Critical changes in hypothalamic gene networks in response to pancreatic cancer as found by single-cell RNA sequencing

OBJECTIVE: Cancer cachexia is a devastating chronic condition characterized by involuntary weight loss, muscle wasting, abnormal fat metabolism, anorexia, and fatigue. However, the molecular mechanisms underlying this syndrome remain poorly understood. In particular, the hypothalamus may play a central role in cachexia, given that it has direct access to peripheral signals because of its anatomical location and attenuated blood–brain barrier. Furthermore, this region has a critical role in regulating appetite and metabolism. METHODS: To provide a detailed analysis of the hypothalamic response to cachexia, we performed single-cell RNA-seq combined with RNA-seq of the medial basal hypothalamus (MBH) in a mouse model for pancreatic cancer. RESULTS: We found many cell type-specific changes, such as inflamed endothelial cells, stressed oligodendrocyes and both inflammatory and moderating microglia. Lcn2, a newly discovered hunger suppressing hormone, was the highest induced gene. Interestingly, cerebral treatment with LCN2 not only induced many of the observed molecular changes in cachexia but also affected gene expression in food-intake decreasing POMC neurons. In addition, we found that many of the cachexia-induced molecular changes found in the hypothalamus mimic those at the primary tumor site. CONCLUSION: Our data reveal that multiple cell types in the MBH are affected by tumor-derived factors or host factors that are induced by tumor growth, leading to a marked change in the microenvironment of neurons critical for behavioral, metabolic, and neuroendocrine outputs dysregulated during cachexia. The mechanistic insights provided in this study explain many of the clinical features of cachexia and will be useful for future therapeutic development

Targeting Nrf2 in healthy and malignant ovarian epithelial cells:Protection versus promotion

Risk factors indicate the importance of oxidative stress during ovarian carcinogenesis. To tolerate oxidative stress, cells activate the transcription factor Nrf2 (Nfe2l2), the master regulator of antioxidant and cytoprotective genes. Indeed, for most cancers, hyperactivity of Nrf2 is observed, and siRNA studies assigned Nrf2 as therapeutic target. However, the cancer-protective role of Nrf2 in healthy cells highlights the requirement for an adequate therapeutic window. We engineered artificial transcription factors to assess the role of Nrf2 in healthy (OSE-C2) and malignant ovarian cells (A2780). Successful NRF2 up- and downregulation correlated with decreased, respectively increased, sensitivity toward oxidative stress. Inhibition of NRF2 reduced the colony forming potential to the same extent in wild-type and BRCA1 knockdown A2780 cells. Only in BRCA1 knockdown A2780 cells, the effect of Nrf2 inhibition could be enhanced when combined with PARP inhibitors. Therefore, we propose that this combination therapy of PARP inhibitors and Nrf2 inhibition can further improve treatment efficacy specifically in BRCA1 mutant cancer cells without acquiring the side-effects associated with previously studied Nrf2 inhibition combinations with either chemotherapy or radiation. Our findings stress the dual role of Nrf2 in carcinogenesis, while offering approaches to exploit Nrf2 as a potent therapeutic target in ovarian cancer. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved

Timed up and go test and long-term survival in older adults after oncologic surgery

BACKGROUND: Physical performance tests are a reflection of health in older adults. The Timed Up and Go test is an easy-to-administer tool measuring physical performance. In older adults undergoing oncologic surgery, an impaired TUG has been associated with higher rates of postoperative complications and increased short term mortality. The objective of this study is to investigate the association between physical performance and long term outcomes. METHODS: Patients aged ≥65 years undergoing surgery for solid tumors in three prospective cohort studies, ‘PICNIC’, ‘PICNIC B-HAPPY’ and ‘PREOP’, were included. The TUG was administered 2 weeks before surgery, a score of ≥12 seconds was considered to be impaired. Primary endpoint was 5-year survival, secondary endpoint was 30-day major complications. Survival proportions were estimated using Kaplan-Meier curves. Cox- and logistic regression analysis were used for survival and complications respectively. Hazard ratios (aHRs) and Odds ratios (aOR) were adjusted for literature-based and clinically relevant variables, and 95% confidence intervals (95% CIs) were estimated using multivariable models. RESULTS: In total, 528 patients were included into analysis. Mean age was 75 years (SD 5.98), in 123 (23.3%) patients, the TUG was impaired. Five-year survival proportions were 0.56 and 0.49 for patients with normal TUG and impaired TUG respectively. An impaired TUG was an independent predictor of increased 5-year mortality (aHR 1.43, 95% CI 1.02-2.02). The TUG was not a significant predictor of 30-day major complications (aOR 1.46, 95% CI 0.70-3.06). CONCLUSIONS: An impaired TUG is associated with increased 5-year mortality in older adults undergoing surgery for solid tumors. It requires further investigation whether an impaired TUG can be reversed and thus improve long-term outcomes. TRIAL REGISTRATION: The PICNIC studies are registered in the Dutch Clinical Trial database at www.trialregister.nl: NL4219 (2010-07-22) and NL4441 (2014-06-01). The PREOP study was registered with the Dutch trial registry at www.trialregister.nl: NL1497 (2008-11-28) and in the United Kingdom register (Research Ethics Committee reference 10/H1008/59). https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/?page=15&query=preop&date_from=&date_to=&research_type=&rec_opinion=&relevance=true. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12877-022-03585-4

Long-Term Survival and Risk of Institutionalization in Onco-Geriatric Surgical Patients:Long-Term Results of the PREOP Study

OBJECTIVES: To evaluate long-term survival and institutionalization in onco-geriatric surgical patients, and to analyze the association between these outcomes and a preoperative risk score. DESIGN: Prospective cohort study with long-term follow-up. SETTING: International and multicenter locations. PARTICIPANTS: Patients aged 70 years or older undergoing elective surgery for a malignant solid tumor at five centers (n = 229). MEASUREMENTS: We assessed long-term survival and institutionalization using the Preoperative Risk Estimation for Onco-geriatric Patients (PREOP) score, developed to predict the 30-day risk of major complications. The PREOP score collected data about sex, type of surgery, and the American Society for Anesthesiologists classification, as well as the Timed Up & Go test and the Nutritional Risk Screening results. An overall score higher than 8 was considered abnormal. RESULTS: We included 149 women and 80 men (median age = 76 y; interquartile range = 8). Survival at 1, 2, and 5 years postoperatively was 84%, 77%, and 56%, respectively. Moreover, survival at 1 year was worse for patients with a PREOP risk score higher than 8 (70%) compared with 8 or lower (91%). Of those alive at 1 year, 43 (26%) were institutionalized, and by 2 years, almost half of the entire cohort (46%) were institutionalized or had died. A PREOP risk score higher than 8 was associated with increased mortality (hazard ratio = 2.6; 95% confidence interval [CI] = 1.7-4.0), irrespective of stage and age, but not with being institutionalized (odds ratios = 1 y, 1.6 [95% CI =.7-3.8]; 2 y, 2.2 [95% CI =.9-5.5]). CONCLUSION: A high PREOP score is associated with mortality but not with remaining independent. Despite acceptable survival rates, physical function may deteriorate after surgery. It is imperative to discuss treatment goals and expectations preoperatively to determine if they are feasible. Using the PREOP risk score can provide an objective measure on which to base decisions. J Am Geriatr Soc 68:1235–1241, 2020

Vitamin Status and the Development of Postoperative Cognitive Decline in Elderly Surgical Oncologic Patients

Background. This study aimed to evaluate the influence that serum levels of vitamin B12, folate, and homocysteine have on the development of short-term postoperative cognitive decline in the elderly surgical oncology patient. Methods. This study was part of a prospective cohort study focused on postoperative cognitive outcomes for patients 65 years of age or older undergoing surgery for a solid malignancy. Postoperative cognitive decline was defined as the change in the combined results of the Ruff Figural Fluency Test and the Trail-Making Test Parts A and B. Patients with the highest change in scores 2 weeks postoperatively compared with baseline were considered to be patients with cognitive decline. Patients with the lowest change were considered to be patients without cognitive decline. To analyze the effect of vitamin levels on the changes in postoperative cognitive scores, uni- and multivariate logistic regression analysis were performed. Results. The study enrolled 61 patients with and 59 patients without postoperative cognitive decline. Hyperhomocysteinemia was present in 14.2% of the patients. Patients with postoperative cognitive decline more often had hyperhomocysteinemia (27.9 vs 10.2%). Hyperhomocysteinemia was associated with a higher chance for the development of postoperative cognitive decline (odds ratio(adjusted), 11.9; 95% confidence interval, 2.4-59.4). Preoperative vitamin B12 or folate deficiency were not associated with the development of postoperative cognitive decline. Conclusion. Preoperative hyperhomocysteinemia is associated with the development of postoperative cognitive decline. The presence of preoperative hyperhomocysteinemia could be an indicator for an increased risk of postoperative cognitive decline developing in the elderly