most commonly used modality for the diagnosis of sepsis-related myocardial dysfunction. With the increasing use of ultrasonography in the intensive care unit, there is a renewed interest in sepsis-related myocardial dysfunction. This review summarises the current scope of literature focused on sepsis-related myocardial dysfunction and highlights the use of basic and advanced echocardiographic techniques for the diagnosis of sepsis-related myocardial dysfunction and the management of sepsis and septic shock.